The Chemical Components of Tobacco and Tobacco Smoke

THE CHEMICAL COMPONENTS OF TOBACCO AND TOBACCO SMOKE

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THE CHEMICAL COMPONENTS OF TOBACCO AND TOBACCO SMOKE Alan Rodgman Thomas A. Perfetti

Boca Raton London New York

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CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2009 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-13: 978-1-4200-7883-1 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Rodgman, Alan. The chemical components of tobacco and tobacco smoke / Alan Rodgman and Thomas A. Perfetti. p. ; cm. “A CRC title.” Includes bibliographical references and index. ISBN 978-1-4200-7883-1 (hardcover : alk. paper) 1. Tobacco--Composition. 2. Tobacco smoke--Composition. I. Perfetti, Thomas Albert, 1952- II. Title. [DNLM: 1. Smoke--adverse effects. 2. Tobacco--chemistry. 3. Smoking--adverse effects. 4. Tobacco--adverse effects. WA 754 R691c 2009] SB275.R63 2009 613.85--dc22

2008018913

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Table of Contents Foreword ...................................................................................................................................................................................... ix Acknowledgments........................................................................................................................................................................ xi The Authors ...............................................................................................................................................................................xiii List of Tables.............................................................................................................................................................................xvii List of Figures ........................................................................................................................................................................... xxv Introduction.............................................................................................................................................................................xxvii Chapter 1 The Hydrocarbons ................................................................................................................................................. 1 I.A The Alkanes......................................................................................................................................................................... 1 I.B The Alkenes and Alkynes ................................................................................................................................................... 7 I.C The Alicyclic Hydrocarbons.............................................................................................................................................. 36 I.D The Monocyclic Aromatic Hydrocarbons ......................................................................................................................... 47 I.E The Polycyclic Aromatic Hydrocarbons............................................................................................................................ 55 I.F Summary ......................................................................................................................................................................... 102 Chapter 2

Alcohols and Phytosterols ..................................................................................................................................111

II.A Alcohols............................................................................................................................................................................111 II.B Phytosterols.......................................................................................................................................................................115 Chapter 3 Aldehydes and Ketones ..................................................................................................................................... 215 The Assertion of Aldehydes and Ketones as Ciliastatic Tobacco Smoke Components ........................................................... 221 Ciliastasis Studies with Cigarette Smoke Condensate Fractions.............................................................................................. 226 Ciliastasis Studies With Individual Cigarette Mainstream Smoke Components ..................................................................... 226 Nose Inhalation of Environmental Tobacco Smoke vs. Mouth Inhalation of Mainstream Smoke .......................................... 227 Chapter 4 Carboxylic Acids .................................................................................................................................................317 IV.A The Carboxylic Acids .......................................................................................................................................................317 IV.B The Amino Acids and Related Compounds .....................................................................................................................318 Chapter 5 The Esters........................................................................................................................................................... 381 Chapter 6 The Lactones ...................................................................................................................................................... 439 Chapter 7

Anhydrides ......................................................................................................................................................... 461

Chapter 8 Carbohydrates and Their Derivatives ............................................................................................................. 465 Chapter 9 Phenols and Quinones ....................................................................................................................................... 487 IX.A Phenols .......................................................................................................................................................................... 487 IX.A.1 Identification and Quantitation of Phenols in Cigarette MSS ....................................................................... 492 IX.A.2 Bioassays to Determine the Contribution of Phenols to Cigarette Smoke Condensate Tumorigenicity ........................................................................................................................... 495 IX.A.3 Determination of the Nature of the Precursors in Tobacco of the Phenols in Mainstream Smoke.................................................................................................................................... 501 IX.A.4 The Effect of Cigarette Design Parameters on Yield of Mainstream Smoke Phenols .................................. 507 IX.B Quinones ....................................................................................................................................................................... 547

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Chapter 10 The Ethers ........................................................................................................................................................ 555 Overall Summary of Oxygen-Containing Components of Tobacco and/or Smoke: Chapters 2 through 10 ........................... 555 Chapter 11

Nitriles................................................................................................................................................................615

Chapter 12

Acyclic Amines ................................................................................................................................................. 627

Chapter 13

Amides .............................................................................................................................................................. 663

Chapter 14

Imides................................................................................................................................................................ 679

Chapter 15 N-Nitrosamines ................................................................................................................................................ 687 XV.A XV.B XV.C XV.D XV.E XV.F XV.G XV.H

Volatile N-Nitrosamines........................................................................................................................................... 691 Nonvolatile N-Nitrosamines..................................................................................................................................... 691 Tobacco-Specific N-Nitrosamines ........................................................................................................................... 699 N-Nitrosamino Acids ............................................................................................................................................... 704 Tobacco-Specific N-Nitrosamines: An Exception among the Major MSS Toxicants ............................................. 707 Direct Transfer of TSNAs from Tobacco vs. Their Formation during the Smoking Process ................................. 708 Infrequently Studied Tobacco and/or Smoke Secondary Amines and Their N-Nitrosamines................................ 708 Flue-Curing and Tobacco-Specific N-Nitrosamines................................................................................................ 712

Chapter 16 Nitroalkanes, Nitroarenes, and Nitrophenols ............................................................................................... 721 Chapter 17 XVII.A

XVII.B

XVII.C XVII.D

Nitrogen Heterocyclic Components................................................................................................................ 727

Monocyclic Four- and Five-Membered N-Containing Ring Compounds ............................................................... 727 XVII.A.1 Background........................................................................................................................................... 727 XVII.A.2 Four-Membered N-Containing Rings................................................................................................... 727 XVII.A.3 Five-Membered N-Containing Rings ................................................................................................... 727 XVII.A.4 Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke With Multiple Five-Membered N-Containing Rings ................................................................................................... 732 Monocyclic Six-Membered N-Containing Ring Compounds.................................................................................. 747 XVII.B.1 Introduction .......................................................................................................................................... 747 XVII.B.2 Biosynthesis of Six-Membered N-Containing Ring Compounds and the Five- and Six-Membered and Multiple Six-Membered Nitrogen Heterocycles of Tobacco................. 748 XVII.B.3 Other Means for the Formation of the Six-Membered N-Containing Ring Compounds Found in Tobacco ................................................................................................................................. 750 XVII.B.4 Six-Membered N-Containing Ring Compounds in Tobacco and Tobacco Smoke................................751 XVII.B.4.1 Piperidine and the Tetra- and Dihydropyridines ............................................................ 752 XVII.B.4.2 Pyridines ......................................................................................................................... 752 XVII.B.4.3 Pyrazines..........................................................................................................................753 XVII.B.4.4 Pyrimidines..................................................................................................................... 754 XVII.B.5 Compounds in Tobacco and Tobacco Smoke Containing a Five-Membered and a Six-Membered N-Containing Ring............................................................................................. 779 XVII.B.5.1 Nicotine and Tobacco Alkaloids with a Six-Membered N-Containing Ring and a Second Five-Membered N-Containing Ring ........................................................ 780 XVII.B.5.2 Compounds in Tobacco and Tobacco Smoke with Two or More Six-Membered N-Containing Rings ........................................................................................................ 790 Lactams .................................................................................................................................................................... 798 Oxazoles and Oxazines............................................................................................................................................ 798

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XVII.E XVII.F

Aza-Arenes............................................................................................................................................................... 806 XVII.E.1 Alternate Exposures to Aza-Arenes ......................................................................................................818 N-Heterocyclic Amines............................................................................................................................................ 834

Chapter 18 Miscellaneous Components............................................................................................................................. 855 XVIII.A Sulfur-Containing Components ............................................................................................................................... 855 XVIII.B Halogenated Components ........................................................................................................................................ 857 Chapter 19 XIX.A

Fixed and Variable Gases................................................................................................................................ 893

Analytical Methods.................................................................................................................................................. 895 XIX.A.1 Carbon Dioxide (CO2) and Carbon Monoxide (CO) ............................................................................ 896 XIX.A.2 Nitrogen Oxides (NO, NO2, N2O, NOx) ............................................................................................... 896 XIX.A.3 Hydrogen Cyanide (HCN).................................................................................................................... 896 XIX.A.4 Ammonia (NH3) ................................................................................................................................... 897

Chapter 20 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts.................................................................... 907 XX.A

XX.B XX.C

XX.D

Elements, Isotopes, and Ions in Plants..................................................................................................................... 907 XX.A.1 Elements, Isotopes, and Ions in Tobacco.............................................................................................. 907 XX.A.2 Elements, Isotopes, and Ions in Tobacco Smoke...................................................................................910 Methods for the Detection and Identification of Metals, Ions, and Isotopes in Tobacco and Tobacco Smoke ..................................................................................................................................................911 The Transference of Elements, Isotopes, and Ions from Tobacco to Tobacco Smoke............................................. 912 XX.C.1 Elements in Tobacco Smoke of Special Interest................................................................................... 912 XX.C.1.a Arsenic (As) .................................................................................................................... 913 XX.C.1.b Beryllium (Be) ................................................................................................................ 915 XX.C.1.c Chromium (Cr), Cadmium (Cd), and Lead (Pb) ............................................................. 915 XX.C.1.d Chromium VI [Cr (VI)] .................................................................................................. 915 XX.C.1.e Nickel (Ni) ...................................................................................................................... 915 XX.C.1.f Cobalt (Co) ...................................................................................................................... 915 XX.C.1.g Mercury (Hg) ...................................................................................................................916 XX.C.1.h Selenium (Se) ...................................................................................................................916 210Polonium (210Po) ...........................................................................................................916 XX.C.1.i Summary...................................................................................................................................................................916

Chapter 21 Pesticides and Growth Regulators ................................................................................................................. 933 XXI.A XXI.B XXI.C XXI.D XXI.E XXI.F

Synthetic Pesticides and Plant Growth Regulator Residues on Tobacco................................................................. 934 Naturally Occurring Plant Growth Regulators and Pesticides in Tobacco.............................................................. 935 Transfer Rates of Pesticides and Plant Growth Regulators to MSS ........................................................................ 936 Decomposition Products of Agrochemicals in Mainstream Smoke ........................................................................ 937 Methods for Analysis of Pesticides and Plant Growth Regulators .......................................................................... 938 Residues of Synthetic Pesticides and Plant Growth Regulators Identified in Tobacco and Tobacco Smoke............................................................................................................................... 938

Chapter 22 XXII.A XXII.B XXII.C

Genes, Nucleotides, and Enzymes.................................................................................................................. 977

General Discussion of Genetics ............................................................................................................................... 977 Tobacco Genetics ..................................................................................................................................................... 978 Genes, Nucleotides, and Enzymes Identified in Tobacco ........................................................................................ 979 Acknowledgments .................................................................................................................................................... 982

Chapter 23 “Hoffmann Analytes” ................................................................................................................................... 1001

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Chapter 24

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients ...........................................1053

Acknowledgment.....................................................................................................................................................1106 Chapter 25 Pyrolysis...........................................................................................................................................................1107 XXV.A XXV.B XXV.C

XXV.D

XXV.E XXV.F

Individual Tobacco Types ....................................................................................................................................... 1111 Extracts from Tobacco ............................................................................................................................................1112 Individual Tobacco Components.............................................................................................................................1115 XXV.C.1 Nicotine ...............................................................................................................................................1116 XXV.C.2 Organic Solvent-Soluble Components (Long-Chained Aliphatic Hydrocarbons, Phytosterols, Solanesol, High Molecular Weight Esters, etc.) ............................................................1118 XXV.C.3 Structural Components of Tobacco (Cellulose, Lignin, Pectins, etc.)................................................ 1124 XXV.C.4 Acids....................................................................................................................................................1129 XXV.C.5 Proteins and Amino Acids ..................................................................................................................1130 Tobacco Additives ...................................................................................................................................................1134 XXV.D.1. Additives Used in Tobacco Production ...............................................................................................1134 XXV.D.1.a Sucker Growth Inhibitors...............................................................................................1134 XXV.D.1.b Pesticides........................................................................................................................1137 XXV.D.2 Additives Used in Cigarette Manufacture ...........................................................................................1139 XXV.D.2.a Casing Materials (Sugars, Cocoa, Licorice)..................................................................1139 XXV.D.2.b Humectants (Glycerol, Propylene Glycol).....................................................................1140 Cigarette Construction Materials (Paper, Adhesives, etc.) .....................................................................................1141 Flavoring Ingredients ..............................................................................................................................................1142

Chapter 26

Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens.............1173

XXVI.A Carcinogens, Tumorigens, and Mutagens ...............................................................................................................1173 XXVI.A.1 The Polycyclic Aromatic Hydrocarbons .............................................................................................1182 XXVI.A.2 Other Classes of Carcinogens, Tumorigens, and Mutagens ................................................................1183 XXVI.A.2.a Aza-Arenes..................................................................................................................1183 XXVI.A.2.b N-Nitrosamines............................................................................................................1189 XXVI.A.2.c N-Heterocyclic Amines ...............................................................................................1190 XXVI.B Anticarcinogens, Inhibitors, and Antimutagens .....................................................................................................1193 XXVI.B.1 Alternate Exposures to Carcinogens, Tumorigens, and Mutagens......................................................1218 XXVI.B.1.a Alternate Exposures to Polycyclic Aromatic Hydrocarbons.......................................1219 XXVI.B.1.b Alternate Exposures to Aza-Arenes ........................................................................... 1223 XXVI.B.1.c Alternate Exposures to N-Nitrosamines..................................................................... 1223 XXVI.B.1.d Alternate Exposures to N-Heterocyclic Amines .........................................................1231 XXVI.C Summary................................................................................................................................................................ 1233 Chapter 27 Free Radicals.................................................................................................................................................. 1235 XXVII.A XXVII.B XXVII.C XXVII.D XXVII.E

Introduction ......................................................................................................................................................... 1235 Analytical Methods for Determination of Free Radicals .................................................................................... 1236 Free Radicals in Tobacco Smoke......................................................................................................................... 1237 Historical Review of Free Radical Research on Cigarette Smoke ...................................................................... 1238 Proposed Mechanisms for the Generation of Free Radicals in MSS .................................................................. 1250

Chapter 28

Summary ........................................................................................................................................................ 1257

Bibliography ...........................................................................................................................................................................1261 Alphabetical Component Index ........................................................................................................................................... 1483

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Foreword The following pages are an attempt to update a situation with regard to the composition of tobacco and tobacco smoke that has existed for almost four decades. Although it is suspected that the chemical components of tobacco and tobacco smoke may have been cataloged in-house at various U.S. and foreign tobacco companies as well as by various governmental agencies, no such catalog has been published since the 1968 review by the highly competent tobacco scientist R.L. Stedman of the U.S. Department of Agriculture (3797). One article published by a tobacco company prior to that of Stedman was a 1963 referenced monograph on tobacco and tobacco smoke components by Philip Morris, Inc. (2939). Its monograph was submitted to the 1964 Advisory Committee for use in preparation of its 1964 report to the U.S. Surgeon General. The Philip Morris monograph had been preceded by the 1959 published review by Johnstone and Plimmer (1971). In subsequent years, several tobacco and tobacco smoke publications dealt with specific types or classes of components, for example, the 1964 compilation of the polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke by Elmenhorst and Reckzeh (1139), the 1969 review by Neurath on the nitrogen-containing components identified in tobacco smoke (2724), and the 1977 review by Schmeltz and Hoffmann on the nitrogen-containing components in both tobacco and tobacco smoke (3491). Several catalogs of the chemical components of only tobacco smoke have been published, for example, the 1954 article by Kosak (2170), but the most recent one was that of Ishiguro and Sugawara (1884) in 1980. Since the 1968 Stedman article in which about 1200 tobacco and smoke components were listed, the number of identified tobacco and tobacco smoke components has increased sevenfold to almost 8400, a number that includes only about 500 of the many thousands of enzymes identified in the tobacco plant. The references cited for a particular tobacco and/or tobacco smoke component may deal with its identification or with a variety of topics pertinent to the particular component. Topics may include such simple items as the isolation and identification of a component, its characterization by classical chemical means, for example, the definition of the structure of solanesol isolated from flue-cured tobacco by Rowland et al. (3359), or the characterization of a component by spectrographic means, for example, UV, IR, NMR, MS, and chromatographic retention time. One example is the identification by Snook et al. of many PAHs (3756–3758) and aza-arenes (3750) in cigarette mainstream smoke (MSS). Many references cited herein describe the search for and elucidation of the precursor in tobacco of a particular component in cigarette MSS (3616), for example, the saturated aliphatic hydrocarbon precursors of the PAHs, including benzo[a]pyrene (B[a]P); the quantitation of the component on a per gram of tobacco basis or on its per cigarette MSS

yield, particularly if the component is considered a health problem; the improvements/developments in analytical technology to determine the per cigarette MSS and/or sidestream smoke (SSS) yield of the component. Also included in citations for a particular MSS, SSS, and environmental tobacco smoke (ETS) component are the publications of results of experimental studies on its biological activity plus discussions and/or assertions of its toxicity and/or tumorigenicity. While their number is much fewer than the opposite point of view, included are references to studies on the inhibition of adverse biological activity of a tobacco smoke component by another smoke component, for example, the inhibition of mouse-skin tumorigenicity of B[a]P by n-hentriacontane and n-pentatriacontane (4314, 4336), the inhibition of N-nitrosodimethylamine (NDMA) mutagenicity by nicotine (2327a, 2327b), the inhibition of mouse-skin tumorigenicity of dibenz[a,h]anthracene (DB[a,h]A) by benz[a]anthracene (B[a]A) (3814), both classified as significant tobacco smoke tumorigens. Also cited are reports on the controversies over the extrapolation of the biological effect of a specific component administered individually vs. its biological effect when it is the component in a highly complex mixture such as MSS and is administered to a different species, by a different route, and at a dose level far in excess of its level in the complex mixture (1318a, 3300, 3627). Lastly, many studies are cited in which cigarette design technologies were generated to control the per cigarette MSS yield of Federal Trade Commission (FTC)-defined “tar” and one or more specific components of concern, for example, reconstituted tobacco sheet, expanded tobacco, ventilated filters, filter-tip and cigarette paper additives. While some of the citations may seem obscure to a reader newly involved in tobacco and/or smoke research, they are included to elucidate the historical background and relationship to more recent studies, for example, publications pertinent to 2-methyl-1,3-butadiene (isoprene), a fairly plentiful component of the vapor phase of cigarette smoke. The publications include the 1913 report by Staudinger et al. (25A68) that pyrolysis of isoprene yielded a “tar.” In 1918, the procedure to successfully generate tumors by animal skin painting was described (4361). Five years later, Kennaway (2073–2076) demonstrated the tumorigenicity of the pyrolysate “tar” from isoprene, and much later, Badger et al. (143) recorded the PAH content of an isoprene pyrolysate. Another example includes a series of references to the research results reported by Roffo that a tobacco “destructive distillate” was tumorigenic (3322, 3325), contained B[a]P (3316), and the B[a]P content and tumorigenicity of the “destructive distillate” were reduced by organic-solvent extraction of the tobacco prior to destructive distillation (3327).

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Our goal was to present to the reader as many pertinent references as we could find for a particular component and permit the reader to decide which references to study. For some components, dozens of references are available, for other components only one or two. The multi-referenced components are usually those considered to be involved in the health problems connected to tobacco smoking. We express our deep appreciation to several scientific staff members of the Verband der Cigaretten-Industrie and the Beiträge zur Tabakforschung International. They reviewed the initial chapter of our opus and made many meaningful suggestions and pointed out the need for several corrections. Most of their input was applied to that chapter and eventually extended to subsequent chapters as we wrote them. One needed correction that was described was a problem with

the electronic address for a specific reference. It was found to be inaccessible at the time of the review. That was corrected since the reference had multiple electronic addresses so the inaccessible one was replaced with an accessible and operative one. However, the finding triggered an examination of all the electronic addresses cited in the Bibliography. Of the nearly 900 such addresses, three more were found to be inaccessible. Fortunately, each was part of a reference with multiple electronic addresses and the inaccessible address for each was replaced with an accessible one. We apologize to the reader for the omission not only of any tobacco or tobacco smoke component from the catalog but also any significant reference by one or more competent investigators who provided information pertinent to one or more specific components.

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Acknowledgments During the many years that this tobacco and tobacco smoke component catalog was being prepared, numerous components were discussed with colleagues, many of whom were involved either in tobacco or tobacco smoke research within the tobacco industry or outside of it. Much meaningful information was obtained during the many discussions and such information has been incorporated into our effort. We greatly appreciate the input not only from those colleagues who are still with us but also from those who are not. In the first group, we are extremely grateful to J. Gilbert Ashburn, Edward Bernasek, Fred W. Best, Michael F. Borgerding, N.M. Chopra, Christopher R.E. Coggins, William M. Coleman III, Lawrence C. Cook, James T. Dobbins, Jr., Michael F. Dube, Curt R. Enzell, Charles R. Green, Dietrich Hoffmann, Paul Kotin, Brian M. Lawrence, Chin K. Lee, John C. Leffingwell, Chuan Liu, Robert A. Lloyd, Jr., William C. Luffman, Dwo Lynm, C.D. McGee, Alan B. Norman, Charles W. Nystrom, Michael W. Ogden, John H. Reynolds IV, Charles H. Risner, Charles E. Rix, Joseph N. Schumacher, Stephen B. Sears, Jeffery I. Seeman, Carr J. Smith, Thomas W. Stamey, Jr., David E. Townsend, and Jack L. White.

In the second group, we are grateful for the contributions of the following late colleagues: Richard R. Baker, Stuart A. Bellin, Herbert R. Bentley, Robert H. Cundiff, Wilbur R. Franks, James D. Fredrickson, Jesse A. Giles, Kurt Grob, Robert A. Heckman, Charles H. Keith, Philip H. Latimer, Jr., Anders H. Laurene, Jerry W. Lawson, Larry A. Lyerly, John G. Mason, Marjorie P. Newell, Thomas S. Osdene, Donald L. Roberts, Ralph L. Rowland, Alex W. Spears, William A. Rohde, Fredrick A. Thome, George P. Touey, John J. Whalen, George F Wright, Ernst L. Wynder, and George W. Young. We also wish to express our gratitude to those who, over the years, have provided us with much information on scientific publications and presentations. They include Frank G. Colby, Charles W. Nystrom, Nell W. Sizemore, and the late William W. Menz and John J. Whalen. Particularly meaningful over the past decade has been the information provided by the extremely diligent Helen S. Chung of the R.J. Reynolds R&D Scientific Information Division. One of us (T.A.P.) wishes to especially thank Patricia F. Perfetti for the encouragement and faith she has shown me as my wife, best friend, faithful colleague, and my partner in many happy and productive years of scientific research.

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The Authors Thomas A. Perfetti, Ph.D. was born in 1952 in Jeannette, Pennsylvania, the second son of Ruth Peters and Bruno Massimo Perfetti. He was one of five children. Perfetti received his elementary education in several schools in the Pittsburgh area. In 1970, he entered Indiana University of Pennsylvania (IUP). He earned a Bachelor of Science degree in Chemistry in 1974. During his stay at IUP he conducted cell transport research with Dr. Richard Hartline and synthesized numerous radiopharmaceuticals. Perfetti’s first publication was on the preferential uptake of d-A-amino adipate by Alcaligens denitrificans in 1975. In 1974, he entered the Virginia Polytechnic Institute and State University (VPI-SU), Blacksburg, VA. His doctoral thesis (1977), under Dr. Michael Ogliaruso, was on the electronic effects associated with the Woodward-Hoffman Rules. While pursuing his doctoral degree in physical organic chemistry, Perfetti worked as a Research Fellow for NASA, taught organic chemistry labs, and tutored undergraduates. In 1976, Perfetti won the President’s Award for Distinguished Teaching at VPI-SU. Perfetti married Patricia Ann Finley, who graduated with him from the Chemistry Department at IUP in 1975. They have two sons, Michael and David. The family now resides in Winston-Salem, North Carolina. In late 1977, Dr. Perfetti joined the R.J. Reynolds Tobacco Company (RJRT) as a research chemist. There, he initiated several research programs on tobacco and smoke chemistry, cigarette design, sensory science, flavor chemistry, and analytical method development. Perfetti was promoted to Senior Research Chemist (1979), to Senior Staff Scientist (1984), then to Master Scientist (1986), and finally to Principal Scientist (1991). Perfetti is a recognized expert in the areas of nicotine and menthol chemistry and in the area of innovation. As Principal Scientist he worked with R.J. Reynolds-Nabisco and R.J. Reynolds International on corporate program development and program management issues. He also acted as a liaison on patent acquisitions, patent applications, and consulting activities on the scientific aspects of litigation against RJRT. Much of his career was spent in the laboratory, although he served as the manager of several divisions. Dr. Perfetti retired from RJRT in 2003. In that same year, he and his wife started Perfetti & Perfetti, LLC, a scientific consulting firm in Winston-Salem, North Carolina. Their company has done quite well, with numerous national and international clients. Perfetti has served as a reviewer for Tobacco Science, the Journal of Food and Chemical Toxicology, and Beiträge zur Tabakforschung International. He has served on several Tobacco Chemists’ Research Conference committees and contributed to two of its symposia (1987, 1993), one of which he chaired (1993).

Perfetti is a member of the American Chemical Society (ACS). He has served as assistant historian to the Division of the History of Chemistry. He is a member and Fellow of the American Institute of Chemists and is a Certified Professional Chemist. He was a co-founder and past president of the North Carolina Chromatography Discussion Group and former chairman of the Education Committee of the Central North Carolina Section of the ACS. Dr. Perfetti has been cited in Who’s Who in America, Who’s Who in Science and Technology, in the International Directory of Distinguished Leadership and Who’s Who in American Leaders in America. In 1993, Dr. Perfetti was presented with the Distinguished Alumni Award, Indiana University of Pennsylvania. In 1995, he and several other RJRT scientists were given the George Land World-Class Innovator Award for outstanding work in instilling the principles of innovation at RJRT Research and Development. Over the last 32 years Perfetti has made over 60 presentations and published numerous papers in peer-reviewed journals in the areas of biochemistry, tobacco and smoke chemistry, sensory perception, mathematics, and innovation. During his career at RJRT he prepared more than 250 formal company research reports. He has written chapters for two books and has developed and presented five courses in the areas of cigarette design and innovation. Dr. Perfetti has 38 U.S. patents and hundreds of foreign patents. Alan Rodgman, M.A., Ph.D. Most of the original text of the following biography was written in 2003 for Alan Rodgman’s nomination for the Tobacco Science Research Conference Lifetime Achievement Award. He was recipient of the 2003 award. In several places, the nominator’s paragraphs have been slightly modified to include additional, more recent information. The author of the 2003 nomination wrote: For here we are not afraid to follow truth wherever it may lead, nor to tolerate any error so long as reason is left free to combat it.——Thomas Jefferson, 1820

The words penned long ago by Mr. Jefferson epitomize the life and professional career of Alan Rodgman. For one year short of a half century Dr. Rodgman has been at the forefront of tobacco science. His increasingly rare combination of keen scientific intellect, unceasing productivity, sense of tobacco science history, and unfailing attention to clear, concise, timely communication make him an ideal choice for the Tobacco Science Research Conference’s (TSRC’s) Lifetime Achievement Award. Not only has Dr. Rodgman made his own prodigious, personal scientific contributions to tobacco and smoke chemistry and their related toxicology, but his mentoring of associates and many other tobacco scientists has allowed him to amplify

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his contributions far beyond those capable of any one man. Dr. Rodgman’s professional “family tree” reads as a “Who’s Who” in tobacco science. Alan Rodgman was born in 1924 in Aberdare, Glamorgan County, Wales, to Arch and Margaret Llewellyn Rodgman. The family moved to Toronto, Ontario, Canada, in 1928. There he was educated at the grade and collegiate levels. Because of the early death of his father when Rodgman was ten years old, he worked after school and on Saturdays at the children’s and adult department of a local branch of the Toronto Public Library from 1937 to 1942. In 1945, Rodgman entered the University of Toronto as recipient of the two highest mathematics, physics, and chemistry scholarships awarded in competition in 1942. Because of a University of Toronto rule on retaining no more than two competitive scholarships, a third chemistry and physics scholarship awarded to Rodgman reverted to the next highest candidate. The 3-year period between earning the scholarships and their implementation was spent on active duty as a volunteer in the Royal Canadian Navy during WWII, with service on the North Atlantic Ocean. Between 1945 and 1949 at the University of Toronto, Rodgman was awarded eight additional scholarships, one in mathematics, physics, and chemistry in 1946; seven in chemistry in 1947, 1948, and 1949. His bachelor’s thesis on N-nitrosamines (1949), master’s thesis on kinetics of the original Diels-Alder reaction (1951), and doctoral thesis on oxymercuration-deoxymercuration (1953) were conducted with Dr. George F Wright* as his advisor. He taught the laboratory aspect of analytical chemistry during the first year of his master’s period. His master’s and doctoral research formed part of eleven publications co-authored between 1952 and 1959 with Dr. Wright who, by the way, from 1954 to 1959, preceded Dr. Dietrich Hoffmann as Dr. Ernst L. Wynder’s tobacco smoke chemistry colleague. Rodgman married Doris Curley in June 1947. They have three sons, Eric, Paul, and Mark, three daughters-in-law, Melody, Ella, and Sara, and seven grandchildren. While pursuing his chemistry degrees, Rodgman conducted carcinogenesis and anticarcinogenesis research from 1947 to 1953 during summers, winter evenings, and weekends with Dr. Wilbur R. Franks, Cancer Research Professor at the Banting and Best Department of Medical Research, University of Toronto. He conducted such research fulltime to mid-1954 after receiving his doctorate in June 1953. Rodgman’s first three scientific publications (on anticarcinogenesis) in 1947 and 1948 preceded the receipt of his bachelor’s degree in chemistry in 1949. From 1951 to mid-1954, he also taught organic and physical chemistry plus mathematics for physical chemistry in evening courses sponsored by the Chemical Institute of Canada. In mid-1954, Rodgman joined the Research Department of the R.J. Reynolds Tobacco Company as a senior research chemist. In October 1954, he initiated its program on *

The lack of a period after Dr. Wright’s middle initial is not a typographical error.

cigarette smoke composition, personally conducting the laboratory research until 1967 and actively directing it and environmental tobacco smoke studies thereafter until 1987. Following successive promotions from senior research chemist to section head to division manager, he became director of research in 1976, and after an R&D reorganization in 1980, he was appointed director of fundamental research. Rodgman became a U.S. citizen in 1961. After more than 60 years, Rodgman is still a member of the American Chemical Society and the Chemical Institute of Canada. Until 2006, he had been a member of the New York Academy of Sciences for over 40 years and also a member of Sigma Xi. He served on the editorial board of Tobacco Science as member and Vice-Chairman (1963– 1967); on the editorial board of Beiträge zur Tabakforschung International (1976–1987); on the Industry Technical Committee, Council for Tobacco Research (1955–1960); on the CORESTA Scientific Commission (1982–1985); and on several U.S. government committees, including, the Tobacco Working Group of the National Cancer Institute’s Smoking and Health Program on the Less Hazardous Cigarette (1976–1977) and the U.S. Technical Study Group of the Cigarette Safety Act of 1984 (1984–1987). From 1960 to 1987, Rodgman served on numerous Tobacco Chemists’ Research Conference (TCRC) committees. In 1972, he was involved in various aspects of the joint CORESTA/ TCRC Conference in Williamsburg, Virginia. In 1976, he persuaded his company’s management to continue its CORESTA membership. In the early 1980s, when a host site for the 1982 CORESTA Symposium did not materialize, Rodgman was instrumental in arranging for his company to sponsor the symposium in Winston-Salem, North Carolina. He served as its vice chairman. Rodgman was the chairman for the 1984, 38th TCRC symposium entitled “Design of Low-‘Tar’ Cigarettes.” On the occasion of TCRC’s 50th Conference in 1996, he coauthored with Charles R. Green a comprehensive review and presentation entitled “The Tobacco Chemists’ Research Conference: A Half Century Forum for Advances in Analytical Methodology of Tobacco and its Products.” The following year at the 51st Conference, he prepared a symposium paper and presentation on “FTC ‘Tar’ and Nicotine in Cigarette Mainstream Smoke: A Retrospective.” In addition, Rodgman has presented many other original research papers at the conference. In the journal Tobacco Science, he has published thirteen scientific papers on tobacco smoke composition. Additionally, the 1986 volume of Tobacco Science was dedicated to Dr. Rodgman to honor his prolific career. In addition to serving as a reviewer for manuscripts submitted to Tobacco Science and Beiträge zur Tabakforschung International, Rodgman has served as a reviewer not only for manuscripts submitted to several other journals, including Recent Advances in Tobacco Science, Journal of Analytical and Applied Pyrolysis, Food and Chemical Toxicology and the Journal of Organic Chemistry but also for the page proofs of several well-known books on tobacco-related topics.

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From 1954 to retirement and from retirement to 2004, Rodgman was involved in consulting activities on the scientific aspects of litigation against R.J. Reynolds Tobacco Company. Over 13,000 pages of his contributions are available at http://tobaccodocuments.org/bliley_rjr/list. Many of the more recent contributions were the consequence of the “Master Settlement” between the states and tobacco companies. Additionally, he has been a major contributor to the scientific content of Beiträge zur Tabakforschung International both through submitted papers and as a volunteer editor. Dr. Rodgman has mined the wealth of documents previously considered proprietary to clarify the intent and content of tobacco and smoke research conducted by himself, his colleagues, and other scientists. The published papers authored/ co-authored by Rodgman during the last decade and a half include the following: Environmental Tobacco Smoke (1992); FTC “Tar” and Nicotine in Cigarette Mainstream Smoke: A Retrospective (1997); Tobacco Smoke Components (1998); The Composition of Cigarette Smoke: A Retrospective, With Emphasis on Polycyclic Components (2000); “Smoke pH”: A Review (2000); “IARC Group 2A Carcinogens” Reported in Cigarette Mainstream Smoke (2000); Studies of Polycyclic Aromatic Hydrocarbons in Cigarette Mainstream Smoke: Identification, Tobacco Precursors, Control of Levels: A Review (2001); “IARC Group 2B Carcinogens” Reported in Cigarette Mainstream Smoke (2001); Some Studies of the Effects of Additives on Cigarette Mainstream Smoke Properties. I. Flavorants (2002); Some Studies of the Effects of Additives on Cigarette Mainstream Smoke Properties. II. Casing Materials and Humectants (2002); The Relative Toxicity of Substituted Phenols Reported in Cigarette Mainstream Smoke (2002); The Composition of Cigarette Smoke: Problems With Lists of Tumorigens (2003); Toxic Chemicals in Cigarette Mainstream Smoke: Hazard and Hoopla (2002, 2003); Some Studies of the Effects of Additives on Cigarette Mainstream Smoke Properties. III. Ingredients Reportedly Used in Various Commercial Cigarette Products in the USA and Elsewhere (2004); The Composition of

Cigarette Smoke: A Catalogue of the Polycyclic Aromatic Hydrocarbons (2006); The Composition of Cigarette Smoke:

A Chronology of the Studies of Four Polycyclic Aromatic Hydrocarbons (2006); Comparisons of the Composition of Tobacco Smoke and the Smokes from Various Tobacco Substitutes (2007); The Expansion of Tobacco and its Effect on Cigarette Mainstream Smoke Properties (2007). At the 2002 CORESTA Congress held in New Orleans, Dr. Rodgman co-authored with Charles R. Green an invited speaker symposium paper entitled “Toxic Chemicals in Cigarette Mainstream Smoke: Hazard or Hoopla.” In this paper the authors critically examined the proper listing and prioritizing of toxic chemicals in cigarette mainstream smoke. Moreover, the authors pointed to a number of disconcerting chemical and biological limitations in existing knowledge which calls into question the veracity of such listing strategies for their oft-stated purposes. This example is included in Alan Rodgman’s nomination to illustrate his lifelong pursuit of the truth. In summary, there is no question that Alan Rodgman has dedicated his professional life to the achievement of the highest standards for tobacco science. Even with this nomination and the accompanying materials, it is impossible to convey to an outsider the tremendous impact that this person has had on our knowledge of tobacco and its smoke. Although his own personal scientific accomplishments are by themselves worthy of TSRC’s Lifetime Achievement Award, the amplification of his life’s work through influence on many other tobacco scientists is difficult to quantify. Beyond his many professional achievements is a man who is widely respected and personally liked both within and outside the tobacco science community. Because his philosophy on publication authorship differed substantially from that of many academic, government agency, and health organization investigators, Rodgman did not insert his name as co-author on the many articles on tobacco and smoke composition presented at conferences and/or published in peer-reviewed journals by his staff members. If he had done what many supervisors do, his list of publications between 1960 and 1987 would be increased by almost 200. However, his contributions to many of the studies are described in the Acknowledgment section of many of his staff/colleagues’ publications.

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List of Tables Chapter 1 The Hydrocarbons I.A-1 Relative percentage composition of tobacco alkanes in tobacco and cigarette smoke, based on mass spectroscopic analysis ...................................................................................................................... 2 I.A-2 Relative percentage composition of n-alkanes in tobacco and cigarette smoke, based on gas-liquid chromatographic analysis ......................................................................................................................................... 2 I.A-3 Alkane content of cigarette mainstream smoke ....................................................................................................... 2 I.A-4 Relative percentage composition of tobacco alkanes based on gas-liquid chromatographic data (Figures rounded from those provided by Mold et al.) ............................................................................................ 3 I.A-5 Alkane isomers identified in cigarette mainstream smoke, 1968 vs. 1992 .............................................................. 3 I.A-6 Melting point and boiling point data for n-alkanes.................................................................................................. 3 I.A-7 Chronology of studies on alkanes in tobacco and tobacco smoke ........................................................................... 4 I.A-8 Polycyclic aromatic hydrocarbons from tobacco aliphatic hydrocarbons pyrolyzed in air at various temperatures ............................................................................................................................................ 5 I.A-9 Ratios for individual polycyclic aromatic hydrocarbons in gasoline engine exhaust “tar” (EET) and cigarette smoke condensate (CSC) .................................................................................................................... 6 I.A-10 Alkanes in tobacco, tobacco smoke, and tobacco substitute smoke .................................................................. 8–16 I.B-1 Alkenes and alkynes in tobacco, tobacco smoke, and tobacco substitute smoke .............................................17–33 I.C-1 Alicyclic hydrocarbons in tobacco, tobacco smoke, and tobacco substitute smoke......................................... 37–45 I.D-1 Monocyclic aromatic hydrocarbons in tobacco, tobacco smoke, and tobacco substitute smoke ..................... 48–54 I.E-1 Chronology of catalogs of PAHs in MSS............................................................................................................... 56 I.E-2 Benzenoid hydrocarbons discussed by Pullman and Pullman......................................................................... 62–63 I.E-3 Polycyclic hydrocarbons reported in tobacco smoke by year-end 1955 ................................................................. 63 I.E-4 Inhibition of tumorigenicity of potently tumorigenic PAHs by non-tumorigenic or weakly tumorigenic PAHs .................................................................................................................................................. 65 I.E-5 Levels of PAH classes in cigarette mainstream smoke .......................................................................................... 65 I.E-6 Polycyclic aromatic hydrocarbons in tobacco, tobacco smoke, and tobacco substitute smoke.......................67–102 I.E-7 Tobacco smoke PAHs discussed in various publications on the relationship between PAH structure and tumorigenicity......................................................................................................................................... 103-109 I.E-8 Distribution of identified hydrocarbons between tobacco and tobacco smoke .....................................................110 Chapter 2 Alcohols and Phytosterols II.A-1 Tobacco and tobacco smoke components identified by classical chemical methods ............................................112 II.A-2 Tobacco and tobacco smoke studies in which components were identified by a combination of spectral technologies ...........................................................................................................................................................113 II.A-3 Tobacco components identified post-1975 .............................................................................................................114 II.A-4 Tobacco and/or smoke alcohols used in flavor formulations.................................................................................116 II.A-5 Alcohols in tobacco, tobacco smoke, and tobacco substitute smoke ............................................................117–204 II.B-1 Studies on identification of phytosterols and phytosteryl derivatives in tobacco and tobacco smoke ................. 207 II.B-2 Phytosterols, their derivatives, and related compounds in tobacco, tobacco smoke, and tobacco substitute smoke.............................................................................................................................................208–214 Chapter 3 III-1 III-2 III-3 III-4 III-5 III-6 III-7 III-8

Aldehydes and Ketones Tobacco smoke components listed by Kosak ........................................................................................................216 Studies on low molecular weight carbonyls in tobacco and tobacco smoke: Derivatizing agents........................217 Analysis of cigarette mainstream smoke by gas chromatography ........................................................................218 Precursors in tobacco of aldehydes and ketones in tobacco................................................................................. 220 Aldehydes and ketones in mainstream smoke from all lamina and all-midrib cigarette..................................... 221 In vitro ciliary activity, cigarette smoke fractions, and dose level ....................................................................... 226 Lowest concentrations in Ringer solution leading to ciliastasis in ciliated rat trachea........................................ 226 Lung retention and mouth absorption of several cigarette mainstream smoke components ............................... 228

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III-9 III-10 III-11 III-12 III-13 III-14 Chapter 4 IV.A-1 IV.A-2 IV.A-3 IV.B-1 IV.B-2 IV.B-3 IV.B-4 IV.B-5 IV.B-6 IV.B-7

Difference between composition of inhaled and exhaled mainstream smoke and between mouth-held and exhaled mainstream smoke ........................................................................................................................... 228 Lung retention and mouth absorption data........................................................................................................... 229 Tobacco and/or tobacco smoke aldehydes and ketones used in flavor formulations.................................................................................................................................................. 230–231 Aldehydes in tobacco, tobacco smoke, and tobacco substitute smoke ......................................................... 232–248 Ketones in tobacco, tobacco smoke, and tobacco substitute smoke..............................................................249–311 Chronology of studies on aldehydes and ketones in tobacco smoke............................................................. 311–315 Carboxylic Acids Acids identified in tobacco and tobacco smoke to date.........................................................................................318 Tobacco and/or tobacco smoke carboxylic acids used in flavor formulations.......................................................319 Carboxylic acids in tobacco, tobacco smoke, and tobacco substitute smoke ............................................... 320–365 Components in pyrolysates from the amino acids lysine, leucine, and tryptophan ............................................. 366 Pyrolysis of phenylalanine. A. Effect of pyrolysis temperature. B. Effect of equimolar addition of tryptophan or pyrrole ....................................................................................................................................... 367 Components in pyrolysates from amino acids (proline and glycine) and proteins (casein and collagen) ........... 368 Amino acid-derived N-heterocyclic amines......................................................................................................... 369 Summary of lists of tumorigenic N-heterocyclic amines in tobacco smoke........................................................ 369 Tobacco and/or tobacco smoke amino acids used in flavor formulations ............................................................ 369 Amino acids and related compounds in tobacco, tobacco smoke, and tobacco substitute smoke ............... 370–379

Chapter 5 The Esters V-1 Esters used as tobacco ingredients by U.S. tobacco product manufacturers................................................ 383–385 V-2 Esters used as tobacco ingredients by tobacco product manufacturers outside of the U.S.................................. 385 V-3 Esters in tobacco, tobacco smoke, and tobacco substitute smoke ................................................................ 386–438 Chapter 6 The Lactones VI-1 Some biological properties of lactones used as additives in foodstuffs as well as in tobacco products ............. 442 VI-2 Tobacco and/or smoke lactones used in flavor formulations ................................................................................ 443 VI-3 Lactones identified in tobacco, tobacco smoke, and tobacco substitute smoke ...........................................444–460 Chapter 7 Anhydrides VII-1 Anhydrides in tobacco, tobacco smoke, and tobacco substitute smoke .......................................................462–463 Chapter 8 Carbohydrates and Their Derivatives VIII-1 Tobacco and/or smoke carbohydrates used in flavor formulations....................................................................... 466 VIII-2 Effect of sugars added to burley tobacco on mainstream smoke aldehyde and ketone yields ............................. 466 VIII-3 Carbohydrates in tobacco, tobacco smoke, and tobacco substitute smoke ..................................................468–486 Chapter 9 Phenols and Quinones IX.A-1 Dibenz[a,h]acridine (I), dibenz[a,j]acridine (II), and 7H-dibenzo[c,g]carbazole (III) in nicotine pyrolysates (Pyr) and mainstream cigarette smoke condensate .............................................................................................. 488 IX.A-2 Tobacco smoke components listed by Kosak ....................................................................................................... 490 IX.A-3 Phenolic components of tobacco smoke listed by Kosak..................................................................................... 491 IX.A-4 Studies of phenolic components of tobacco smoke omitted from the 1954 listing by Kosak.............................. 491 IX.A-5 Tobacco smoke phenols catalogued by Johnstone and Plimmer.......................................................................... 493 IX.A-6 Publications/presentations (1952–1964) pertinent to identification of phenolic components of tobacco smoke.............................................................................................................................. 493 IX.A-7 Tobacco smoke phenols catalogued by Stedman (3797) ...................................................................................... 494 IX.A-8 Presentations at Tobacco Chemists’ Research (TCRC) and Tobacco Science Research Conferences (TSRC) on phenolic components of tobacco products ......................................................................................... 495 IX.A-9 Reports of research pertinent to phenolic compounds in tobacco and tobacco smoke 1964 to 2005 .................................................................................................................................................496–497 IX.A-10 Variation in bioassay results with phenols or phenol-containing materials ......................................................... 498 IX.A-11 Inhibitors and anticarcinogens in tobacco smoke ................................................................................................ 500 IX.A-12 Tobacco smoke phenols with anticarcinogenic or antipromoting properties ....................................................... 501

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IX.A-13 IX.A-14 IX.A-15 IX.A-16 IX.A-17 IX.A-18 IX.A-19 IX.A-20 IX.A-21 IX.A-22 IX.B-1 IX.B-2 IX.B-3

Precursors in tobacco of phenols in tobacco smoke............................................................................................. 503 Pyrolysis of tobacco, tobacco components, and spinach: Phenol content of pyrolysate ...................................... 504 Pyrolysis of tobacco components: Generation of phenols.................................................................................... 505 Smoke chemistry data: NCI study of cocoa addition ........................................................................................... 506 Studies on the selective filtration of phenolic compounds in cigarette mainstream smoke................................. 508 Effect of tobacco expansion on levels of mainstream smoke phenols.................................................................. 509 Studies involving nitrate addition to tobacco ................................................................................................ 511–512 Effect of cut width on mainstream smoke properties............................................................................................513 Theoretical relationship between phenols in tobacco and several phenols in tobacco smoke ..............................514 Phenols in tobacco, tobacco smoke, and tobacco substitute smoke ............................................................. 515–546 Comparison of the tumorigenicities of aromatic hydrocarbons, their diols (phenols), and their diones (quinones)................................................................................................................................... 547 Quinones identified in tobacco, tobacco smoke, and tobacco substitute smoke ...........................................549–551 Chronology of identification of quinones in tobacco and/or smoke…..........................................................552–553

Chapter 10 The Ethers X-1 Tobacco and/or smoke ethers used in flavor formulations ................................................................................... 556 X-2 Ethers in tobacco, tobacco smoke, and tobacco substitute smoke.................................................................557–614 X-3 Distribution of identified oxygen-containing components between tobacco and tobacco smoke.........................614 Chapter 11 Nitriles XI-1 Nitriles identified and/or discussed in tobacco smoke by the mid-1960s..............................................................616 XI-2 Nitriles in tobacco, tobacco smoke, and tobacco substitute smoke...............................................................617–625 Chapter 12 Acyclic Amines XII-1 IARC evaluation of carcinogenicity of various aromatic amines in tobacco smoke (1870) ................................ 628 XII-2 Amines identified in tobacco, tobacco smoke, and tobacco substitute smoke ............................................. 630–661 Chapter 13 Amides XIII-1 Amides identified in tobacco, tobacco smoke, and tobacco substitute smoke ............................................. 665–677 Chapter 14 Imides XIV-1 Imides identified in tobacco, tobacco smoke, and tobacco substitute smoke...............................................680–685 Chapter 15 XV-1 XV-2 XV-3 XV-4 XV-5 XV-6 XV-7 XV-8

N-Nitrosamines Major N-nitrosamines in tobacco and/or tobacco smoke ..................................................................................... 690 Summary of lists of tumorigenic N-nitrosamines in tobacco and tobacco smoke............................................... 692 A brief chronology of the research on volatile N-nitrosamines from 1937 to 1990..................................... 693–698 A brief chronology of the research on tobacco-specific N-nitrosamines ..................................................... 700–704 N-Nitrosamines in tobacco and/or tobacco smoke............................................................................................... 708 Aliphatic secondary amines and volatile N-nitrosamines in tobacco and tobacco smoke .................................. 709 Aromatic and cyclic secondary amines and N-nitrosamines in tobacco and tobacco smoke.......................710–711 N-Nitrosamines in tobacco, tobacco smoke, and tobacco substitute smoke .................................................713–720

Chapter 16 Nitroalkanes, Nitroarenes, and Nitrophenols XVI-1 Nitroalkanes, nitroarenes, and nitrophenols in tobacco, tobacco smoke, and tobacco substitute smoke............................................................................................................................................................ 722–725 Chapter 17 XVII.A-1 XVII.A-2 XVII.A-3 XVII.A-4

Nitrogen Heterocyclic Components 4-Membered N-containing ring compounds in tobacco, tobacco smoke, and tobacco substitute smoke............ 728 Studies on the pyrolysis of amino acids ............................................................................................................... 730 Distribution of 5-membered N-containing ring compounds between tobacco and tobacco smoke..................... 732 5-Membered N-containing ring compounds in tobacco, tobacco smoke, and tobacco substitute smoke.............................................................................................................................................................733–746

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XVII.A-5 XVII.B-1 XVII.B-2 XVII.B-3 XVII.B-4 XVII.B-5 XVII.B-6 XVII.B-7 XVII.C-1 XVII.D-1 XVII.D-2 XVII.E-1 XVII.E-2 XVII.E-3 XVII.E-4 XVII.E-5 XVII.E-6 XVII.E-7 XVII.E-8 XVII.F-1 XVII.F-2 XVII.F-3 XVII.F-4 XVII.F-5 XVII.F-6 XVII.E-7 XVII.E-8

Compounds in tobacco, tobacco smoke, and tobacco substitute smoke with multiple 5-membered N-containing rings.........................................................................................................................................746–747 Distribution of 6-membered N-containing ring compounds between tobacco and tobacco smoke…..................751 Compounds in tobacco, tobacco smoke, and tobacco substitute smoke with a 6-membered N-containing ring ..........................................................................................................................................755–779 Distribution of components with a 6-membered N-containing ring and a second 5-membered N-containing ring between tobacco and tobacco smoke........................................... 780 Compounds in tobacco, tobacco smoke, and tobacco substitute smoke with a 6-and a 5-membered N-containing ring ..........................................................................................................................................781–789 Distribution of components with two or more 6-membered N-containing rings between tobacco and tobacco smoke .................................................................................................................................. 791 Compounds in tobacco, tobacco smoke, and tobacco substitute smoke with two or more 6-membered N-containing rings .................................................................................................................. 792–797 Tobacco and tobacco smoke compounds with 6-membered rings, with a 5- and a 6-membered ring, or with two or more 6-membered N-containing rings ................................................................................ 797 Lactams in tobacco, tobacco smoke, and tobacco substitute smoke… .........................................................799-804 The distribution of oxazole- and oxazine-related compounds identified in tobacco and tobacco smoke............ 806 Oxazole- and oxazine-related compounds in tobacco, tobacco smoke, and tobacco substitute smoke............................................................................................................................................................ 807–809 Dibenz[a,h]acridine {I}, dibenz[a,j]acridine {II}, and 7H-dibenzo[c,g]carbazole {III} in nicotine pyrolysates (Pyr) and mainstream cigarette smoke condensate (CSC)...............................................811 Chronology of selected aza-arenes: Dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g]carbazole, quinoline ............................................................................................................813–817 Summary of lists of tumorigenic aza-arenes in tobacco smoke............................................................................818 Tobacco smoke components related to aza-arenes in tumorigen lists...................................................................819 Aza-arene sources other than tobacco smoke… ...................................................................................................819 Aza-arenes and other polycyclic nitrogen compounds in tobacco, tobacco smoke, and tobacco substitute smoke ....................................................................................................................... 820–833 Structures of aza-arenes in tobacco and tobacco smoke… .................................................................................. 834 Derivatives of fused N-containing-ring compounds with two or more nitrogens in the rings..................... 835–840 Mutagenic activities of N-heterocyclic amines towards Salmonella typhimurium….......................................... 840 Summary of lists of tumorigenic N-heterocyclic amines in tobacco smoke........................................................ 844 N-Heterocyclic amines: Mutagenicity of beverages, heated foods, and heated food components...............845–846 Mutagenicity of common beverages vs. cigarette smoke condensate .................................................................. 846 Benzo[a]pyrene equivalency of extracts of charred fish and meat....................................................................... 847 Components related to N-heterocyclic amines in tobacco smoke: Identification and biological properties .............................................................................................................................. 847–848 Chronology of N-heterocyclic amine studies…………………………………………………….….. .............. 849–851 N-Heterocyclic amines in tobacco, tobacco smoke, and tobacco substitute smoke……………….….......... 852–853

Chapter 18 Miscellaneous Components XVIII.A-1 Sulfur-containing components in tobacco, tobacco smoke, and tobacco substitute smoke............................................................................................................................................................ 858–872 XVIII.B-1 Halogenated components identified in tobacco and tobacco smoke… ................................................................ 876 XVIII.B-2 The distribution of halogenated components identified in tobacco and tobacco smoke ...................................... 876 XVIII.B-3 Halogenated and related components in tobacco, tobacco smoke, and tobacco substitute smoke............................................................................................................................................................ 877–892 Chapter 19 XIX-1 XIX-2 XIX-3 XIX-4 XIX-5

Fixed and Variable Gases Volume percentages of fixed gases in the Earth’s atmosphere............................................................................. 894 Volume percentages of some variable gases (inorganic and organic) in the atmosphere. ................................... 894 Fixed gases in the vapor phase of MSS…............................................................................................................ 895 Major fixed and variable gases in non-filtered whole tobacco smoke… .............................................................. 895 Fixed and variable gases in tobacco, tobacco smoke, and tobacco substitute smoke .................................. 898–905

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Chapter 20. Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts XX-1 Elemental composition of a typical plant ............................................................................................................. 908 XX-2 Percent transfer of selected metallic and nonmetallic elements between tobacco and tobacco smoke ............... 913 XX-3 IARC classification and references to agents, groups of agents, mixtures and exposure circumstances evaluated by IARC that are metals, metallic compounds, radioisotopes, or tobacco or tobacco smoke-related materials .....................................................................................................914 XX-4 Distribution of metallic and nonmetallic elements, isotopes and ions between tobacco and tobacco smoke ......917 XX-5 Metallic and nonmetallic elements and ions in tobacco, tobacco smoke, and tobacco substitute smoke............................................................................................................................................................ 918–926 XX-6 Various ionic and covalently bonded organic and inorganic compounds containing metals and nonmetals, miscellaneous ions, and organometallic compounds found in tobacco, tobacco smoke, and tobacco substitute smoke............................................................................................................................................ 927–932 Chapter 21 XXI-1 XXI-2 XXI-3

Pesticides and Growth Regulators Percent transfer of intact agrochemicals to mainstream smoke........................................................................... 938 Degradation products of pesticides in mainstream smoke................................................................................... 939 Synthetic and natural pesticides and plant growth regulators in tobacco, tobacco smoke, and tobacco substitute smoke ....................................................................................................................... 940–976

Chapter 22 Genes, Nucleotides, and Enzymes XXII-1 Relative size of genomes and number of genes by species .................................................................................. 980 XXII-2 Enzymes, genes, clones in tobacco............................................................................................................... 983–999 Chapter 23 “Hoffmann Analytes” XXIII-1 Hoffmann contributions on smoke components to the 1985 IARC Working Group on Tobacco Smoking ............................................................................................................................... 1002 XXIII-2 Hoffmann-related lists of toxicants in tobacco and tobacco smoke................................................................... 1002 XXIII-3 The basis for the “Hoffmann Analytes”: The lists of toxicants issued by Hoffmann et al. from 1986 to 2001.......................................................................................................... 1003–1007 XXIII-4 An abbreviated chronology of the use of the term “Hoffmann Analyte” or its equivalent in tobacco smoke-related scientific literature .............................................................................................................1009–1011 XXIII-5 “Hoffmann analytes” in tobacco, tobacco smoke, and tobacco substitute smoke ....................................1012–1048 XXIII-6 Reported yields of “Hoffmann Analytes” in 1R4F and 2R4F mainstream smoke; proposed MSS “Hoffmann Analyte” yield analyses.....................................................................1049–1051 Chapter 24 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients XXIV-1A As listed by Doull et al. individual ingredient components used in U.S. smoking products.. ...................................................................................................................................................1056–1059 XXIV-1B As listed by Baker et al. individual ingredient components not used in U.S. smoking products but used outside of the U.S .................................................................................................................. 1059 XXIV-2 Tobacco and/or tobacco smoke components used as tobacco ingredients… ............................................1060–1101 XXIV-3 A summary of tobacco ingredient studies conducted from 1997 to date.................................................. 1103–1105 Chapter 25 XXV-1 XXV-2 XXV-3

XXV-4 XXV-5 XXV-6 XXV-7 XXV-8

Pyrolysis Precursor relationships between tobacco leaf components and tobacco smoke components ................... 1108–1110 Pyrolysis studies on n-hexane extract from tobacco ..........................................................................................1113 Comparison of polycyclic aromatic hydrocarbon fraction levels, phenol yields, and acid yields in 700°C pyrolysates from tobacco, petroleum ether extractables (PEE), and the tobacco residue (RES) after extraction.....................................................................................................................................................1115 Dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole in nicotine pyrolysates (Pyr) and mainstream cigarette smoke condensate (CSC) ...........................................................................................1118 Organic solvent-soluble components of tobacco identified post-1955.................................................................1119 Polycyclic aromatic hydrocarbons from aliphatic tobacco hydrocarbons pyrolyzed in air at various temperatures ....................................................................................................................................................... 1120 Total, free, and bound sterols in cigarette tobacco..............................................................................................1121 Component distribution in eight subfractions from a petroleum ether extract of tobacco (8% of tobacco weight) .......................................................................................................................................1123

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XXV-9 XXV-10 XXV-11 XXV-12 XXV-13 XXV-14 XXV-15 XXV-16 XXV-17 XXV-18 XXV-19 XXV-20 XXV-21 XXV-22 XXV-23 XXV-24 XXV-25 XXV-26 XXV-27 XXV-28 XXV-29 XXV-30 XXV-31 XXV-32

Conversion of tobacco leaf constituents to total mainstream smoke polycyclic aromatic hydrocarbons. ..........1123 Polycyclic aromatic hydrocarbons from tobacco components pyrolyzed in a N2 atmosphere at 650°C.............1125 Conversion of components in tobacco to benzo[a]pyrene during pyrolysis........................................................1126 Conversion of pectins, starch, and cellulose to specific polycyclic aromatic hydrocarbons and phenols during smoking ......................................................................................................................................1127 Pyrolysis vs. actual smoking conditions: Conversion of glucose, fructose, and cellulose to benzo[a]pyrene ...1129 Pyrolysis of leaf acids: Generation of selected phenols and polycyclic aromatic hydrocarbons ........................1130 Conversion of trimyristin added to tobacco to polycyclic aromatic hydrocarbons during actual cigarette smoking ...............................................................................................................................................1131 Components in pyrolysates from lysine, leucine, and tryptophan ......................................................................1132 Pyrolysis of phenylalanine. A. Effect of pyrolysis temperature B. Effect of equimolar addition of tryptophan (Try) or pyrrole (Pyr) .......................................................................................................................1133 Components in pyrolysates from amino acids (proline and glycine) and proteins (casein and collagen) ..........1134 Amino acid-derived N-heterocylic amines…......................................................................................................1135 Summary of lists of tumorigenic N-heterocyclic amines identified in tobacco smoke.......................................1135 Precursor relationships between N-containing tobacco leaf components and tobacco smoke components.......1136 NCI study (second set of experimental cigarettes): Effect of long chained alcohols sucker growth inhibitors on cigarette smoke properties..............................................................................................................................1137 NCI study (fourth set of experimental cigarettes): Effect of pesticides addition on cigarette smoke properties...................................................................................................................................1138 Pyrolysis of licorice vs. flue-cured tobacco: Benzo[a]pyrene generation….......................................................1139 NCI study (third set of experimental cigarettes): Effect of a humectant (glycerol) or casing material (sugar or cocoa) on cigarette smoke properties.....................................................................................1140 Benzo[a]pyrene in the pyrolysates from various humectants used or proposed for use in cigarette fabrication............................................................................................................................................................1140 Benzo[a]pyrene in the pyrolysates from various materials used or proposed for use in cigarette fabrication ............................................................................................................................................1142 Pyrolysis of cellulose and starch: Comparison of benzo[a]pyrene data from Kröller with those from Gilbert and Lindsey ....................................................................................................................................1142 Pyrolysis of tobacco and tobacco smoke components plus their effect on smoke composition when added to tobacco .............................................................................................................................. 1144–1165 Pyrolysis of non-tobacco and non-tobacco smoke components and/or their effect on smoke composition when added to tobacco...........................................................................................................1166-1168 Pyrolysis of miscellaneous tobacco product components plus their effect on smoke composition when added to tobacco ........................................................................................................................................1169 Summary of tobacco ingredient studies from 1994–2005… .................................................................... 1169–1171

Chapter 26 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens XXVI-1 Tumorigens, carcinogens, and toxicants listed by Hoffmann and colleagues............................................1174–1178 XXVI-2 The polycyclic aromatic hydrocarbon paradoxes ...................................................................................... 1184–1187 XXVI-3 Dibenz[a,h]acridine {I}, dibenz[a,j]acridine {II}, and 7H-dibenzo[c,g]carbazole {III} in nicotine pyrolysates (Pyr) and mainstream cigarette smoke condensate (CSC) ...............................................................1188 XXVI-4 N-Nitrosamines in tobacco smoke............................................................................................................. 1190–1193 XXVI-5 Summary of tumorigenic N-heterocyclic amines in tobacco smoke...................................................................1193 XXVI-6 Chronology of N-heterocyclic amine studies ........................................................................................... 1194–1196 XXVI-7A Anticarcinogens, inhibitors, and antimutagens in tobacco and tobacco smoke........................................1199–1201 XXVI-7B Anticarcinogens, inhibitors, and antimutagens in tobacco and tobacco smoke........................................ 1202-1204 XXVI-7C Anticarcinogens, antitumorigens, inhibitors, and antimutagens in tobacco, tobacco smoke, and tobacco substitute smoke ....................................................................................................................1205–1218 XXVI-8 Exposures to tumorigens and mutagens from sources other than mainstream and environmental tobacco smoke .............................................................................................................................1219 XXVI-9 Personal exposure to tobacco smoke polycyclic aromatic hydrocarbons listed as tumorigens… .............................................................................................................................................1220–1221

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XXVI-10 XXVI-11 XXVI-12 XXVI-13 XXVI-14 XXVI-15 XXVI-16 XXVI-17 XXVI-18 XXVI-19 XXVI-20 XXVI-21 XXVI-22

Polycyclic aromatic hydrocarbon sources… ...................................................................................................... 1222 Levels of benzo[a]pyrene and benz[a]anthracene in common foodstuffs…...................................................... 1223 Cigarette equivalents of benzo[a]pyrene (B[a]P) and benz[a]anthracene (B[a]A) in common foodstuffs ........ 1224 Comparison of daily dietary and inhalation intake of benzo[a]pyrene ............................................................. 1224 Aza-arenes sources other than tobacco smoke................................................................................................... 1225 N-Nitrosamines in foods and beverages (ng/g) ................................................................................................. 1226 Volatile and nonvolatile N-nitrosamines in foodstuffs and beverages .....................................................1227–1228 Comparison of dietary and environmental tobacco smoke................................................................................ 1229 Tobacco-specific N-nitrosamines in indoor air .................................................................................................. 1229 Non-tobacco exposures to tobacco/tobacco smoke N-nitrosamines .................................................................. 1230 Mutagenicity of beverages, heated foods, and heated food components ..................................................1232–1233 Mutagenicity of common beverages vs. cigarette smoke condensate ................................................................ 1233 Benzo[a]pyrene equivalency of extracts of charred fish and meat..................................................................... 1233

Chapter 27 Free Radicals XXVII-1 Free radicals in tobacco, tobacco smoke, and tobacco substitute smoke .................................................1253–1254 Chapter 28 Summary XXVIII-1 Distribution of chemical components between tobacco and tobacco smoke ............................................1258–1259

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List of Figures I.B-1

Phytadienes with potential to yield Diels-Alder adducts and subsequently alkylanthraquinones and anthraquinonecarboxylic acids ........................................................................................................................ 35 I.B-2 Phytadienes with little or no potential to form Diels-Alder adducts...................................................................... 35 I.C-1 Possible sterol degradation products ...................................................................................................................... 46 I.C-2 Phytadiene dimers .................................................................................................................................................. 47 I.E-1 The L region, K region, and bay region of benz[a]anthracene............................................................................... 60 II.A-1 The degradation products from ozonized solanesol..............................................................................................112 II.A-2 Tobacco and/or tobacco smoke alcohols related to cembrene...............................................................................115 II.B-1 Theoretical conversion of cholesterol to 1,2-dihydro-3-methylbenz[ j]aceanthrylene ......................................... 205 II.B-2 Possible sterol degradation products .................................................................................................................... 205 III-1 Approximate composition of cigarette mainstream smoke...................................................................................218 III-2 Cigarette mainstream smoke components: Logarithmic plot................................................................................219 III-3 Phenolic alcohol components of lignin ................................................................................................................ 221 VI-1 Relationships between coumarin, its derivatives, and dicumarol ........................................................................ 440 IX.A-1 A substituted phenol ............................................................................................................................................. 491 IX.A-2 Potential precursors in tobacco of 1,2-benzenediol (catechol) in tobacco smoke................................................ 505 X-1 Cembranoid ethers identified in tobacco and/or tobacco smoke .......................................................................... 556 XII-1 Oxygenated N-containing components of tobacco and tobacco smoke…………………… ................................. 628 XII-2 Structural similarities of alkylamines and pyrrolidines ...................................................................................... 628 XIV-1A The amide, imide, and lactam configurations ...................................................................................................... 679 XIV-1B The amide {II}, imide {III}, and lactam {IV} configurations in 1-acetyl-3-ethyl-1,5-dihydro4-methyl-2H-pyrrol-2-one {I} .............................................................................................................................. 679 XV-1 N-Nitrosodiethanolamine (NDELA) and N-nitrosomorpholine (NMOR)........................................................... 699 XV-2 Tobacco-specific N-nitrosamines ......................................................................................................................... 700 XV-3 References pertinent to tobacco-specific N-nitrosamines, 1983–2004 ................................................................ 704 XV-4 Relationships among amino acids, N-nitrosamino acids, their esters, and N-nitrosamines ................................ 706 XV-5 Indole {XLII}, carbazole {XLIII}, and 1H-benzimidazole {XLIV} ................................................................... 712 XVII.A-1 Representative structures of the 4- and 5-membered N-containing ring compounds in tobacco, tobacco smoke, and tobacco substitute smoke ..................................................................................................... 728 XVII.A-2 Porphyrin .............................................................................................................................................................. 732 XVII.B-1 Proposed biosynthetic pathways for production of several pyridine alkaloids .................................................... 749 XVII.B-2 Structures of the 6-membered N-containing compounds found in tobacco and tobacco smoke......................... 752 XVII.B-3 Common tobacco alkaloids found in tobacco and tobacco smoke....................................................................... 789 XVII.B-4 Common tobacco alkaloids found in tobacco and tobacco smoke with two or more 6-membered N-containing rings .......................................................................................................................... 791 XVII.C-1A The imide and lactam configurations…………………………................................................................................... 798 XVII.C-1B The imide {II} and lactam {III} configurations in 1,7-dihydro-6H-purine-2,6-dione (xanthine) {I}.................. 798 XVII.D-1 Parent structures of the oxazoles and oxazines identified in tobacco and tobacco smoke................................... 805 XVII.E-1 Quinoline and naphthalene....................................................................................................................................810 XVII.E-2 Some polycyclic components of tobacco smoke ...................................................................................................810 XVII.E-3 Some amino acid-derived N-heterocyclics identified in tobacco smoke.............................................................. 812 XVII.F-1 Pyrocoll, norharman, and harman….................................................................................................................... 834 XVII.F-2 N-Heterocyclic amines, the “cooked food” mutagens.......................................................................................... 834 XVII.F-3 Theoretical conversion of glutamic acid {XII} to aminobutanoic acids {XIII, XIV} and aminopyridines {XV-XVII} .......................................................................................................................... 841 XVII.F-4 Theoretical routes for conversion of glutamic acid-derived aminopyridines to possible tobacco smoke components................................................................................................................................................ 842

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XVII.F-5 XXV-1 XXV-2 XXVI-1 XXVI-2 XXVII-1

Possible tryptophan-derived compounds in tobacco smoke................................................................................. 843 Possible sterol degradation products ...................................................................................................................1122 The picene configuration present in glycyrrhizic acid ........................................................................................1139 “Tar” and nicotine deliveries, sales weighted average basis ...............................................................................1181 Structural similarity of several polycyclic aromatic hydrocarbons and aza-arenes............................................1183 Chemical structures of 4-POBN, PBN, MNP, PNO, 4-methyl-PNO, and DMPO spin-traps [From McCormick et al.] ................................................................................................................................... 1237

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Introduction History balances the frustration of how far we have to go with the satisfaction of how far we have come. It teaches us tolerance for the human shortcomings and imperfections which are not uniquely of our generation, but of all time. —Lewis F. Powell, Jr., Associate Justice of the Supreme Court of the United States (1972–1987)

THE INTENT OF THE WORK Years from now, just as we were surprised how paltry was the number of identified tobacco smoke components cataloged in 1954 by Kosak (2170), others will no doubt have similar remarks concerning this catalog. We hope the reader will be satisfied rather than frustrated with the progress that has been made by tobacco scientists over the last fifty plus years in furthering our knowledge base of components identified in tobacco and tobacco smoke. It should be noted the last published detailed catalog of tobacco and tobacco smoke components was that of Stedman (3797) in 1968.

THE CHEMICAL COMPOSITION OF TOBACCO The Master Catalog, collected over a fifty-year period, is our tabulation of all the information on the components identified in tobacco and tobacco smoke. The Master Catalog contains all of the information on components in tobacco and tobacco smoke that is contained in each chapter of this book as well as the information in the Bibliography and Alphabetical Component Index sections of the book. During the creation of the book, the information contained in the Master Catalog was searched to extract all of the components by functional group (alcohols, esters, aldehydes, etc.) to be includes in the separate tables for each chapter of the book. The Bibliography was separated from the Master Catalog as a separate section of the book. An Alphabetical Component Index was then created as a ready resource for readers to access particular information on each component and to locate the chapters and tables in the book chapters where that class of components is discussed. The original Master Catalog that we developed as such is not part of this book but was subdivided into numerous tables of components identified in tobacco and tobacco smoke by chemical functionality, the Bibliography, and the Alphabetical Component Index. Tobacco is a fascinating organism. This plant, as all plants do, takes the simplest of molecules (carbon dioxide, nitrogen, and water), light, and a series of metals (as micronutrients) and through a sophisticated internal process converts these materials to complex molecules for plant growth, regulation, and maintenance. Tobacco has been called a chemical factory. It has been cultivated for the purpose of collecting nicotine for

use as an insecticide and for starting material for numerous commercial chemicals such as the pyridines. More recently, it has been studied as a source of plant protein [Fraction 1 (F-1) and Fraction 2 (F-2) protein] (3974c). There are many different botanical classifications for tobacco plants. The genus Nicotiana has over sixty known species; each has been examined as to its genetic, physiological, botanical, and chemical characteristics (3972, 3973). Two tobacco species are grown commercially: Nicotiana rustica, primarily for nicotine and solanesol collection; and Nicotiana tabacum, for use as cigarette, pipe, cigar, snuff, and chewing tobaccos. To date, approximately 4200 components have been identified in tobacco. This number does not include the nontobacco components listed as added flavorants by Doull (1053) and Baker and Bishop (172a) or the hundreds of enzyme and other proteinaceous components listed in our Master Catalog. This is a tremendous achievement compared to the number of tobacco components reported as 3044 in 1988 by Roberts (3215), reported as 2549 tobacco compounds in 1982 by Dube and Green (1067), the 200 identified compounds reported in 1960 (2338), the 199 organic compounds and 21 inorganic elements reported as identified in tobacco in 1959 (1971), and the accounting of less than 10 tobacco constituents by Frankenburg (1221) in 1946. It should be noted that in the classification by Frankenburg, the tobacco constituents listed were not individual compounds but classes of compounds such as alkaloids, proteins (soluble and insoluble fractions), nitrate-nitrogen, amino nitrogen, etc. It is estimated that literally tens of thousands of unidentified compounds are yet to be discovered in tobacco. This estimate is based on the assumptions that there have already been thousands of organic, inorganic, and organometallic compounds identified in tobacco, that each plant contains hundreds of extremely complex compounds, for example, various types of DNA and RNA, numerous types of complex enzymes, proteins, sugar and amino acid oligomers, needed for plant growth, regulation, and maintenance, and that numerous fragments of these complex molecules have already been reported in tobacco. If it were not for scientists’ curiosity and the tremendous advances in analytical chemistry over the last fifty to sixty years, the need for this up-to-date catalog of compounds in tobacco and tobacco smoke would not be critical. Over the last fifty to sixty years literally tens of thousands of scientific articles on varied topics in tobacco and tobacco smoke science have been written. Our understanding of these two areas of science has advanced tremendously in the recent past. As noted by Knipling [see the Preface in Tso (3974c)]: Pioneering tobacco research was the foundation of plant science at the dawn of modern development, in such areas as light, nutrition, genetics, growth control, disorders and metabolism. Tobacco research led to current advancements

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in plant biotechnology. In addition, tobacco plant research contributed significantly to public health research in radioactive elements, mycotoxins, and air pollutants. However, public support for tobacco research has today greatly declined to almost total elimination because of a sense of political correctness … tobacco is one of the most valuable research tools, and is a most abundant source of scientific information. Research with tobacco plants will contribute far beyond the frontiers of agricultural science: tobacco can be a source of food supply with nutrition value similar to that of milk; tobacco can be a source of health supplies including medical chemicals and various vaccines; tobacco can be a source of biofuel. All we need is to treat tobacco with respect; the use of tobacco is only in its initial stages.

For nearly fifty years, our Master Catalog of components identified in tobacco and smoke has been in the process of assembly. Each component has one or more corresponding references. The tobacco literature was diligently searched for components identified in tobacco and tobacco smoke. As new components in tobacco and tobacco smoke were reported by R.J. Reynolds Tobacco Co. R&D personnel and in the published scientific literature, they were entered into the Master Catalog. Data on components in mainstream smoke (MSS), sidestream smoke (SSS), and environmental tobacco smoke (ETS) were collected from studies on the smokes from a variety of tobacco types and blends and numerous forms of smoking articles, such as cigarettes, cigars, and cigarillos. Data on tobacco components were collected from studies on numerous species of Nicotiana (primarily Nicotiana tabacum). The tobacco component data were collected from studies not only on all stages of plant development (seed to harvested plant) but also from tobacco processed in various ways (aged, fermented [to various degrees], steamed, cut, rolled, expanded, converted to reconstituted sheet [by various methods], treated with additives) prior to use as a smoking material. The Master Catalog contains an enormous variety of species from nearly every class of chemical components. We have separated and combined the identified components in tobacco and tobacco smoke into classes of components, for example, hydrocarbons, alcohols, acids, esters, aza-arenes, and each class will be discussed in a separate chapter. For the reader’s information, tobacco and tobacco smoke components possessing multifunctional groups will appear in each of the appropriate chapter lists but will be only tallied once as a tobacco component and/or a tobacco smoke component. For example, 2-furancarboxylic acid (2-furoic acid) is listed in the chapter on carboxylic acids and the chapter on ethers; 4-hydroxy-3-methoxybenzaldehyde (vanillin) is listed in each of the chapters on aldehydes, ethers, and phenols. The Master Catalog and the chapters on the various classes of tobacco components do contain some items not identified as tobacco components per se. They include items that (1) are not identified components of untreated tobacco and/or its smoke but are individual compounds added to the tobacco in a flavor formulation to improve consumer acceptability

of commercial products;* (2) are the pesticides, herbicides, nematicides, growth control agents, etc. (or their residues) that improve the agronomic situation for tobacco cultivation or have been found on tobacco; (3) are mycotoxic products of microorganisms found on tobacco plants, for example, aflatoxins; and (4) thermal degradation products from (1), (2), and (3) found in tobacco smoke. Many of the components in (1) were identified as added tobacco ingredients in the reports by Doull et al. (1053), Baker and Bishop (172a), and Baker et al. (174b). Many of the components in (2) are retained in the tobacco after harvesting and curing, are transferred intact to the smoke, and in some cases are degraded to compounds not usually expected in tobacco smoke. As noted previously, the items in (1) and (3) were not included in the 4200 identified tobacco components discussed earlier. Also not included in our Master Catalog are the additives comprising mixtures from naturally occurring products, for example, alfalfa extract, basil oil, honey. These will be discussed in the chapter on tobacco additives. During the 1920s and 1930s, plant nutrition was an active area of research and tobacco served as the model in much of that work. The results of research on nitrogen assimilation, light as a factor in nitrogen fixation, and how weather contributed to nutrient uptake contributed greatly to our understanding of plant science. All these advancements seem trivial today in light of the sophisticated work in genomics, but were nonetheless initially due to the pioneering work of scientists working with tobacco (3972, 3973). The presence of some micro-elements in tobacco was reported as early as 1921. Today, nearly all of the common elements, including alkali, alkali earth, heavy metal, and rare elements, have been reported to be present in tobacco, for example, Al, As, Ba, B, Cs, Cr, Co, Cu, F, Au, I, Pb, Li, Mg, Mn, Hg, Mo, Ni, Pt, Po, Ra, Rb, Se, Si, Ag, Sr, S, Ta, Ti, Sn, U, V, and Zn. Many heavy metal radioactive components have been reported in tobacco, including those from the uranium series, for example, 234U, 226Ra, 228Ra, 222Rn, 210Po, and others, such as 38Cl, 46Sc, 134Ce, 59Fe, and 40K. The presence of such elements in tobacco may be accidental, acquired from soil or from other sources. Scientists curious to understand the role of these assorted elements conducted research studies from the 1920s in order to understand the role of each element in plant growth and development. The effect of boron on plant growth was first noted in 1929, zinc in 1942, and copper in 1942. The concept of metals as catalysts in plant growth advanced the areas of chemical catalysis and its use in industrial fermentation (3972, 3973). The transfer of elements, particularly some of the metallic ones noted above, from tobacco to its smoke has been studied since the mid1950s, for example, see Cogbill and Hobbs (769). *

Among the flavor formulation compounds listed as tobacco ingredients by Baker and Bishop (172a), Baker et al. (174b), and Doull et al. (1053) was a substantial number of compounds reported as identified components of additive-free tobacco and/or its smoke [see Tables 1, 5, and 7A in (3266)]. That number was increased recently because of the identification of several additional listed flavor formulation compounds in flue-cured tobacco by Peng et al. (2917a) and in Perique tobacco by Leffingwell and Alford (2339a).

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Elemental isotopes have also been used in tobacco research for over fifty years. Studies with single, double, and even triple labeled compounds incorporating 15N, 3H, and 14C were reported by personnel at the U.S. Department of Agriculture (USDA) in the early 1950s in their studies on plant metabolism (3972, 3973). Tobacco is a very labor-intensive and sensitive crop. Hundreds of agronomic and physical processing steps occur from seed planting to final use in commercial products. The type of tobacco (flue-cured, burley, Maryland, Oriental, as well as dark air-cured tobacco and various cigar tobaccos) and how the tobacco is produced and cured affect the type and level of chemical compounds in tobacco leaf and in smoke. Among the chemicals applied to tobacco are insecticides, acaricides, miticides, nematicides, and growth control agents, for example, sucker-control and yellowing agents. These were developed to control pests and plant growth, to reduce labor, and ultimately produce a better, healthier, and more profitable crop. Their number and types are large. Over the years, new chemical agents were developed and commercialized as others were either banned or found to be less effective. Nonetheless, some pesticide residues remain in the soil and are often transported to the plant. All the commercial pesticides (as well as herbicides) are tested thoroughly and can be safely used (822a). As an example, today the most widely used sucker-control agents are fatty compounds, including fatty acids, alcohols, esters, and some of their derivatives. These sucker-control agents significantly inhibit axillary growth without causing undesirable side effects to the plant or the public (3972, 3973). The genetic makeup of tobacco includes 25000 to 50000 genes. Gene mapping of tobacco is being conducted in the Plant Pathology Department, North Carolina State University Centennial Campus, College of Agricultural and Life Sciences, Raleigh, North Carolina, in a project known as the Tobacco Genome Initiative (TGI). Its goal is to sequence and catalog more than 90% of the genome of cultivated tobacco, Nicotiana tabacum. Although tobacco has been cultivated for more than 500 years and is a crop of great economic significance, relatively little information exists on its genome structure and organization. A complete tobacco gene catalog will provide information needed to investigate the physiological and genetic processes in the plant kingdom, in general, and in Nicotiana tabacum specifically. Understanding the genetic processes occurring within the tobacco plant could potentially provide valuable information on ways to reduce the harm associated with cigarette smoking and also provide information on agronomic traits associated with disease and pest resistance genes for use in improving traditional and molecular breeding projects aimed at enhancing the performance of tobacco as a crop. The plants within the agriculturally important Solanaceae family, which includes tobacco, tomato, potato, eggplant, and pepper crop plants, will all benefit from gene discovery in Nicotiana tabacum. Available for public use are additional databases that contain listings of enzymes, enzymatic pathways, and reaction

products of metabolic and catabolic processes occurring in tobacco species. Many of these are listed as references in our chapter catalogs: r
GenBank (tobacco): For references see, http://www. ncbi.nlm.nih.gov/Genbank/index.html (1282a). r
BRENDA: The Comprehensive Enzyme Information System, Entry of hydroxymethylglutarylCoA reductase (NADPH) (EC-Number 1.1.1.34) Nicotiana, KEGG Link 00100 Steroid Biosynthesis, see: http://www.genome.jp/dbget-bin/show_ pathway?map00100+1.1.1.34 (429c). r
BRENDA: The Comprehensive Enzyme Information System; http://www.genome.jp/dbget-bin/ show_pathway?map00500+2.4.1.35 (429b). r
Kyoto Encyclopedia of Genes and Genomes (KEGG); see Kanehisa, M. and S. Goto: KEGG: Kyoto Encyclopedia of Genes and Genomes; Nucleic Acids Res. 28 (2000) 27–30 (429b). r
Lyon, G.D.: Host pathogen interactions and crop protection; Metabolic pathways of the diseased potato at: http://www.scri.sari.ac.uk/publications/ annualreports/98Indiv/21Metabo.pdf (429b). Plant scientists have long known that all organic components are dynamic in nature and change in numerous ways when present in biological systems. Chemical, catalytic, enzymatic, and bacteriological processes occur continuously during plant growth in the field and until these biological processes are quenched at harvest and during processing. Tobacco scientists have extensively studied the metabolism and catabolism occurring in Nicotiana plants because the change or formation of each compound may affect its final quality and thus its usability. Organic compounds are formed, transformed, and interact during plant growth in the field, during post harvest handling processes of curing, aging, and fermentation, and during manufacturing, including interaction with additives, and during blending (3972, 3973). The chemical composition of tobacco determines the chemical composition and yield of components in its tobacco smoke. For example, leaf protein (F-1 and F-2 protein) is abundant in tobacco and turns over and decomposes continuously to produce a vast array of protein subunits, amino acids, and amino acid oligomers (3974c). Tobacco leaf protein by itself contributes little to smoking quality, but it is a major precursor of hundreds of tobacco smoke components, for example, numerous nitrogenous compounds, amino acids. Similarly, other major tobacco components, such as the carbohydrates, carboxylic acids, pigments, polyphenols, fatty compounds, phytosterols, and many primary or secondary compounds play a significant role in producing a myriad of tobacco smoke compounds (3972, 3973). Tobacco has been used in one form or another in civilized society for nearly five centuries. Eventually in the late nineteenth century investigations as to its composition began but they were not particularly numerous. The major driving force in the escalation in the mid-twentieth century of studies on

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tobacco composition was the attempt to define (1) its components that contributed to the consumer acceptability of the taste and aroma of tobacco itself and its smoke and (2) the precursors in tobacco of the toxicants in its smoke. The latter investigations were triggered by the following events: (1) The publications from 1950 to 1953 of the results from several retrospective studies on lung cancer in smokers and nonsmokers [Doll and Hill (1027), Mills and Porter (2556), McConnell et al. (2515), Sadowsky et al. (3375a), Schrek et al. (3529), Wynder and Graham (4306b)]. The results suggested an association between cigarette smoking and cancer of the lung, particularly the lung cancer tumor type defined as squamous cell carcinoma. (2) The 1953 presentation and publication by Wynder et al. (4306a) of their findings on the production of malignant tumors in a susceptible strain of mice skin painted daily with massive doses of solutions of cigarette smoke condensate (CSC) supposedly generated under conditions simulating the human smoking of a cigarette. These statistical and biological findings augmented by the results of additional similar studies led to an escalation in the research to define the composition of cigarette smoke and to determine which of its components were responsible for the observed biological response. When a particular class of components — the polycyclic aromatic hydrocarbons (PAHs) — was considered responsible, studies escalated to define the precursors in tobacco of the PAHs in its smoke. Previous detailed reports on the composition of tobacco included those issued by Brückner in 1936 (451), Latimer in 1955 (2270), Johnstone and Plimmer in 1959 (1971), Shmuk in 1961 (3657), Stedman in 1968 (3797), Roberts et al. in 1975 (3224), Schmeltz and Hoffmann on nitrogen-containing tobacco components in 1977 (3491), Enzell and colleagues on terpenoid-derived tobacco components between 1976 and the late 1980s (1149, 1150, 1156, 4089, 4090). One thing has become apparent since the mid-1950s: No other consumer product that involves a complex mixture has been defined in such detail as tobacco and/or its smoke, for example, the number of components identified to date in tobacco is almost twice that of the number identified in coffee.

IDENTIFIED COMPONENTS OF TOBACCO AND TOBACCO SMOKE IN THE MASTER CATALOG Many of the components identified in tobacco have also been identified in its smoke because they transfer in part from tobacco to its smoke during the smoking process. Many other identified tobacco components are not found in smoke because they decompose during the smoking process. The level of many tobacco components considered to contribute to the acceptable taste of its smoke are augmented by inclusion in various additive formulations used in the U.S. Tobacco Industry (1053, 3263). Figure 0.1 illustrates the increase in number of identified components in tobacco and its smoke. Green and Rodgman (1373) discussed the contribution of improved analytical technologies to the periodic escalation in the number of identified components in each.

6000 5000 E 4000 3000 D

2000 1000 0

Tobacco Smoke

C B

A 50

55

60

65

70

75

80 Year

85

90

95

00

05

FIGURE 0.1 Number of identified tobacco and tobacco smoke components reported since 1954: Accumulative by year: A = prior to 1953: “classical” chemical techniques; B = 1953–1960: column chromatography; C = 1960–1970: gas chromatography; D = 1970 to mid-1970s: glass capillary gas chromatography coupled with mass spectrometry; E = mid-1970s to date: derivatives for HRGC, HPLC, mass spectrometry.

An enormous number of references exist pertinent to the isolation, identification, and biological studies of the great number of components in tobacco and tobacco smoke. To avoid considerable repetition, these are presented as a unified Bibliography which contains the references cited not only in this Introduction but also in each chapter. It is obvious that some references have been omitted but we assure the reader that any omission was not by design but was done unwittingly. The references cited for a particular tobacco and/or tobacco smoke component may deal simply with its identification or with a variety of topics pertinent to the particular component. Such topics may include the following: 1. The isolation and identification of the component. 2. The characterization of the component by classical chemical means, for example, the definition of the structure of solanesol isolated from flue-cured tobacco by Rowland et al. (3359), the characterization of a component by spectrographic means such as UV, IR, NMR, MS, and chromatographic retention time, for example, the identification by Snook et al. of numerous PAHs (3756-3758) and aza-arenes (3750) in cigarette MSS. 3. The search for the precursor in tobacco of a particular component in cigarette mainstream smoke (MSS) (3616). 4. The quantitation of the component on a per gram of tobacco basis or on its per cigarette MSS yield. 5. Improvements/developments in the analytical technology to determine the per cigarette MSS and/or sidestream smoke (SSS) yield of the component, for example, see Table 6 in (3306b). 6. Studies on the biological activity of a particular component. 7. Discussions and/or assertions of the toxicity and/or tumorigenicity of a component in MSS, SSS, or ETS.

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8. Studies on the inhibition of adverse biological activity of a tobacco smoke component by another component of the smoke, for example, the inhibition of the mouse-skin tumorigenicity of B[a]P by n-hentriacontane and n-pentatriacontane (4314, 4336), the inhibition of the mouse-skin tumorigenicity of DB[a,h]A by B[a]A (3814), the inhibition of the mutagenicity of N-nitrosodimethylamine (NDMA) by nicotine (2327a, 2327b). 9. Controversies over the extrapolation of the biological effect of a specific component administered individually vs. its biological effect when the component in a highly complex mixture such as MSS is administered to a different species, by a different route, and at a dose level far in excess of its level in the complex mixture (1318a, 3300, 3627). 10. Description of the design technologies to control the per cigarette MSS yield of Federal Trade Commission (FTC)-defined “tar” and a particular component, for example, see Table 16 in (3300). In many instances, the references cited for a particular component may also contain additional references pertinent to the component. The categories of chemical components in tobacco and tobacco smoke derived from our Master Catalog will be presented in the sequence shown in Table 0.1. These chapters will be followed the Bibliography and then an Alphabetical Component Index section. As information for the reader, Table 0.2 depicts the first page of the catalog for the alkanes (Table I.A-10). A similar component catalog is present in the chapter for each component class. Tobacco smoke, particularly cigarette smoke, is an aerosol comprising literally millions of liquid droplets suspended in a gaseous system [see Ingrebrethsen (1860)]. The liquid droplet portion of this smoke is defined as the particulate phase (PP); the gaseous portion as the vapor phase (VP). The particulate phase is also described alternatively in several ways depending on the context of the discussion; for example, the particulate phase collected by a variety of collection techniques such as the Cambridge filter pad, electrostatic precipitation, jet impaction, etc. [cf. review by Dube and Green (1067)] is termed wet total particulate matter (WTPM). Correction for the water content yields total particulate matter (TPM). Subtraction of the nicotine level from total particulate matter gives the FTCdefined “tar.” The reasons for exclusion of nicotine and water to give the FTC “tar” value were the long recognized nontoxicity of water plus the low toxicity of cigarette smoke nicotine as described in the 1964 report of the Advisory Committee to the U.S. Surgeon General (3999). Thus, we have the following relationships among these entities:

TABLE 0.1 Sequence of Chemical Component Categories Chapter 1. I.A. I.B. I.C. I.D. I.E. I.F.

The Hydrocarbons The Alkanes The Alkenes and Alkynes The Alicyclic Hydrocarbons The Monocyclic Aromatic Hydrocarbons The Polycyclic Aromatic Hydrocarbons Summary

Chapter 2. II.A. II.B.

Oxygen-Containing Components Alcohols and Phytosterols Alcohols Phytosterols

Chapter 3. Chapter 4 IV.A. IV.B. Chapter 5. Chapter 6. Chapter 7. Chapter 8. Chapter 9. IX.A. IX.B. Chapter 10.

Aldehydes and Ketones Acids Carboxylic Acids Amino Acids The Esters The Lactones Anhydrides Carbohydrates and Their Derivatives Phenols and Quinones Phenols Quinones The Ethers

Chapter 11. Chapter 12. Chapter 13. Chapter 14. Chapter 15. Chapter 16. Chapter 17. XVII.A. XVII.B. XVII.C. XVII.D. XVII.E. XVII.F. Chapter 18. XVIII.A. XVIII.B. Chapter 19. Chapter 20. Chapter 21. Chapter 22. Chapter 23. Chapter 24. Chapter 25. Chapter 26. Chapter 27. Chapter 28.

Nitrogen-Containing Components Nitriles Acyclic Amines Amides Imides N-Nitrosamines Nitroalkanes, Nitroarenes, and Nitrophenols Nitrogen Heterocyclic Components Monocyclic Four- and Five-Membered N-Containing Ring Compounds Monocyclic Six-Membered N-Containing Ring Compounds Lactams Oxazoles and Oxazines Aza-arenes N-Heterocyclic Amines Miscellaneous Components Sulfur Compounds Halogenated Compounds Fixed and Variable Gases Metallic and Nonmetallic Elements, Isotopes, Ions and Salts Pesticides and Growth Regulators Genes, Nucleotides, and Enzymes “Hoffmann Analytes” Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients Pyrolysis Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens Free Radicals Summary

WTPM = TPM + H2O = FTC “tar” + nicotine + H2O The equation most frequently used in the United States since the late 1960s is the following: FTC “tar” = WTPM nicotine H2O

In many instances, the collected cigarette smoke particulate phase is called CSC. In many countries, cigarette “tar” is determined by use of the International Organization of Standardization (ISO)

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TABLE 0.2 Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

method. The “tar” yield in the ISO method ISO 4387-1991 is calculated in the same manner as in the FTC method [Pillsbury et al. (2962)], that is, by subtraction of the water and nicotine from the WTPM collected (ISO 1991). The ISO

cigarette equilibration and smoking procedure differ slightly from those in the FTC procedure [see Table 1, p. 496 in Rustemeier and Piadé (3369a)]. These differences typically result in slightly lower measured yields for the ISO method

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vs. the FTC method. The measured values between FTC and ISO methods are within the detection limits of the test. They differ by no more than 0.4 mg for “tar” and no more than 0.04 mg for nicotine for cigarettes that yield over about 10 mg of “tar.” As described by Dixon and Borgerding (988a), under standard smoking regimes the ISO and FTC methods give very similar results. The physical nature of cigarette smoke is discussed below. Periodically during the past five decades, various reviews and catalog on the composition of tobacco smoke, with particular emphasis on cigarette MSS, have been published. These have dealt with the components of total MSS (the vapor-phase and the particulate-phase components) [Kosak (2170), Bentley and Berry (282, 283), Berry (296), Johnstone and Plimmer (1971), Izawa (1900), Philip Morris, Inc. (2939), Stedman (3797), Ishiguro and Sugawara (1884), IARC (1871)], with MSS particulate-phase components only or with MSS vapor-phase components only [Elmenhorst and Schultz (1140)], with both MSS and SSS components [Sakuma et al. (3394, 3397, 3398), R. J. Reynolds Tobacco Company (RJRT) (3190), Klus (2133), Klus and Kuhn (2142)], with MSS, SSS, and ETS components [Brunnemann et al. (462), Eatough et al. (1099, 1100)], and with particular classes of smoke components, for example, nitrogen-containing components [Neurath (2724), Schmeltz and Hoffmann (3491)] or PAHs [Elmenhorst and Reckzeh (1139)]. The majority of these reviews described the composition of smoke from cigarettes with a filler that was primarily tobacco. Although not published in the readily available scientific literature, substantial data are available from studies conducted on the smoke from cigarettes whose filler was not primarily tobacco but a “tobacco substitute” or a tobacco: “tobacco substitute” mixture. Inclusion of tobacco in the filler mixture ensures that the smoke will include the components usually found in an all-tobacco cigarette. Such data appear not only in documents from Celanese describing the composition of MSS from cigarettes containing only its Cytrel® product or in documents by Imperial Tobacco and Imperial Chemical Industries describing the MSS composition from cigarettes containing only their New Smoking Material® (NSM®) product but also in RJRT R&D reports which outline its studies on the composition of smoke from cigarettes made with Cytrel® only, NSM® only, the Sutton Smoking Material (SSM) only, or J-10 only (a tobacco substitute, comprising a puffed grain, developed in-house at RJRT). Recently, an article by Green et al. (1375a) on the effect of several tobacco substitutes on cigarette MSS composition has been published. At RJRT, all available data on the composition of MSS from cigarettes made with various tobacco types, tobacco blends, various “tobacco substitutes,” and/or cellulose have been routinely cataloged by R&D personnel, including one of the present authors (A.R.), for over five decades (2270, 2292a, 3224, 3245, 3252, 3253, 3301-3304, 3308). Until the early 1980s, the majority of the studies on tobacco smoke composition dealt with the composition of cigarette MSS. Particulate-phase composition was the major

research topic throughout the 1950s with studies on vaporphase composition receiving increased emphasis in the early 1960s when the biological response in laboratory animals could not be explained by nature and/or the level of any of the particulate-phase components acting individually or in concert.

TOBACCO SMOKE AND THE EXAMINATION OF ITS TUMORIGENICITY IN LABORATORY ANIMALS The initial research efforts were directed at attempts to identify the components in the CSC that could be responsible for the observed biological response in the CSC-painted animals. Immediately, the class of compounds selected for intense investigation was the PAHs. Why was this class of compounds selected? Primarily it was because of the twenty years of research effort since the initial findings in the early 1930s (194, 2078) that had shown that many PAHs were tumorigenic to mouse skin (1544), with several being classified as highly potent carcinogens to mouse skin (3306b). After more than a century of research during which investigators attempted to induce malignant tumors in laboratory animals by administration of a variety of industrial tars, soots, oils, etc., success was finally achieved by Yamagiwa and Ichikawa (4361) who reported the first induction of tumors in laboratory animals skin-painted with coal tar solutions. Their findings, which subsequently led to extensive research on the induction of malignant tumors by skin painting of laboratory animals with various tars and oils, also led to the definition in 1923 of the terms carcinogen, carcinogenesis, and carcinogenicity. Carcinogenesis was defined as the induction of a carcinoma by the treatment. In 1930, a synthetic pentacyclic PAH, dibenz[a,h]anthracene (DB[a,h]A) {I} (760, 1184), was reported to be highly carcinogenic to mouse skin by Kennaway and Hieger (2078). In the early 1930s, Cook et al. (796a, 797) isolated several PAHs from two tons of coal tar. One of the PAHs, initially unknown, was demonstrated by characterization and synthesis to be benzo[a]pyrene (B[a]P) {II}, another pentacyclic PAH structurally similar to DB[a, h]A (see Figure 0.2). Subsequently it was demonstrated by Barry et al. (194) that B[a]P was also a potent carcinogen for the skin of susceptible mouse strains. The finding of the carcinogenicity of these two individual compounds, DB[a,h] A and B[a]P, was the stimulus for the synthesis and bioassay of literally hundreds of PAHs (and structurally similar nitrogen analogs) and their alkyl derivatives. Many of the PAHs with four or more fused rings were reported to be carcinogenic to mouse skin. A wealth of data was generated from research on attempts to correlate carcinogenic potency with PAH structure [Coulson (829), Pullman and Pullman (3003), Lacassagne et al. (2247a)]. The carcinogenic potency to mouse skin is dependent on the PAH structure and its substituents; for example, benz[a]anthracene (B[a]A) {III} is a relatively weak carcinogen to mouse skin whereas its 7,12dimethyl homolog (DMBA) {IV} is an extremely potent one

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Dibenz[a,h]anthracene {I} CAS No. 53-70-3

Benzo[a]pyrene {II} CAS No. 50-32-8 CH3

CH3 Benz[a]anthracene {III} CAS No. 56-55-3

7,12-Dimethylbenz[a]anthracene {IV} CAS No. 57-97-6 CH3 H3C H3C CH3

Phenanthrene {V} CAS No. 85-01-8

1,2,3,4-Tetramethylphenanthrene {VI} CAS No. 4466-77-7

FIGURE 0.2 Polycyclic aromatic hydrocarbons.

(983). The tricyclic PAH phenanthrene {V} is noncarcinogenic to mouse skin but its 1,2,3,4-tetramethyl homolog {VI} is slightly carcinogenic (983). Kennaway (2073–2076) reported that pyrolysis of a variety of organic compounds (methane, acetylene, isoprene, cholesterol) or mixtures containing organic compounds yielded pyrolysates which were tumorigenic to mouse skin. Subsequently, it was reported that a variety of carcinogenic PAHs, including B[a]P, were components of similar pyrolysates; for example, the pyrolysates from the tobacco smoke components methane [Burrows and Lindsey (529a)] and isoprene [Oró et al. (2864b)], as well as the pyrolysate from the tobacco phytosterols structurally similar to cholesterol [Wynder et al. (4355), Van Duuren (4022), Schmeltz et al. (3511), Severson et al. (3616)]. For several years in the early 1950s, whether PAHs were present in tobacco smoke was a highly controversial subject. The early claims of the presence of B[a]P in cigarette smoke were criticized by Kosak et al. (2177) in 1956 and by Fieser (1181) in 1957 because of the failure to duplicate the reported findings when similar analytical techniques were used. Logic dictated that the PAHs, including B[a]P, would indeed be present because they arise pyrogenetically from organic compounds under a variety of conditions. Several of the demonstrated PAH precursors are known to be components of tobacco used in a cigarette, cigar, or pipe. The smoking process involves pyrolysis and/or combustion. The differences between the effect of pyrolysis of an individual compound vs. the effect of the cigarette smoking process on the same compound in

the complex tobacco mixture were discussed by Rodgman et al. (3307) and their discussion will be summarized in a later chapter. However, even as late as 1957, Fieser, one of the eminent American authorities on tumorigenic PAHs, was not convinced that the presence of B[a]P in cigarette smoke had been demonstrated. Fieser (1181) discussed the available published data from various laboratories as follows: British [Cooper and Lindsey (820)] and American groups [Lefemine et al. (2335), Alvord and Cardon (55), Cardon and Alvord (593)] have claimed identification of benzpyrene following extensive chromatography of tars from cigarette smoke, but in each case the evidence of identity is correspondence of the smoke factor with the synthetic carcinogen in fluorescence spectrum, coupled with the correspondence of the two materials in one region of the ultraviolet absorption spectrum … In the absence of complete ultraviolet correspondence, the smoke-factor reported by the two groups of investigators can be described as nothing more than a benzpyrene-like substance, which may or may not be carcinogenic … Kuratsune (2237) [examined] the smoke from cigarettes of two Japanese brands and detected no benzpyrene … In my laboratory 20 g of cigarette smoke tar (from 500 cigarettes) to which 9.7 μg/g of benzpyrene was added was chromatographed … and rechromatographed … the recovery [of benzpyrene] was 7.8 μg/g of tar (80%) … In a parallel experiment with 20 g of the same tar and no additive, fractions corresponding to the positive fractions of the control were all negative … Our estimate was that benzpyrene could be present in amounts no greater than 1 part in 5 million parts of tar. Present evidence thus indicates that benzpyrene is formed in trace amounts on pyrolysis of constituents of tobacco (probably cellulosic), but that no appreciable amount passes into the smoke, and hence that this hydrocarbon is not the agent responsible for the observed carcinogenicity to mice of cigarette smoke tar [Wynder et al. (4306a)].

Fieser also reported that his colleagues Huang and Johnston failed to detect B[a]P in the MSS from American cigarettes even though they determined its level (80% recovery) in CSC “spiked” with B[a]P (1181). In Japan, Kuratsune, unable to demonstrate the presence of B[a]P in the CSC from Japanese cigarettes, was able to demonstrate its presence in roasted coffee beans and various other pyrolysates [Kuratsune (2237), Kuratsune and Hueper (2238)]. After subsequent studies by Orris et al. (2865) and Kiryu and Kuratsune (2099) or assessment of more complete laboratory data, Fieser (1182) and other critics reversed their earlier positions and eventually accepted that B[a]P was indeed present in tobacco smoke. The ultimate confirmation of the presence of B[a]P in cigarette smoke was its isolation in crystalline form and characterization by chemical means rather than reliance solely on the correspondence of the ultraviolet spectrum of the isolate with that of an authentic sample. Isolation of crystalline B[a]P from the MSS of a 70-mm nonfiltered cigarette was reported in 1956 by Rodgman (3240), by Hoffmann [see Wynder and Hoffmann (4307)] in 1959, and from a filtered cigarette in 1960 by Rodgman and Cook (3273). Fieser, the major architect of the chapter on smoke composition in the 1964 report of the Advisory Committee to the U.S. Surgeon General (3999), had access to the published data by

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Wynder and Hoffmann (4307) on the isolation of crystalline B[a]P from cigarette smoke. However, numerous proponents of the adverse effect of cigarette smoke, for example, Wynder and Wright (4282a, 4354) and Wynder and Hoffmann (4307, 4312) asserted that the level of B[a]P in CSC or the levels of several tumorigenic PAHs, including B[a]P, could only account for a few percent of the biological response observed in mouse skin-painting studies with CSC. Since much of the post-1950 effort on MSS composition was directed to the definition of the cancer-causing agents in MSS possibly responsible for the association between lung cancer and cigarette smoke in smokers, it is a requisite that the various terms used in laboratory studies of tumor generation be understood. In their 1990 list, Hoffmann and Hecht (1727) cataloged the tobacco and/or tobacco smoke components classified as “tumorigenic agents” and the range of the per cigarette MSS yields of each. Prior to examining the individual components on the list, an important distinction between “tumorigenicity” and “carcinogenicity” should be noted. In the 27th edition in 1988 of Dorland’s Medical Dictionary (1051b), the definition of carcinogenesis, first enunciated in 1923, is the same as that listed in the 13th edition issued in 1927 (1051b). Some investigators incorrectly use the term “carcinogenesis” for the production of any tumor type, not just for a carcinoma. The correct term, if used in this manner, is “tumorigenesis.” The term “carcinogen” is often applied, again often incorrectly, to any factor that induces any type of tumor. Common in the past, but seldom used now, was the term “sarcogenesis” used to describe the production of sarcoma, the endpoint obtained in many investigations in which the mode of administration of the compound under test, for example, a PAH, was by subcutaneous injection. Additionally, terms such as carcinogen, carcinogenicity, and/or carcinogenesis or sarcogen, sarcogenicity, and/or sarcogenesis should not be considered as fixed properties of compounds. It should be noted that in several of their early publications, Wynder and Hoffmann (4342, 4343a, 4346) and Hoffmann and Wynder (1801) carefully differentiated among the terms carcinogenesis, sarcogenesis, and tumorigenesis but eventually discontinued this practice. Other investigators have done the same. Because of the successful induction of cancer in a laboratory animal by Yamagiwa and Ichikawa (4361) and the discovery that several PAHs were tumorigenic when painted on the skin of laboratory animals (194, 797, 2078), the tumorigenicity of literally hundreds of PAHs (and structurally similar nitrogen analogs) and their alkyl derivatives was studied from 1932 to 1941. Many of the assertions made about the correlation between the laboratory findings and human experience were extremely farfetched and caused much confusion. This led to the request for Shear of the U.S. National Cancer Institute to attempt to return order to the field of carcinogenicity. The result was the classical description by Shear and Leiter (3627), a description whose pertinence is still valid. Carcinogenicity is a variable property, depending on a number of factors. It differs from other properties of a

compound that are fixed, for example, melting point, boiling point, refractive index, specific gravity, crystalline form. As noted by Shear and Leiter (3627), Hartwell (1544), and many others, a substance or factor can show a range of effects from carcinogenicity to noncarcinogenicity to anticarcinogenicity and the response will differ in the laboratory depending on the animal used (species, strain, sex, age), dose, route of administration (inhalation, ingestion, injection [subcutaneous, intravenous, intraperitoneal], skin painting, douching), mode of administration (single vs. multiple doses, neat, in solution, as an aerosol, as a vapor), diet supplied the animals, and cage care.

SMOKE-FORMATION PROCESSES, DISTRIBUTION (MSS, SSS, ETS), CHEMICAL COMPOSITION, AND ANALYTICAL METHODS FOR IDENTIFICATION Cigarette smoke composition is dependent on two major processes occurring during the smoking of tobacco: the direct transfer by vaporization of volatile tobacco components directly to the smoke and the pyrogenesis of smoke components from tobacco components. The pyrogenesis involves a variety of reactions, including oxidation, reduction, aromatization, hydration, dehydration, condensation, cyclization, polymerization, depolymerization, etc. Table 0.3, adapted from Kosak (2170), lists the fewer than 100 tobacco smoke components reported in the scientific literature to that date. Examination of his compilation reveals the following: 1. Of the approximately eighty entries, the identities of thirty-three (over 40%) of the components were questioned by Kosak because he did not “consider the evidence cited in the literature to be definitive proof” of their identities. 2. Two of the listed items (B[a]P, “condensed aromatics”) were reported by Roffo (3323, 3324) whose research did not involve the study of tobacco smoke but involved a study of material obtained by the “destructive distillation” of tobacco. 3. Several of the alkaloid-related components (A-, B-, and G-socratine, obelin, lohitam, anodmin, lathraein, poikiline, and gudham) first reported by Wenusch and Schöller (4210, 4211) and listed under Alkaloids were subsequently demonstrated to be mixtures or a component listed elsewhere in Table 0.3. For example, Kuffner et al. (2224) demonstrated that obelin was a salt of ammonia, Aand B-socratine were mixtures of nicotyrine and 2,3`-bipyridine, and G-socratine was l-nornicotine. Poikiline was characterized as 4-amino-1-(3pyridyl)-butanone. Many of these characterization corrections are described in Johnstone and Plimmer (1971).

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TABLE 0.3 Tobacco Smoke Components Listed by Kosak (2170) Class

Component

Class

Component

Class

Component

Hydrocarbons

Hentriacontane (?) Acetylene “Unsaturated hydrocarbons” Azulene Phenanthrene (?) Anthracene (?) Benzopyrene (?) “Condensed aromatics” (?)

Ketones

3-Pentanone 4-Heptanone 17-Tritriacontanone (?) 2,3-Butanedione “Higher” ketones (?)

Acids

Alcohols and Phenols

Methanol Glycerol Diethylene glycol a Ethylene glycol a Phenol (?) Catechol (?)

Alkaloids

Nicotine Pyridyl ethyl ketone Myosmine Nicotyrine A-Socratinec B-Socratinec G-Socratinec Obelinc Lohitamc Anodminc Lathraeinc Poikilinec Gudhamc

Miscellaneous Components

Formic acid Acetic acid Butyric acid Valeric acid Caproic acid C7 and C8 aliphatic acids (?) Succinic acid (?) Fumaric acid (?) Citric acid (?) Benzoic acid (?) Phenolic acids (?) Levoglucosan d “Phytosterol” (?) C10H14O (a furan ?) “Resins” (?) “Resin acids” (?)

Aldehydes

Formaldehyde Acetaldehyde Butyraldehyde Acrolein (?) Benzaldehyde 2-Furaldehyde (?) b

Other Ncontaining components

Pyrrole (?) “Pyrroles” (?) “N-Methylpyrrolidines” (?) Pyridine “Picoline” (?) “Lutidine” (?) “Collidine” (?) “Pyridine bases” (?) Methylamine (?) “Chlorophyll degradation products” (?) “Uric acids” (?)

Inorganic Components

Ammonia Carbon monoxide Carbon dioxide Hydrogen cyanide Hydrogen sulfide Thiocyanic acid (?) Oxygen Arsenic e “Acetates” (?) “Chlorides” (?) “Cyanides” (?) “Nitrates” (?)

a

In smoke because of transfer of an humectant added to tobacco. The question mark indicates that Kosak did not consider the evidence in the literature to be definitive proof of the identity of the component. c Subsequent study demonstrated this component was not a well-defined compound but an artifact, a mixture, or an ammonium salt [see discussion by Johnstone and Plimmer (1971)]. d 1,6-Anhydro-B-D-glucopyranose. e Probably present as As O . 2 3. b

4. Kosak listed references to phenol (1857, 4202), catechol (2107, 4202), and “phenolic acids” (3324) as tobacco smoke components. However, he failed to report the 1952 presentation by Rayburn (3089) of the unequivocal identification of phenol, guaiacol (2-methoxyphenol), o-cresol (2-methylphenol), and m-cresol (3-methylphenol) in the smokes from the four major tobacco types (flue-cured, burley, Maryland, and Oriental).

5. Azulene, a bicyclic C10H8 hydrocarbon isomeric with naphthalene, was first reported as a tobacco smoke component by Ikeda (1857) and subsequently by Gilbert and Lindsey (1287, 1288), Lindsey (2365), and Lyons (2426). Despite improved analytical technology and hundreds of studies on the identification of PAHs in tobacco smoke, very few reports of its identification have appeared since those in the 1950s. This suggests

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the possibility that the azulene reported in tobacco smoke condensate in the 1940s and 1950s may have been formed artifactually. In summary, Kosak’s 1954 list, shown in Table 0.3, included only about fifty components the identities of which were certain. The number of identified components in cigarette tobacco smoke has increased almost 100-fold from the fifty definitively identified tobacco smoke components listed by Kosak (2170) to the more than 5300 components identified to date and cataloged by RJRT personnel. Components were originally included in the RJRT catalog only if their identification criteria satisfy the identification criteria of classical organic chemistry. Later, identification criteria from modern analytical chemistry were employed. From 1950 to 1955, the early years of the great escalation of interest in the composition of cigarette smoke, “isolations” were often accomplished with no regard to the possibility of artifact formation. Also, “identifications” of tobacco smoke components were often based on less than complete spectral data, for example, the PAHs and their ultraviolet spectra, Rf values, color tests, and the like. Because of the state of the art of the isolation techniques available in the early 1950s, the level in smoke of a component under investigation often precluded its isolation in quantities sufficient for application of the classical chemical techniques (melting point and mixture melting point determinations, derivative preparation, elemental analysis, etc.) used for identification. The authors of some of the early reviews and catalogs on tobacco smoke composition listed the smoke components reported in the literature without regard to the analytical validity of their identification. This problem has progressively decreased over the years as analytical technology has increased in sophistication. Few, if any, commercial products have experienced the analytical scrutiny that has been applied to tobacco smoke or tobacco. The composition of coffee has been examined but the number of components identified is less than 25% of the number identified in tobacco smoke. Despite the identification of over 5200 additional smoke components since the 1954 listing by Kosak, various investigators have estimated from gas chromatographic scans that for each component identified in tobacco smoke there are five to twenty components present at extremely low per cigarette yields that have not yet been identified. Thus, as noted by Wakeham (4103) when the identified tobacco smoke components numbered about 1350: “Gas chromatographic scans indicate there are many more, probably over ten thousand, possibly even a hundred thousand [tobacco smoke components].” Grob (1422), one of the pioneers of the use of glass capillary gas chromatography in tobacco smoke composition studies, as well as other tobacco smoke investigators, also noted that the number of peaks, each of which represented at least one component, in the chromatographic scans far exceeded the number of components identified.

In addition to the advancement in knowledge of the chemical composition of cigarette smoke was the advancement in the knowledge of its physical properties, that of an aerosol. An aerosol is defined as a colloidal system of dispersed liquid or solid material in a gaseous medium. Cigarette smoke is an aerosol comprising liquid droplets in a gas. For nearly two decades, investigators have accumulated knowledge on the conditions involved in the formation of MSS and SSS aerosols during the smoking of a cigarette and the factors contributing to or modifying their yields and composition. Theories on smoke formation in vogue in the late 1950s and early 1960s were demonstrated to be incorrect; for example, many investigators thought that all smoke components not originally present in tobacco and thus appearing in the MSS by pyrogenesis from the tobacco were formed at or near the fire cone at temperatures in excess of 900°C. New and more nearly correct theories replaced the old ones. Advances in our knowledge of smoke formation and transport were possible because of improved technologies developed to accomplish the following tasks, see Townsend (3941a): 1. Accurately measure temperatures during puffs and during the smolder period between puffs at various sites within the burning cigarette and its fire cone. 2. Follow the formation of specific components and their subsequent passage and transport, in the case of MSS components, through the tobacco rod by puff-driven volatilization, repetitive condensations and revolatilizations, filtration by tobacco rod and filter tip material, etc. 3. Follow the formation of specific components and their subsequent emission, in the case of SSS components, to the atmosphere. Baker (163a, 166) has written at length on his original research and that of others on MSS and SSS aerosols and the conditions involved in the cigarette in their formation and transport. He has also periodically authored or coauthored several excellent and detailed reviews (167, 169, 170a, 171a, 171b, 174d) on this subject. It is now known that the fire cone temperature of 900+°C measured during the puff primarily generates gaseous components such as the carbon oxides, water, ammonia, nitric oxide, etc. During the puff, pyrogenesis of most MSS components occurs in a 3- to 4-mm cylinder of the tobacco rod a few millimeters behind the fire cone:tobacco rod interface where the temperature ranges from 500 to 650°C. During the smolder period, the fire cone temperature is 500 to 600°C, and it is at this temperature range that SSS is generated from the tobacco. Just as profound quantitative differences exist among the chemical compositions of fresh and aged MSS, fresh and aged SSS, and ETS, there are several differences in the physical properties of these smokes. One physical property

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important in these various types of cigarette smoke, their inhalation, and their retention is their particle size. There are several ways to describe particle size. A frequently used one is mean mass aerodynamic diameter (MMAD). In his review of the aerosol studies on cigarette smoke, Ingebrethsen (1860) points out that two factors are extremely important with respect to the measured particle size of an aerosol: (1) the time between aerosol generation and particle size measurement, and (2) the concentration of the aerosol. High aerosol concentration and extended time between generation and measurement result in increased coagulation of particles and increased particle size. Freshly generated MSS and SSS have the major fraction of particle sizes, expressed as MMAD, in the range 0.3 to 0.4 μm [Ingebrethsen (1860c)]. Since SSS—both intra- and inter-puff generated—is the major contributor, estimated at 85% to 90%, to ETS, it is important to realize that its physical properties are constantly and progressively changing. These changes begin the moment it is generated and continue during its extensive dilution as it disperses through the room until it is eventually perceived as ETS. Depending on the proximity of the measuring device to the source of the SSS, it is obvious that a range of particle sizes could be found, ranging from that measured in freshly generated SSS to that found in essentially equilibrated ETS. The behavior of particles in SSS under carefully controlled conditions has been studied in detail by Ingebrethsen and Sears (1860e). Another problem of determining the contribution of ETS to a given air space (home, office, restaurant, aircraft, etc.) is that other non-ETS contributors to VP and PP are measured at the same time as the contribution of ETS to VP and PP is measured. These include contributions from cooking oils and foods in homes and restaurants, cleaning preparations and furniture polishes, personal products (perfumes, after-shave lotions, hair sprays, deodorants, etc.), and vehicular exhausts where the air space is adjacent to much traveled roads. Chromatographic scans of samples collected in a conference room before and after a two-hour meeting during which smoking was permitted revealed that chromatographic peaks, some representing compounds from nontobacco sources, were much larger than those known to be due to ETS (1352a). Similar findings were reported by Bayer and Black (223), who compared volatile organic contaminants (VOCs) in the offices of smokers and nonsmokers. The authors noted: Building materials and furnishings are the most common source of these VOCs. [The] VOC building background makes it difficult to distinguish ETS contamination from the VOCs out-gassing from other sources.

A major distinction between MSS and SSS that affects particle size is that MSS is acidic*, with a pH ranging from 6.0 to 6.6, whereas the pH of SSS ranges from 6.7 to 7.5. The SSS from most cigarettes is alkaline, with pH above 7.0. Under acidic conditions (pH < 7.0), smoke amines such as nicotine are considered to be protonated and have relatively *

The MSS from cigarettes fabricated from dark air-cured tobacco or aircured cigar-type tobacco shows a slightly alkaline pH.

low volatility. Under alkaline conditions (pH > 7.0), such amines are considered to be nonprotonated, that is, “free,” and are relatively more volatile. The differences and similarities in the physical properties among MSS, SSS, and ETS are summarized in Table 0.4. When freshly generated MSS is inhaled during smoking, the aerosol particles in the smoke are exposed in the respiratory tract to an atmosphere whose temperature is 37°C and whose relative humidity exceeds 95%. As a result, the inhaled particles absorb water and increase in size. Those particles that are exhaled are, on average, 20% to 25% larger than the inhaled particles (273, 1860b, 1860d, 1860e). When these water-saturated exhaled MSS particles (temperature at 37°C) are released into the atmosphere (temperature generally below 30°C and relative humidity below 50%), they cool, and immediately undergo several evaporative processes which are completed in a few milliseconds. These processes include the following: 1. Components, usually gaseous under ambient conditions, evaporate from the particle. 2. Components with modest vapor pressures evaporate from the particle. 3. Water, incorporated into the particle either during the smoke formation process in the tobacco rod or during its residence time in the highly humid confines of the respiratory tract, evaporates. SSS particles behave much differently than MSS particles. Although little research has been conducted on fresh, undiluted SSS, it is reasonable to expect that the particles are physically similar to those in MSS. However, the high dilution that occurs almost immediately upon generation has the effect of preventing coagulation and promoting evaporative losses. Also, because of the alkalinity of SSS, basic components are nonprotonated and readily evaporate from the particle. Studies in 1985 by Eudy et al. (1169) on SSS and ETS, both generally alkaline (pH > 7.0), indicated that little (<5%) of the nicotine remains in the ETS particle; the bulk of it (>95%) evaporates from the particle and appears in the VP. As a result of these various processes, the SSS and exhaled MSS particles, on their way to contribute to ETS, decrease both in particle mass and in particle size to an MMAD ranging from 0.15 to 0.20 μm for the major fraction of the particles. Experimental data for the decrease in SSS particle size were presented by Ingebrethsen and Sears (1860e, 1860f). Ten minutes after smoke generation, a major fraction of the SSS particles showed a particle size with an average MMAD of 0.198 μm. It should be noted that these various evaporative processes involve relatively volatile smoke components. The particle size is not diminished to any appreciable degree by evaporation of nonvolatile and high molecular weight components, such as the PAHs (B[a]P, DB[a,h]A, indeno[1,2,3-cd]pyrene, dibenz[a,i]pyrene) listed by Hoffmann and Hecht (1727) and Hoffmann and Hoffmann (1740, 1741), and other components such as solanesol, the phytosterols, A-tocopherol, and the

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TABLE 0.4 Physical Propertiesa of Mainstream Smoke (MSS), Sidestream Smoke (SSS), and Environmental Tobacco Smoke (ETS) Properties Number of identified components

Approximate temperature of

r
àSF
DPOF

r
TNPLF
GPSNBUJPO Approximate % of tobacco rod consumedb Particle size, μm

Particle concentration, number/cm3 Retention of particulate matter in respiratory tract

Smoke pH

MSS

SSS

ETS

Over 4300 in particulate phase (PP); about 1000 in vapor phase (VP). Some components are present in both the PP and VP; e.g., HCN, simple phenols, volatile N-nitrosamines.

Composition assumed to be qualitatively similar to that of MSS; i.e., the number and identity of the SSS and ETS components are the same as those in MSS. Quantitative differences in component levels are substantial. The distribution of a component between PP and VP depends on the nature (acid, base, neutral) and the physical properties (vapor pressure, etc.) of the particular component. The decay (decrease) of an individual ETS component is also dependent on numerous factors such as its nature, its physical properties, and the temperature, relative humidity (RH), ventilation, and nature of surfaces (carpets, drapes, upholstered furnishings, etc.) in the smoke space.

850-950°C 500-600°C 30-40

500-650°C 500-600°C 50-60

Fresh whole MSS particles have MMAD = 0.3-0.4 μm c contain volatile components which readily vaporize from the particles.

Fresh SSS particles are about the same size as MSS particles; within a short time (<10 min) after generation, the MMAD > 0.2 μmc for SSS particles.

Because of coagulation, hydration, evaporative transfer and other physical processes, e.g., the cloud effect, MSS particles behave as though they have a MMAD in the micron range c. 109 to 1010

During dilution to ETS, exhaled MSS particles lose H2O and other volatile PP components; particle size decreases to a MMAD = 0.15-0.20 μmc. SSS particles lose H2O and other volatile PP components such as nicotine, amines, etc. Thus, particle size decreases to a MMAD = 0.15-0.20 μmc. ~1-5 x 105

50 to 90%

10 to 11%

Percentage retention as measured by weight loss between time of inhalation and exhalation due to mechanical trapping plus loss of volatiles from inhaled particles.

Low percentage retention as measured by weight loss is due to virtual absence of coagulation and other physical phenomenon, e.g., cloud effects, and lack of water and other volatile components which may be lost by inhaled ETS particles. Neutral (pH 7.0) to slightly alkaline.

6.0 to 6.6 for cigarette MSS d.

Inhalability of smoke into lungs

MSS inhalability favored by pH less than 7.0.

Nicotine behavior

99+% of nicotine in cigarette MSS is in the PP; because the MSS pH is much less than 7.0, amines such as nicotine are protonated; nicotine in MSS PP is presumed to be protonated by the low molecular weight acids present in MSS e

6.7 to 7.5 for cigarette SSS. Some investigators have reported SSS pH values as high as 8.0 Inhalability of smoke (whether cigarette SSS, pipe MSS, or cigar MSS) is progressively diminished as smoke pH increases above pH 7.0.

Because of alkalinity of SSS and the high concentration of SSS particles near the burning cone, nicotine (and other volatile smoke components) are distributed between the SSS PP and SSS VP; PP-VP equilibrium for these compounds is not attained adjacent to the cigarette burning cone.

Because of extreme dilution by air and near neutrality (pH close to 7.0), the inhalability of ETS is nearly the same as that of air. Because of the extremely high dilution of ETS and its pH at or slightly above 7.0, little nicotine (or other amines) is found in ETS PP; more than 95% of the nicotine in ETS is in the non- protonated form and is found in ETS VP. (Continued)

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TABLE 0.4 (CONTINUED) Physical Propertiesa of Mainstream Smoke (MSS), Sidestream Smoke (SSS), and Environmental Tobacco Smoke (ETS) Properties Relationship of smoke yield to cigarette design

MSS MSS controllable by r
UPCBDDP
SPE
MFOHUI
BOE
DJSDVNGFSFODF r
àMUFS
UZQF
BOE
EJNFOTJPOT r
àMUFSUJQ
BEEJUJWFT r
UPCBDDP
CMFOE
BOE
XFJHIU r
QSPDFTTFE
UPCBDDP
SFDPOTUJUVUJPO
expansion) r
QBQFS
BOE
QBQFS
BEEJUJWFT r
BJS
EJMVUJPO
QBQFS
QPSPTJUZ
BOE
àMUFS
perforation)

SSS Inter-puff SSS, the major contributor to total SSS, is primarily controlled by cigarette tobacco blend and weight and to a lesser degree by paper properties and additives.

ETS Since ETS comprises 85-90% diluted and aged SSS plus 10-15% exhaled MSS, the control of ETS resides primarily with those factors which control intrapuff SSS generation.

a

Properties listed are those for unaged and undiluted smoke. Tobacco rod not consumed during smoking estimated at 5 to 8% for filtered cigarettes; 20 to 25% for non-filtered cigarettes. c MMAD value listed is that for a major fraction of the smoke. d The MSS from cigarettes fabricated from dark air-cured tobacco or air-cured cigar-type tobacco shows a slightly alkaline pH. e Protonation of nicotine in tobacco due to long-chained acids (palmitic acid, stearic acid, etc.) and polycarboxylic acids (oxalic acid, malic acid, citric acid). b

saturated aliphatic hydrocarbons. These components remain in the particles. In addition to the dilution that occurs when the ETS particles disperse through the room space, an additional dilution occurs by the deposition of ETS particles on the surfaces present. These processes—evaporation, dispersion, and deposition—decrease the concentration of ETS particles. Ventilation, air exchanges per unit time, nature of the surfaces (fabric, plastic, wood, etc.), temperature, relative humidity, number of cigarettes smoked per unit time, and number of persons present are some of the known variables that will also influence the concentration of ETS particles. Questions are frequently raised about the particle size of MSS, SSS, and ETS and the relationship between particle size and retention in the respiratory tract of the inhaled smoke. Usually, particle size plays an important role in determining mainstream particulate retention in the lungs. Based on a comparison of particle size, one might expect ETS and MSS to be retained similarly in human lungs on a percentage basis. Empirical data demonstrate that this is not the case. In the case of MSS, other factors come into play. These drastically alter the amount of MSS particulate matter that is retained. Weight-loss measurements give values ranging from 50% to 90% for the percentage retention of inhaled MSS (1860c). The percentage retention is a characteristic of the individual smoker. The retention of inhaled MSS is much higher than would be predicted by the measured MMAD of fresh smoke, 0.3 to 0.4 μm. Ingebrethsen (1860c) reviewed the literature on the retention of MSS and identified five factors that may be responsible for increased MSS particle retention. These include coagulation, electrical charge, growth by

water condensation, evaporative transfer, and cloud effects. Evaporative transfer and cloud effects were deemed to be the most significant factors. Recently, Moldoveanu et al. (2601b) and Moldoveanu and St. Charles (2601a) reported on the different degrees of retention by humans of 160 cigarette MSS components by comparison of their levels in smoking machine-generated MSS vs. their levels in smoker-exhaled MSS. ETS particles behave quite differently from MSS particles in terms of human retention. Unlike MSS, the retention of ETS in the lung is not affected by evaporative transfer and cloud effects. Instead, ETS retention is influenced mainly by particle size. Theoretical calculations indicate that the percentage retention of particles equivalent in size to ETS particles should vary between 10% and 20%. A value within the theoretical range was obtained: Hiller et al. from studies with human mouth-breathing volunteer nonsmokers who orally inhaled polystyrene latex spheres of particle sizes similar to those of diluted sidestream smoke (1654a) and five volunteers who inhaled a tobacco smoke defined as “sidestream smoke at a concentration similar to that encountered indoors with smokers present” (1654b), estimated the percentage retention of the smoke to be 11%. The difference in particle retention between MSS and ETS is due largely to the high dilution that SSS particles experience almost upon formation. This dilution causes ETS particles to behave as model, nonvolatile, inert particles by preventing coagulation, obviating cloud effects, and promoting evaporation prior to inhalation. As noted earlier (Table 0.4), numerous technologies introduced sequentially from the mid-1950s to the late 1960s were

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Replacement of all-flue-cured or all-Oriental tobaccos with a blend of flue-cured, burley, and Oriental tobaccos

1913

50.0

3.00 Filter tips Reconstituted tobacco Paper additives

40.0

2.50

Paper porosity 2.00

Ventilation

30.0

1.50 20.0

NICOTINE, mg

‘TAR,’ mg

Expanded tobacco

1.00 10.0

0.50 ‘TAR’

0.0 1954

1958

NICOTINE 1962

1966

1970 Year

1974

1978

1982

0.00 1986

FIGURE 0.3 “Tar” and nicotine yields, sales-weighted average basis, U.S. cigarette products.

incorporated into cigarette design to control MSS yield and composition, which some have characterized as a “less hazardous” cigarette when included in cigarette design [Gori and Bock (1334b), National Cancer Institute (2683), USPHS (4005, 4009)]. These technologies include: 1. 2. 3. 4.

Tobacco blend and weight Tobacco rod length and circumference Filter tips (material type and additives) Processed tobaccos (reconstituted tobacco sheet, expanded tobacco) 5. Paper (type and additives) 6. Air dilution (increased paper porosity, filter tip perforations)

The chronology of introduction of these technologies in U.S. cigarette products is noted in Figure 0.3. Over the years, use of these technologies in concert and to various degrees in cigarette design has provided the consumer with a great variety of products whose number has increased from about a dozen in the mid-1950s to nearly 1250 in 1995 (1177c). It should be remembered that the cigarette is a system: All of these technologies used in cigarette design are interactive, that is, inclusion of or change in the level of use of any particular technology may require other adjustments in the cigarette design to maintain certain attributes acceptable to the consumer. In contrast, by current technology, SSS yield is controlled almost totally by tobacco blend and weight. The SSS is not subjected to filtration, the effect of filter-tip

additives that specifically remove certain MSS components from MSS (phenols, volatile N-nitrosamines), or air dilution effects. Adams et al. (31) reported data on MSS and SSS yields of fourteen components in the smokes from four U.S. commercial cigarettes of different design: a nonfilter cigarette, two filtered cigarettes, and a perforated filter cigarette. MSS and SSS yield data for TPM; nicotine; a PAH, (B[a]P); a phenol, catechol; a volatile N-nitrosamine, N-nitrosodimethylamine (NDMA); and a tobacco-specific N-nitrosamine, N-nitrosonornicotine (NNN) are summarized in Table 0.5. The SSS TPM yields shown in Table 0.5 for the nonfiltered and two filtertipped cigarettes are, on average, about 58% higher than the SSS TPM yield from the perforatedfilter cigarette. Most perforated-filter cigarettes, such as Perforated Filter-D in Table 0.5, not only incorporate a perforated filter with a high percentage air dilution to reduce MSS TPM but also incorporate substantial levels (30% to 50%) of expanded tobacco in the cigarette design. The inclusion of such a large percentage of expanded tobacco in the blend substantially reduces the weight of tobacco in the tobacco rod and the weight of tobacco consumed during the SSSgenerating smolder periods. Thus, these data show the SSS TPM yield from the perforated-filter cigarette is substantially less (37%) than the average of the SSS TPM from the other three cigarettes. In a more recent study on the MSS and SSS yields from cigarettes classified as low tar, Chortyk and Schlotzhauer (723, 724a) provided data that differ substantially from

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TABLE 0.5 MSS/SSS Distribution of Selected Components Delivered by Four U.S. Commercial Cigarettes Non-Filtered A Smoke Component, Yield/cig TPM, mg Nicotine, mg Catechol, mg B[a]P, ng NDMA, ng NNN, ng

Filtered B

MSS

SSS

MSS

20.1 2.04 41.9 26.2 31.1 1007

22.6 4.62 58.2 67.0 735 857

15.6 1.50 71.2 17.8 4.3 88

the Adams et al. (31) data in Table 0.5 and from other data (3190) reported for comparable “tar”-yield cigarettes. The differences in the data for comparable FTC “tar”-yield cigarettes were found for cigarettes delivering approximately 23, 10, and 7 mg. In their MSS and SSS collection and analysis, Chortyk and Schlotzhauer (724a) used their previously reported SSS collection procedure (723) in the generation of their data. Green (1353) commented on several deficiencies in the procedures used and interpretations made by Chortyk and Schlotzhauer (724a) from their data. Examination of their data and comparison of them with the Adams et al. (31) and RJRT (3190) data (see Table 0.6) reveal an additional problem: For the three cigarette categories (23-, 10-, and 7-mg FTC “tar” yields), the SSS/MSS ratios for the TPMs in the Chortyk–Schlotzhauer study were between two and seven times greater than those reported in the other studies. Similarly for nicotine, the Chortyk–Schlotzhauer SSS/MSS ratios were from about 1.5 to over seven times greater than those reported in the other studies. This strongly suggested a problem with their SSS collection procedure.

Filtered C

Perforated Filter D

SSS

MSS

SSS

MSS

SSS

24.4 4.14 89.9 45.7 597 307

6.8 0.81 26.9 12.2 12.1 273

20.0 3.54 69.5 51.7 611 185

0.9 0.15 9.1 2.2 4.1 66.3

14.1 3.16 117 44.8 685 338

The escalation of the number of identified tobacco and tobacco smoke components is depicted in Figure 0.1. This tremendous increase in the number of identified tobacco smoke (and tobacco) components was made possible by successive advances in analytical technology, particularly the technology pertinent to the separation of components in complex mixtures. It is realized that investigators who pioneered an emerging analytical technology were often involved with the development and/or use of the technology prior to the period indicated in Figure 0.3. No slight of their noteworthy contributions is intended. The periods indicated in Figure 0.3 are those when the analytical technology in question was sufficiently advanced and used by almost all investigators involved in the analysis of tobacco smoke and/or definition of its composition. Prior to the early 1950s, the major part of tobacco smoke component isolation effort involved so-called “classical” chemical techniques, that is, separation of the smoke condensate into neutral, acidic (acids and phenols), and basic

TABLE 0.6 Comparison of SSS/MSS Ratios for Different Cigarette Types Chortyk and Schlotzhauer

Adams et al.(31) 20-mg Cigarette a

23-mg Cigarette (724a)

23-mg Cigarette (723)

Analyte

MSS

SSS

SSS/MSS

MSS

SSS

SSS/MSS

MSS

SSS

SSS/MSS

TPM Nicotine

20.1 2.04

22.6 4.62

1.12 2.26

21.8 1.68

56 9.08

2.57 5.40

22.9 1.30

54.9 5.29

2.40 4.07

R.J. Reynolds (3190)

Chortyk and Schlotzhauer (724a)

1R4F

10-mg Cigarette

10-mg Cigarette

Analytea

MSS

SSS

SSS/MSS

MSS

SSS

SSS/MSS

MSS

SSS

SSS/MSS

TPM Nicotine

11.5 0.79

16.9 5.60

1.47 7.09

10.4 0.90

60 9.10

5.77 10.11

9.5 1.05

53 10.46

5.58 9.96

Adams et al. (31)

Chortyk and Schlotzhauer (724a)

7-mg Cigarette Analyte

a

TPM Nicotine a

7-mg Cigarette

6-mg Cigarette

6-mg Cigarette

MSS

SSS

SSS/MSS

MSS

SSS

SSS/MSS

MSS

SSS

SSS/MSS

MSS

SSS

SSS/MSS

6.8 0.81

20.0 3.54

2.94 4.37

6.7 0.58

59 8.95

8.81 15.43

5.4 0.22

60 7.04

11.11 32.00

6.0 0.55

50 8.06

8.33 20.77

mg/cig

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fractions by partitioning between water-immiscible organic solvents and water, aqueous basic solutions, and/or aqueous acidic solutions, followed by crystallizations and/or distillations of the subfractions. In the early 1950s, liquid column chromatography on column packings such as alumina, silicic acid, or Fluorosil® of the neutral, acidic, or basic fractions, as appropriate, permitted further separation of the components prior to application of the classical chemical techniques. UV and IR spectrometry were also available and used not only to combine chromatographic fractions rich in a specific component but also to assist in the identification of the component. UV absorption and fluorescence spectrophotometry were extremely useful in identification of the PAHs in tobacco smoke. In the late 1950s to early 1960s, commercial equipment for gas chromatography became available. This technique, coupled with those mentioned previously, augmented the investigator’s ability to separate, isolate, and identify smoke components. Mass spectrometry and nuclear magnetic resonance equipment and techniques were also more readily available and became additional tools that facilitated component identification. In the early days of gas chromatography, there were fewer than a dozen chromatographic column packings commercially available and most of these did not permit satisfactory separations above 200°C. By the late 1960s, the number of available column packings had increased, and the properties of newly designed column packing materials permitted separations at temperatures approaching 350°C. In the early 1960s, investigators such as Grob (1413) began study on capillary gas chromatography and subsequently glass capillary gas chromatography. A major contribution by Grob was his development of methods to prepare and coat the inner wall of a capillary tube to increase its effectiveness and efficiency in separations. By the late 1960s to early 1970s, this emerging technology, glass capillary gas chromatography, had become an extremely powerful analytical tool and was used to great advantage in the study of the complex mixtures tobacco smoke, see Grob (1416–1419, 1422) and Grob and Völlmin (1426, 1427), and tobacco extracts [Lloyd et al. (2389)]. The glass capillary column was usually a smalldiameter (about 1 mm or so) glass or quartz tube, extremely long (50 to 300–400 m) whose interior was not packed with a solid adsorbent or an inert material mixed with a liquid adsorbent as in the previously used gas chromatographic columns. The inner wall of the narrow-bore capillary was coated with a thin layer of a liquid adsorbent. This technology not only enhanced separation capability but permitted separations to be made with extremely small samples. These advances in analytical technology were usually accompanied by a break and an increased slope in the plot of number of identified tobacco smoke components vs. time (see Figure 0.1). The next break in the plot and increased slope occurred in the mid-1970s when more and more investigators enhanced the effectiveness of glass capillary gas chromatography by coupling the gas chromatograph to a mass spectrometer. This permitted separation of the components of the particular tobacco smoke fraction under study and

determination of the molecular weight and/or fracture pattern of each component as it exited the chromatograph and was analyzed in the mass spectrometer. Interpretation of the data thus obtained, usually in concert with findings from UV, IR, and/or NMR spectra, permitted very rapid and unequivocal identification of the components from the smoke fraction (1426, 1427). An outstanding example of the use of gas chromatography-mass spectrometry in the definition of tobacco smoke composition is the study by Snook et al. (3756–3759) on the PAHs in cigarette MSS. Over 500 individual PAHs and their homologs were detected, and many were identified unequivocally. The early- to mid-1970s also saw the emergence of high performance liquid chromatography (HPLC) (830a, 1361), a highly efficient and effective variation of liquid column chromatography. The traditional method used to examine CSC (or a tobacco extract) usually involved its initial partition between an aqueous alcohol solution and a water-immiscible organic solvent such as hexane, cyclohexane, or diethyl ether. The organic solvent-soluble material was then separated into several neutral, acidic, and basic fractions. These, in turn, were then subjected to the various analytical techniques available at the time. Considerable success was attained in isolation and identification of the organic solvent-soluble smoke components. For many years, however, there was no satisfactory technique available to separate, isolate, and identify the many components in the aqueous alcohol fraction from the aqueous alcohol-water immiscible organic solvent partition. Many of the aqueous alcohol-soluble components are highly polar, highly oxygenated compounds, and no chromatographic system was available to effect clean separations. In addition, many of these components, because of their structures, were highly labile at the temperatures used in gas chromatographic separation. By use of the technology known as silylation, these sometime heat-sensitive, highly polar components were converted to chromatographable stable silyl derivatives which can be readily separated by glass capillary gas chromatography and identified by mass and other spectral techniques. By use of the latest analytical technology available at the time, the mainstream CSC from a typical cigarette was reexamined with particular emphasis on the composition of the aqueous alcohol-soluble material. The separation and identification of over 750 previously unidentified tobacco smoke components were described by Schumacher et al. (3553), Newell et al. (2769), and Heckman and Best (1587). A striking example of the effectiveness of the improved analytical technology on tobacco smoke component identification is the following. In 1977, Schmeltz and Hoffmann (3491) cataloged about 420 nitrogen-containing components identified in MSS. They indicated that the number of identified nitrogen-containing tobacco smoke components had increased by about 200 since a previous review of nitrogen-containing tobacco smoke components by Neurath (2724). In a presentation and publication, Heckman and Best (1587) described the separation and identification of nearly 270 new nitrogen-containing smoke components, an increase of more than 60% over the

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number described by Schmeltz and Hoffmann (3491) in their review article. The following is another example of the impact the improved analytical technologies had on the ability to further define the composition of tobacco smoke: In the late 1950s to early 1960s, the composition of an aliphatic ester fraction isolated from flue-cured tobacco by Rowland and Latimer (3358) and from cigarette MSS by Rodgman et al. (3294) was partially defined in both cases by Rodgman et al. (3294). By saponification of the aliphatic ester fraction, followed by separation of the alcohol and acid moieties, Rodgman et al. showed that the tobacco- and tobacco smokederived aliphatic ester fractions were qualitatively the same and theoretically comprised at least 272 esters formed from at least seventeen aliphatic acids [myristic (C14) to octacosanoic (C28), oleic, linoleic, and linolenic] and sixteen normal long-chained, primary aliphatic alcohols [1-dodecanol (C12) to 1-heptacosanol (C27)]. In 1984, with improved chromatographic capability and a mass spectrometric system capable of detecting much higher molecular weights than those used by Rodgman et al. in 1961, Arrendale et al. (103) reexamined the aliphatic ester fraction from tobacco. The saponification and subsequent separation of acids and alcohols were no longer required. Arrendale et al. were able to identify unequivocally many of the individual esters by glass capillary gas chromatography and mass spectroscopic examination of the aliphatic ester fraction isolated from the tobacco. The alcohol moiety of the esters identified ranged from 1-tetradecanol (C14) to 1-dotriacontanol (C32); the acid moiety ranged from lauric acid (C12) to n-dotriacontanoic acid (C32) plus numerous iso- (from C13 to C28) and anteiso(C13 to C18 plus C20) isomers of several saturated aliphatic acids. Since each ester reported by Rodgman et al. was found in tobacco and smoke (3294), logic dictates that each new tobacco ester found by Arrendale et al. is also present in smoke (103). Thus, the findings by Arrendale et al. substantially increased both the number of known components in tobacco and tobacco smoke. Most of the studies reported in the literature from the mid-1950s to the late 1970s to early 1980s on tobacco smoke composition dealt with the composition of the MSS from the cigarette. Gradually during the late 1970s, more and more studies were reported describing the composition of cigarette SSS [see Klus and Kuhn (2142)]. Presently, the major emphasis on tobacco smoke composition involves the composition of ETS, health problems reportedly associated with passive smoking, that is, exposure to ETS, and the levels of specific components reported to be associated with these health problems [Ecobichon and Wu (1108a), Environmental Protection Agency (1148, 1148a, 1148b), Guerin et al. (1445)]. SSS and ETS are discussed in later sections. Because of the relative efforts expended on cigarette MSS, cigarette SSS, and ETS, the numbers of identified components in each of these smokes were reported as approximately 4800, 500, and 100, respectively (3255). Given sufficient time and effort, any component identified in MSS could eventually be identified in SSS and ETS.

The approximate (and general) composition of cigarette MSS is well defined. An 85-mm cellulose acetate filtertipped commercial cigarette (65-mm tobacco rod, 20-mm filter tip) whose filler, a typical American blend of tobaccos, weighed approximately 1000 mg was machine smoked with the Federal Trade Commission (FTC)-prescribed smoking parameters (35-ml puff volume, 2-sec puff duration, 1 puff/min; 25°C; 60% relative humidity; FTC-specified butt length) (1177b). This cigarette gave approximately 500 mg of total MSS. To separate the tobacco smoke aerosol into its two major phases, the particulate phase and the vapor phase, the smoke was passed through a Cambridge filter pad which retains more than 99.9% of the particulate phase, defined as total wet particulate matter (WTPM). The vapor phase is that portion of the smoke aerosol which passes through the Cambridge filter pad, and the major portion of its weight is due to the components of air drawn through the cigarette during the smoking process (nitrogen, oxygen, argon, etc.). The distribution and approximate composition of the total MSS emerging from this cigarette are summarized in Figure 0.4. The data in Figure 0.4 represent a consolidation of composition data from several sources, including data from RJRT R&D [Laurene (2299a)] plus data from Keith and Tesh (2068), Norman (2799a), and Browne et al. (445). To simplify the calculations throughout Figure 0.4, one value was deliberately adjusted slightly for convenience: the total MSS collected actually weighed slightly in excess of 497 mg, but the value 500 mg was used to calculate the percentages shown throughout Figure 0.4. In addition, no attempt was made with these data to define the degree of partition of some components between the particulate and the vapor phases. Because of their vapor pressure properties, significant quantities of some smoke components are found in both the particulate and vapor phases of cigarette MSS. These include hydrogen cyanide, several of the simple phenols (phenol, o-cresol, m-cresol, p-cresol), and several of the volatile N-nitrosamines. It is obvious from the data in Figure 0.4 that the particulate matter, whether described as WTPM, TPM, or FTC “tar,” comprises less than 5% (100 × 22.5/500 = 4.5%) of the total MSS emerging from the cigarette. This is true of nearly all commercial U. S. cigarettes no matter what the FTC “tar” yield. The composition of the MSS vapor phase has been almost completely defined. It is estimated that components representing less than 1 mg of the particulate phase (5.1% of the FTC “tar,” less than 0.2% of the total MSS) remain unidentified. If the number of unidentified components is as high (as many as 100000) as some investigators estimate (1422, 4103), then the level of each unidentified component must average in the low nanogram range. The extremely wide variations in the yields of components delivered in the MSS during the smoking of a cigarette have presented unique challenges to those involved not only in the identification of smoke components but also in their quantitation. Table 0.7 is a minor modification of the initial version presented in 1996 by Green and Rodgman (1373). In it, the

© 2009 by Taylor & Francis Group, LLC 78836_C000.indd 44

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logarithmic presentation is a more concise depiction of this wide variation in the levels of selected smoke components. For most of the components shown in Table 0.7, there obviously is a range of values, and the extent of the range for each component is dependent on the cigarette type under study (filtered, nonfiltered) and the weight of tobacco consumed during the smoking of the cigarette for the analysis. In general, the locations of the various components on the logarithmic plot have been adjusted for a cigarette yielding about 18 to 20 mg/cigarette of FTC “tar.” If the design of the cigarette has been modified to reduce FTC “tar” yield, diminution of the yields of the other components will occur but not necessarily to the same extent as the decrease in FTC “tar” yield. Cigarette design parameters (tobacco rod length and dimensions, filter type and dimensions, filter-tip additives, tobacco blend and weight, processed tobaccos [reconstituted tobacco sheet, expanded tobacco], paper and paper additives, and air dilution [paper porosity and filter perforation]) have profound effects on cigarette MSS yield and

composition. Also shown in Table 0.7 are those components listed by Hoffmann and colleagues (1727, 1740, 1741, 1743, 1744) as “tumorigenic components of tobacco and tobacco smoke” and cited as such by the U.S. Surgeon General (4012), the U.S. Environmental Protection Agency (EPA) (1148a), and the U.S. Occupational Safety and Health Administration (OSHA) (2825). The validity and meaning of their classification of specific tobacco smoke components as tumorigenic were discussed by Rodgman (3265). Yields for the vapor-phase components range from a high of 50 to 60 mg/cigarette for carbon dioxide to lows in the nanogram range for vinyl chloride and the volatile nitrosamines such as N-nitrosoethylmethylamine. The major portion of the nitrogen (>300 mg/cigarette) and oxygen (>65 mg/ cigarette) in MSS is derived from the air drawn through the cigarette during the smoking process. The number of components identified in various tobacco types also increased substantially during the 1950s, 1960s,

© 2009 by Taylor & Francis Group, LLC 78836_C000.indd 45

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TABLE 0.7 Cigarette Mainstream Smoke Components - Logarithmic Listing of Per Cigarette Yields Vapor Phase

Yield/cig

Nitrogen

Oxygen, carbon dioxide

Water, carbon monoxide

Acetaldehydea Isoprenee Limonene Nitric oxide

HCN

Acrolein 1,3-Butadienee

Formaldehydea 2-Furaldehyde Crotonaldehydea Benzenea Acrylonitrilea

¹ º ­ »

-400 mg - 200 -100 mg -80 -40 -20 -10 mg -8 -4 -2 -1000 Og = 1 mg -800 -400 -200 -100 Mg -80 -40 -20 -10 Mg -8 -4 -2 -

Particulate Phase

ª « FTC “tar” ¬

Water

Humectants (glycerol, propylene glycol) Nicotine Total alkanes

The 5 acids: palmitic, stearic, oleic, linoleic, linolenic

Saturated aliphatic esters Catechol

Solanesol Phytosterols

Total alkylpyridines

Phenol

Solanesyl esters

o-Cresol Phytyl esters

A-Tocopherol Solanesyl acetate

Indole Indole, 3-methylAnabasine

NABa,b; indole, 3-ethyl-; NNNa,b; quinolinea

© 2009 by Taylor & Francis Group, LLC 78836_C000.indd 46

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TABLE 0.7 (CONTINUED) Cigarette Mainstream Smoke Components - Logarithmic Listing of Per Cigarette Yields Vapor Phase

Yield/cig

Particulate Phase

NDEAa,b

- 1 Mg = 1000 ng - 1000 ng - 800 - 400 - 200 - 100 ng - 80 - 40 -

Hydrazinea

- 20

Arsenica

1-Naphthylamine

Ethyl carbamatea

- 10 ng - 8 -

Chromiuma

2-Naphthylaminea

Propane, 2-nitro-a

NDMAa,b

NPYRa,b

NEMAa,b Vinyl chloridea

-

Nornicotine

Indole, dimethylNNKa,b AACe

A- and B-Duvanediols A-Levantenolide

Indole, trimethyl-, Carbazole

Anthracene Pyrene; chrysenea Fluoranthene Benz[a]anthracenea

Leada, cadmiuma B-Levantenolide MeAACe; PhIPe Carbazole, 2,9dimethylCarbazole, 3,9dimethyl-

Benz[e]acephenanthrylene,c Indeno[1,2,3-cd]pyrenePyrenea; benzo[a]pyrenea ; Benzo[j]fluoranthene a Carbazole, 1,9dimethyl-

4

- 2 - 1000 pg = 1 ng - 800 - 400 - 200 - 100 pg - 80

Carbazole, 9-ethyl-; Carbazole, 4,9dimethylBiphenyl, 4-amino-a

Dibenz[a,h]anthracenea; Dibenzo[rst]pentaphenea,d Dibenz[a,j]acridinea Glu-P-1e & P-2e Trp-P-2e MeIQ Dibenzo[c,g]carbazolea

Chrysene, 5- methyl-a

IQe Trp-P-1e

Dibenz[a,h]acridinea

a

This tobacco smoke component was included in a list published by Hoffmann and Hecht (1727) in which the component was one of 43 components defined as a “tumorigenic agent in tobacco and tobacco smoke.” b NDEA = N-nitrosodiethylamine NDMA = N-nitrosodimethylamine NEMA = N-nitrosoethylmethylamine NPYR = N-nitrosopyrrolidine NAB = N’-nitrosoanabasine NNK = 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone NNN = N’-nitrosonornicotine (Continued)

© 2009 by Taylor & Francis Group, LLC 78836_C000.indd 47

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TABLE 0.7 (CONTINUED) Cigarette Mainstream Smoke Components - Logarithmic Listing of Per Cigarette Yields c

Benz[e]acephenanthrylene is the currently accepted name for benzo[b]fluoranthene. Benzo[rst]pentaphene is the currently accepted name for dibenzo[a,i]pyrene. e In a modified list of “tumorigenic agent in tobacco and tobacco smoke,” Hoffmann and Hoffmann (1740) increased the number of components from 43 to 60 and included several of the “cooked food” mutagens as well a several other MSS components (1,3-butadiene, isoprene, etc.). Trp-P-1 = 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole Trp-P-2 = 3-amino-1-methyl-5H-pyrido[4,3-b]indole Glu-P-1 = 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole Glu-P-2 = 2-aminodipyrido[1,2-a:3’,2’-d]imidazole AAC = 2-amino-9H-pyrido[2,3-b]indole MeAAC = 2-amino-3-methyl-9H-pyrido[2,3-b]indole IQ = 2-amino-3-methylimidazo[4,5-b]quinoline PhIP = 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine d

and 1970s both within and outside the tobacco industry. The purpose of such studies was essentially twofold: to define the tobacco components that (1) provided taste and aroma to the smoke to render it acceptable to the consumer and (2) were precursors of the smoke components asserted to be responsible for the health problems induced by tobacco smoke. Participating investigators over the years included USDA personnel initially under the leadership of Stedman in Philadelphia and subsequently by Chortyk after the move of the USDA tobacco research group from Philadelphia, Pennsylvania to Athens, Georgia. The precursor research will be discussed in much greater detail in subsequent chapters dealing with those precursors in tobacco of MSS components considered adverse to the smoker, for example, the precursors in tobacco of the PAHs, the phenols, aldehydes and ketones, the N-nitrosamines, and the N-heterocyclic amines. It is interesting to note that even the precursor studies led to differences of opinion among the scientists with views on the health problems associated with components in cigarette MSS. In 1942, Roffo (3327) proposed that the precursors of PAHs in the destructive distillate of tobacco were the tobacco phytosterols. In 1957, Fieser commented that the major precursor in tobacco of PAHs in MSS was probably cellulose (1181). Coauthors of several presentations and publications, Wynder, Wright, and Lam differed in their views on the major precursors in tobacco of PAHs in tobacco smoke. Because of his research findings from 1955 to 1959, Lam was a proponent of the concept that the longchained aliphatic hydrocarbons were the major precursors in tobacco of the PAHs, including B[a]P, in MSS (2255–2258). Wynder was a proponent of the concept that the major precursors in tobacco of PAHs in MSS were the long-chained aliphatic hydrocarbons and the phytosterols (4354).* Wright, a colleague of Wynder from the early to the late 1950s, held a different view from that of Wynder and that of Lam. Wright *

Even though this article was co-authored by Wynder and Wright, the view held by Wright on the major precursors in tobacco of PAHs in smoke was omitted from the manuscript by Wynder.

considered the major precursors of PAHs in MSS to be the phytosterols and long-chained terpenoids such as solanesol (4282). Eventually, precursor studies by Rodgman and Cook (3269) in 1958 indicated that the view held by Wright was the correct one. Their 1958 findings were subsequently confirmed in the late 1970s at the USDA by Severson et al. (3616). There were significant contributions by Rowland et al. in the early 1950s from their studies on the composition of flue-cured tobacco, studies that resulted in the isolation and identification by classical chemical means of the 45-carbon terpenoid alcohol solanesol (3359), its acetate and several other of its esters (3294, 3296, 3358), neophytadiene (3345), A-tocopherol and solanachromene (3347), the four isomeric 4-(2-butenylidene)-3,5,5-trimethyl-2-cyclohexen-1-ones (the megastigmatrienones) (3355), and several cyclotetradecanediols (3220, 3221, 3351, 3360) plus their oxabicyclo derivatives (3361). Over a decade later, with more advanced analytical technology, Lloyd et al. (2389) identified several hundred previously unidentified flue-cured tobacco components. From their early composition studies, similar to those of Rowland on flue-cured tobacco, Schumacher and Vestal isolated and identified numerous previously unidentified Oriental tobacco components (3561), including sclareolide (3533) and the first glucose tetraester (3535). Schumacher also defined numerous components in Maryland tobacco (3550). Roberts and Rohde, in their study of the composition of burley tobacco, identified numerous previously unidentified tobacco burley components, including several cyclotetradecanediols (3219). As analytical methodology advanced after the 1950s, the number of identified tobacco and tobacco smoke components escalated dramatically. In addition to its study of tobacco smoke by Arnap (91–94) and Enzell et al. (1153, 1154), the R&D staff at the Swedish Tobacco Company published nearly one hundred articles on the composition of tobacco, primarily Oriental tobacco. The many Swedish Tobacco Company investigators included Aasen, Almqvist, Behr, Enzell, Hlubucek, Kimland, Nishida, and Wahlberg, all of whom coauthored many articles on tobacco composition (1–13, 52,

© 2009 by Taylor & Francis Group, LLC 78836_C000.indd 48

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53, 84, 91–94, 227, 229–236, 1149–1157a, 1205a, 1660–1662, 2092–2095, 3315, 4083–4102). Excellent detailed summaries of the identification of hundreds of tobacco components and their generation from various terpenoid structures such as the noncyclic and cyclic carotenoids and the cyclotetradecane derivatives were presented and published in the late 1970s and early 1980s by Enzell (1149, 1150), Enzell and Wahlberg (1156), and Wahlberg and Enzell (4089, 4090). In the 1960s and 1970s, the Demoles and their colleagues at Firmenich SA in Switzerland also studied the composition of flue-cured, burley, and Oriental tobaccos and characterized many previously unreported compounds in each, for example, the studies by Demole and colleagues on burley tobacco composition (936–944), on flue-cured tobacco composition (945, 946, 948), and on Oriental tobacco composition (947). As noted previously, it was estimated by Wakeham (4103) and Grob (1422) from their examination of gas chromatograms that the number of components in tobacco smoke far exceeded the number of identified components. A similar situation exists with the composition of tobaccos. As early as the mid-1970s, DeJong and Lam (922d) commented that the estimated number of enzymes in green leaves, including tobacco, ranged from 1000 to 10000. Our Master Catalog from which the various lists of component classes are derived

comprises nearly 8400 components. The chapter on enzymes will list many of the tobacco enzymes but obviously will not include all of the great number of enzymes reported in tobacco. The MSS yields for components of the particulate phase range from that of FTC “tar” itself, shown as a yield of about 20 mg/cigarette in Table 0.7 (1373), to that of dibenz[a,h]acridine at an MSS yield of 0.1 ng/cigarette (100 pg/cigarette).* The magnitude of the range of yields for cigarette MSS components is demonstrated by the following: The ratio of the per cigarette yield of nitrogen (the most plentiful MSS component shown in Table 0.7) to that of dibenz[a,h]acridine (the lowest yield shown) is >3 × 10 9, that is, >300 mg vs. 0.1 ng). The need for analytical methodology to determine smoke components from the high milligram to the low picogram yield was one of the driving forces behind many of the developments and improvements in analytical technology for the study of complex mixtures.

*

Several new entries concerning N-heterocyclic amine data that were not available in 1996 for inclusion by Green and Rodgman (1373) are included in Table 0.7.

© 2009 by Taylor & Francis Group, LLC 78836_C000.indd 49

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The Alphabetical Index to Components Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke The index was created for two purposes. The first was to capture in one site all the basic information on the identified tobacco and tobacco smoke components discussed in the chapters of the book. The components are listed alphabetically in the index. Second, the index may permit the reader to easily retrieve or search for information on a specific tobacco and/or smoke component or class of components so that further study will be facilitated. To achieve these goals, the index was constructed to include the following: (1) The CAS No. for many of the components, (2) an indication of the component identification in tobacco, tobacco smoke, or both, (3) the structure of many of the components, (4) the table number and chapter in which the component is not only referenced but its properties are described, particularly if they are considered adverse, (5) for multifunctional components, several chapters and table numbers are cited. Additionally, the publishers have provided the index on CD. Hopefully, the searchable format of the CD will aid the reader in retrieving any desired information. The index comprises almost 8700 components completely or partially identified in tobacco, tobacco smoke, and tobacco substitute smoke. It not only includes over 8400 identified components but also several hundred compounds not identified in tobacco or tobacco smoke but reported by Doull et al. (1053) as tobacco ingredients used in the United States and by Baker et al. (172a, 174b) as tobacco ingredients used outside the United States, as well as in a summary by Rodgman (3266) and in our Chapter 24. Because the transfer from a tobacco product to smoke of very few of the added ingredients has been examined, they primarily are listed as tobacco components. Exceptions include several humectants used in tobacco products for many years. However, it should be noted that the detailed pyrolysis study by Baker and Bishop (172a) indicated that many such added ingredients would transfer in part to MSS during the tobacco smoking process. In some instances, the reader may wonder about the peculiar nature of the component listing. For example, a tobacco smoke component initially reported as 2-butene was later shown to be present in the smoke as cis- and trans-2-butene. Thus, three items are listed in the index for 2-butene, namely,

2-butene (CAS No. 107-10-7), 2-butene, (Z)- (CAS No. 59018-1), and 2-butene, (E)- (CAS No. 624-64-6). References to the identification of each are provided in Chapter 1, Section I.B. 2-Butenedioic acid is similarly listed: 2-butenedioic acid (CAS No. 6915-18-0), 2-butenedioic acid, (Z)- (maleic acid) (CAS No. 110-16-7), 2-butenedioic acid, (E)- (fumaric acid) (CAS No. 110-17-8). The reader will also find in the index certain broad classifications of components, like oxidases and free radicals. These and similar examples in the index are not there to confuse the reader, as many of the individual components in the broad classifications have specific CAS numbers. Generally, the references associated with these classes of components (found within the chapters noted in the index) will provide the reader with information of a common nature. In nearly all cases, individual components such as ascorbate oxidase, choline oxidase, cytochrome oxidase, and glycolate oxidase follow after the broadly classified component, oxidase. Likewise, specific free radicals such as methyl-acyl radical, ethyl-acyl radical, and propyl-acyl radical {2 isomers} may be found in the index. For some components in the index, several partially identified isomers exist, their number noted, and included in the total number of components identified in tobacco and/or smoke. Although the number of enzymes, genes, and nucleotides listed in the index is fewer than 500, their known number, as noted in Chapter 22, exceeds many thousands. The paltry number of enzymes, genes, and nucleotides listed in Chapter 22, Table XXII-2, was never intended to represent the total biological agents operating in the plant. Those selected for inclusion were from texts, research manuscripts, and patents where active research was conducted in the past in attempts to better understand the physiology and biochemistry of tobacco. As future genetic research develops, it is envisioned that the identity and function of hundreds of thousands of additional chemicals will be published. The authors hope that the format of the index and accompanying CD will help the reader to reach a better understanding of the components of tobacco and tobacco smoke.

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1

The Hydrocarbons

I.A THE ALKANES In his catalog of tobacco smoke components reported in early 1954, Kosak (2170) listed hentriacontane as the only alkane identified in tobacco smoke. Subsequently, numerous investigations resulted in the identification of a great number of alkanes in tobacco and tobacco smoke. Over 120 alkanes, ranging from the C1 hydrocarbon methane to the C36 hydrocarbon hexatriacontane, have been identified in tobacco and tobacco smoke. Many of the higher molecular weight alkanes have been reported to be present in three isomeric forms, that is, the normal, the iso (2-methyl-), and the anteiso (3-methyl-) isomer: n-alkane iso-alkane anteiso-alkane

H3C-(CH2)n-CH3 H3C-CH(CH3)-(CH2)n-1-CH3 H3C-CH2-CH(CH3)-(CH2)n-2-CH3

In 1958, Barbezat-Debreuil (181), using column chromatography and x-ray analysis to examine the alkanes in tobacco and tobacco smoke, reported her identification of branched isomers in the alkane fraction from both sources. The next year, Carruthers and Johnstone (613) reported the results of their study on the long-chained alkanes in tobacco and the smoke from cigarettes containing it. Their analyses involved gasliquid chromatography and mass spectroscopy. They also noted that the minor differences between the mass spectroscopic data for tobacco and smoke were not significant because, at that time, the precision of such an analysis was not high. Their findings are summarized in Tables I.A-1 and I.A-2. Cuzin et al. (883) in their study of Gauloise cigarette mainstream smoke (MSS) reported that 1.2% of the total particulate matter (TPM) consisted of n-C25, n-C26, n-C28, n-C29, n-C30, n-C31, and n-C32 alkanes and 75% of this weight involved the C30, C31, and C32 compounds. They reported that their evidence indicated no n-alkane higher than the n-C32 alkane was present. However, in 1960 Kosak and Swinehart (2176) reported the presence in cigarette MSS of the n-alkanes from C22 to C36 and branched alkanes from C21 to C32. Table I.A-3 summarizes their findings. Possibly due to the status of analytical methodology at the time, Dymicky and Stedman (1081) had earlier suggested the possible presence of n-tetracontane (C40H82) in tobacco but their finding has never been confirmed. In 1967, Ivanov and Ognyanov (1893b) reported the isolation of a crystalline alkane mixture, m.p. 62–64°C, which they proposed might contain a series of alkanes from C25 to C40. Carugno (619) reported the C31 alkanes to be the most abundant in tobacco but also noted that the C27, C29, C30, C32, and C33 homologs were present in appreciable amounts. Only a small portion of the alkanes in the alkane fraction from the

MSS from four tobacco types and a commercial tobacco blend was found with carbon chain lengths equal to or less than C24; only trace amounts of alkanes at or below n-hexadecane were found by Spears et al. (3768). They also reported that nearly 48% of an alkene-free alkane fraction (0.75 mg/cig) from MSS consisted of n-hentriacontane (0.182 mg/cig), n-dotriacontane (0.108 mg/cig), and n-tritriacontane (0.069 mg/cig). In their article on the pyrolysis of tobacco constituents, Badger et al. (142) reproduced a gas chromatogram provided by Reid on the alkanes in a tobacco sample. The peaks for the alkanes from C23 to C33 are readily discernible in the chromatogram. Badger et al. estimated that the tobacco alkane fraction amounted to 0.32% of the tobacco weight. Based on their pyrolysis studies, Badger et al. also proposed an elaborate mechanism for the formation of the polycyclic aromatic hydrocarbons (PAHs). It involved the degradation of the alkanes to smaller fragments, followed by recombination of the fragments into substituted cyclic entities and their aromatization. As listed in Table I.A-4, adapted from Mold et al. (2595), about 25% to 50% of the total alkanes in tobacco comprise nearly equal amounts of the iso and anteiso isomers of the alkanes. In the series of normal- and iso-alkanes, the homologs with odd-numbered carbons predominate, with the C31 and C33 homologs being present in the largest amounts. In the anteiso-alkanes, the alkanes with even-numbered carbons predominate, with the C32 homolog being present in the largest amount. The data provided by Mold et al. (2595) were reproduced by Tso in his 1990 book (3973). As Stedman (3797) noted in his 1968 review of the composition of tobacco and smoke, it was thought at one time that anteiso-alkanes comprised only those homologs with evennumbered carbons, but eventually homologs with odd-numbered carbons were reported by Carugno and Rossi (625) and Chortyk et al. (727). Carugno and Rossi (625) reported the presence of both normal and branched C21 to C34 alkanes in cigarette smoke condensate (CSC). In a later comparison of the composition of the alkane fraction in a reference tobacco (University of Kentucky 1R1) and its cigarette MSS, Chortyk et al. (727) reported that “the ratio among the constituents in leaf paraffins is almost identical [with] the ratio among the smoke paraffins.” It is possible, however, that changes in agronomic practices over the years since the 1970s may have resulted in tobaccos whose contents of alkanes and distribution among the alkane homologs are substantially different from those of the tobaccos studied in the 1960s and 1970s. This, of course, would also affect the content and distribution among the alkane homologs in the tobacco smoke. Table I.A-5 summarizes the tobacco smoke alkane isomers described by Stedman (3797) and those known to be 1

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The Chemical Components of Tobacco and Tobacco Smoke

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TABLE I.A-1 Relative Percentage Composition of Tobacco Alkanes in Tobacco and Cigarette Smoke, Based on Mass Spectroscopic Analysis (613) Tobacco No. of Carbons 25 26 27 28 29 30 31 32 33 Total

iso-

Total

n-

iso-

Total

0.9 0.6 3.0 0.1 6.6 0.9 24.1 3.9 10.8 50.9

0 0 0.9 0 15.9 2.5 24.4 2.4 3.3 49.3

0.9 0.6 3.9 0.1 22.5 3.4 48.5 6.3 14.1 100.3

0 0.5 5.2 0.5 5.2 1.0 25.7 4.3 14.3 56.7

0 0 0.8 0 15.3 1.5 20.2 1.9 3.5 43.2

0 0.5 6.0 0.5 20.5 2.5 45.9 6.2 17.8 99.9

TABLE I.A-2 Relative Percentage Composition of n-Alkanes in Tobacco and Cigarette Smoke, Based on Gas-Liquid Chromatographic Analysis (613) No. of Carbons n-24 n-25 n-26 n-27 n-28 n-29 n-30 n-31 n-32 n-33 n-34

Tobacco … 0.5 0.3 7.5 0.6 8.8 3.9 47.0 12.5 18.9 …

Cigarette Smoke 0.1 0.6 0.4 6.3 1.1 7.4 3.8 48.4 13.0 22.8 1.1

TABLE I.A-3 Alkane Content of Cigarette Mainstream Smoke (2176) No. of Carbons 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 % of Total

Normal … 0.11 0.49 0.92 2.50 1.40 6.60 1.80 6.30 3.30 22.90 4.80 9.70 1.20 0.97 0.05 63.0

Cigarette Smoke

n-

Branched 0.16 0.21 0.21 0.21 0.16 1.63 0.87 13.90 2.31 15.33 0.90 1.13 … … … … 37.0

present in 1992. The number of identified alkanes in these three isomeric forms was almost doubled during the period 1968 to 1992. Many of the isomeric C8 through C36 alkanes have been identified in the organic solvent-soluble extracts from one or more of the major tobacco types (flue-cured, burley, Oriental, Maryland). Their presence in tobacco smoke is the result of their volatilization during the puff and smolder phases of the smoking process and subsequent direct transfer from the tobacco to its MSS and sidestream smoke (SSS). The bulk of these higher alkanes are found in the particulate phase of the smoke aerosol with traces of the lower ones (C8-C12) in the vapor phase. The lower molecular weight alkanes (C1 through C7) are found predominately in the vapor phase of the MSS and SSS aerosols, and are readily separated and identified by a variety of analytical techniques. In general, the n-alkanes from C1 to C4 are gases, those from C5 to C16 are liquids, and those above C17 are solids. The melting points and boiling points of some of the solid alkanes in tobacco and smoke are summarized in Table I.A-6. As a result of the successful induction in the mid-1950s of carcinomas on the skin of mice painted repeatedly with concentrated solutions of CSC (4306a), the search for the causative agent in the condensate began. The demonstration in the early 1930s of the tumorigenicity of dibenz[a,h]anthracene (DB[a,h]A) (2078) and benzo[a]pyrene (B[a]P) (796a, 797) to mouse skin triggered an enormous research effort between 1932 and 1953, excluding the World War II years, which involved the synthesis of hundreds of PAHs and their testing for tumorigenicity. Because many of them were found to be tumorigenic to mouse skin, particularly those tetracyclic and higher, the PAHs were proposed in the mid-1950s by many investigators as possible causative agents for the lung cancer type (squamous cell carcinoma) observed in cigarette smokers. This proposal led to the demonstration of the presence of numerous PAHs in CSC, determination of their levels, and studies to elucidate their precursors in the tobacco.

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The Hydrocarbons

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TABLE I.A-4 Relative Percentage Composition of Tobacco Alkanes Based on Gas-Liquid Chromatographic Data [Figures rounded from those provided by Mold et al. (2595)] Commercial Tobacco Blend No. of Carbons 25 26 27 28 29 30 31 32 33 34

Flue-Cured Tobacco

Burley Tobacco

Oriental Tobacco

n-

iso-

ante-

n-

iso-

ante-

n-

iso-

ante-

n-

iso-

ante-

1.7 0.8 7.7 0.9 6.7 3.2 26.3 4.9 10.8 —

— — — — 1.2 — 10.9 — 5.6 —

— — — 0.1 — 5.6 — 13.0 — 1.2

2.0 1.0 5.7 1.4 5.9 3.1 24.5 4.2 7.2 —

— — — — 3.1 — 14.3 — 6.4 —

— — — 0.4 — 6.7 — 11.3 — 2.9

1.15 0.5 4.8 1.1 5.4 2.9 27.5 5.6 8.1 —

— — — — 2.5 — 12.6 — 6.5 —

— — — 0.4 — 6.8 — 11.7 — 2.6

1.4 0.7 8.6 1.8 7.9 5.5 23.2 7.4 12.8 —

— — — — 1.8 — 6.7 — 4.9 —

— — — 0.2 — 5.3 — 8.9 — 2.3

TABLE I.A-5 Alkane Isomers Identified in Cigarette Mainstream Tobacco Smoke, 1968 vs. 1992 1968a

1992

Carbon Number

a

Carbon Number

normal

iso

anteiso

normal

iso

anteiso

C1-C9 C12-C36 … … …

C4-C6 C27-C33 … … …

C6 … … … …

C1-C36 … … … …

C4-C6 C8-C9 C11-C13 C16-C18 C21-C36

C6-C8 C11-C12 C16-C18 C21-C36 …

From Stedman (3797).

Despite the fact that in 1942 the phytosterols in tobacco had been proposed by Roffo (3327) as the precursors in tobacco of PAHs in a “destructive distillate” of tobacco, the tobacco phytosterols were essentially ignored in the early 1950s. Because of the research results described by Lam (2255–2258) on the pyrogenesis of PAHs from alkanes, the high molecular weight alkanes in tobacco

were proposed as the precursors of the PAHs in tobacco smoke. Roffo’s suggestion on phytosterols was discounted by Wynder and Hoffmann (4320, 4322) because his research did not involve tobacco smoke but involved the composition and specific tumorigenicity of “destructive distillates” from control and organic solvent-extracted tobacco.

TABLE I.A-6 Melting Point and Boiling Point Data for n-Alkanes n-Alkane Undecane Dodecane Tridecane Tetradecane Pentadecane Hexadecane Heptadecane Octadecane Nonadecane Eicosane

Formula C11H24 C12H26 C13H26 C14H30 C15H32 C16H34 C17H36 C18H38 C19H40 C20H42

m.p. °C

b.p. °C

25.6

9.6

6 5.5 10 18.1 22.0 28.0 32.0 36.4

196 216 230 251 268 280 303 308 330 343

n-Alkane Heneicosane Docosane Tricosane Tetracosane Pentacosane Triacontane Pentatriacontane Hexatriacontane Tetracontane Pentacontane

Formula

m.p. °C

b.p. °C

C21H44 C22H46 C23H48 C24H50 C25H52 C30H62 C35H72 C36H74 C40H82 C50H102

40.4 44.4 47.4 51.1 53.3 66.0 74.6 75 81.0 92

357 369 380 391 402 450

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The Chemical Components of Tobacco and Tobacco Smoke

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TABLE I.A-7 Chronology of Studies on Alkanes in Tobacco and Tobacco Smoke Selected Studies Of Year

Alkanesa in Tobacco

1901 1930 1934 1934, 1937 1935 1936 1941 1942 1954 1955, 1956 1956 1956 1956 1956, 1957

Thorpe and Holmes (3914) Kurilo (2239, 2240) Chibnall et al. (701)

1956, 1957 1957 1957 1958 1958 1958 1958 1958 1958, 1959 1959 1959 1959, 1960 1960 1961 1962 1962, 1963 1964, 1967 1965, 1966 1966, 1967 1967 1968 1968 1970 1974, 1975 1978 1979 1989 2003 a

Schürch and Winterstein (3562) Brückner (450) Palfray et al. (2890) Hukusima and Oike (1848)

Alkanes in Tobacco Smoke

Alkanes as Polycyclic Aromatic Hydrocarbon Precursors

Wenusch (4184, 4192, 4194) Schürch and Winterstein (3562)

Kosak (2170) Lam (2255–2257)

Lam (2255–2257) Dickey and Touey (966)

Onishi and Yamasaki (2863) Wright and Wynder (4354)

Kosak (2172) Kosak et al. (2177) Wright and Wynder (4284) Wynder and Wright (4354) Rodgman (3240, 3242)

Rowland (3345) Clemo (767) Cuzin et al. (876) Rayburn and Wartman (3091) Rayburn et al. (3092) Rodgman and Cook (3269) Dymicky and Stedman (1081) Gladding and Wright (1308) Stedman and Rusaniwskyj, (3807, 3808)

Carugno (619) Wynder and Hoffmann (4319, 4332) Ivanov and Ognyanov (1893, 1893a) Carugno and Rossi (625) Mokhnachev et al. (2583) Hoffmann and Wynder (1798)

Chortyk et al. (727)

Izawa et al. (1905) Clemo (765) Cuzin et al. (876) Trillat and Cuzin (3964) Van Duuren and Kosak (4030)

Rayburn and Wartman (3091) Rayburn et al. (3092) Rodgman and Cook (3269) Wynder et al. (4355, 4356)

Carruthers and Johnstone (613) Cuzin (877) Schepartz (3431) Kosak and Swinehart (2176) Izawa (1900) Carugno (619) Spears et al. (3768) Wynder and Hoffmann (4319, 4332) Osman et al. (2875). Carugno and Rossi (625) Hoffmann and Wynder (1798)

Schepartz (3431)

Wynder and Hoffmann (4319, 4332) Badger et al. (142) Mokhnachev et al. (2583) Hoffmann and Wynder (1798) Schlotzhauer and Schmeltz (3465)

Jenkins et al. (1935) Chortyk et al. (727) Severson et al. (3608)

Severson et al. (3616) Bass et al. (208) Coleman and Gordon (776)

Most of the studies dealt with alkanes C10 and greater.

Although Zeise (4406) and Kissling (2100, 2102) reported the isolation of alkane-like components from tobacco and tobacco smoke, Kosak (2170) in his catalog of smoke components classified their data as inconclusive. However, the

evidence provided by Thorpe and Holmes (3914) left little doubt as to the presence of the alkanes in tobacco leaf. The Thorpe-Holmes report was followed by numerous descriptions of the isolation of alkanes from tobacco and tobacco smoke

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The Hydrocarbons

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Table I.A-8 Polycyclic Aromatic Hydrocarbons from Tobacco Aliphatic Hydrocarbons Pyrolyzed in Air at Various Temperatures Quantity (μg) of PAH Formed on Pyrolysis (in air) of Aliphatic Tobacco Hydrocarbons (1.0 g) At 800°C Polycyclic Aromatic Hydrocarbon Naphthalene Acenaphthene Acenaphthylene Phenanthrene Anthracene Pyrene Fluoranthene Chrysene Perylene Benzo[a]pyrene Benzo[e]pyrene Dibenzo[def,mno]chrysene TOTALS

At 700°C

At 600°C

PAH, µg/g

PAH/ B[a]P a

PAH, µg/g

PAH/ B[a]P a

PAH, µg/g

14260 0 3520 3840 580 960 1700 400 34 340 400 42 26076

41.94 [2/5]b 0 [3/5]c 10.35 [3/5]c 11.29 [3/5]c 1.71 [3/5]c 2.82 [4/5]d 5.00 [4/5]d 1.18 [4/5]d 0.10 [5/5]e 1.00 1.18 [5/5]e 0.12 [6/5]f 86.87

4760 0 480 580 110 320 24 86 4 30 80 <1 6474

158.7 0 16.00 19.33 3.67 10.67 0.80 2.87 0.13 1.00 2.67 <0.03 21.47

0 0 0 0 0 0 0 0 0 0 0 0 0

B[a]P = benzo[a]pyrene [2/5] = bicyclic/pentacyclic B[a]P c [3/5] = tricyclic/pentacyclic B[a]P d [4/5] = tetracyclic/pentacyclic B[a]P e [5/5] = pentacyclic/pentacyc lic B[a]P f [6/6] = hexacyclic/pentacyclic B[a]P a

b

(see Table I.A-7 for a cross section of some of the published reports, particularly those issued prior to the 1980s). Also included in Table I.A-7 are references to some of the studies in which the alkanes were investigated as PAH precursors by pyrolysis or by “spiking” of the tobacco filler in a cigarette. In 1934, Chibnall et al. (701) were among the first investigators to report that the alkane fraction, comprising a mixture of several individual alkanes, melted sharply over a narrow temperature range (63.3–63.8°C), a melting point behavior for a mixture that was contrary to the organic chemistry teachings of the day. From the results of studies on the pyrolysis of the “tobacco paraffins,” which comprise the n-, iso-, and anteiso-alkanes, it was suggested by Lam (2255–2258), Wynder et al. (4356), Wynder and Hoffmann (4319, 4332), and Hoffmann and Wynder (1798) that these components were the major precursors in tobacco of the PAHs in tobacco smoke. However, in 1958, Rayburn and his colleagues (3091, 3092) challenged the proposal that the tobacco alkanes were the major precursors of the smoke PAHs, but their experimental data were not overly conclusive in support of their challenge. Nevertheless, it should be realized that in one sense Rayburn et al. were partly correct: as PAH precursors, the tobacco alkanes do contribute to the PAHs in tobacco smoke but their contribution is much less significant than other precursors (the phytosterols and terpenoids such as solanesol) in tobacco [cf. Wright (4282), Rodgman and Cook, (3269, 3286), Severson et al. (3616)]. Table I.A-8, adapted from Lam (2257), demonstrates the relationship between PAH generation and pyrolysis

temperature for aliphatic tobacco hydrocarbons (the alkanes) pyrolyzed in air at several temperatures. Calculation of the yield ratios [PAH µg/g:B[a]P µg/g] of the other PAHs vs. B[a]P reveals significant information: in this simple case of pyrolysis, there is little consistency between the change in ratios of PAH/B[a]P as the temperature is increased from 700°C to 800°C. For example, in the case of the tetracyclic hydrocarbons, the PAH/B[a]P ratio decreases for pyrene and chrysene but increases for fluoranthene. For the pentacyclic hydrocarbons, the ratio decreases for both perylene and benzo[e] pyrene. For the hexacyclic hydrocarbon dibenzo[def,mno] chrysene, the ratio increases. These same trends exist whether the PAH/B[a]P ratios are calculated in terms of molar yields or, as in Table I.A-8, in terms of the absolute quantities (micrograms of PAH generated per gram of aliphatic tobacco hydrocarbons pyrolyzed). The significance of these data and calculations is their demonstration in 1956 that in even the simplest pyrolysis situation,* B[a]P is not a valid “indicator” or “marker” for the PAHs with four or more rings and/or their *

For several decades, Wynder, Hoffmann, and some other investigators asserted that the fate of a given tobacco component during inert atmosphere pyrolysis was equivalent to its fate in the oxygen-deficient (but not oxygen-free) atmosphere in the tobacco rod during the cigarette smoking process [see Wynder and Hoffmann (4320, 4332), Hoffmann and Wynder (1798)]. At the same time, many other investigators maintained that the two processes were not equivalent. Hoffmann and colleagues demonstrated in 1979 with radiolabeled nicotine that the two processes were not equivalent, and they suggested that this nonequivalence observed for the fate of nicotine was applicable to the fate of other tobacco components (3512).

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The Chemical Components of Tobacco and Tobacco Smoke

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supposed relationship to tumorigenic activity as suggested by Wynder and Hoffmann (4317, 4320, 4332). In addition to these data by Lam, other contrary data that demonstrated the invalidity of the concept of B[a]P as an “indicator” or “marker” for PAHs with four or more rings and the tumorigenicity of the substrate (CSC, pyrolysate, etc.) containing them were generated not only in studies by Wynder et al. (4355, 4356), but also in studies by Campbell and Lindsey (583), Rodgman (3240), Rodgman and Cook (3269, 3286), Gori (1329, 1330, 1332, 1333), the National Cancer Institute (2683), and Severson et al. (3616). When used as a solvent for B[a]P in mouse skin-painting tests, the C10, C12, or C16 n-alkanes—although noncarcinogenic per se in this bioassay—were reported by Horton et al. (1835) to accelerate the tumor-producing capability of B[a]P and 1,2dihydro-3-methylbenz[j]aceanthrylene (3-methylcholanthrene). Horton et al. reported that n-octane, the C8 alkane, did not exhibit this property. The acceleration finding of the C10, C12, or C16 n-alkanes was incorporated by Carruthers and Johnstone (613) into an explanation of why the percent of tumor-bearing animals (% TBAs) was much greater in mice painted with CSC than could be predicted by the levels of tumorigenic polycyclic hydrocarbons in the CSC. They extrapolated the finding of this property of the C10, C12, and C16 n-alkanes to the longer chained homologs in cigarette smoke. In contrast, however, to the findings of Horton et al. (1835), Wynder and Hoffmann (4314, 4319, 4332) reported that the specific tumorigenicity of B[a]P in mouse skin-painting experiments was significantly “inhibited” when it was administered with the individual alkanes n-hentriacontane (C31H64) or n-pentatriacontane (C35H72) and the ratio of the alkane: B[a]P was either 200:1 or 100:1. These ratios are much less than those encountered in CSC. Wynder and Hoffmann also reported that increasing the level of the alkane fraction in the applied CSC from 3% to 4% (a 33% increase) resulted in a decrease (from 40% to 24%) in the % TBAs after 19

months and a decrease (from 24% to 18%) of % TBAs with malignant tumors. Surprisingly, Wynder and Hoffmann did not consider these decreases significant! These alkane-B[a] P data, originally presented at an American Association for Cancer Research meeting (4314), did not appear in any journal but were included in the Wynder-Hoffmann review (4319) and book (4332) on tobacco smoke carcinogenesis. Although they did not catalog their bioassay findings from the alkane-B[a]P experiments in their extensive tabulation of the induction of carcinoma in skin-painting studies with tobacco products [see pp. 330–331 in (4319) and pp. 370–371 in (4332)], Wynder and Hoffmann offered the following explanation for the result observed: The effect of alkanes may not be inhibitory to tumorigenicity but rather a consequence of having influenced resorption. The tumor response data of these experiments clearly express a delay of tumor appearance, a result that we believe to be due to the retarding effect of the n-alkanes.

Earlier, Wynder and Wright (4354) had reported that the slight tumorigenicity observed with an alkane fraction of tobacco smoke condensate in a mouse skin-painting bioassay was due not to the alkanes per se but to trace amounts of PAHs in the alkane fraction. In later experiments with gasoline engine exhaust “tar” vs. CSC, the observed tumorigenicities observed by Wynder and Hoffmann (4315) did not parallel the levels of the PAHs considered to be the major contributors to the observed skin tumors. To explain the difference (and the less than anticipated tumorigenicity of the exhaust “tar”), the authors attributed the depressed tumorigenicity of the exhaust “tar” not only to alkanes but also to nontumorigenic PAHs present in engine exhaust “tar” at levels far in excess of those of the tumorigenic PAHs such as B[a]P and DB[a,h]A (see Table I.A-9). Although the ratios are not as great for CSC as for exhaust “tar,” it should be noted that the levels of nontumorigenic

TABLE I.A-9 Ratios for Individual Polycyclic Aromatic Hydrocarbons in Gasoline Engine Exhaust “Tar” (EET) and Cigarette Smoke Condensate (CSC) Polycyclic Aromatic Hydrocarbon

Ratio PAHEET:PAHCSC

Polycyclic Aromatic Hydrocarbon

Ratio PAHEET:PAHCSC

Benz[a]anthracene Benz[a]anthracene, alkylBenz[e]acephenanthryleneb Benzo[ghi]fluoranthene Benzo[j]fluoranthene Benzo[k]fluoranthene 11H-Benzo[b]fluorene Benzo[ghi]perylene Chrysene Chrysene, alkyl- a Dibenz[a,h]anthracene

600:1 >10:1 640:1 1500:1 85-110:1 200-360:1 100:1 255-340:1 87-115:1 33-45:1 17-25:1

Dibenzo[def,mno]chrysenec Benzo[a]pyrene Benzo[a]pyrene, alkylBenzo[e]pyrene Fluoranthene Fluoranthene, alkylIndeno[1,2,3-cd]pyrene Indeno[1,2,3-cd]fluoranthene Pyrene Pyrene, alkylTriphenylene

>440:1 45:1 >10:1 4200:1 275-390:1 230-275:1 >80:1 >30:1 500-700:1 3-4:1 4400:1

a

Similar to 5-methylchrysene Formerly known as benzo[b]fluoranthene c Formerly known as anthanthrene b

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 6

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The Hydrocarbons

(and antitumorigenic) PAHs in CSC far exceed those of the tumorigenic PAHs. Wynder and Hoffmann (4315) summarized their findings as follows: It was anticipated that the … exhaust gas “tar” and nicotine would be many times more active than tobacco smoke condensate. However, … it is only approximately twice as active. This relatively small increase in biological activity of exhaust gas “tar” raises the question of possible anticarcinogenic factors that may be more prevalent in engine exhaust “tar” … one may theorize that some of the noncarcinogenic polynuclear hydrocarbons that are present in engine exhaust gas “tar” in far greater concentrations than in tobacco smoke condensate may interfere with the resorption of the “tar.” Some of the oily materials in gasoline engine exhaust “tar” and the paraffins in tobacco smoke condensate may also act as anticarcinogens.

In their comparison of the composition of the alkane fraction in a reference tobacco (University of Kentucky 1R1) and its cigarette MSS, Chortyk et al. (727) reported that “the ratio among the constituents in leaf paraffins is almost identical [with] the ratio among the smoke paraffins.” They interpreted this finding as suggesting the paraffins undergo little pyrolytic degradation during the smoking process. Although octatriacontane has not been identified in either tobacco or tobacco smoke, Bass et al. (208) employed [18-14C]octatriacontane to study its transfer to cigarette smoke. Their findings with this alkane agreed with those of Chortyk et al. (727) on the series of alkanes in tobacco and their transfer to smoke and with those of Jenkins et al. (1935) on the transfer of [16,17-14C] dotriacontane from tobacco to smoke. Table I.A-10 lists the alkanes identified in mainstream tobacco smoke. The citations do not necessarily include every reference to the identification or discussion of a particular alkane.

I.B THE ALKENES AND ALKYNES In his summary of the identified components of tobacco smoke, Kosak (2170) listed only one unequivocally identified alkene or alkyne. It was ethyne (acetylene). Johnstone and Plimmer (1971) listed the following alkenes and alkynes identified in tobacco smoke: cis- and trans-butene, 1,3-butadiene, methyl-1,3-butadiene (isoprene), ethene, ethyne, methylethyne, propene, methylpropene, squalene and isosqualene, and several phytadienes. Less than a decade later, Stedman (3797) described and/or discussed nearly 235 acyclic alkenes and alkynes identified in tobacco smoke. This number includes the cis and trans isomers in the homologous monoalkene series discussed below. In Table I.B-1 are listed the nearly 330 acyclic alkenes and alkynes in tobacco smoke whose identifications have been reported to date. The lower molecular weight acyclic unsaturated hydrocarbons (alkenes, alkadienes, alkynes, etc.) occur primarily, if not totally, in the vapor phase of mainstream smoke (MSS). Even though some of the vapor-phase components of cigarette MSS have been shown to be significant in vitro ciliastats, the low

7

molecular weight hydrocarbons (alkanes, alkenes, alkynes) were not considered by Caroff et al. (604, 605) to be involved because of their low concentrations in the smoke. The smoke components (aldehydes, ketones, hydrogen cyanide, formic and acetic acids, phenol) reported to be significant in vitro ciliastats are relatively highly water-soluble, whereas the low molecular weight hydrocarbons, generally considered non-ciliastatic in in vitro systems, show extremely low solubility in water. Rodgman et al. (3306) and Dalhamn et al. (892, 893) described the differences in oral absorption of the tobacco smoke components isoprene (20%) vs. acetaldehyde (60%) or acetone (56%). It has also been noted by Wynder and Hoffmann (4332) that these compounds do not appear to play a significant role in tobacco smoke carcinogenesis: “Their [the alkenes] level in the smoke is rather low (0.01%) and they would, therefore, not be active even if they were tumor promoters.” In the National Cancer Institute study on the “less hazardous” cigarette, which involved chemical and biological (mouse skin-painting bioassay) studies on four series* (1329, 1330, 1332, 1333) of experimental cigarettes and appropriate controls, an interesting correlation was reported with the first series of cigarettes (1329): although no correlations were observed between the benzo[a]pyrene (B[a]P) content or the benz[a]anthracene (B[a]A) content of the cigarette smoke condensate (CSC) and the percent of tumor-bearing animals (% TBA), a correlation— classified as significant—was observed between the isoprene content of the MSS and the % TBA. This observed isoprene-% TBA correlation was heatedly discussed and debated for the following year. In the second, third, and fourth series of cigarette, the isoprene-% TBA correlation was not observed, that is, it had disappeared! It should be noted that the manipulations involved in the collection and preparation of the CSCs for the bioassay virtually preclude the presence of isoprene in the material applied to the host animals. In its review of smoke composition and the relationship between smoke components and health, the International Agency for Research on Cancer (IARC; 1870) devoted very little space to the volatile acyclic hydrocarbons and just two paragraphs to the nonvolatile members of this compound group. Among the alkenes listed as tobacco smoke components are several series of isomeric isoprenoid compounds, including the phytadienes (3247), the solanesenes (3297), and the squalenes (2175, 3297, 4033), plus several homologous series of monoalkenes (1144). A series of phytadiene isomers with a pair of conjugated double bonds in different internal and terminal positions were identified in the MSS from cigarettes containing the American blend (3247). Similar series of phytadienes were identified in the MSSs from cigarettes containing individual tobaccos (flue-cured, burley, Oriental). The evidence indicated the presence of at least the following four basic combinations of the conjugated linkages within an isoprenoid unit *

The four series of cigarettes involved a total of 98 test cigarettes and about 30 reference (Kentucky Reference 1R1) and standard cigarettes, divided almost equally among the four series.

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 7

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The Chemical Components of Tobacco and Tobacco Smoke

8

TABLE I.A-10 Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.







)





!"!+!(!,



'!
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)&&!-$/!
( !1




))
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© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 8

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The Hydrocarbons

9

TABLE I.A-10 (CONTINUED) Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


(





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&
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& ,"0%

    





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(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 9

11/13/08 6:40:36 PM

The Chemical Components of Tobacco and Tobacco Smoke

10

TABLE I.A-10 (CONTINUED) Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke.

1561-00-8

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 10

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The Hydrocarbons

11

TABLE I.A-10 (CONTINUED) Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


&











  


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(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 11

11/13/08 6:40:41 PM

The Chemical Components of Tobacco and Tobacco Smoke

12

TABLE I.A-10 (CONTINUED) Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


)





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'!
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© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 12

11/13/08 6:40:43 PM

The Hydrocarbons

13

TABLE I.A-10 (CONTINUED) Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


(





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&
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(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 13

11/13/08 6:40:45 PM

The Chemical Components of Tobacco and Tobacco Smoke

14

TABLE I.A-10 (CONTINUED) Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke





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''


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© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 14

11/13/08 6:40:48 PM

The Hydrocarbons

15

TABLE I.A-10 (CONTINUED) Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


'





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%
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(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 15

11/13/08 6:40:50 PM

The Chemical Components of Tobacco and Tobacco Smoke

16

TABLE I.A-10 (CONTINUED) Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


'





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%
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© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 16

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The Hydrocarbons

17

TABLE I.B-1 Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 17

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18

The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 18

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The Hydrocarbons

19

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 19

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20

The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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The Hydrocarbons

21

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 21

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22

The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 22

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The Hydrocarbons

23

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 23

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24

The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 24

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The Hydrocarbons

25

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 25

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26

The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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The Hydrocarbons

27

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 27

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28

The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 28

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The Hydrocarbons

29

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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30

The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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The Hydrocarbons

31

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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32

The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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The Hydrocarbons

33

TABLE I.B-1 (CONTINUED) Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C001.indd 33

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34

The Chemical Components of Tobacco and Tobacco Smoke

Phytadienes I to IV with the potential to generate anthraquinonecarboxylic acids in the reaction sequence described are CH3 CH2 shown in Figure I.B-1. Phytadienes I, II (n = 3), and IV can {  exist as cis and trans isomers. The remaining phytadienes in Figure I.B-1 can exist as cis cis, cis trans, trans cis, and trans -CH=C-CH=CH=CH-C-CH2-CH2trans isomers. In Figure I.B-2 are shown the phytadienes (V, CH3 CH2 VI) that do not appear to form Diels-Alder adducts. {  As noted previously, even if they did form the Diels-Alder -CH2-C-CH=CH=CH-C=CH-CH2adducts, they would not yield alkylanthraquinones because of the absence of hydrogen atoms at the 1- and/or 4-posiThe mixture of smoke phytadienes was separated into tions. Figure I.B-1 also summarizes the various anthraquigroups of phytadienes by alumina column chromatography. nonecarboxylic acids which could arise from the phytadienes Because Rowland (3345) had used the Diels-Alder reaction depicted. of neophytadiene with 1,4-naphthoquinone to great advantage In their study of the smoke from British cigarettes, Johnstone in its characterization, this same reaction sequence was used and Quan (1973) reported that at least 99% of the acyclic phytain the phytadiene study. Treatment of each phytadiene fracdienes comprised neophytadiene. They made no comment on the tion with 1,4-naphthoquinone gave Diels-Alder adducts which presence of phytadiene isomers in the remaining 1%. Since no were converted to anthraquinonecarboxylic acids by sequenquantitative data were provided by Rodgman (3247) in his study tial oxidations, first to alkylanthraquinones and then to carof the phytadiene isomers in tobacco smoke, comparisons of the boxylic acids. The number and positions of the carboxyl groups two investigations are not possible. The Johnstone-Quan study permitted assignment of the conjugated double bonds in the involved the study of tobacco smoke from flue-cured tobacco phytadiene. The phytadiene series contained 3-methylene-7,11, cigarettes, whereas the Rodgman study involved smoke from 15-trimethyl-1-hexadecene (neophytadiene), 3,7,11,15-tetramcigarettes containing a cased American blend (flue-cured, burley, ethyl-1,3-hexadecadiene, 2,6,10,14-tetramethyl-1,3-hexadecaOriental, and Maryland tobaccos). diene, a 1,2,4-trialkyl-1,3-butadiene, and possibly as many as Because of the similarities among the infrared absorpnine other conjugated phytadienes (excluding cis and trans isotion spectra of the gross phytadiene fraction in cigarette mers). No evidence was obtained to indicate that six of the possible isomeric conjugated phytadienes were present in MSS. MSS (3247), the mixture of phytadiene isomers described by They may have either been unreactive in the Diels-Alder reacRowland (3345), and the mixture of phytadienes generated by tion with 1,4-naphthoquinone or, if reactive, gave an adduct heating neophytadiene (180ºC, 2.5 h), Rodgman suggested that was not oxidizable to an alkylanthraquinone. that the isomeric conjugated phytadienes in tobacco smoke The several groups of possible conjugated phytadienes are resulted from thermal isomerization of neophytadiene during more completely defined in structures I through VI: the smoking process. However, as Lam et al. (2260) suggested, CH2 CH3 CH3 e  e H[CH2-CH-CH2-CH2]n-CH2-C-CH=CH-[CH2-CH-CH2-CH2]3-n-H I CH3 CH3 CH3 e e e H[CH2-CH-CH2-CH2]n-CH=C-CH=CH-[CH2-CH-CH2-CH2]3-n-H II CH3 CH3 CH3 CH3 e e e e H[CH2-CH-CH2-CH2]m-CH2-CH-CH2-CH=CH-C=CH-CH2-[CH2-CH-CH2-CH2]2-m-H III CH3 CH3 CH2 CH3 e e e e H[CH2-CH-CH2-CH2]m-CH2-CH-CH2-CH=CH-C-CH-CH2-[CH2-CH-CH2-CH2]2-m-H IV CH3 CH3 CH3 CH3 e e e e H[CH2-CH-CH2-CH2]m-CH2-CH-CH=CH-CH=C-CH2-CH2-[CH2-CH-CH2-CH2]2-m-H V CH3 CH3 CH3 CH3 e e e e H[CH2-CH-CH2-CH2]m-CH2-C=CH-CH=CH-CH-CH2-CH2-[CH2-CH-CH2-CH2]2-m-H VI

or between contiguous units:

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35

I, n = 3a

III, m = 2d

I, n = 2b

III, m = 1d

I, n = 1b

III, m = 0d

I, n = 0b II, n = 0b

IV, m = 2b

II, n = 3c

IV, m = 1b

II, n = 2d

IV, m = 0b

II, n = 1d LEGEND anthraquinone-2-carboxylic acid. bYields anthraquinone-1,3-dicarboxylic acid. cYields anthraquinone-1,2-dicarboxylic acid. dYields anthraquinone-1,2,4-tricarboxylic acid. aYields

FIGURE I.B-1 Phytadienes with potential to yield Diels-Alder adducts and subsequently alkylanthraquinones and anthraquinonecarboxylic acids.

it is highly possible that the various phytadienes may be generated during the smoking process from phytol or phytyl esters in the tobacco. VanDeMeent et al. (4015) reported that chlorophyll-bound phytol yielded several phytadienes when various geological materials containing chlorophylls were pyrolyzed at 610ºC. Lam et al. (2260) reported the presence of at least five different phytadienes in a pyrolysate from phytol heated at 550°C. Neither VanDeMeent et al. nor Lam et al. described the structures of the phytadienes they had identified. Another series of isoprenoid hydrocarbons isolated from cigarette MSS by Rodgman et al. (3297) comprised the solanesol-related solanesenes. Dehydration of solanesol or pyrolysis of solanesyl acetate yields a mixture of solanesenes similar to that isolated from cigarette MSS. VII and VIII are the major components of the solanesene mixture in tobacco smoke. CH2 CH3  R-CH2-C-CH=CH2 VII

e R-CH=C-CH=CH2 VIII CH3

e where R = H-[CH2-C=CH-CH2]8-

Sodium-alcohol reduction of the mixture gave dihydrosolanesene whose infrared spectrum vs. that of the solanesenes was consistent with the migration of the terminal double bond to an internal position. The Diels-Alder reaction sequence used by Rowland (3345) in the characterization of neophytadiene from tobacco and the various phytadienes in cigarette MSS by Rodgman (3247) was applied to the solanesene mixture. It provided confirmatory evidence for the presence of the solanesene VII: reaction of the isolated solanesene mixture with 1,4-naphthoquinone, followed by air oxidation of the adduct, apparently yielded a single 2-alkylanthraquinone rather than the anticipitated mixture of 2-alkyl- and 1,2-dialkylanthraquinones. Only anthraquinone-2-carboxylic acid was isolated and identified as a product of the alkylanthraquinone-to-anthraquinonecarboxylic acid oxidation. The failure to demonstrate the presence of anthraquinone-1,2-dicarboxylic acid was attributed to the inertness of solanesene VIII in the Diels-Alder reaction. Wynder and Hoffmann (4319) reported that the phytadienes did not produce hyperplasia or destroy sebaceous glands when applied to mouse skin. They also reported (4316) that removal of terpenoid hydrocarbons such as the phytadienes from a polycyclic aromatic hydrocarbon (PAH)enriched fraction did not significantly alter its sebaceous gland suppression. From this result they concluded that “the

V, m = 2

VI, m = 2

V, m = 1

VI, m = 1

V, m = 0

VI, m = 0

FIGURE I.B-2 Phytadienes with little or no potential to form Diels-Alder adducts.

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36

terpenes may not contribute significantly to the tumorigenic activity of tobacco smoke.” Entwhistle and Johnstone (1144) described six homologous series of monoalkenes isolated from tobacco smoke, including all of the possible cis and trans isomers. They reported the total delivery of these series in cigarette MSS to be about 3 μg/cigarette. These series did not appear to be present in tobacco leaf. Their precursors in tobacco have not been defined. However, Carruthers and Johnstone (614) earlier had reported that long-chained alkenes in tobacco smoke did not result from the dehydration of the corresponding alcohol during the smoking process. Monoalkene Series H2C=CH-(CH2)n-CH3 H2C=C(CH3)-(CH2)n-CH3 CH3-CH=CH-(CH2)n-CH3 a CH3-C(CH3)=CH-(CH2)n-CH3 CH3-CH=CH-(CH2)n-CH=(CH3)2 a CH3-CH=CH-(CH2)n-CH(CH3)-CH2-CH3 a a cis and trans isomers

n= 7 through 25 9 through 28 9 through 28 8 through 27 7 through 26 6 through 25

Rodgman et al. (3294) described the composition of an aliphatic ester fraction isolated from MSS generated by cigarettes fabricated from an American tobacco blend, burley tobacco, or Oriental tobacco. Aliphatic ester fractions almost identical with those from the smokes were also isolated from flue-cured tobacco, burley, and Oriental tobaccos. With the analytical technology available in the early 1960s, the aliphatic ester fraction was shown to consist of a series of esters whose alcohol moiety varied from 1-dodecanol (C12) to 1-heptacosanol (C27), inclusive. The acid moiety ranged from tetradecanoic acid (C14) to octacosanoic acid (C28), inclusive, plus the C18 unsaturated acids, oleic and linolenic. More than two decades later, Arrendale et al. (103) extended the identification of the components of the aliphatic ester fraction from tobacco. The alcohol moiety ranged from 1-hexadecanol (C16) to 1-tetratriacontanol (C34). Esters with 1-hentriacontanol and 1-tritriacontanol as the alcohol moieties were not detected. The acid moiety ranged from dodecanoic acid (C12) to dotriacontanoic acid (C32). An ester with hentriacontanoic acid as the acid moiety was not detected. For a given number of carbons, the acid moiety not only included the normal acid but also in several cases included the iso and/ or anteiso acid, for example, esters were identified with n-, iso-, and anteiso-pentadecanoic acid as the acid moieties. Even though Arrendale et al. (103) limited their study to an ester fraction isolated from tobacco, it seems logical to assume, based on the findings of Rodgman et al. (3294) on the equivalence of the aliphatic ester fractions isolated from various smokes and tobaccos, that each ester identified by Arrendale et al. would appear in tobacco smoke. Controlled thermal degradation of higher molecular weight aliphatic esters generates an alkene and an acid (950c, 3294).

Thermal degradation during the smoking process of the aliphatic esters identified in tobacco could conceivably yield some of the alkenes in the series described by Entwhistle and Johnstone (1144). R-CH2-CH2-OOC-R1 l R-CH=CH2 + R1-COOH 2,6-Dimethyl-2,4,6-octatriene (alloöcimene) was reported by Wynder and Hoffmann (4316) as a significant tobacco smoke component (0.5% of CSC) with cocarcinogenic activity. However, Mold et al. (2597) presented contradictory data which indicated that if 2,6-dimethyl-2,4,6-octatriene were present in smoke, its level was less than 0.006%.

I.C THE ALICYCLIC HYDROCARBONS The cyclic aliphatic hydrocarbons in tobacco and tobacco smoke include compounds whose ring sizes range from cyclopropane through cyclooctane, cyclononane, cycloundecane, and cyclotetradecane. Theoretically, cyclooctatetraene could be included in the listing of monocyclic aromatic hydrocarbons. Numerous hydrocarbons with cyclopentane and cyclohexane rings were reported as tobacco and tobacco smoke components in the late 1950s through the mid-1960s (see Table I.C-1). Tobacco smoke hydrocarbons with a cyclobutane ring were reported by Stedman in 1963 (3795). Three dimethylcyclopropanes were reported in 1970 by Bartle and Novotny (200). 1,3,5-Cycloheptatriene and cyclooctatetraene were reported by Enzell et al. (1154) and Mauldin (2506), respectively. A hydrocarbon with the cycloheptatriene ring had been reported previously as a tobacco smoke component in 1947 by Ikeda (1857): the bicyclic aromatic hydrocarbon azulene, an isomer of naphthalene. Several fused-ring alicyclic hydrocarbons obviously derived from tobacco sterols were reported in 1989 in tobacco smoke by Benner et al. (273). In addition to a low level of cholesterol {1a}, tobacco usually contains substantial levels of several phytosterols [campesterol {Ib}, B-sitosterol {Ic}, stigmasterol {Id}, ergosterol {1e}] structurally similar to cholesterol. These phytosterols differ slightly from cholesterol in the structure of the long side chain (Figure I.C-1). They are present in tobacco in both the free and bound form (as glycosides, esters, etc.), and they are transferred as such to mainstream smoke (MSS). The sterols constitute about 0.2% of the tobacco weight. As shown in Figure I.C-1, pyrolysis of cholesterol {Ia} yields chrysene {III}, Diels hydrocarbon {IV}—a methylcyclopentaphenanthrene—and numerous other polycyclic aromatic hydrocarbons (PAHs). Both PAHs noted have also been identified in pyrolysates of the major tobacco phytosterols [Wynder et al. (4356), Van Duuren, (4022)]. While none of the sterols {Ia-Ie} has been shown to generate the potent tumorigen 1,2-dihydro-3-methylbenz[j]aceanthrylene (3-methylcholanthrene) on pyrolysis, Falk et al. (1171) reported that cholesterol and cholesterol esters do generate the mouseskin tumorigens 4-cholesten-3-one {Va} and 3,5-cholestadiene {VIa}. Veldstra (4042a) reported that the pyrolysis of cholesteryl oleate also yielded 3,5-cholestadiene {VIa}.

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TABLE I.C-1 Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.C-1 (CONTINUED) Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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TABLE I.C-1 (CONTINUED) Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.C-1 (CONTINUED) Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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TABLE I.C-1 (CONTINUED) Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.C-1 (CONTINUED) Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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TABLE I.C-1 (CONTINUED) Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.C-1 (CONTINUED) Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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TABLE I.C-1 (CONTINUED) Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

Cholesteryl oleate was probably a component of the mixture of steryl esters described in flue-cured tobacco by Rowland and Latimer (3358) and in tobacco smoke by Rodgman et al. (3296). The steryl esters included sterols esterified with a series of saturated (palmitic, stearic, etc) and unsaturated (oleic, linoleic, etc.) acids. In the late 1950s to early 1960s, Rodgman proposed that the tobacco phytosterols—campesterol, B-sitosterol, stigmasterol, and ergosterol—might generate compounds analogous to those generated from cholesterol, that is, 4-campesten-3 -one {Vb}, 3,5-campestadiene {VIb}, B-4-sitosten-3-one {Vc}, 3,5-sitostadiene {VIc}, 4-stigmasten-3-one {Vd}, 3,5-

stigmastadiene {VId}, ergosten-3-one {Ve}, 3,5-ergostatriene {VIe}on thermal degradation of these tobacco phytosterols or their esters during the smoking process. These campesterol-, B-sitosterol-, stigmasterol- and ergosterol-related compounds might also be mouse-skin tumorigens as are their cholesterol counterparts. For nearly a decade, Rodgman and Cook (3286) were unsuccessful in their periodic efforts to isolate any of these steryl ketones or dienes from cigarette smoke condensate (CSC) and identify them. However, Benner et al. (273) did subsequently identify two of these 3,5-dienes, 3,5-campestadiene {VIb} and 3,5-stigmastadiene {VId}, in tobacco smoke, see also Eatough et al. (1099, 1100).

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LEGEND Sterol, R

CH3

CH3

CH3

CH3 H3C IV CH3

R CH3

CH3

O

V

R

CH3

CH3 CH3

HO II

I

CH3

R=

Ia Ib Ic Id Ie II

cholesterol -(CH2)3-CH(CH3)2 campesterol -(CH2)2-CH(CH3)-CH(CH3)2 β-sitosterol -(CH2)2-CH(C2H5)-CH(CH3)2 stigmasterol -CH=CH-CH(C2H5)-CH(CH3)2 ergosterola -CH=CH-CH(CH3)-CH(CH3)2 1,2-dihydro-3-methylbenz[j]aceanthrylene (3-methylcholanthrene)

III

chrysene

IV

Diels hydrocarbon

Va Vb Vc Vd Ve

4-cholesten-3-one 4-campesten-3-one β-4-sitosten-3-one stigmasten-3-one ergostadien-3-one

VIa VIb VIc VId VIe

3,5-cholestadiene 3,5-campestadiene β-3,5-sitostadiene 3,5-stigmastadiene 3,5,7-ergostatriene

a

Ergosterol has a double bond at the 7-position

VI

III

FIGURE 1.C-1 Possible sterol degradation products.

Johnstone and Quan (1973) reported that flue-cured tobacco smoke contains several hydrocarbons related to neophytadiene: An aliphatic acyclic hydrocarbon norphytene (2,6,10,14-tetramethyl-1-pentadecene) and the four alicyclic hydrocarbons {VII-X, Figure I.C-2} that are dimers of neophytadiene. These dimers are identical with the major products generated when neophytadiene is heated at 190 to 200°C. The dialkylethenylcyclohexenes {IX and X} were a small proportion of the mixture. The more plentiful pair {VII and VIII} each absorbed two equivalents of hydrogen to form saturated hydrocarbons and were readily dehydrogenated to p- and m-alkylbenzene derivatives readily separable by column chromatography on alumina. Nitric acid oxidation of these benzenoid hydrocarbons generated p-benzenedicarboxylic (terephthalic) and m-benzenedicarboxylic (isophthalic) acids, respectively. Johnstone and Quan (1973) considered and rejected the possibility that the dimer mixture may have been artifactually produced during the laboratory generation, collection and fractionation of the CSC. They noted that “At no time was the condensate subjected to temperatures above 80°C, and that only for short periods, so it is likely that the dimers were formed during the smoking process.” The isolation and identification in the late 1950s and early 1960s of several polyhydronaphthalene derivatives in tobacco and smoke, for example, A- and B-levantenolide* (799, 801,

*

α- and β-Levantenolide are listed by Chemical Abstracts as decahydro3,3’a,6’,6’,9’a-pentamethyl- and 3’a,4’,5’,5’a,6’,7’,8’,9’,9’a,9’b-decahydro3,3’a,6’,6’,9’a-pentamethylspiro[furan-2(3H),2’(1’H)-naphtho[2,1-b] furan]-5(4H)-one, respectively.

1299), A2-levantanolide† (1290, 1300), 12A-hydroxy-13epimanoyl oxide‡ (800, 1298, 3281), sclareolide§ (3272, 3533), and sclaral¶ (3534), subsequently led to the identification of many more such derivatives [see Enzell and Wahlberg reviews (1156, 1157, 4089, 4090)] among which were several polyhydronaphthalenes, such as decahydronaphthalene (222– 224), 4,7-dimethyl-1,2,3,5,6,8a-hexahydro-1-(1-methylethyl)naphthalene, (1156, 1256, 4090), and its isomer 4,7-dimethyl-1, 2,4a,5,6,8a-hexahydro-1-(1-methylethyl)-naphthalene (A-muurolene) (404), and two isomers of 1,8a-dimethyl7-(1-methylethenyl)-1,2,3,5,6,7,8,8a-octahydronaphthalene (valencene and eremophilene) (404). A similar situation occurred with the cyclotetradecanes. Subsequent to the isolation and identification of several hydroxy derivatives and epoxy derivatives of unsaturated cyclotetradecane from tobacco (3195, 3220, 3221, 3361) and smoke (3361), several trimethyl-(1-methylethyl)-substituted cyclotetradecatrienes and tetraenes were identified in tobacco (1149, 1149a, 3853) and/or smoke (2726). Table I.C-1 lists the cyclic aliphatic hydrocarbons identified in tobacco and tobacco smoke.

†

‡

§

¶

α2-Levantanolide is listed by Chemical Abstracts as dodecahydro-3, 3’a,6’,6’,9’a-pentamethylspiro[furan-2(5H),2’(1’H)-naphtho[2,1-b]furan]5-one. 12α-Hydroxy-13-epimanoyl oxide is listed by Chemical Abstracts as 3-ethenyldodecahydro-3,4a,7,7,10a-pentamethyl1H-Naphtho[2,1-b] pyran-2-ol. Sclareolide is listed by Chemical Abstracts as decahydro-3a,6,6,9atetramethylnaphtho[2,1-b]furan-2(1H)-one. Sclaral is listed by Chemical Abstracts as dodecahydro-3a,6,6,9atetramethylnaphtho[2,1-b]furan-2-ol.

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47

R

R

R

R

R

R

R

R VII

VIII

IX

X

R = -CH2 -{(CH2)2 -CH(CH3)-CH2}3 -H

FIGURE I.C-2 Phytadiene dimers.

I.D THE MONOCYCLIC AROMATIC HYDROCARBONS In this section, monocyclic aromatic hydrocarbons are defined as those compounds with one or more nonfused aromatic rings, for example, benzene, biphenyl, terphenyl, and stilbene. Some authors might classify the aromatic hydrocarbons with two or more nonfused rings as polycyclic aromatic hydrocarbons (PAHs). Table I.D-1 lists the monocyclic aromatic hydrocarbons identified in tobacco and/or tobacco smoke. None of these compounds was included in Kosak’s 1954 catalog of tobacco smoke components (2170). Johnstone and Plimmer (1971) listed only five such compounds [benzene, ethenylbenzene (styrene), methylbenzene (toluene), 1,2,4trimethylbenzene (pseudocumene), 1,3,5-trimethylbenzene (mesitylene)]. By 1964, Elmenhorst and Reckzeh (1139) listed eleven such hydrocarbons (see Table I.D-1). In 1968, Stedman (3797) listed twenty monocyclic aromatic hydrocarbons. The list presented in 1980 by Ishiguro and Sugawara (1884) indicated this number had doubled. To date, over eighty monocycylic aromatic hydrocarbons have been identified in tobacco and/or its smoke. In its 1986 review of tobacco smoke components and their relationship to health, the IARC (1870) discussed only three monocyclic aromatic hydrocarbons, namely, benzene, methylbenzene (toluene), and ethenylbenzene (styrene): Tobacco smoke contains traces of other volatile compounds found to be carcinogenic in humans or in experimental animals. Benzene, a human carcinogen [IARC (1868)], has been reported in the MS of cigarettes (12–48 μg/cigarette) and in the SS of a 100-mm U.S. filter cigarette (453 μg/cigarette) [Wynder and Hoffmann (4332); Elmenhorst and Schultz (1140); Jermini et al. (1947)]. It can be assumed that benzene is formed during the burning of tobacco either from precursors with an aromatic or cyclohexane ring or by pyrosynthesis from primary radicals such as C6H5. … The most abundant volatile hydrocarbon in tobacco smoke is toluene (methylbenzene), which has been reported to occur at levels of up to 164 μg/cigarette in MS and 904 μg in the SS of a 100-mm U.S. nonfilter cigarette (1140, 1947, 4332).

With regard to the carcinogenic activity (actually its leukemogenic activity) of benzene, it was noted: “Sufficient evidence

in animals with new data from US National Toxicology Program (sufficient evidence in humans).” The carcinogenicity of ethenylbenzene was described as follows: “Limited evidence [in] animals (inadequate evidence in humans).” In 1989, Hoffmann and Hecht (1727) included benzene in their list of forty-three tumorigens in tobacco and tobacco smoke. They discussed the role of exposure to benzene in tobacco smoke as follows: Significant amounts of benzene are found in cigarette MS (up to 50 μg/cigarette). Sufficient evidence exists that this aromatic hydrocarbon causes leukemia in humans [IARC (1868)]. On the basis of analytical data for exhaled breath, it has been calculated that a smoker inhales about 2 mg of benzene per day while a nonsmoker inhales only 0.2 mg per day [Wallace et al. (4111)]. Former epidemiological studies have not demonstrated a strong association of smoking and leukemia [IARC (1868)]. However, a recent prospective study among 248,000 U.S. veterans indicates that cigarette smokers have a significant increase in mortality from leukemia [Kinlen and Rogot (2096)].

Examination of the compendia of compounds tested for carcinogenicity [Hartwell (1543, 1544), Shubik and Hartwell (3664, 3665), Thompson et al. (3908)] reveals that not only has benzene been tested for its carcinogenicity per se to skin (mouse, rat, guinea pig, rabbit, monkey) but also it has been used as the solvent for application of hundreds of compounds (PAHs, their alkyl and other derivatives, plus their nitrogen, oxygen, and sulfur analogs; quinones; aromatic aza-arenes; aromatic amines; sterols and sterol-related compounds) to the skin of a variety of laboratory animals. In many of these latter experiments, groups of “solvent control” animals were painted with benzene at the same time as other test groups were painted with benzene solutions of the compound(s) under investigation. Despite the hundreds of animals skinpainted with benzene, only in very few cases were carcinomas or other tumors observed at the painting site in the “solvent control” benzene-treated animals or in the animals treated in the benzene carcinogenicity studies. Examination of the references listed for benzene provides an indication of the amount of research and discussion pertinent to the presence of benzene in tobacco smoke. Rodgman and Green (3300) in their discussion of toxicants in tobacco and tobacco smoke noted that subsequent lists and

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The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.D-1 Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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TABLE I.D-1 (CONTINUED) Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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TABLE I.D-1 (CONTINUED) Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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TABLE I.D-1 (CONTINUED) Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.D-1 (CONTINUED) Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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TABLE I.D-1 (CONTINUED) Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.D-1 (CONTINUED) Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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discussions generated after that of IARC (1870) included not only benzene but also ethenylbenzene (styrene) [see Table 2 in (3265) and Table 1 in (3300)] and methylbenzene (toluene) [see Table 1 in (3300)].

I.E

THE POLYCYCLIC AROMATIC HYDROCARBONS

Classified as toxicants in many of the substances to which humans are exposed are the polycyclic aromatic hydrocarbons (PAHs). Such exposures include air pollutants from a variety of sources, foodstuffs and beverages, and tobacco smoke. Since the early 1950s, the composition of the latter has been more completely defined than that of any other consumer product. Over 5200 components have been identified in tobacco smoke and among these are over 500 PAHs either completely or partially identified. Because of the tumorigenicity of many PAHs, much research has been conducted in attempts to define the relationship between the PAH structures and their specific tumorigenicities in laboratory animals. None of the theories to date completely answers all the questions. In 2006 Rodgman and Perfetti (3306a) cataloged the PAHs completely or partially identified in cigarette smoke, as a prelude to an attempt to develop a more reasonable PAH structure-tumorigenicity relationship. Additionally, they tabulated the PAHs considered in several previous studies on structure-tumorigenicity relationships, studies that dealt primarily with all-benzenoid PAHs. The majority of the information included in Section I.E comes from the 2006 article from Rodgman and Perfetti (3306a). Tobacco and tobacco products in the forms of leaf, shredded or grounded tobacco, and various forms of cigars and cigarettes have been available to individuals for ages. For centuries people have enjoyed tobacco but have been admonished of its potential health concerns. Health concerns for cigarette smokers have increased steadily since the early 1950s due to the rapid development and advancement in separation sciences, toxicology and medicine. In his 1954 publication, Kosak (2170) was the first person to catalog compounds reported in tobacco smoke. His list contained fewer than 100 compounds and a significant number were incorrectly characterized. Today over 5200 compounds have been identified as components in tobacco smoke [see Figure 1, p. 140 in (1373)]. Over the past fifty years, the tobacco industry has made significant progress in both the identification of tobacco and smoke components and the development of technologies to reduce cigarette smoke yields. Significant efforts continue in government, academia, and especially the tobacco industry to understand the health effects of smoking and to develop cigarette products with reduced health risks for smokers. One class of tobacco smoke components that has been studied extensively and intensively is the polycyclic aromatic hydrocarbons (PAH) due to their potential health concerns. Periodically, tobacco researchers have reported the progress on the identification of tobacco and smoke components. Review articles by Johnstone and Plimmer (1971) and Izawa (1900) detailed the tobacco and smoke research conducted

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over 100 years. Izawa listed 440 identified smoke components by 1961. Quin (3059) published a review of components found in tobacco and smoke. Herrmann (1625) reviewed phenolic compounds in tobacco smoke. In 1963, Philip Morris (2939) published a monograph on tobacco and smoke composition, a copy of which was provided to the Advisory Committee on smoking and health to the U.S. Surgeon General (3999). In 1964, Elmenhorst and Reckzeh (1139) tabulated the aromatic hydrocarbons identified in tobacco smoke. Kuhn (2226) published an article on alkaloids in tobacco and smoke. In their 1967 book, Wynder and Hoffmann (4332) discussed tobacco and smoke chemistry and the results of animal studies with tobacco smoke. Elmenhorst and Schultz (1140) listed 250 low-boiling components and vapor-phase components identified in tobacco smoke. In his 1968 review, Stedman (3797) listed nearly 1200 identified tobacco and smoke components. The next year, Neurath (2724) reported on the presence of 180 nitrogen-containing compounds in smoke. With the meaningful advancements in analytical methodology, the number of tobacco and smoke components increased dramatically (1371). At R. J. Reynolds Tobacco Company (RJRT), Schumacher et al. (3553), Heckman and Best (1587), and Newell et al. (2769) identified over 1500 compounds in the water-soluble and ether-soluble fractions of tobacco smoke. In 1977, Schmeltz and Hoffmann (3491) cataloged nearly 500 N-containing compounds identified in tobacco smoke but their catalog did not include the more than 230 N-containing compounds newly identified in tobacco smoke by Heckman and Best (1587). Between 1974 and 1978, Snook et al. (3732, 3756–3759) published the results of their massive study of the PAHs identified in tobacco smoke, a study that was followed by an equally definitive one published in 1981 on the aza-arenes in tobacco smoke (3750). In 1980, Ishiguro and Sugawara (1884) listed 1889 identified tobacco smoke components in their monograph. However, a tally of the reported tobacco smoke components at that time exceeded 2500. No additional catalogs of the total number of identified components of cigarette mainstream smoke (MSS) have been published since the 1980 Ishiguro and Sugawara (1884) publication. Smith et al. (3712) recently reported the chemical structures of the 253 identified phenols reported in cigarette MSS. Numerous catalogs of PAHs identified in MSS have been compiled from 1955 through 2005. Table I.E-1 is a chronology of catalogs of PAHs in MSS. It contains the year of each catalog, author (and reference), and the number of PAHs listed. The catalogs prior to 2006 contain much overlap in terms of the PAHs identified. In 2006 Rodgman and Perfetti (3306a) published a report that attempted to eliminate the overlap and clearly present the 539 PAHs identified in MSS. The intent of this section is to present a referenced catalog of the completely or partially characterized* PAHs in tobacco, tobacco MSS, and MSS of tobacco substitutes. The catalog to follow (Table I.E-6) contains the CAS registration number, chemical name, structure, and alphabetical listing of references on PAHs. *

The term “partially characterized” or “partially identified” indicates that the position of one or more alkyl substituents was not determined.

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TABLE I.E-1 Chronology of Catalogs of PAHs in MSS Year 1954 1955 1957 1958 1959 1960 1962 1963 1963 1964 1965 1967 1968 1975 1976 1977 1978 1980 1997 2005

Author Kosak Latimer Latimer and Rodgman Rodgman Johnstone and Plimmer Rodgman and Menz Rodgman et al. Philip Morris Rodgman et al. Elmenhorst and Reckzeh Rodgman et al. Rodgman and Woosley Stedman Roberts et al. Snook et al. Snook et al. Snook et al. Ishiguro and Sugawara Williams et al. Rodgman and Perfetti

No. of PAHs Listed a

4 10 33 36 57 68 77 61 77 70 85 85 79 206 252b 157b 438b 191 427c 539d

Ref. 2170 2270 2292a 3245 1971 3301 3303 2939 3304 1139 3302 3308 3797 3224 3758 3756 3757 1884 4249 3306a

a

Three of the PAHs listed were identified in a destructive distillate of tobacco, not in tobacco smoke.

b

In the three articles on the PAH study by Snook et al. (3756–3758), some identified PAHs were listed in more than one article.

c

In several instances, more than one isomer was reported for some monoalkyl-, dialkyl-, trialkyl-, and tetraalkyl-PAHs but the positions of the alkyl groups were not determined. In the case of such multiple alkyl isomers, only one was listed in this report.

d

This list includes the number of isomers of monoalkyl-, dialkyl-, trialkyl-, and tetraalkyl-PAHs reported where the positions of the alkyl groups were not determined.

The significant increase in the number of studies on tobacco smoke composition was triggered by the following events: (a) The results in the early 1950s from several retrospective epidemiology studies (1026a, 1027, 3529, 4306b) in which it was reported that an association existed between cigarette smoking and the incidence of lung cancer in smokers, (b) a 1953 report of the production of skin carcinoma in susceptible laboratory animals skin painted repeatedly with a concentrated solution of cigarette MSS condensate supposedly produced under conditions simulating the human smoking of a cigarette (4306a), (c) the realization in 1954 that very little (2170) was known about the composition of tobacco smoke to which consumers had been exposed for nearly 400 years, and (d) the incorporation of chromatography into the overall methodology of the fractionation of complex mixtures such as tobacco smoke. Naturally, these findings raised several questions. The first dealt with the identity of the cigarette MSS component(s) responsible for the smoking-lung cancer association in smokers and the skin tumor induction in laboratory animals. Because

of extensive data generated on the specific tumorigenicity of about 25% of the hundreds of PAHs synthesized between 1929 and the early 1950s (1543, 1544), PAHs were considered the most likely tumorigenic agents in cigarette MSS even though their presence was not certain. Eventually, numerous PAHs were identified in cigarette MSS. Because of its MSS level and its high specific tumorigenicity in several bioassays, one PAH was subjected to intense scrutiny: Benzo[a]pyrene (B[a]P). As a carcinogen, B[a]P elicited carcinomas at the painting site in the mouse-skin bioassay. As a sarcogen, B[a] P elicited sarcomas in rodent bioassays involving subcutaneous injection. One class of tobacco smoke components studied extensively is the polycyclic aromatic hydrocarbons. As reported by Rodgman (3262), between 1950 and 1970, an extensive amount of research was conducted on tobacco- and cigarette smoke-related topics. The information generated led to the development of several significant cigarette design technologies that resulted in the modification of the delivery and composition of cigarette MSS. The following is a brief chronology of the events occurring in the tobacco smoke-PAH situation. In 1939, the PAHs anthracene, phenanthrene, and B[a]P were reported as components of a tobacco-related material by Roffo (3323–3325) and his son (3316, 3318). In discussions of tobacco smoke, the Roffo findings are generally disregarded because the three PAHs they reported were not detected in tobacco smoke but in a destructive distillate of tobacco. However, Roffo did report another finding that led to much research both within and outside the tobacco industry. Roffo reported that comparison of the destructive distillate of tobacco with that of an ethanol-extracted tobacco indicated (3327) that the PAH content and specific tumorigenicity of the extracted tobacco destructive distillate were reduced from those of the destructive distillate from the control tobacco. Roffo speculated that the precursors of the tumorigenic PAH components of his distillates were ethanol-soluble phytosterols. Eventually his prediction, as far as it went, was found to be true for cigarette MSS (3269, 3616). Because he was unaware of the presence in tobacco of long-chained terpenoids such as solanesol, identified in flue-cured tobacco in 1957 by Rowland et al. (3359), Roffo obviously could not include them in his 1942 precursor prediction. It should be noted that the findings by Roffo on destructive distillates of tobacco were subsequently equivalent to the effects observed in smoked tobacco, that is, organic solvent-extraction of a tobacco or tobacco blend which was then incorporated into cigarettes gave MSS with reduced PAH levels and specific tumorigenicity to mouse skin compared to the MSS from control tobacco. However, usually the reduction in specific tumorigenicity was less than the reduction in PAHs, particularly B[a]P. The generation in the early 1950s of carcinomas in laboratory animals (mice) skin-painted with a solution of the mainstream “tar” from commercial cigarettes (4306a) led to numerous studies to identify the possible causative agent(s) in the “tar.” Since much more tumorigenicity data and knowledge were available on PAHs than on any other class of

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compounds, most of the effort was concentrated on identifying PAHs in cigarette smoke condensate (CSC) as the possible cause of the tumorigenicity. Because of its demonstrated potency as an initiator of carcinomas on skin painting and the wealth of information on it, B[a]P became the target of much research on CSC. In 1951, Hartwell (1544) listed nearly 350 studies on the tumorigenicity of B[a]P administered in various ways to various species. The other previously studied PAHs were dibenz[a,h]anthracene (DB[a,h]A) and 1,2dihydro-3-methylbenz[ j]aceanthrylene (3-methylcholanthrene) with 240 and 303 reported biological studies, respectively. Benz[a]anthracene (B[a]A) and 7,12-dimethylbenz[a] anthracene (DMB[a]A) were listed with twenty and thirtytwo studies, respectively. In the twenty studies reported by Hartwell (1544), a malignant tumor was noted in only one instance with B[a]A. Although B[a]P was reported as a CSC component in the mid-1950s by several American (55–57, 592–594) and British investigators (820) on the basis of spectral evidence, Fieser, as late as 1957 (1181), considered the published evidence to be inadequate as proof of the presence of B[a]P in CSC. Obviously, in 1957 Fieser was unaware of the report by Rodgman in 1956 (3240) on the isolation of crystalline B[a] P from MSS or the reports by Falk and Kotin in 1955 and 1956 (1172) on the determination of the per cigarette yields of B[a]P (plus B[a]A and dibenzo[def,p]chrysene) in MSS and sidestream smoke (SSS). Shortly thereafter, in 1959, Wynder and Hoffmann reported the isolation of B[a]P in crystalline form from CSC (4307), thus ending the controversy about its presence in cigarette smoke. In 1954, knowledge of cigarette MSS composition was extremely limited. As mentioned earlier, Kosak (2170) listed fewer than 100 components reported in tobacco smoke and many of those listed were incorrect. Some of the early research on cigarette MSS composition, particularly the PAHs, was conducted at RJRT.* Complete details of the experimental procedures and findings are available on the Internet at www.rjrtdocs.com. The initial RJRT PAH investigation involved eleven PAHs in the MSS from nonfiltered cigarettes (3240, 3244) [(see Table 1 in (3262)]. Naphthalene, anthracene, pyrene, fluoranthene, and B[a]P, isolated in crystalline form, were characterized by UV absorption spectral data as well as by classical chemical means (mixture melting point, IR spectra, derivatization, and derivative properties). The other six PAHs were identified on the basis of agreement of their UV absorption spectra with those of authentic samples or with published UV data.

*

Numerous formal in-house reports and memoranda authored by RJRT R&D personnel are cited herein. Many have been published totally or in part in peer-reviewed journals and/or presented totally or in part at scientific conferences (Tobacco Chemists’ Research Conferences, American Chemical Society Symposia on Tobacco and Smoke, CORESTA Conferences, etc.). Whether published, presented, or neither, copies of all RJRT reports cited are stored in various repositories such as the one in Minnesota. Their contents are available on the Internet address indicated. Experimental procedures used, data collected, and interpretations summarized here are described in detail in the reports cited.

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The second RJRT investigation involved the MSS from filter-tipped cigarettes (3249, 3273) [see Table 2 in (3262)]. In that study forty-four PAHs, including the eleven PAHs found in the initial study were identified (3240, 3244). Of the forty-four PAHs, fourteen were isolated in crystalline form and characterized by both UV spectral and classical chemical means [see Table 1 in (3262)]. B[a]P, B[a]A, DB[a,h]A, and several other PAHs were also isolated in crystalline form from the CSC (3240, 3244, 3273). The other thirty were identified from the agreement of their UV absorption spectra with those of authentic samples or with published spectra. B[a]P, B[a]A, and DB[a,h]A had been reported to be tumorigenic to mouse skin although the bioassay data for B[a]A were contradictory (983, 1543, 1544). Although much of the early research at RJRT R&D on the identification of PAHs in MSS and the effect of various tobacco blends and/or treatments on their MSS yields was summarized in several recent publications (3262, 3307), other members of the U.S. tobacco industry were also much involved in similar research in the 1960s and 1970s. The following paragraphs provide a few examples of their early efforts. At Philip Morris in 1963, Robb et al. (3191) described the identification of fourteen PAHs (naphthalene, fluorene, anthracene, 9-methylanthracene, phenanthrene, fluoranthene, pyrene, 1-methylpyrene, B[a]P, B[e]P, DB[a,h]A, benz[e]acephenanthrylene, perylene, benzo[ghi]perylene), biphenyl, and the aza-arene, carbazole, in cigarette MSS. Almost all the details in this 1963 Philip Morris in-house report were subsequently presented at the 1964 CORESTA meeting and published in 1965 (3191). Also at Philip Morris, Carpenter (606a) in 1964 described the per cigarette B[a]P yields from several commercial cigarettes; Oakley (2817a) in 1965 reported the per cigarette B[a]P yields from cigarettes fabricated from different tobacco types (flue-cured, burley, Oriental); Segura (3579a) in 1966 reported the contribution of cigarette paper to the per cigarette B[a]P yield; Johnson (1962b) in 1965 described the effect of a tobacco additive, aluminum chloride, on the MSS B[a]P yield; and Oakley (2817b) in 1966 determined the difference in per cigarette B[a]P yield in MSS and SSS. At British American Tobacco Company (BAT) in 1966, Chakraborty and Thornton (646a) studied the effect of various additives on MSS PAHs. The changes in the per cigarette yields of a variety of PAHs were determined. They included anthracene, B[a]A, benzo[ghi]fluoranthene, benzo[k]fluoranthene, B[a]P, B[e]P, chrysene, fluoranthene, fluorene, methylfluorene, phenanthrene, several alkylphenanthrenes, dimethylphenanthrene, pyrene, and several benzofluorenes.† Although studies on PAHs in MSS were conducted at RJRT and Liggett and Myers Tobacco Company (L&M) in the 1960s, publications only dealt with analytical techniques. For example, in 1963 Mold et al. (2596a) at L&M described †

At the Internet address, http://legacy.library.ucsf.edu/cgi, by inserting the topic “aromatic polycyclic hydrocarbons,” one may access over twenty BAT and Brown and Williamson (B&W) memoranda by Chakraborty, Thornton, and others on PAHs in tobacco smoke.

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the use of a compound, tetramethyluric acid, that complexes with polycyclic compounds. It was a procedure reminiscent of the finding of the water-soluble purine-PAH complex defined by Weil-Malherbe (4161a), a finding subsequently developed into an alternative analytical method for the determination of PAHs and aza-arenes in tobacco smoke and other media by Rothwell and Whiteheart (3337–3340). Although the study was not described as relating to tobacco smoke, Cundiff and Markunas (869) at RJRT in 1963 reported a titrimetric analysis of the nitro groups in numerous PAH:2,4,7-trinitrofluorenone complexes as a means to define the molecular weight of the PAH. All but one of the PAH:2,4,7-trinitrofluorenone complexes could be obtained from the PAH fraction of cigarette MSS. Of course, there were also methods developed for the in-house determination of specific PAHs, particularly B[a] P by Bell (239a) at Lorillard, Oakley and Stahr (2820a) at Philip Morris, and Walker (4110) and Stamey et al. (3787, 3789) at RJRT. These and many other in-house reports on PAHs demonstrate that the early PAH research was not limited to academic or governmental laboratories or to laboratories at private institutions such as the Sloan-Kettering Institute, American Health Foundation, or Roswell Park Memorial Institute. Many of the tobacco industry reports on PAHs listed above may now be accessed at the Internet addresses cited in the references. Additional PAHs, both tumorigenic and nontumorigenic, were subsequently identified in CSC but the level of B[a] P in CSC could account for very little (1056, 3310, 3311, 4354) or less than 2% of the observed skin-painting effect (4312, 4354), the contribution of all the known tumorigenic PAHs in CSC could account for not much more than 3% of the observed effect. These findings led to the proposal by Wynder and Wright (4354) that CSC contained a PAH that either possessed the same specific tumorigenicity as B[a]P but was present at about fifty times the B[a]P level or present in MSS was an unknown PAH that was “supercarcinogenic” compared to B[a]P, that is, its specific tumorigenicity to mouse skin was forty to fifty times that of B[a]P. After an eighteen-month search, Wright, a colleague of Wynder from the early to the late 1950s, concluded that neither type of PAH was present in CSC. Subsequently, the absence of a “supercarcinogen” in CSC was confirmed by the identification of hundreds of PAHs in the PAH fraction of CSC by Snook et al. (3756–3759). Detailed examination of their lists does not reveal the presence of a PAH structurally different from any of those previously classified with regard to their specific tumorigenicity on mouse-skin painting. No other CSC fraction possessed specific tumorigenicity to mouse-skin comparable to the PAH fraction. In the mid1950s, the tumorigenicity of the N-nitrosamines in CSC was not an issue, for several reasons: (1) the tumorigenicity of an N-nitrosamine was first defined in 1956 (2441a), (2) the presence of N-nitrosamines in MSS was not suggested until the early 1960s (422, 423, 1057), and (3) of the more than 300 N-nitrosamines tested for tumorigenicity, only one type not found in tobacco smoke—the N-nitrosoalkylureas—was

The Chemical Components of Tobacco and Tobacco Smoke

found to be tumorigenic to mouse skin [e.g., see Appendixes A–D in (2991)]. Consideration of all the tumorigenic PAHs and their levels in CSC could account for no more than 3% of the observed biological activity in mouse skin-painting studies. In 1961, Wynder and Hoffmann (4312) stated: The polynuclear aromatic hydrocarbons are mainly formed during the combustion of tobacco. The tobacco of our standard cigarettes contains only very minute quantities of benzo(a)pyrene [sic] (0.02 ppm). A bioassay indicates that these polycyclic hydrocarbons of the condensate by themselves, however, can account for not more than 3 per cent of the total biological activity.

In 1967, they reiterated their 1961 comment (4340): Without belaboring the point as to whether BaP as such contributes to the carcinogenicity of tobacco smoke condensate, we can certainly agree that the concentration of BaP may be regarded as an “indicator” of carcinogenic PAH in tobacco smoke condensate … While BaP and other carcinogenic PAH can by themselves account for only a small portion of the total tumorigenic activity of cigarette smoke condensate, probably less than 2%, they are, nevertheless, of obligatory importance as tumor initiators.

Hoffmann and Wynder (1800) reported that the major carcinogenicity of CSC resided in the CSC fraction containing the bulk of the PAHs. However, the levels in CSC of the nonalkylated carcinogenic PAHs could explain no more than 1% to 3% of the observed activity. They also reported that the artificial doubling and tripling of the levels of the seventeen known tumorigenic PAHs in CSC significantly increased the tumorigenicity of the CSC. However, their biological findings were contradicted by those of Roe (3310, 3311) and Lazar et al. (2320) who reported that increasing the level of B[a] P in CSC by a factor of ten or thirty, respectively, produced no increase in the specific carcinogenicity of the CSC. Roe (3310, 3311) also noted that the CSC level of B[a]P, despite its known tumorigenic potency, accounted for very little of the observed specific tumorigenicity of CSC to mouse skin. The opposite of these observations were the findings that potently tumorigenic PAHs such as DB[a,h]A on subcutaneous injection [Dobrovolskaia-Zavadskaia (1021)] and B[a]P on mouse skin painting [Poel et al. (2970a)] exhibited a threshold value. Wynder et al. (4303) reported that mice skin painted with the equivalent of the B[a]P content of the CSC from over 500 current cigarettes developed no carcinomas. Rabbits were found to be even more resistant to higher dose levels of B[a]P. Paralleling the research on the presence or absence of PAHs in cigarette MSS, their precursors in tobacco, their mechanism of formation, their contribution to laboratory animal tumorigenesis, and their possible involvement in the smoking-health issue was extensive research on ways to generate a “less hazardous” cigarette by removal of PAHs from or reduction of their per cigarette yields in MSS. To successfully resolve these questions, much pioneering research and development were initiated in late 1954 (3262). When the question of the presence of PAHs in MSS was resolved, with

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many PAHs identified, and their per cigarette MSS yields determined, much effort was expended to develop technologies to reduce their MSS yield, particularly the yields of those PAHs reported to be tumorigenic to CSC-painted mouse skin. In the early 1960s, a “less hazardous” cigarette was defined on the basis of three criteria [see p. iii in (1329); p. 372 in (4319); pp. 503, 531 in (4332)]: (1) the per cigarette yield of a specific toxicant has been lowered, (2) the ratio of the specific toxicant to MSS “tar” has been lowered, and (3) the specific tumorigenicity of the MSS “tar” as measured in the mouse skin-painting bioassay has been lowered. With the advent of meaningful tests for mutagenicity and genotoxicity, criterion (3) has been modified to include them. The tobacco industry and nonindustry scientists investigated many additional approaches in the attempt to design a “less hazardous” cigarette [see Table 5 in (3262), Table 14 in (3300)]. Two examples of technologies that appeared to be promising but presented other toxicant problems were the organic solventextraction of tobacco and the use of oxidative additives. The extraction concept was patterned after the findings of Roffo (3327) with one addition, the hexane extract of the tobacco was partitioned between hexane and aqueous ethanol to separate the flavorful compounds from those considered to be the PAH precursors, that is, the phytosterols, the aliphatic hydrocarbons, the long-chained terpenoids (116, 121, 3189). When the extracted tobacco was smoked in cigarette form, its CSC showed much lower PAH levels than the control tobacco CSC (3241, 3246, 4356) and reduced tumorigenicity (4356). The flavorful components, when returned to the extracted tobacco and smoked in cigarette form, contributed little to the total PAHs or B[a]P in the MSS [see Figure 1, Table 3, and accompanying text in (3262)]. The solvent extraction removed from the tobacco not only many of the PAH precursors but also much of several potent anticarcinogens to such tumorigens as B[a]P and DB[a,h]A, for example, long-chained aliphatic hydrocarbons, d-limonene, A-tocopherol, A- and B-1,5,9-trimethyl-12-(1-methylethyl)4,8,13-cyclodecatriene-1,3-diol [see Table 11 in (3300)]. Thus, because of their removal from the tobacco, the anticarcinogens obviously could not be transferred to MSS during smoking. Before some of the problems were discovered, the investigation of the benefits supposedly derived from the organic solvent-extraction of tobacco led to several patents on the technology (121, 2713, 2717, 3189). The earliest major non-tobacco industry proponents of the contribution of the extraction technology to a “less hazardous” cigarette eventually dismissed it with the comment that the technology was “impractical both technically and economically” (4311) and “of academic interest only” (4306d). Most of the findings on tobacco components that were, and tobacco components that were not, significant precursors of MSS PAHs in this early study were confirmed some years later by Severson et al. (3616). The problems arising from the organic solvent extraction included the increased levels of nitrate and the biopolymers cellulose, starch, and pectin in the solvent-extracted tobacco. These consequences increased the yields of nitric oxide, N-nitrosamines, and phenols (3277) in the MSS.

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Although nitrate addition reduced the per cigarette yields of FTC “tar,” MSS PAHs, phenols, and CSC tumorigenicity to mouse skin (1797), it was subsequently shown, as predicted (1798), to significantly increase the yields of MSS N-nitrosamines and nitrogen oxides (480). Thus, the recommendation to add nitrate to tobacco to reduce MSS PAHs was eventually replaced by the recommendation to use lownitrate tobacco in the cigarette blend and/or remove nitrate from the tobacco (480). This reversal of recommendations was paralleled by another concerning the level of longchained hydrocarbons such as n-hentriacontane in tobacco: Originally, it was proposed to reduce MSS PAHs by selection of tobaccos with low levels of such components or remove the PAH precursors by organic solvent extraction. This was replaced by a proposal to select tobaccos with high levels of such components (480). By the early 1960s, several cigarette design technologies developed by the tobacco industry and used in commercial products were categorized as significant in their contribution to the “less hazardous” cigarette (4310). Ultimately, the initial four design technologies (tobacco blend, effective and efficient filtration, reconstituted tobacco sheet (RTS), and air dilution via cigarette paper porosity) were increased to eight (tobacco blend, filter tip, filter tip additives, RTS, paper additives, expanded tobacco, air dilution [paper porosity], and air dilution [filter tip perforation]). Their significance was recognized in “less hazardous” cigarette design by the National Cancer Institute (NCI) (2683)* and the U.S. Surgeon General [see Table 6 in (3262), Table 15 in (3300), 3999, 4005, 4009, 4010]. It should be noted that the first two technologies considered significant were used before 1954. Tobacco or tobacco blend selection had been used since 1913, even before the first tumors were induced in a laboratory animal by skin painting with a solution of coal tar (4361). RTS was introduced into cigarette blends in 1953 when little was known about the chemical composition or biological properties of tobacco smoke (2170) or the effect of RTS inclusion in the blend on them. When knowledge of tumor induction with CSC and the presence of PAHs including B[a]P became available, it was shown that use of these two technologies resulted in a cigarette whose MSS was in compliance with that in the definition of a “less hazardous” cigarette (3300). Of course, the initial thrust of this across-the-board reduction was aimed at reducing the MSS “tar” delivery because of extrapolation by Wynder et al. (4351) of their 1957 mouseskin bioassay findings: Although it is difficult to estimate a comparable exposure level for man, the human data in line with the animal data indicate that a reduction in total tar exposure will be followed *

All eight cigarette design technologies eventually classified as significant by NCI, several U.S. Surgeon Generals, and other investigators on the basis of the 10-year NCI Smoking and Health Program on the “less hazardous” cigarette had been incorporated into one or more U.S. commercial cigarette products prior to the first meeting of the Tobacco Working Group formed in 1968 for the NCI program. In other words, from 1968 to 1978, no new design technology was generated in the NCI Smoking and Health Program on the “less hazardous” cigarette.

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by a decrease in tumor formation. For this reason, measures directed toward this reduction are of utmost importance … The minimum dose of tar capable of producing papillomas in mice is about one third, of producing cancer one half, that of the optimum dose …The practical implications of these data and their relationship to the human cancer problem have been emphasized.

In his 1957 testimony during the filter-tipped cigarette hearings, Wynder reiterated this opinion that reducing “tar” exposure dose by 40% to 50% would substantially reduce lung cancer induction in smokers (4296). Examination of the sales-weighted average “tar” delivery for U.S. commercial cigarettes reveals that the 40% to 50% reduction in MSS “tar” delivery considered vital by Wynder in 1957 was achieved in the late 1960s, that is, a reduction from 38 to 39 mg/cigarette to 19 to 20 mg/cigarette. Further examination reveals that by the early 1980s, the sales-weighted average “tar” was reduced to about 12 mg/cigarette, that is, an additional 40% reduction had been achieved [see Figure 3 in (3262)]. Corresponding reductions in the per cigarette yields of total PAHs in general, B[a]P in particular (4158), and nicotine were also observed. These reductions were also accompanied by a reduction in the specific tumorigenicity (mouse-skin painting) of the MSS CSC (4005). By year-end 1963, ninety-one of the ninety-seven PAHs identified in MSS were reported in the published literature. Six PAHs, identified in MSS by Rodgman and Cook (3273), had not been reported publicly at that time. However, by 1970, identification in MSS of all but one (cholanthrene) of the ninety-seven had been reported. Despite the availability of such information, only eighteen MSS PAHs were discussed by the Advisory Committee in its 1964 Report to the U.S. Surgeon General, thirteen as mainstream CSC components and five as carbon black components (3999). The detailed discussion of so few MSS PAHs and citation of so few publications were done despite the fact the committee had been provided with a detailed Philip Morris monograph on tobacco and smoke composition, a monograph that listed sixty-one PAHs identified in tobacco smoke plus many pertinent published references to them (2939, 3262). The Advisory Committee did note, however, that twenty-seven other nontumorigenic PAHs—none specifically named—had been identified in tobacco smoke. The twenty-seven unnamed PAHs had to include several of those PAHs, for example, naphthalene,

anthracene, phenanthrene, fluoranthene, pyrene, which had been reported to significantly inhibit the action of potently tumorigenic PAHs such as B[a]P and DB[a,h]A in laboratory animal studies. Of the ninety-seven PAHs known to him, Rodgman (3262) discussed the forty-four PAHs identified at RJRT plus thirty-four other PAHs reported in the literature in numerous reports between 1954 and 1964 and in a summary 1964 report on ten-year research on cigarette MSS (3251). Interestingly, Chapter 6, in the Advisory Committee’s report on cigarette smoke chemistry and the tumorigenic PAHs, was primarily authored by Fieser, one of the two eminent American PAH authorities at that time. For over half a century, numerous theories have been advanced in attempts to explain the relationship between the tumorigenicity of polycyclic aromatic hydrocarbons (PAHs) in treated laboratory animals and a variety of their structural properties, including such properties as their K-, L-, and bayregions, electron distribution, bond orders, bond strengths, resonance, octanol-water partitioning, and the like (Figure I.E-1). Such studies were triggered by the discovery that certain PAHs when administered to laboratory animals via skin painting or subcutaneous injection induced carcinomas or sarcomas, respectively. DB[a,h]A, synthesized independently by Clar (760) and Fieser and Dietz (1184) in 1929, was shown to be a potent tumorigen to laboratory animals by Kennaway and Hieger (2078). Shortly thereafter, Cook et al. (797) isolated several PAHs from coal tar, characterized one of them as the previously unknown benzo[a]pyrene (B[a]P), and demonstrated that it too was a potent tumorigen to laboratory animals (194). Over the next two decades, the first demonstrations of the carcinogenicity of two pure compounds, DB[a,h] A and B[a]P, led to the synthesis and subsequent testing for tumorigenicity in laboratory animals of literally hundreds of PAHs and their alkyl derivatives plus other derivatives. During this time, the variation in biological responses observed with laboratory animals to individual PAHs eventually led to numerous unacceptable extrapolations of the results to PAH-exposed humans. To put the laboratory animalto-human extrapolation in perspective, Shear and Leiter (3627) in 1941 issued a list of pertinent factors to be considered in such an extrapolation. Despite a diminution in PAH synthesis and tumorigenicity research during World War II, the wealth of experimental data available in the late 1940s to early 1950s on the high-to-slight tumorigenic potency of some PAHs and the nontumorigenicity of other PAHs

Bay region L region

K region

FIGURE I.E-1 The L region, K region, and bay region of benz[a]anthracene.

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induced investigators to seek reasons for the observed differences in tumorigenicity and to attempt to develop explanations for them. Among those involved in the generation of the major early theories on the relationship between PAH structural properties and PAH tumorigenicity or lack of it were Coulson (829), Pullman and Pullman (3003), Daudel and Daudel (906a), Fieser et al. (1180a), Fieser (1180b), and Lacassagne et al. (2247a). Much meaningful input to these theories was provided by other investigators such as Pauling (2910a) in the United States, Boyland, Weigert, and Mottram (423a) in the United Kingdom, and Buu-Hoï in France [see more than thirty Buu-Hoï references listed in (2247a)]. More recent studies include those by Herndon et al. (1623a, 2435a), Rubin (3365), Trosko (3966a), L. Zhang et al. (4410c), and Y. Zhang, a graduate student under Herndon (4410d). Because it was issued at the beginning of the extensive research on the composition of tobacco smoke with particular emphasis on the nature and levels of the PAHs in it, it is interesting to examine the lengthy 1955 review by Pullman and Pullman (3003) on the relationship between electronic structure and the tumorigenicity of a number of benzenoid hydrocarbons. Their publication was a detailed update of the 1953 review by Coulson (829) and included much data generated in the interim. The Pullmans used calculations based on three theoretical indexes of the K and L regions of the aromatic hydrocarbons. The indexes included carbon localization energy (CLE), bond localization energy (BLE), and para localization energy (PLE) [see Table 1 in (3003)]. The Pullmans (3003), by use of their CLE, BLE, and PLE calculations pertinent to the K and L regions in the PAHs, also attempted to relate the structures of various PAHs and their alkylated derivatives not only to their tumorigenicity but also to their rate of reaction in certain well-known reactions, for example, the Diels-Alder reaction with maleic anhydride, reaction with osmium tetroxide, reaction with lead tetraacetate, and photooxidation. Table I.E-2 lists the hydrocarbons discussed by the Pullmans in 1955 with an indication of those, thirty-four in all, that were identified in tobacco smoke before and after 1955. The Pullmans did introduce into their discussion various PAH metabolites, their diols and phenols, but not the epoxides which were unknown at that time. Even though it had been known since 1951 (3814), no explanation was offered for the inhibition of the activity of a potently tumorigenic PAH by co-administration of a weakly tumorigenic or nontumorigenic PAH. Lastly, of course, neither the Pullmans nor Coulson discussed the fact that a bioassay finding with a highly susceptible strain or species of laboratory animal administered an individual PAH in an excessive dose has little relationship to the situation where a human is exposed by a different administration route to a mixture of PAHs with various degrees of tumorigenicity plus other known antitumorigenic compounds. By year-end 1955, very few of the PAHs considered by the Pullmans had been reported as tobacco smoke components. More had been identified in other sources such as air pollution. In the following discussion, the comments in the early

61

1950s about the inadequacy of the evidence indicating the presence of B[a]P in tobacco smoke (1181) are disregarded. Table I.E-3 lists the PAHs reported in tobacco smoke at that time. Of the fourteen PAHs reported, only eight were included by the Pullmans in their assessment: naphthalene, anthracene, phenanthrene, B[a]A, B[a]P, B[e]P, dibenzo[def,mno] chrysene, and pyrene. Of course, only one of the eight, B[a]P, was considered at that time a significant and potent tumorigen to mouse skin. At that time, the tumorigenicity of B[a]A was questioned, and still was questioned in the mid-1980s (983). As noted previously, Pullman and Pullman not only updated the electronic structure-tumorigenicity information generated after the Coulson 1953 review but also attempted to extend the theory to alkyl-PAHs. Examination of their review reveals that they discussed, in addition to 1,2-dihydro3-methylbenz[j]aceanthrylene, a total of twelve alkyl-PAHs (see Table I.E-3). It is obvious from their discussion that the prediction of tumorigenicity for most of these twelve PAHs was not calculated but derived from published biological data. However, examination of the biological data in Hartwell (1543, 1544) and Shubik and Hartwell (3664, 3665) indicates that at least sixty-four totally benzenoid alkyl-PAHs had been tested for tumorigenicity by 1955. Several 1,2-dihydromethylbenz[j] aceanthrylenes had been tested for tumorigenicity by 1955, but they were not included in our count of sixty-four. This raises the question: Why was the prediction not calculated for more of the sixty-four alkyl-PAHs, the tumorigenicity of which was known at that time (1543, 1544, 3664, 3665)? Pullman and Pullman noted: “It must be acknowledged that the extension of the theory to substituted derivatives of polycyclic hydrocarbons is at present far from having achieved a completely consistent and satisfactory form.” Many of the more recent theories on the relationship between PAH structural properties and tumorigenicity suffer somewhat from this and other deficiencies [see Herndon et al. (1623a, 2435a), Rubin (3365), Trosko (3966a), L. Zhang et al. (4410c), and Y. Zhang (4410d)]. Much studied in recent years has been the application of the quantitative structure-activity relationship (QSAR) method to PAHs. Although many theories have involved the relationships between observed laboratory-derived biological data on individually administered PAHs and their structural elements, do they speak to the exposure situation experienced by humans? Whether the exposure is by inhalation of air pollutants or tobacco smoke, by ingestion of foodstuffs or beverages, by dermal contact, or by a combination of the exposures, very few of any human exposures involve exposure to a single PAH similar to the exposure of laboratory animals treated with a single PAH by skin painting or subcutaneous injection. One such example of human exposure to a single PAH was the past use of naphthalene as the major ingredient in mothballs. Numerous PAHs have been either completely of partially characterized in many air pollutants, foodstuffs, beverages, and contact tars and dusts. Of all the products to which humans are exposed, none has been characterized to the extent of tobacco smoke. Over 5200 components have been identified in it, nearly twice as many as in the next consumer

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TABLE I.E-2 Benzenoid Hydrocarbons Discussed by Pullman and Pullman (3003) Aromatic Hydrocarbon Discussed

CAS No.

No. in Pullman and Pullman (3003)

Considered Tumorigenica in 1955

Monocyclic Benzeneb

71-43-2

I

no

Bicyclic Naphthalene

91-20-3

II

no

Tricyclic Anthracene Phenanthrene

120-12-7 85-01-8

III IV

no no

Tetracyclic Naphthacene Benz[a]anthracene Benz[a]anthracene, 2,10-dimethylBenz[a]anthracene, 7,12-dimethylBenz[a]anthracene, 7-methylBenzo[c]phenanthrene Benzo[c]phenanthrene, 1,2-dimethylChrysene Chrysene, 2,3-dimethyl- c Triphenylene Pyrene

92-24-0 56-55-3 — 57-97-6 2541-69-7 195-19-7 — 218-01-9 — 217-59-4 129-00-0

VII VI XLIII XLII XLIV V XLVIII VIII XLIX X IX

no ? ? yes yes yes no ? no no no

Pentacyclic Benzo[b]chrysene Benzo[c]chrysene Benzo[g]chrysene Pentacene Benzo[a]naphthacene Dibenz[a,h]anthracene Dibenz[a,j]anthracene Pentaphene Perylene Picene Benzo[b]triphenylene Benzo[a]pyrene Benzo[a]pyrene, 2-methyl- d Benzo[a]pyrene, 3-methylBenzo[a]pyrene, 5-methylBenzo[a]pyrene, 6-methylBenzo[a]pyrene, 7-methylBenzo[a]pyrene, 8-methylBenzo[a]pyrene, 9-methylBenzo[e]pyrene Dibenzo[b,g]phenanthrene Dibenzo[c,g]phenanthrene Benz[j]aceanthrylene, 1,2-dihydro-3-methyl- e

214-17-5 194-69-4 196-78-1 135-48-8 226-88-0 53-70-3 224-41-9 222-93-5 198-55-0 213-46-7 215-58-7 50-32-8 — — — 2381-39-7 63041-77-0 63041-76-9 — 192-97-2 195-06-2 188-52-3 56-49-5

XXIII XIII XIV XVIII XVII XII XV XIX XXV XXI XX XI XLVII XLVII XLVII XLVII XLVII XLVII XLVII XVI XXIV XXII XLV

no yes yes no no yes yes no no no no yes yes yes yes yes yes no no no no no yes

195-00-6 222-54-8 189-55-9 189-96-8 189-64-0 217-54-9 196-28-1 191-26-4 191-30-0

XXXV XXXVII LIV LVII XXVII XXXVI LVI XXXI XXVI

no no (yes) f no yes no no no yes

Hexacyclic Anthra[1,2-a]anthracene Benzo[c]pentaphene Benzo[rst]pentaphene Benzo[pqr]picene Dibenzo[b,def]chrysene Dibenzo[b,k]chrysene Dibenzo[c,mno]chrysene Dibenzo[def,mno]chrysene Dibenzo[def,p]chrysene

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63

TABLE I.E-2 (CONTINUED) Benzenoid Hydrocarbons Discussed by Pullman and Pullman (3003) Aromatic Hydrocarbon Discussed

CAS No.

No. in Pullman and Pullman (3003)

Considered Tumorigenic a in 1955

Dibenzo[a,j]naphthacene Dibenzo[a,l]naphthacene Dibenzo[fg,op]naphthacene Naphtho[1,2,3,4-def]chrysene Naphtho[2,1,8-qra]naphthacene Naphtho[1,2-b]triphenylene

227-04-3 226-86-8 192-51-8 192-65-4 196-42-9 215-26-9

XXXIII XXXIV XXIX XXVIII XXX XXXII

no no no ? no no

Heptacyclic Benzo[a]naphtho[8,1,2-lmn]naphthacene Dibenzo[fg,qr]pentacene

190-01-2 197-74-0

LV XL

no no

Octacyclic Dinaphtho[1,2-b:1,2-k]chrysene Naphthaceno[2,1,12,11-opqra]naphthacene Phenanthro[1,10,9,8-opqra]perylene

214-13-1 188-42-1 190-39-6

XXXIX LVIII XLI

no ?g no

Nonacyclic Dinaphtho[1,2-b:1,2-n] perylene

—

XXXVIII

no

Decacyclic Pentacenopentacene

—

LIX

?g

a

Tumorigenic in mouse skin-painting study. Benzene was reported as a component of the vapor phase of tobacco smoke in 1955 by Resnik and Holmes (3106) and Laurene (2293). c A dimethylchrysene was subsequently reported in tobacco smoke, but the positions of the methyl groups were not defined. d At least two methyl B[a]Ps were subsequently reported in tobacco smoke, but the position of the methyl group in each case was not defined. e This PAH is not totally benzenoid; its structure includes a cyclopentanoid ring.. f In 1955, the tumorigenicity of benzo[rst]pentaphene had not been determined; later it was reported to be tumorigenic. g Although no calculation was made on this PAH, Pullman and Pullman (3003) predicted it would be tumorigenic. b

TABLE I.E-3 Polycyclic Hydrocarbons Reported in Tobacco Smoke by Year-End 1955 References Issued in the Year Hydrocarbon Acenaphthylenea Azulenea, b Anthracene Anthracene, 2-methylBenz[a]anthracene Benzo[ghi]perylene Benzo[a]pyrene Benzo[e]pyrene Dibenzo[def,mno]chrysene Fluoranthene a Naphthalene Naphthalene, 2-methylPhenanthrene Pyrene

1947

1953

1954

1955

818

819, 821

818

785, 819

820, 2365 2365 820, 2352, 2365, 3578 820 2352, 2425, 2426 820, 2365, 2425, 2426 55–57, 593, 1172, 2011, 2365, 3578, 4353 2352 820, 2365 820, 2365 3578 820 820, 2365 820, 2352, 2365, 2425, 2426

1857

819 785, 819, 821, 2335 819 819

818

819 785, 819

a

Molecule has a cyclopentanoid ring, thus it was not considered by Pullman and Pullman (3003).

b

Molecule does not possess a benzenoid structure.

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product, coffee, subjected to detailed compositional analysis. Of the identified tobacco smoke components, about 11% were either completely or partially identified as PAHs. It should also be noted that in the detailed examination of tobacco smoke, the over 5200 identified components account for over 98% of the weight of cigarette MSS. It has been estimated, based on detailed gas chromatograms, that the number of actual components in cigarette MSS may be twelve to twenty times the number of identified ones (4103). Of the more than 500 PAHs either completely or partially identified in cigarette MSS, relatively few PAHs, originally thirteen in all, were repeatedly defined as significant tumorigens (1727, 1808, 1871). Eventually, the International Agency for Research on Cancer (IARC) redefined the tumorigenicity of chrysene. Thus, it was deleted from all subsequent lists (1740, 1741, 1743, 1744, 2825) except one (1217). MSS is not the only source of most of the twelve PAHs still considered as significant tumorigens in cigarette MSS. Except for 5-methylchrysene, most have also been identified as significant PAH components of gasoline and diesel engine exhaust gases (1406a, 4315) and many common foodstuffs and beverages (1345, 2438). When one is dealing with a complex mixture, which in turn contains an assortment of PAHs ranging from bicyclic to decacyclic, one cannot extrapolate the biological effect observed by administration of an individual PAH to the biological effect of that PAH in such a complex mixture. It has long been known from laboratory studies that certain nontumorigenic or slightly tumorigenic PAHs when administered by skin painting or subcutaneous injection in an equimolar dose level with a highly tumorigenic PAH partially or totally inhibit its tumorigenicity. Few studies have been done to determine the effect of a non- or low-tumorigenic PAH on the tumorigenicity of a highly tumorigenic PAH when its level greatly exceeds that of the potent tumorigen. Also, there are differences in the classification of the potency of the tumorigenicity of some PAHs. For example, B[a]A is classified by some as a potent or significant tumorigen (1871) but by others as only slightly tumorigenic (983). The list of either totally or partially identified PAHs in CSC gradually increased but in the mid-1970s the massive definitive PAH study by United States Department of Agriculture (USDA) personnel in Athens, Georgia, increased the number of known PAHs in CSC to well over 500 (3732, 3756–3759). Although not isolated individually, their identifications, whether total or partial, have generally been accepted across the board. Numerous authors, including Hoffmann and Hecht (1727), listed the PAH dibenzo[a,l]pyrene as a significant tumorigen in tobacco smoke. However, Hecht eventually stated (1557) that “the presence in cigarette smoke of dibenzo[a,l]pyrene, a highly carcinogenic PAH, had not been confirmed.” One should weigh the comment by Hecht against the current status of defined MSS composition. Since the appreciable decline in detailed tobacco smoke composition studies after the late 1970s, no individual investigator or no research group has reported the confirmation of the identities of

The Chemical Components of Tobacco and Tobacco Smoke

many of the PAHs (3756-3759), aza-arenes (3750, cf. 3414), nitrogen-containing components (1587), or ether- (2769) and water-soluble components (3553) reported in cigarette MSS in the 1970s. While many components have been confirmed by other investigators at the same institution as the authors, examination of the post-1980 literature indicates that the identities of nearly half the new components described in the above-mentioned studies have not been confirmed by investigators at other institutions. Because of such a situation, would Hecht also discount their presence in cigarette MSS in the same way as he discounted the presence of dibenzo[a,l]pyrene? Although most of the past theories have attempted to define the relationship between structural properties of the PAHs and their specific tumorigenicity as measured individually in skin-painting studies, little has been done to explain the behavior of a PAH when it is present in a complex mixture that includes a host of PAHs some of which are known antitumorigens as well as numerous known non-PAH antitumorigens (1174). It has been known for over sixty years that co-administration of a potently tumorigenic PAH with an equimolar quantity of a nontumorigenic PAH often results in substantial reduction in percent tumor bearing animals (%TBA). In 1953, Coulson noted [see p. 51 in (829)]: The action of inhibitors may be thought of as a competition between the carcinogenic and noncarcinogenic compounds for available sites on the enzyme. If sufficient noncarcinogenic molecules are able to occupy suitable sites, then the irreversible mutation cannot occur. We can see that inhibitors, in order to compete with the carcinogenic compounds, should themselves possess a K-region.

Some of the PAHs that substantially reduce or totally inhibit the tumorigenicity of several of the most potent tumorigens known are listed in Table I.E-4. Obviously, neither naphthalene nor anthracene has a K-region, a requirement proposed by Coulson for the inhibitory property. Although many of the inhibition studies were conducted with the tumorigenic and inhibiting PAHs administered in equimolar quantities, it should be remembered that this is not the case in the PAH mixture in CSC. Table I.E-5 is derived from CSC PAH data presented by Hoffmann and Wynder (1788, 1798) and Rodgman (3273). The per cigarette yield data in Table I.E-5 were the averages of the data generated from two different commercial American cigarettes. One was unfiltered and yielded 36.8 mg/cigarette of total particulate matter (TPM) (1788); the other was a filtered cigarette that yielded 37.5 mg/cigarette of TPM (3273). The disparity between the relative yields in each category was less than 5%. In the early structure-biological activity studies, PAHs with a pentacyclic ring were not included in the discussion of most theories but pentacyclic compounds in which the pentacycle contained nitrogen were, that is, benzacridines (829, 2247a). In the discussion of his theory, Coulson (829) did mention several cyclopentanoid compounds: six benzacridines and

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TABLE I.E-4 Inhibition of Tumorigenicity of Potently Tumorigenic PAHs by Non-Tumorigenic or Weakly Tumorigenic PAHs PAH a

CAS No.

Effective Against

References

Naphthalene Anthracene Phenanthrene Fluoranthene Pyrene Benz[a]anthracene Benzo[e]pyrene Benzo[b]triphenylene

91-20-3 120-12-7 85-01-8 206-44-0 129-00-0 56-55-3 192-97-2 215-58-7

B[a]P, DB[a,h]A B[a]P, DB[a,h]A DMB[a]A B[a]P, DMB[a]A DB[a,h]A, DMB[a]A B[a]P, DB[a,h]A B[a]P, DB[a,h]A, DMB[a]A MC b, DB[a,h]A, DMB[a]A

844 844 976, 3685 976, 3685, 3686 976, 3685, 3686 426, 4332 976, 3685, 3686 976, 3683, 3686

a

Each PAH listed is a component of cigarette MSS.

b

MC = 3-methylcholanthrene = 1,2-dihydro-3-methylbenz[j]aceanthrylene.

two PAHs, 2,3-dihydro-1H-benzo[a]cyclopent[h]anthracene and 10,11-dihydro-9H-benzo[a]cyclopent[i]anthracene. In her 1996 thesis, Zhang (4410d) noted the numerous sources of PAHs to which humans are exposed, for example, air pollutants, foodstuffs and beverages, effluents from factories, vehicles, and heat and power sources. Zhang particularly stressed tobacco smoke, its complexity, and some of the PAHs contained therein: Tobacco smoke is a complex mixture which is estimated to contain at least 150 compounds in the gas phase and more than 2000 compounds have been identified in the particulate phase. Table 1a lists some PAHs that exist in the particulate phase of cigarette smoke.

In her Table 1, Zhang (4410d) listed nineteen MSS PAHs reported in 1978 by Hoffmann et al. (1781). Unfortunately, the inconsistent use of PAH nomenclature sometimes makes it difficult to follow the phases of the study by Zhang [see Table 7 and Appendix A in (4410d)]. Another study, initiated by Martin et al. (2479), involved an attempt to develop a meaningful relationship between PAH structure, chemical properties, and biological properties, specifically the effect of PAHs on specific tumorigenicity in skin painting. Reported for naphthalene- and pyrene-related PAHs were the following molecular parameters: the measured and calculated log of the octanol-water partition coefficient (MlogP, ClogP), molecular volume (MgVol), calculated

TABLE I.E-5 Levels of PAH Classes in Cigarette Mainstream Smoke Mainstream Smoke Yielda PAH Category Bicyclic Tricyclic Tetracyclic Pentacyclic B[a]P Non-B[a]P pentacyclic Hexacyclic TOTALS

Assumed Approximate mol. wt.

Yield ng/cig

128b 178c 228 278 252 278 328

4140 (77.1)d 720 (13.4) 420 (7.9) 72 (1.3) 27 (0.49)f 45 (0.81)f 14 (0.3)

Approximate Nanomoles e 32.3 4.0 1.8 0.26 0.11 0.16 0.04

Nanomolar Ratio, PAH:B[a]P 293 36 16 2.4 1.0 1.5 0.36

5366 (100.0)

a

Data reported by Hoffmann and Wynder (1788, 1798) from a nonfiltered cigarette, total particulate matter = 36.8 mg/cig, were averaged with data reported by Rodgman and Cook (3273) for a filtered commercial cigarette, total particulate matter = 37.5 mg/cig.

b

The molecular weight of naphthalene = 128, that of indene = 116. It is realized that the average molecular weight of the bicyclic PAH mixture will differ slightly from those of the parent PAH because of the presence of numerous homologs (methylnaphthalenes, dimethylnaphthalenes, etc.).

c

The presence of tricyclic PAH homologs results in molecular weight slightly different from 178.

d

Values in parentheses represent the fraction % of the PAH category in the total PAH fraction.

e

Nanomoles calculated with the approximate molecular weights in Column 2.

f

The sum of the fraction % of B[a]P and the fraction % of non-B[a]P pentacyclic PAHs equals 1.3%.

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molar refractivity (CMR), and the number of valence electrons (NVE). The second phase of the study involved similar data for anthracenes, phenanthrenes, and indenes (3300a). All PAHs in the first two phases of this study (2479, 3300a) are reported components of cigarette MSS. The ultimate goal is to use these data to facilitate a QSAR on MSS PAHs. If such a meaningful relationship can be derived for the more than 500 MSS PAHs, then it probably can be applied to any PAH from any source. As a prelude to this attempt to develop a possibly reasonable explanation for the PAH structure-tumorigenicity relationship, the PAHs completely or partially identified in cigarette smoke have been cataloged. For each PAH, the nomenclature used in Tables I.E-1, I.E-4, and I.E-5 is the most recent proposed by the International Union of Pure and Applied Chemistry (IUPAC). The tobacco smoke PAH references cited in Table I.E-6 are not necessarily all that are available, particularly for those PAHs such as B[a]P and DB[a,h]A that have been the subject of much research and discussion for over half a century. In most cases, included is a reference to the publication or presentation by the investigator(s) who first reported a particular PAH in MSS. References of articles and/or presentations on specific PAHs that contained evidence later criticized are included plus references to the misinterpretations or errors. The criticism by Fieser (1181) in 1957 of the shortcomings of the evidence (55–57, 592-594, 820) supposedly indicating the presence of B[a]P in cigarette smoke has already been mentioned. Two other notable situations involved 1,2-dihydrobenz[j] aceanthrylene (cholanthrene) and dibenzo[def,p]chrysene (formerly named dibenzo[a,l]pyrene, initially 1,2,3,4-dibenzopyrene). These two PAH identifications, based solely on UV spectral data, were found to be incorrect. In their study, Rodgman and Cook (3273) incorrectly defined a PAH as 1,2dihydrobenz[j]aceanthrylene (cholanthrene). In the massive study by USDA personnel on the identification of MSS PAHs, 1,2-dihydrobenz[j]aceanthrylene was not among the several benzocyclopentanthracenes reported (3756, 3759). The other incorrectly characterized PAH was dibenzo[def,p]chrysene. For its identification, not only Rodgman and Cook (3273) but also Bonnet and Neukomm (397), Lyons and Johnson (2430), Lyons (2427), Wynder and Wright (4354), and Pyriki (3033) relied on published UV spectral data purportedly those of synthetic dibenzo[def,p]chrysene (dibenzo[a,l]pyrene). However, in 1966, Lavit-Lamy and Buu-Hoï (2314) determined that the published UV spectral data were not those of dibenzo[a,l] pyrene but of the isomeric dibenz[a,e]aceanthrylene (dibenzo[a,e]fluoranthene), generated during the supposed synthesis of dibenzo[a,l]pyrene. The authentic dibenzo[def,p] chrysene (dibenzo[a,l]pyrene) was identified in MSS in 1977 (3756), but its MSS level has never been reported. Some authorities insist that the B[a]P and 4-(methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK) in cigarette smoke are the major causes of lung cancer in cigarette smokers [Hecht (1557), Hecht and Hoffmann (1571a), Hoffmann and Hecht (1727), the World Health Organization (4279a)] despite the following:

The Chemical Components of Tobacco and Tobacco Smoke

1. Neither B[a]P nor any other PAH in CSC either individually or in combination with the other PAHs in CSC can explain more than a few percent of the biological response observed in skin painting with CSC [Druckrey (1056), Roe (3310, 3311), Wright and Wynder (4283), Wynder (4296), Wynder and Hoffmann (4307, 4312, 4343, 4343a, 4354)]. 2. Neither B[a]P nor any other PAH in CSC either individually or in combination with the other PAHs and assorted promoters (phenols) in CSC can explain more than a few percent of the biological response observed in skin painting with CSC (4332). 3. In general, the N-nitrosamines in CSC are not tumorigenic to mouse skin but are organ-specific tumorigens [Preussmann and Stewart (2991),*] a point stressed in numerous reviews issued between the mid-1960s and the late 1990s on N-nitrosamines [Rodgman (3256)] and recognized by Hoffmann and Hecht [see p. 75 in (1727)]. 4. NNK has never been shown to induce lung cancer in a laboratory animal by inhalation (1727). While the minor contribution of B[a]P to the tumorigenicity of CSC to mouse skin has been recognized since the mid-1950s (4353, 4354), its presence in CSC has elicited continued interest since that time. Examination of the references to various smoke components reveals an interesting fact about B[a]P: When all the cigarette smoke components are tabulated with regard to similar selection of references across the board, very few tobacco smoke components exceed B[a] P in the number of pertinent references available. Obviously, the smoke component discussed most in publications and presentations between the mid-1950s and 2005 was nicotine. Next was acetaldehyde, followed by B[a]P. Another interesting fact about B[a]P is that, despite its minimal contribution to mouse-skin tumorigenicity from CSC, almost every year since the mid-1950s there has been at least one publication on a new and/or improved method to quantitate the yield of B[a]P in MSS [see Table 6 in (3306b)]. In 2004, CORESTA published its recommended method for the determination of B[a]P in tobacco smoke (825a). Much emphasis has been placed on the determination of B[a]P in the MSS from fewer and fewer cigarettes. Before the advent of all the newly introduced and subsequently improved spectral and chromatographic systems, estimations of individual PAHs required the CSC from many cigarettes. For example, in their studies on the effect of various treatments of tobacco on the PAHs in MSS, Rodgman and Cook (3241, 3246, 3269, 3274, 3275) chemically analyzed the MSS from 3600 cigarettes for each control and treated sample. For the MSS PAH *

Subsequent to the publication of the Preussmann and Stewart review (2991), Deutsch-Wenzel et al. (956a) reported that in a skin-painting study with N’-nitrosonornicotine (NNN), tumors were initiated at the site of application. The specific tumorigenic potency of NNN was estimated to be only 0.8% of that of B[a]P. However, no dose response relationship was observed with NNN over a treatment range of 12.5 to 200 μg.

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TABLE I.E-6 Polycyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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analyses in the fifty treated and control samples described in (3246), more than 183000 cigarettes were smoked, the condensate collected, and processed. Nowadays, only a few cigarettes are needed for similar analyses. To permit comparison of the chemical data with the biological findings of Wynder et al. (4306a), the smoking procedure used by them was initially duplicated in the Rodgman-Cook studies in the 1950s, that is, the cigarettes on a manifold were machine smoked (35-ml puff volume, 2-sec puff duration, 3 puffs/min) with a collection system that duplicated the one described by Wynder et al. (4306a). This smoking regime differed from the usual 35-ml puff volume, 2-sec puff duration, 1 puff/min described by Bradford et al. (423b) in 1936 and used by most investigators in smoke studies after that date. Table I.E-7 summarizes the PAHs identified in CSC that were included in earlier descriptions of proposed structuretumorigenicity theories. Examination of Table I.E-7 indicates that most of the PAHs considered in the various theoretical systems designed to establish a relationship between molecular structure and tumorigenicity are totally benzenoid. Only a few PAHs with a combined benzenoid-cyclopentanoid structure were included in the early studies. Lacassagne et al. (2247a) in their discourse on structure-tumorigenicity relationship mentioned a few benzenoid PAHs but their major emphasis was on the structure-tumorigenicity relationship of

numerous angular benzacridines. While the number of azaarenes, including the benzacridines, in CSC is less than the number of PAHs, nearly 200 have been identified, many by the USDA group at Athens, Georgia (3750). With the knowledge that CSC contains nontumorigenic PAHs that have been shown to substantially reduce the tumorigenicity of several potently tumorigenic PAHs, consideration of the study of Lacassagne et al. raises several interesting questions with regard to tobacco smoke composition. (1) Do any of the benzacridines or other aza-arenes in CSC partially or totally inhibit the tumorigenicity of the tumorigenic benzacridines or other aza-arenes? (2) Do any of the benzacridines inhibit the tumorigenicity of tumorigenic PAHs? (3) Do any of the PAHs reduce the tumorigenicity of the tumorigenic aza-arenes? The mixture known as CSC is so complex that it is not possible to ascribe its biological activity to any individual component because of the known behavior of that component when administered individually.

I.F SUMMARY Detailed examination of the lists presented in the five sections on hydrocarbons indicates that over 1200 hydrocarbons have been identified to date in tobacco and tobacco smoke. The data are summarized in Table I.E-8.

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PAH Discussed Acenaphthylene Acenaphthylene, 1,2-dihydroAnthracene Anthracene, dimethyl- a Anthracene, 9,10dimethylAnthracene, 1-methylAnthracene, 2-methylAnthracene, 9-methylAnthracene, trimethylAzulene Benz[a]aceanthrylene Benz[j]aceanthrylene, 1,2-dihydroBenz[j]aceanthrylene, 1,2-dihydro-3-methylBenz[e]acephenanthrylene Benz[e]acephenanthrylene, methylBenz[a]anthracene Benz[a]anthracene, dimethyl- a Benz[a]anthracene, 7,12-dimethylBenz[a]anthracene, ethylBenz[a]anthracene, 1-methylBenz[a]anthracene, 2-methylBenz[a]anthracene, 3-methylBenz[a]anthracene, 4-methylBenz[a]anthracene, 5-methylBenz[a]anthracene, 6-methyl-

Coulson (829)

Fieser et al. (1180a)

Herndon (1623a, 2435a)

Lacassagne et al. (2247a)

Martin et al. (2479)

PullmanPullman (3003)

Rubin (3365)

Trosko-Upham (3966a)

Zhang et al. (4410c)

Y. Zhang (4410d)

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TABLE I.E-7 Tobacco Smoke PAHs Discussed in Various Publications on the Relationship Between PAH Structure and Tumorigenicity

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TABLE I.E-7 (CONTINUED) Tobacco Smoke PAHs Discussed in Various Publications on the Relationship Between PAH Structure and Tumorigenicity

PAH Discussed

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Herndon (1623a, 2435a)

Lacassagne et al. (2247a)

Martin et al. (2479)

PullmanPullman (3003)

Rubin (3365)

Trosko-Upham (3966a)

Zhang et al. (4410c)

Y. Zhang (4410d)

X

—

—

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Benz[a]anthracene, 8-methylBenz[a]anthracene, 9-methylBenz[a]anthracene, 10-methylBenz[a]anthracene, 12-methylBenz[a]anthracene, propylBenz[a]anthracene, tetramethylBenz[a]anthracene, trimethylBenzo[b]chrysene 1H-Benzo[a]cyclopent[h] anthracene, 2,3-dihydro9H-Benzo[a]cyclopent[i] anthracene, 10,11dihydroBenzo[ghi]fluoranthene Benzo[ghi]fluoranthene, 2-methylBenzo[ghi]fluoranthene, 3-methylBenzo[j]fluoranthene Benzo[k]fluoranthene Benzo[k]fluoranthene, methyl7H-Benzo[c]fluorene Benzo[a]naphthacene Benzo[rst]pentaphene Benzoperylene Benzo[ghi]perylene Benzo[c]phenanthrene Benzo[c]phenanthrene, methylBenzopyrene d Benzo[a]pyrene

Coulson (829)

Fieser et al. (1180a)

13H-Dibenzo[a,i]fluorene Dibenzo[a,j]naphthacene Dibenzo[de,qr] naphthacene Dibenzo[fg,op] naphthacene Dibenzopyrene Fluoranthene Fluoranthene, 2-methylFluoranthene, 3-methyl-

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Benzo[a]pyrene, 7,8-dihydroBenzo[a]pyrene, dimethyl- a Benzo[a]pyrene, methyl- b 3H-Benzo[cd]pyrene, 4,5-dihydroBenzo[e]pyrene Benzo[e]pyrene, dimethylBenzo[e]pyrene, methylBenzo[e]pyrene, trimethylBenzo[b]triphenylene 1,1’-Binaphthalene 1,1’-Binaphthalene, methylChrysene Chrysene, dimethyl- a Chrysene, 1-methylChrysene, 2-methylChrysene, 3-methylChrysene, 4-methylChrysene, 5-methylChrysene, 6-methylCoronene 4H-Cyclopenta[def] chrysene Cyclopenta[cd]pyrene Dibenz[a,e]aceanthrylene Dibenz[a,h]anthracene Dibenz[a,j]anthracene Dibenzo[b,def]chrysene Dibenzo[def,mno]chrysene Dibenzo[def,p]chrysene

106

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TABLE I.E-7 (CONTINUED) Tobacco Smoke PAHs Discussed in Various Publications on the Relationship Between PAH Structure and Tumorigenicity

PAH Discussed

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© 2009 by Taylor & Francis Group, LLC

Herndon (1623a, 2435a)

Lacassagne et al. (2247a)

Martin et al. (2479)

PullmanPullman (3003)

Rubin (3365)

Trosko-Upham (3966a)

Zhang et al. (4410c)

Y. Zhang (4410d)

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The Chemical Components of Tobacco and Tobacco Smoke

Fluoranthene, 7-methylFluoranthene, 8-methyl9H-Fluorene Indeno[1,2,3-cd]pyrene Indeno[1,2,3-cd]pyrene, dimethylIndeno[1,2,3-cd]pyrene, methylNaphthacene Naphthalene Naphthalene, dihydroNaphthalene, dihydromethylNaphthalene, 1,2-dihydro3-methylNaphthalene, 1,2-dihydro1,1,6-trimethylNaphthalene, 1,2-dihydro1,5,8-trimethylNaphthalene, dimethylNaphthalene, 1,2-dimethylNaphthalene, 1,3-dimethylNaphthalene, 1,4-dimethylNaphthalene, 1,5-dimethylNaphthalene, 1,6-dimethylNaphthalene, 1,7-dimethylNaphthalene, 1,8-dimethylNaphthalene, 2,3-dimethylNaphthalene, 2,6-dimethyl-

Coulson (829)

Fieser et al. (1180a)

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(Continued)

The Hydrocarbons

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Naphthalene, 2,7-dimethylNaphthalene, dimethyl2-ethenylNaphthalene, dimethylethylNaphthalene, dimethyl2-phenylNaphthalene, dimethyl1,2,3,4-tetrahydroNaphthalene, 1-ethenylNaphthalene, 2-ethenylNaphthalene, 2-ethenylmethylNaphthalene, 1-ethylNaphthalene, 2-ethylNaphthalene, ethylmethylNaphthalene, 1-ethyl3-methylNaphthalene, 1-ethyl7-methylNaphthalene, 1-ethyl8-methylNaphthalene, 2-ethyl3-methylNaphthalene, 2-ethyl6-methylNaphthalene, 2-ethyl7-methylNaphthalene, hexamethylNaphthalene, methylNaphthalene, 1-methylNaphthalene, 2-methylNaphthalene, (1-methylethyl)Naphthalene, methylphenylNaphthalene, methyl2-phenylNaphthalene, 1-(1methylpropyl)Naphthalene, methyl1,2,3,4-tetrahydroNaphthalene, 2-methyl1,2,3,4-tetrahydro-

108

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TABLE I.E-7 (CONTINUED) Tobacco Smoke PAHs Discussed in Various Publications on the Relationship Between PAH Structure and Tumorigenicity

PAH Discussed

© 2009 by Taylor & Francis Group, LLC

Herndon (1623a, 2435a)

Lacassagne et al. (2247a)

Martin et al. (2479)

PullmanPullman (3003)

Rubin (3365)

Trosko-Upham (3966a)

Zhang et al. (4410c)

Y. Zhang (4410d)

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The Chemical Components of Tobacco and Tobacco Smoke

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Naphthalene, pentamethylNaphthalene, 1-phenylNaphthalene, 2-phenylNaphthalene, 1-propylNaphthalene, 2-propylNaphthalene, 1,2,3,4tetrahydro-1,1,6trimethylNaphthalene, tetramethylNaphthalene, trimethylNaphthalene, 1,2,4-trimethylNaphthalene, 1,2,6-trimethylNaphthalene, 1,3,6-trimethylNaphthalene, 1,4,5-trimethylNaphthalene, 1,6,7-trimethylNaphthalene, 2,3,6-trimethylNaphtho[1,2,3,4-def] chrysene Naphtho[2,1,8-qra] naphthacene Naphtho[1,2-b] triphenylene Ovalene Pentacene Pentaphene Perylene Phenanthrene Phenanthrene, dimethylPhenanthrene, methylPhenanthrene, tetramethylPicene Pyrene Pyrene, dihydro-

Coulson (829)

Fieser et al. (1180a)

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The Hydrocarbons

78836_C001.indd 109

Pyrene, dimethylPyrene, 3,4-dimethylenePyrene, hexamethylPyrene, 1-hexylPyrene, methylPyrene, 1-methylPyrene, 2-methylPyrene, 4-methylPyrene, pentamethylPyrene, tetramethylPyrene, trimethyl5H-Tribenzo[a,f,l]trindene, 10,15-dihydroTriphenylene Triphenylene, methyla

The positions of the two methyl groups were not specified. The position of the methyl group was not specified. c Number in square brackets indicates the number of isomers included in the study. d The nature of the benzopyrene was not specified. b

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The Chemical Components of Tobacco and Tobacco Smoke

110

TAble I.e-8 Distribution of Identified hydrocarbons between Tobacco and Tobacco smoke number of Identified hydrocarbons in Tobacco and Tobacco smoke hydrocarbon Alkanes Alkenes and alkynes Alicyclics Monocyclic aromatic Polycyclic aromatic

Table

Total

smoke

Tobacco

Table I.A-10 Table I.B-1 Table I.C-1 Table I.D-1 Table I.E-6

132 363 142 98 586a

111 347 95 89 575a

96 42 61 39 86

75 25 16 30 74

1321

1217

324

220

Totals a

smoke and Tobacco

This number includes the various isomers of alkyl-PAHs reported in which the position of the alkyl group or groups has not been precisely defined.

It is obvious from the tabulation that the PAHs represent nearly 44% of the hydrocarbons identified to date and a substantial number of them are smoke components. The one category in the PAHs that is found to an appreciable extent in a particular type of tobacco, Latakia tobacco, is the bicyclic aromatic hydrocarbon naphthalene and its homologs (1135, 2784). The few remaining PAHs present in both tobacco and

its smoke include several tricyclic, tetracyclic, and pentacyclic PAHs, for example, anthracene, phenanthrene, pyrene, and B[a]P. As a result of the study by Bentley and Burgan (285) in the early days of the concern about B[a]P in tobacco smoke and its origin, the presence of B[a]P and the other PAHs in tobacco is usually attributed to its contamination by pollutants during transportation, curing, etc.

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2

Alcohols and Phytosterols

II.A Alcohols Periodically, tobacco researchers have reported the progress on the identification of tobacco and smoke components. Review articles by Johnstone and Plimmer (1971) and Izawa (1900) detailed much of the tobacco and smoke research conducted over the preceding century. Izawa listed 440 identified smoke components by 1961. The next year, Quin (3059) published a review of components found in tobacco and smoke. Herrmann (1625) reviewed phenolic compounds in tobacco smoke. In 1963, Philip Morris (2939) published a monograph on tobacco and smoke composition, a copy of which was provided the Advisory Committee on smoking and health to the U.S. Surgeon General (3999). In 1964, Elmenhorst and Reckzeh (1139) tabulated the aromatic hydrocarbons identified in tobacco smoke. Kuhn (2228, 2229) published articles on alkaloids in tobacco and their pyrolysis products in smoke. In their 1967 book, Wynder and Hoffmann (4332) discussed tobacco and smoke chemistry and the results of animal studies with tobacco smoke. Elmenhorst and Schultz (1140) listed 250 low-boiling components and vapor-phase components identified in tobacco smoke. In his 1968 review, Stedman (3797) listed nearly 1200 identified tobacco and smoke components. The next year, Neurath (2724) reported on the presence of 180 N-containing compounds in smoke. With the meaningful advancements in analytical methodology, the number of identified tobacco and smoke components increased dramatically (1373). In an in-house catalog assembled at R. J. Reynolds Tobacco Company (RJRT) in 1975, Roberts et al. (3224) listed 2783 identified components of tobacco and tobacco smoke. During the mid-1970s at RJRT, Schumacher et al. (3553), Heckman and Best (1587), and Newell et al. (2769) identified over 1540 compounds in the water-soluble and ether-soluble fractions of tobacco smoke. Of these, over 820 compounds were newly reported as tobacco smoke components. In 1977, Schmeltz and Hoffmann (3491) cataloged nearly 500 N-containing compounds identified in tobacco smoke but their catalog did not include the more than 230 N-containing compounds newly identified in tobacco smoke by Heckman and Best (1587). Between 1974 and 1978, Snook et al. (3756–3758) published the results of their massive study of the PAHs and a number of benzofurans identified in tobacco smoke, a study that was followed by an equally definitive one on the identification of aza-arenes and monocyclic N-containing compounds in tobacco smoke (3750). In 1980, Ishiguro and Sugawara (1884) listed 1889 identified tobacco smoke components in their monograph. However, a tally of the tobacco smoke components reported at that time exceeded 2500. No additional catalogs of the total number of identified components

of cigarette mainstream smoke (MSS) have been published since the 1980 Ishiguro and Sugawara (1884) publication. Smith et al. (3712) recently reported the chemical structures of the 253 identified phenols reported in cigarette MSS. In the past, different authors had different views on the classification of alcohols in tobacco and tobacco smoke. In our catalog, we employ a system different from those used by our forerunners. In 1954, Kosak (2170), in his smoke component compilation, listed seven “alcohols”: four alcohols (methanol, glycerol, diethylene glycol, and ethylene glycol) and three phenols (phenol, “phenols,” and catechol). He did not list either levoglucosan or a “phytosterol” as an alcohol but listed both as miscellaneous smoke components. In 1959, Johnstone and Plimmer (1971) listed thirteen alcohols plus five phytosterols identified in tobacco and/or smoke. In his 1968 review, Stedman (3797) divided the alcohols into three categories, namely, alcohols, sterols, and oxygenated isoprenoid constituents. The latter category contained constituents other than those with an alcoholic hydroxyl group, for example, farnesyl acetone (a ketone), solanachromene (a phenol), the tocopherols (phenols), and the levantanolides and levantenolide (ether-lactone combinations). In the category usually considered alcohols, Stedman listed a total of twenty-five alcohols (fifteen aliphatic, two aromatic, five polyols, and three cyclic). In our catalog, we have considered three types of components with hydroxyl groups: (1) components with a carboxyl group and its hydroxyl group (discussed in Chapter IV), (2) components with an hydroxyl group attached to a monocyclic or polycyclic benzenoid nucleus, that is, a phenol (discussed in Chapter IX), and (3) an hydroxyl group attached to a saturated or unsaturated aliphatic, alicyclic, or nonbenzenoid nucleus, which may or may not include another functional entity. An example of category (3) is the first item in Table II.A-1, hydroxyacetaldehyde (glycolaldehyde), which is both an alcohol and aldehyde. The saturated aliphatic alcohols range from methanol to 1-triacontanol with alkyl homologs included in some cases, for example, 1-butanol and 2-methyl1-propanol. The unsaturated aliphatic alcohols include 2-propen-1-ol (allyl alcohol) and such terpenoid structures as the C10 alcohol 3,7-dimethyl-1,6-octadien-3-ol (linalool), the C20 alcohol 3,7,11,15-tetramethyl-2-hexadecen-1-ol (phytol), and the C45 alcohol 3,7,11,15,19,23,27,31,35-nonamethyl-2, 6,10,14,18,22,26,30,34-hexatriacontanonaen-1-ol (solanesol). Examples of the alicyclic alcohols range from cyclopentanol to various carotenediols and triols to numerous cyclotetradecadienols, diols, and triols. Other alicyclic alcohols include a great variety of carbohydrates such as glucose and fructose plus the cases where such carbohydrates are linked to another component such as a phytosterol to form a glycoside. 111

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Table II.A-1 Tobacco and Tobacco Smoke Components Identified by Classical Chemical Methods Year

Investigator (Reference)

1953 1956 1956 1956 1957 1958 1958 1958 1959 1959 1959 1959 1959 1960 1960 1960 1962 1962 1962 1962 1964 1965

Sasaki (3413) Rowland et al. (3359) Rowland (3345) Rowland (3347) Kosak et al. (2178) Kosak and Swinehart (2175) Philippe and Hackney (2941) Wender et al. (4164) Dieterman et al. (969) Dymicky and Stedman (1082) Gladding et al. (1307) Rodgman and Cook (3271) Kobashi and Sakaguchi (2145) Carruthers and Johnstone (614) Schumacher (3535) Yang et al. (4376) Roberts and Rowland (3221) Cook and Rodgman (801) Rodgman and Cook (3280) Yang and Wender (4378) Philippe and Honeycutt (2943) Zane et al. (4402)

Component(s) Identified 2,3-Butanedione Solanesol Neophytadiene α-Tocopherol, solanachromene Stigmasterol Squalene Nitrous oxide, methyl nitrite Scopoletin Esculetin Campesterol Neophytadiene α-Tocopherol Glucose, fructose, arabinose, xylose Docosanol, solanesol β-D-Glucopyranose, 6-acetate 2,3,4-tris((+)-3-methylpentanoate) Caffeic acid α- and β-4,8,13-Duvatriene1,3-diol α- and β-Levantenolide Eugenol, isoeugenol Protocatechuic acid, 5-hydroxymethylfurfural Methyl isocyanate 4-O-Caffeoylquinic acid

With our method of defining an alcohol in tobacco and/ or smoke, the alcohols number over 1400. We realize that some readers may disagree with our classification of several hydroxypyridines as alcohols but the ones listed appear not only in this chapter, but also appear in Chapter XVII.B, in which monocyclic N-containing six-membered ring compounds are described and cataloged. Present analytical technology to identify a component in a complex mixture such as tobacco smoke or a tobacco extract involves the generation of a variety of spectra from which the compound may be characterized. The spectra may include separation of the component from the mixture by glass capillary gas chromatography, its retention time, plus those generated by ultraviolet, infrared, nuclear magnetic resonance, and mass spectroscopy studies. Nowadays, seldom is the component in the complex isolated in a tangible amount. In the early days, the study of the composition of tobacco was accomplished by so-called classical chemical procedures. The following example illustrates how an isolated terpenoid alcohol was subsequently characterized: Ozonization of the compound followed by degradation of the ozonide and derivatization of the degradation products with 2,4-dinitrophenylhydrazine yielded the 2,4-dinitrophenylhydrazones of the compounds shown in Figure II.A-1: Glycolic aldehyde (hydroxyacetaldehyde) {II}, levulinaldehyde (4-oxopentanal) {III}, and acetone (2-propanone) {IV}. These findings led to the assignment in 1956 of the structure {I}in Figure 11.A-1 by Rowland et al. (3359) to the terpenoid alcohol they named solanesol.

Smoke

Tobacco

+ — — — + + — + — — + + + — — + — + + + + —

— + + + — — + — + + + — — + + — + — — — — +

In the mid-1950s, the determination of the molecular weight of compounds with a molecular weight above 300 to 400 was difficult and often inaccurate. As a result, Rowland et al. were unable to precisely define the molecular weight of solanesol and therefore its structure. Originally, they had intended to report that solanesol was either a C45 compound (I, n = 8 in Figure II.A-1) or a C50 compound (I, n = 9 in Figure II.A-1) but were forced to choose one or the other. Because the majority of known isoprenoids at that time were terpenoids, that is, multiples of C10, and relatively few were sesquiterpenoids, that is, multiples of C15, Rowland et al. elected to report solanesol as a pentaterpenoid, that is, a C50 compound. In 1957, Mold and Booth (2590) reported the identification of solanesol in cigarette mainstream smoke (MSS). Subsequently, with more advanced analytical technology, Erickson et al. (2A01)) and Shunk et al. (2A03) reported in back-to-back publications in 1959 that a more precise

CH3

CH3

HOCH2-CH=C-CH2-CH2-CH=C-CH3 n I HOCH2-CH=O

H3C-CO-CH2-CH2-CH=O

II

III

H3C-CO-CH3 IV

Figure II.A-1  The degradation products from ozonized solanesol.

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Alcohols and Phytosterols

molecular weight method indicated that solanesol was a C45 compound (I, n = 8 in Figure II.A-1) with the formula C45H74O (molecular weight, 630), 3,7,11,15,19,23,27,31,35-nonamethyl2,6,10,14,18,22,26,30,34-hexatriacontanonaen-1-ol. Since its characterization in 1956, solanesol has had an interesting history as a tobacco component. It is present:

1. In the different types of tobacco (flue-cured, burley, Oriental, Maryland) (3295) 2. In the smoke from each when smoked in cigarette form (2559, 3270, 3295) 3. As a variety of esters in tobacco [Rowland and Latimer (3358)] and tobacco smoke [Rodgman and Cook (3270), Rodgman et al. (3286)]



It generates isoprene [Gil-Av and Shabtai (1286); Grossman et al. (1431, 1432)], several solanesenes [Rodgman et al. (3297)], and numerous polycyclic aromatic hydrocarbons [Rodgman and Cook (3269), Severson et al. (3616)] during the smoking process. It was proposed by Wright (4282) as a more significant precursor in tobacco of polycyclic aromatic hydrocarbons (PAHs) in MSS than the aliphatic long-chained hydrocarbons, and eventually was found to be such by Rodgman and Cook (3269) and Severson et al. (3616). More recently solanesol was studied as an indicator of environmental tobacco smoke (ETS) in room space [Ogden (2829), Ogden and Maiola (2833, 2834), Robinson et al. (3230), Tang et al. (3868)]. In the early tobacco and tobacco smoke studies, the chemical nature of one or two components was defined by means of classical chemical procedures and described in an appropriate publication, for example, the identification of the previously discussed terpenoid alcohol solanesol in flue-cured tobacco (3359), the phenols eugenol and isoeugenol identified in the mainstream smoke (MSS) from Oriental tobacco (3280), and

maltol identified in the MSS from an ingredient-free German tobacco blend (1131). A random selection of several of these early studies is presented in Table II.A-1. However, as analytical methodology became more sophisticated and precise, many more components—sometimes several hundred newly identified in tobacco or smoke—were reported in a single publication. In his pioneer research on glass capillary gas chromatography in 1965, Grob (1416), in his study of the MSS from cigarettes containing additivefree tobacco, identified sixty-three components, a number of which were polar components. Later, some of the polar components in MSS identified by Grob are also listed in the Doull et al. catalog of cigarette flavor ingredients (1053). In the 1950s, the organic solvent extraction of tobacco was studied extensively with the purpose of removing PAH precursors from the tobacco. Incorporated into one process was an aqueous alcohol-hexane partition to separate the polar, more flavorful tobacco components from the lipophilic PAH precursors. At that time, almost nothing was known about the nature of the polar tobacco components, although it was apparent they made a considerable positive contribution to the flavor and aroma of cigarette MSS. Despite the lack of knowledge about the precise nature of the polar components, it was demonstrated they were not significant PAH precursors (3262). Our inability at that time to separate highly polar compounds in a complex mixture contributed to our lack of knowledge of the nature of the polar components in tobacco and/or tobacco smoke. This situation continued during years of intensive effort on cigarette MSS composition but was finally resolved and utilized by Schumacher et al. (3553) in the 1970s. Of the total of 1545 MSS components identified by Schumacher et al. (3553), Newell et al. (2769), and Heckman and Best (1587), 828 (53.6%) were new to the tobacco smoke literature at the time of the publication and a great number of them were highly polar compounds (see Table II.A-2).

Table II.A-2 Tobacco and Tobacco Smoke Studies in Which Components Were Identified by a Combination of Spectral Technologies Year

Investigator (Reference)

1965 1973/74 1974/76 b 1974/77 1975 1976 1977 1978 1978 1982/82 2004 2005

Grob (1416) Schumacher and Vestal (3561) Lloyd et al. (2389) Schumacher et al. (3553) Newell et al. (2769) Snook et al. (3758) Snook et al. (3756) Snook et al. (3757) Heckman and Best (1587) Schumacher (3550) Peng et al. (2917a) Leffingwell and Alford (2339a)

No. of Identified Components

Smoke

Tobacco

Newa

63 118 323 479 643 115 157 536 423 97 408 334

+ — — + + + + + + — — —

— + + — — — — — — + + +

27 25 132 387 173 NIc NI NI 268 1 NI 49

Newly reported components to tobacco and/or smoke at the date of the publication. The first date is that of a scientific conference presentation, the second is that of a publication in a peer-reviewed scientific journal. c NI = not indicated was the number of components not previously identified in tobacco or tobacco smoke. a

b

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With regard to tobacco components, Lloyd et al. (2389) identified 275 previously unidentified components of additive-free flue-cured tobacco, 132 new to all additive-free tobacco types. Many of these compounds were highly polar and considered significant contributors to MSS flavor and aroma. Similar detailed studies were conducted on the composition of burley tobacco by Roberts and Rohde (3219), Oriental tobacco by Schumacher and Vestal (3561), and Maryland tobacco by Schumacher (3550). Years later, it became apparent that many of the highly polar components of tobacco and tobacco smoke were identical with similar to many of the components used in the flavor formulations, that is, the “top dressing,” added to a specific tobacco blend to impart its unique smoking characteristics (1053). Randomly selected publications on the identification of many additivefree tobacco and/or tobacco smoke components are listed in Table II.A-2. The description of the isolation and/or identification of a great number of tobacco and/or smoke components was not always the case even after the development of sophisticated analytical technologies that generated informative spectral data. Between the early 1970s and the late 1980s, the research group at the Swedish Tobacco Company in Stockholm, Sweden, generated a great number of publications on fluecured and Oriental tobacco composition in many of which only a single component or a few newly identified tobacco components were described. Admittedly, much attention was paid to the definition of the stereoisomerism of some of the components described individually. Selected examples of their extensive study of tobacco composition are presented in Table II.A-3. Periodically between the mid-1970s and late 1980s, the Swedish Tobacco Company group published excellent reviews of their tobacco component studies and other meaningful related studies in the scientific literature, for example, Enzell (1149, 1149a), Enzell and Wahlberg (1156), Enzell et al. (1157), Wahlberg and Eklund (4086a), and Wahlberg and Enzell (4089, 4090).

In addition to his isolation of the alcohol solanesol and contribution to its characterization, Rowland was involved in the isolation and characterization of the hydroxylated flue-cured tobacco components solanachromene and α-tocopherol, each of which is a phenol. The solanachromene has not been identified in tobacco smoke but α-tocopherol, a well-known anticarcinogen, was identified as a cigarette MSS component in 1959 (3271) and many times since in MSS and ETS, for example, see Risner (3170). In their 1962–1963 study of hydroxylated tobacco components, Rowland and colleagues next isolated several 1,3- and 1,5-diols from tobacco. Structurally, these diols were shown to be related to the alicyclic diterpenoid hydrocarbon cembrene, previously isolated in 1951 from plant tissue by Haagen-Smit et al. (2A02) and characterized in 1962 as 3,7,11-trimethyl-14(1-methylethyl)-1,3,6,10-cyclotetradecatetraene (see {V} in Figure II.A-2) by Dauben et al. (905a). The 1,3-diol and 1,5-diol isolates were demonstrated to possess the cyclotetradecatriene structures shown as {VI} and {VII}, respectively, in Figure II.A-2 [Rowland (3351, 3352), Rowland and Roberts (3360)]. Additional studies indicated the presence in tobacco not only of the diols {VI} and {VII} but also the two oxabicyclo compounds {VIII} and {IX} derived from the 1,5-diol {VII}. A third oxabicyclo type {X} was eventually identified in tobacco (9, 12, 4089–4091). The four compounds {VI} to {IX} were reported by Rowland et al. to be present in cigarette MSS (3361). Cembrene {V} was eventually identified in 1966 in tobacco by Reid (1097a) and in Japanese tobacco in 1980 by Takagi et al. (3853). The reports of these cyclotetradecatrienediols and their ethers by Rowland, Roberts, and their colleagues led to an intensive study of tobacco by the Swedish Tobacco Company research team. Their study involved the isolation, characterization, and stereochemical definition of nearly 100 compounds containing the 14-carbon ring [Aasen et al. (12), Arndt et al. (94a), Behr et al. (235, 236), Wahlberg et al. (4083–4085, 4091, 4098–4100), Wahlberg and Eklund (4086a, 4088), Wahlberg and Enzell (4091)].

Table II.A-3 Tobacco Components Identified Post-1975 Year

Investigator (Reference)

1971 1971 1974 1975 1977 1977 1978 1979 1982 1983 1983 1984 1986

Aasen et al. (9a) Enzell et al. (1155) Aasen et al. (6) Aasen et al. (1) Behr et al. (230) Behr et al. (231) Behr et al. (229) Behr et al. (234) Wahlberg et al. (4084) Wahlberg et al. (4087) Wahlberg et al. (4098) Wahlberg et al. (4083) Wahlberg et al. (4102)

Components Identified 5-Methoxy-6,7-dimethylbenzofuran Norsolanesene (9R)-9-Hydroxy-4-megastigmen-3-one, 5,6-Epoxy-3-hydroxy-7-megastigmen-9-one (2 isomers) 3,3-Dimethyl-7-hydroxy-2-octanone 2,6-Dimethyl-10-oxo-3,6-undecadien-2-ol, 3-methyl-4-oxo-2-nonen-8-ol 2,6-Dimethyl-2,7-octadiene-1,6-diol 5,8-Epoxy-6-megastigmene-3,9-diol, 3,6-epoxy-7-megastigmene-5,9-diol 8,11-Epoxy-2,6-cembradiene-4,12-diol 7,8-Epoxy-4-basmen-6-one Hydroperoxycembratrienediols [5 in all] Cembratrienols [6 in all] A new sucrose ester

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H3C 1

14

11

3

10

H3C

9

11 6

8

7

10

CH3

7

5 V

H2C

CH3

11

9

8 1

O

3

4

1 2

3

10 CH3

123

13

CH3

CH3

H 3C HO

11

12

9

8 O

CH3

VIII 1,5-Dimethyl-11-methylene-8-(1methylethyl)-15oxabicyclo[10.2.1]pentadeca-2,6dien-5-ol

1

4

5

OH

3

4

OH

VII

CH3

OH 5

7 2

6

2

1

CH3

H3C

6

10

9 14

7

1,5,11-Trimethyl-8-(1methylethyl)- 2,6,11cyclotetradecatriene-1,5-diol

CH3

H3C

8

11

1,5,9-Trimethyl-12-(1methylethyl)- 4,8,13cyclotetradecatriene-1,3-diol

OH 5

7 2

OH

OH

VI

6

10

5

13 4

CH3

3,7,11-Trimethyl-14-(1methylethyl)-1,3,6,10cyclotetradecatetraene {cembrene} H3C

12

CH3

3

IX

O

13 14 1 2

12 11 10

9

3

6

5

4 CH3

CH3 8 7

OH

O X

1,5,11-Trimethyl-8-(1methylethyl)-15oxabicyclo[9.3.1]pentadeca-2,6diene-5,12-diol

8-Hydroxy-4,8,14-trimethyl-11(1-methylethyl)-15oxabicyclo[12.1.0]pentadeca4,9-dien-6-one

Figure II.A-2  Tobacco and/or tobacco smoke alcohols related to cembrene.

Much research was conducted after the mid-1950s to identify alcohol components in the particulate phase of cigarette MSS primarily because some were found to contribute consumer acceptable flavor and aroma properties to the MSS. As noted by Rodgman (3266), many components, including alcohols, used by the tobacco industry in its flavor formulations [see listing by Doull et al. (1053)] are known components of additive-free tobacco and/or its smoke. Thus, such additives are not strangers to the tobacco and/or its smoke but their addition increases the consumer acceptable flavor. Table II.A-4 lists some of the tobacco and/or tobacco smoke alcohol components that have been or are used in flavor formulations. Table II.A-5 is a catalog of the alcohols identified in tobacco and/or tobacco smoke. Of the 1462 alcohols identified to date, 531 have been reported in tobacco smoke, 1152 in tobacco, and 221 in both tobacco and tobacco smoke.

II.B PHYTOSTEROLS The alcohol category in tobacco and tobacco smoke includes the phytosterols, the plant-derived sterols. The sterols have been examined in considerable detail over the years, an examination that did not actually originate in the study of tobacco and/or its smoke. In 1928, Kennaway and Sampson demonstrated the tumorigenicity of the pyrolysate from the sterol cholesterol (2080). Their study preceded the first reports of induction of skin cancer in laboratory animals with two individual compounds, the PAHs dibenz[a,h]anthracene (DB[a,h]A) in 1930 by Kennaway and Hieger (2078) and benzo[a]pyrene (B[a]P) in 1932 by Cook et al. (796a, 797). Both PAHs subsequently were classified as highly potent tumorigens. Based on the results of their detailed study of the

tumorigenicity of several PAHs, Barry et al. (194) reported that a third PAH, 3-methylcholanthrene, was also a highly potent tumorigen. 3-Methylcholanthrene was subsequently named 1,2-dihydro-3-methylbenz[j]aceanthrylene. Because of their structural similarity, 1,2-dihydro-3-methylbenz[j] aceanthrylene became the object of the search in the pyrolysate from cholesterol (Figure II.B-1). Cholesterol and several similarly structured phytosterols (campesterol, β-sitosterol, and stigmasterol) are components of tobacco and a portion of each is transferred intact to smoke during the smoking process. The phytosterols in tobacco have been reported by numerous investigators, for example, Traetta-Mosca (3942b), Kobel and Neuberg (2153a), Shmuk (3656a), Khanolkar et al. (2087), and Venkatarao et al. (4042b). All have been reported in tobacco as glycosides by Bolt and Clarke (390), Dymicky and Stedman (1079), Kallianos et al. (2018, 2019), and Khanolkar et al. (2087) and long-chained saturated and unsaturated acid esters (3296). Theoretically, all could yield 1,2-dihydrobenz[j]aceanthrylene and/or 1,2-dihydro-3-methylbenz[j]aceanthrylene during the smoking process. To date, the identification of this PAH in tobacco smoke has been reported by only one investigator, Kröller (2191). Dihydrobenz[j]aceanthrylene (cholanthrene) was not among the several PAHs isomeric with 1,2-dihydrobenz[j]aceanthrylene reported by Snook et al. (3756–3758). In the late 1940s there was much interest in 1,2-dihydro-3-methylbenz[j] aceanthrylene because of its possible generation from cholesterol during the heating of cholesterol-containing foodstuffs. While 1,2-dihydro-3-methylbenz[j]aceanthrylene could actually be synthesized from cholesterol by a series of sophisticated chemical reactions (1184a), attempts to generate it by pyrolysis of cholesterol were unsuccessful.

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Table II.A-4 Tobacco and/or Smoke Alcohols Used in Flavor Formulations Identified In CAS No.

Chemical Abstracts Nomenclature

60-12-8 100-51-6 105-13-5 98-85-1 122-97-4 507-70-0 107-88-0 71-36-3 98-55-5 562-74-3 112-30-1 7212-44-4 64-17-5 57-48-7 59-23-4 50-99-7 57-50-1 50-99-7 111-27-3 104-76-7 544-12-7 31103-86-3 78-70-6 106-25-2 111-87-5 3391-86-4 106-22-9 71-41-0 57-55-6 56-81-5 78-83-1 104-54-1 118-71-8 50-70-4

Benzeneethanol Benzenemethanol Benzenemethanol, 4-methoxyBenzenemethanol, α-methylBenzenepropanol Bicyclo[2.2.1]heptane-2ol, endo-1,7,7,-trimethyl1,3-Butanediol 1-Butanol 3-Cyclohexene-1-methanol, α,α,4-trimethyl3-Cyclohexen-1-ol, 4-methyl-1-(1-methylethyl)1-Decanol 1,6,10-Dodecatrien-3-ol, 3,7,11-trimethylEthanol D-Fructose D-Galactose α-D-Glucose α-D-Glucopyranoside, β-D-fructofuranosyl-  {sucrose} α-D-Glucose 1-Hexanol 1-Hexanol, 2-ethyl3-Hexen-1-ol Mannose 1,6-Octadien-6-ol, 3,7-dimethyl2,6-Octadien-1-ol, 3,7-dimethyl1-Octanol 1-Octen-3-ol 6-Octen-1-ol, 3,7-dimethyl1-Pentanol 1,2-Propanediol 1,2,3-Propanetriol 1-Propanol, 2-methyl2-Propen-1-ol, 3-phenyl4H-Pyran-4-one, 3-hydroxy-2-methylSorbitol a

a

As Listed by Doull et al. (1053)

Smoke

Tobacco

phenethyl alcohol benzyl alcohol anisyl alcohol α-methylbenzyl alcohol 3-phenyl-1-propanol borneol 1,3-butanediol butyl alcohol α-terpineol 4-carvomenthol capric alcohol nerolidol ethyl alcohol sugars sugars sugars sugars sugars hexyl alcohol 2-ethyl-1-hexanol 3-hexen-1-ol sugars linalool nerol 1-octanol 1-octen-3-ol dl-citronellol amyl alcohol propylene glycol glycerol isobutyl alcohol cinnamyl alcohol maltol glucitol

+ + — — + + + + + + — + + + + + + + — + — + — — — — + — + + + + + —

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + — + +

 orbitol (glucitol)) is not included in the Doull et al. list (1053) but is included in flavor formulations used by cigarette manufacturers outside of the U.S. S [see Table 7A in (3266)].

As shown in Figure II.B-2, pyrolysis of cholesterol {Ia} yields chrysene {III}, Diels′ hydrocarbon {IV}—a methylcyclopentaphenanthrene—and numerous other PAHs. Both PAHs noted have also been identified in pyrolysates of the major tobacco phytosterols [Wynder et al. (4356), Van Duuren (4022)]. More recently in the early 1970s, Hecht et al. (1560) discussed the generation of chrysene and alkylchrysenes by pyrolysis of phytosterols. Although none of the sterols {Ia–Id} has been shown to generate the potent tumorigen 1,2-dihydro-3-methylbenz[j] aceanthrylene (3-methylcholanthrene) on pyrolysis, Falk et al. (1171) reported that cholesterol and cholesterol esters on pyrolysis do generate the mouse-skin tumorigens 4-cholesten-

3-one {Va} and 3,5-cholestadiene {VIa}. Veldstra (4042a) reported that the pyrolysis of cholesteryl oleate also yielded 3,5-cholestadiene {VIa}. Cholesteryl oleate was probably a component of the mixture of phytosteryl esters described in flue-cured tobacco by Rowland and Latimer (3358). Its analogs stigmasteryl oleate and β-sitosteryl oleate were among the phytosteryl esters in tobacco smoke characterized by Rodgman et al. (3296). The other identified phytosteryl esters included stigmasterol and β-sitosterol esterified with saturated acids (lauric, palmitic, stearic, and myristic) and unsaturated acids (linolenic and linoleic) (3296). Relative to the low level of cholesterol {1a}, tobacco usually contains substantial levels of several phytosterols

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Table Ii.A-5 Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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Table Ii.A-5 (continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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119

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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121

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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123

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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125

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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127

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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129

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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131

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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133

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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135

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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137

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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139

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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141

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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143

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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145

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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147

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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151

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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157

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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159

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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161

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Alcohols and Phytosterols

165

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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166

The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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167

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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168

The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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169

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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170

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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171

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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172

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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173

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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174

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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175

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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176

The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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177

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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178

The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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179

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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180

The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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181

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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182

The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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183

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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184

The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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185

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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186

The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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187

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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188

The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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189

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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190

The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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191

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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192

The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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193

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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194

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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195

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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196

The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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197

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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198

The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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199

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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200

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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201

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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202

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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203

Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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204

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Table Ii.A-5 (Continued) Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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205

Alcohols and Phytosterols

H 3C CH3 H3C

H3C

CH3

CH3

H3C HO Cholesterol

1,2-Dihydro-3-methylbenz[j]aceanthrylene

Figure II.B-1  Theoretical conversion of cholesterol to 1,2-dihydro-3-methylbenz[j]aceanthrylene.

R

CH3

CH3

CH3

CH3 H3C IV

CH3

R CH3

O CH3

CH3

R

V

CH3

CH3

CH3

HO

II

VI

I

III

LEGEND Sterol,

R=

Ia

cholesterol

-(CH2)3-CH(CH3)2

Ib

campesterol

-(CH2)2-CH(CH3)-CH(CH3)2

Ic

β-sitosterol

-(CH2)2-CH(C2H5)-CH(CH3)2

Id

stigmasterol

Ie

ergosterola

-CH=CH-CH(C2H5)-CH(CH3)2

II

-CH=CH-CH(CH3)-CH(CH3)2

1,2-dihydro-3-methylbenz[j]aceanthrylene (3-methylcholanthrene)

III

chrysene

IV

Diels´ hydrocarbon

Va

4-cholesten-3-one

VIa

3,5-cholestadiene

Vb

4-campesten-3-one

VIb

3,5-campestadiene

Vc

β-4-sitosten-3-one

VIc

β-3,5-sitostadiene

Vd

stigmasten-3-one

VId

3,5-stigmastadiene

Ve

ergostadien-3-one

VIe

3,5,7-ergostatriene

a

Ergosterol has a double bond at the 7-position

Figure II.B-2  Possible sterol degradation products.

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206

[campesterol {Ib}, β-sitosterol {Ic}, stigmasterol {Id}, and ergosterol {Ie}] structurally similar to cholesterol. Phytosterols {Ib}, {Ic}, and {Id} differ slightly from cholesterol in the structure of the long side chain whereas ergosterol {Ie} not only differs slightly from cholesterol in the structure of its long side chain but also has an extra double bond at the 7-position (Figure II.B-2). They are present in tobacco in both the free and bound form (as glycosides and esters), and they are transferred as such to mainstream smoke (MSS). The sterols constitute about 0.2% of the tobacco weight. In the late 1950s to early 1960s, Rodgman proposed that the tobacco phytosterols—campesterol, β-sitosterol, stigmasterol, and ergosterol—might generate compounds analogous to the tumorigenic 4-cholesten-3-one {Va} and 3,5-cholestadiene {VIa} generated from cholesterol, that is, 4-campesten-3-one {Vb}, 3,5-campestadiene {VIb}, β-4sitosten-3-one {Vc}, 3,5-sitostadiene {VIc}, 4-stigmasten-3 -one {Vd}, 3,5-stigmastadiene {VId}, ergosten-3-one {Ve}, and 3,5,7-ergostatriene {VIe}, on thermal degradation of these tobacco phytosterols or their esters during the smoking process. These campesterol-, β-sitosterol-, stigmasterol-, and ergosterol-related compounds might also be mouse-skin tumorigens as are their cholesterol counterparts. For nearly a decade, Rodgman and Cook (3286) were unsuccessful in their periodic efforts to isolate any of these phytosteryl ketones or dienes from CSC and identify them. However, Benner et al. (273) did subsequently identify two of these 3,5-dienes, 3,5-campestadiene {VIb} and 3,5-stigmastadiene {VId}, in tobacco smoke, see also Eatough et al. (1099, 1100). In 1939, the PAHs anthracene, phenanthrene, and B[a]P were reported as components of a tobacco-related material by Roffo (3323, 3325, 3326) and his son (3316–3318). In discussions of tobacco smoke, the Roffo findings are generally disregarded because the three PAHs they reported were not detected in tobacco smoke but were identified in a destructive distillate of tobacco. However, Roffo did report another finding that led to much research both within and outside the tobacco industry. Roffo (3327) reported that comparison of the destructive distillate of tobacco with the destructive distillate of an ethanol-extracted tobacco indicated that the PAH content, particularly B[a]P, and the specific tumorigenicity of the extracted tobacco destructive distillate were reduced from those of the destructive distillate from the control tobacco. Roffo speculated that the precursors of the tumorigenic PAH components of his distillates were ethanol-soluble phytosterols. Eventually his prediction, as far as it went, was found to be true for cigarette MSS (327, 398). In July 1954, Rodgman—a newly hired scientist at RJRT R&D—described the findings of the Roffos (3316–3318, 3323, 3325, 3327) to two colleagues who were previously unaware of them. He particularly emphasized the organic-solvent extraction of tobacco to remove PAH precursors. The discussion resulted within a week of one of the colleagues proposing an extraction method for removal of the phytosterols from tobacco (114). A few months later, Rodgman initiated a lengthy study of the effect of organic-solvent extraction on the PAH content

The Chemical Components of Tobacco and Tobacco Smoke

of its MSS (3240–3242, 3246, 3251). All of the extractions of different tobacco types and blends with different organic solvents and the fabrication of the cigarettes from the extracted and control tobaccos were conducted by Ashburn (116, 117). Two major mechanisms were proposed for the pyrogenesis of PAHs in tobacco smoke. (1) PAHs are formed by degradation of organic tobacco components to simpler molecules and/or free radicals during the pyrolysis processes occurring in the burning cigarette, followed by recombination of these simpler fragments to yield PAHs (the degradation-combination mechanism) [see Badger et al. (142–144) and earlier papers]. (2) PAHs are formed unimolecularly by cyclization, dehydration, aromatization, ring expansion, etc., of high molecular weight tobacco components such as the phytosterols, the tetradecacyclic duvanes, long-chained saturated and unsaturated hydrocarbons, alcohols, and esters, etc. (the aromatization reaction) [Rodgman and Cook (3269, 3286)]. Obviously, the mechanism of formation of PAHs is not an either-or situation. Experimental data indicate that both mechanisms are operative in PAH formation in the burning cigarette. Evidence for unimolecular aromatization was provided by pyrolysis data and by MSS PAH data from cigarettes “spiked” with phytosterols (3269, 3286). The relatively large increase in the levels of chrysene and methylcyclopentaphenanthrene (Diels’ hydrocarbon) vs. those for B[a]P and other tetra- and pentacyclic PAHs are more readily explained by the unimolecular aromatization of the tetracyclic sterol than by the degradation-recombination mechanism. The formation of several PAHs (chrysene, picene, several cyclopentaphenanthrenes, etc.) from various sterols had been reported by Diels, Ruzicka, and their colleagues in the 1920s and 1930s [see historical summary by Fieser and Fieser (1949)]. Early research on PAHs in roasted and/or grilled meats evolved from the theory that cholesterol when heated would generate the highly potent tumorigen 1,2-dihydro-3-methylbenz[j] aceanthrylene (3-methylcholanthrene). As noted previously, sterols in tobacco include cholesterol plus much higher levels of several phytosterols whose structures differ only slightly from that of cholesterol. In 1959, Wynder et al. in an addendum to their publication (4356) reported that the pyrolysis of tobacco phytosterols at 720°C and 850°C gave B[a]P and other PAHs plus low levels of alkyl derivatives of phenanthrene, pyrene, and chrysene. Much of the early research on the isolation and identification of phytosterol and their derivatives from tobacco and tobacco smoke is summarized and referenced in the 1959 review by Johnstone and Plimmer (1971) and the 1968 review by Stedman (3797). Table II.B-1 chronicles many of the reported studies on phytosterols and their derivatives in tobacco and tobacco smoke plus the studies on the pyrolysis of phytosterols. Table II.B-2 lists the 111 phytosterols and phytosteryl derivatives identified in tobacco and tobacco smoke. Of these 111 components, 44 have been reported as tobacco smoke components, 102 as tobacco components, and 35 in both tobacco and tobacco smoke.

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Identification in Tobacco of Year

Phytosterols

1913 1928 1935 1937 1939 1942 1943 1949 1955 1957

Traetta-Mosca (3942b)

1958

Rowland (3346), Dymicky and Stedman (1079), Grossman and Stedman (1433) Dymicky and Stedman (1080, 1082) Stedman and Rusaniwskyj (3808) Giles (1291), Reid (3097)

1959 1960 1961 1963 1965 1968 1971 1972 1974/5 1976 1977 1978 1979 1984 1998 2000 2001 a

Derivatives of Phytosterols

Identification In Tobacco Smoke of Phytosterols

Derivatives of Phytosterols

Pyrolysis Studies on Sterols or their Inclusion in a Smoked Cigarette

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Table II.B-1 Studies on Identification of Phytosterols and Phytosteryl Derivatives in Tobacco and Tobacco Smoke

Kennaway and Sampson (2080) Schürch and Winterstein (3562)

Kobel and Neuberg (2153a) Shmuk (3656a)

Veldstra (4042a) Roffo (3327) Venkatarao et al. (4042b) Falk et al. (1171) Khanolkar et al. (2087)

(G)a Khanolkar et al. (2087)

(G) Dymicky and Stedman (1079)

Kosak et al. (2178), Rodgman and Chappell (3268) Carruthers and Johnstone (612) (E) Rodgman et al. (3296)

(G) Dymicky and Stedman (1080, 1081) Sakaguchi and Kobashi (3391) (G) Kallianos et al. (2019)

Wynder et al. (4355), Rodgman and Cook (3269) Wynder et al. (4356)

(G) Kallianos et al. (2018) (G) Kallianos et al. (2019)

Ehrhardt et al. (1117) Cheng et al. (690) Grunwald et al. (1434) Davis (907a) Schmeltz et al. (3484) Tancogne and Chouteau (3867), Lotti et al. (2400) Davis (909), Menser et al. (2531), Tojib et al. (3920), Tancogne (3866) Severson et al. (3612)

Schmeltz et al. (3484)

Severson et al. (3616) Chopra and Al-Kubaisi (705) Forehand and Moldoveanu (1214) Britt et al. (435) Britt et al. (433)

(G) = glucosides, (E) = esters

207

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The Chemical Components of Tobacco and Tobacco Smoke

Table II.B-2 Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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209

Table II.B-2 (continued) Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table II.B-2 (continued) Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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211

Table II.B-2 (continued) Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table II.B-2 (continued) Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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213

Table II.B-2 (continued) Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table II.B-2 (continued) Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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3

Aldehydes and Ketones

The publication in the early 1950s of the results of several retrospective studies on association between cigarette smoking and respiratory tract cancer, particularly lung cancer, and the study on induction of skin carcinoma in a susceptible strain of mice painted with massive doses of cigarette tar for the better part of their life span [Wynder et al. (4306a)] triggered intensive interest in the composition of cigarette mainstream smoke (MSS). Because the cigarette smoke condensate (CSC), or total particulate matter (TPM), the phase of the smoke aerosol reported to be the mouse-skin tumorigen, embodied the particulate phase of the cigarette smoke aerosol, considerable effort was devoted to defining its composition with emphasis on the presence in it of tumorigenic polycyclic aromatic hydrocarbons (PAHs), particularly benzo[a]pyrene (B[a]P). This effort was conducted by research groups both within and outside of the tobacco industry. However, because knowledge of the composition of tobacco smoke was so sketchy in the mid-1950s, several research groups initiated the detailed examination of the tobacco smoke aerosol to define not only its physical characteristics but also the composition of its vapor phase. For most of the balance of the 1950s, the results from the composition studies of cigarette smoke vapor phase received little attention compared to that directed at the particulate-phase composition results. In 1954, Kosak (2170) published a list of components reported to be present in tobacco smoke. His list is shown in Table III-1. The aldehydes listed included formaldehyde, acetaldehyde, acrolein (2-propenal), butyraldehyde (butanal), benzaldehyde, and 2-furaldehyde. In several instances, Kosak questioned whether the analytical data reported were sufficient to define unequivocally the identity of the smoke component. The ketones listed by Kosak included 3-pentanone (diethyl ketone), 4-heptanone (di-n-propyl ketone), 17-tritriacontanone (dipalmityl ketone), 2,3-butanedione (biacetyl), and “higher” ketones. Because the low molecular weight aldehydes such as formaldehyde, acetaldehyde, propionaldehyde (propanal), acrolein (propenal), and butyraldehyde (butanal) and ketones such as acetone, methyl ethyl ketone (2-butanone), and diethyl ketone (3-pentanone) in cigarette MSS occur primarily in the vapor phase, their identification and analysis in the 1950s and 1960s were facilitated by conversion to less volatile compounds. Many of these low molecular weight carbonyl compounds form stable compounds with various derivatizing agents and in many instances the derivative formation is almost quantitative. The use of Girard T (trimethylamine) or Girard P (pyridine) reagent to derivatize tobacco smoke carbonyl compounds was described by Seligman (3581) and Resnik and

Seligman (3108). The derivatives were separated by paper chromatography and identified from their mass spectra. A reagent that proved to be an excellent one to derivatize tobacco MSS aldehydes, ketones, and keto acids was 2,4dinitrophenylhydrazine. Individual hydrazones were isolated by various chromatographic means (column chromatography, paper chromatography, and eventually HPLC) and their levels estimated spectrophotometrically. Another ingenious use of 2,4-dinitrophenylhydrazine was the following: The less stable Girard T or Girard P derivatives were decomposed and the carbonyl compounds released were converted to the highly stable 2,4-dinitrophenylhydrazones for identification and quantitation. Subsequently, the 2,4-dinitrophenylhydrazine procedure was adapted to the investigation of carbonyl compounds in tobacco, in its headspace vapors, in sidestream smoke (SSS), and in environmental tobacco smoke (ETS). A third reagent used for the estimation of aliphatic aldehydes in tobacco smoke was 3-methylbenzothiazolone hydrazone hydrochloride [Weaving (4155), Davis and Sneade (915)]. Table III-2 summarizes some of the studies on low molecular weight carbonyl components of tobacco smoke in which various derivatizing reagents were used, the derivatives formed were separated by a variety of techniques (column, paper, TLC, HPLC), and identified and estimated by spectral means (UV, IR, mass, colorimetry). The results of many of these studies provided quantitative data on the per cigarette MSS yield of several carbonyl compounds of interest. As the interest in the overall composition of tobacco smoke escalated in the 1950s and 1960s, the potential of the utilization of gas chromatography to examine and define the vapor-phase composition was examined. For example, Seligman et al. (3584), in their gas chromatographic study of the components of a synthetic mixture comprising seventeen compounds known to be present in tobacco smoke, demonstrated the feasibility that the seventeen diverse compounds could be successfully separated by gas chromatography. Among the seventeen standard compounds, ranging from methane to water, were acetaldehyde, propionaldehyde, and acetone. Subsequent to the successful separation of the compounds, the identity of each was confirmed by mass spectroscopy. As a requisite and adjunct to their study of selective filtration of tobacco smoke components and the effect of carbon filters on cigarette MSS composition, Laurene et al. (2305) developed and described a gas chromatographic analysis of acetaldehyde, acrolein, and acetone in cigarette MSS. In addition to the analytical methodology, Laurene et al. also provided data on the MSS yields of acetaldehyde, acetone, and acrolein from 65-mm nonfiltered cigarettes containing 215

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216

The Chemical Components of Tobacco and Tobacco Smoke

Table III-1 Tobacco Smoke Components Listed by Kosak (2170) Class

Component

Class

Component

Class

Component

Hydrocarbons

Hentriacontane (?) Acetylene “Unsaturated hydrocarbons” Azulene Phenanthrene (?) Anthracene (?) Benzopyrene (?) “Condensed aromatics” (?)

Ketones

3-Pentanone 4-Heptanone 17-Tritriacontanone (?) 2,3-Butanedione “Higher” ketones (?)

Acids

Formic acid Acetic acid Butyric acid Valeric acid Caproic acid C7 and C8 aliphatic acids (?) Succinic acid (?) Fumaric acid (?) Citric acid (?) Benzoic acid (?) Phenolic acids (?)

Alcohols and Phenols

Methanol Glycerol Diethylene glycol Ethylene glycol Phenol (?) Catechol (?)

Alkaloids

Nicotine Pyridyl ethyl ketone Myosmine Nicotyrine α-Socratinec β-Socratinec γ-Socratinec Obelinc Lohitamc Anodminc Lathraeinc Poikilinec Gudhamc

Miscellaneous Components

Levoglucosand “Phytosterol” (?) C10H14O (a furan ?) “Resins” (?) “Resin acids” (?)

Aldehydes

Formaldehyde Acetaldehyde Butyraldehyde Acrolein (?) Benzaldehyde 2-Furaldehyde (?)a

Other N-containing components

Pyrrole (?) “Pyrroles” (?) “N-Methyl-pyrrolidines” (?) Pyridine “Picoline” (?) “Lutidine” (?) “Collidine” (?) “Pyridine bases” (?) Methylamine (?) “Chlorophyll degradation products” (?) “Uric acids” (?)

Inorganic Components

Ammonia Carbon monoxide Carbon dioxide Hydrogen cyanide Hydrogen sulfide Thiocyanic acid (?) Oxygen Arsenicb “Acetates” (?) “Chlorides” (?) “Cyanides” (?) “Nitrates” (?)

The question mark indicates that Kosak did not consider the evidence in the literature to be definitive proof of the identity of the component. Probably present as As2O3. c Subsequent study demonstrated this component was not a well-defined compound but an artifact, a mixture, or an ammonium salt [see discussion by Johnstone and Plimmer (1971)]. d 1,6-Anhydro-β-D-glucopyranose a

b

individual tobacco types (flue-cured or burley or Oriental tobacco) or a blend of all three (50 mm of the tobacco rod smoked). The effect of a charcoal filter tip on the MSS levels of these carbonyl compounds was also determined. Their data are summarized in Table III-3. Modifications of gas chromatographic methods to determine vapor-phase carbonyl compounds in cigarette MSS continued for more than three decades, for example, see Miyake and Shibamoto (2564). Figure III-1 shows the approximate composition of MSS from a cigarette that delivers about 22.5 mg of wet total particulate matter (WTPM) and 17.6 mg of Federal Trade

Commission (FTC) “tar.” Excluding carbon monoxide and carbon dioxide, acetaldehyde is the vapor-phase component usually found at the highest level in cigarette MSS. The non-filtered cigarette MSS yield of acetaldehyde ranged from 18 µg/cigarette [Huynh et al. (1853a)] to 2815 µg/cigarette [Miyake and Shibamoto (2564)]. The acetone yield was slightly less than 50% of the acetaldehyde yield. Acrolein is the next most plentiful aldehyde, followed by formaldehyde, 2-furaldehyde, and crotonaldehyde. Per cigarette formaldehyde MSS yields ranged from 3.4 µg for filtered cigarettes to 283 µg in nonfiltered cigarettes [Schaller et al. (3427), Miyake and Shibamoto (2564)].

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Table III-2 Studies on Low Molecular Weight Carbonyls in Tobacco and Tobacco Smoke: Derivatizing Agents Description Girard T or Girard P reagent Aldehydes and ketones in cigarette MSS separated by conversion to Girard T or Girard P derivatives; derivatives separated by paper chromatography. Girard T or Girard P derivatives of cigarette MSS aldehydes and ketones were characterized my mass spectroscopy. 4-Nitrophenylhydrazine (4-NPH) To isolate and identify the low boiling aldehydes and ketones in cigarette MSS, they were derivatized with p-nitrophenylhydrazine. 2,4-Dinitrophenylhydrazine (2,4-DNPH) Classification of the structures of various carbonyl compounds from the UV and IR spectra of their 2,4-DNPH derivatives. Cigarette MSS aldehydes and ketones, regenerated from Girard T or Girard P derivatives, were characterized by conversion to their 2,4-DNPH derivatives. 2,4-DNPH derivatives of tobacco smoke carbonyls were separated by paper and column chromatography. Various keto acids in tobacco seeds were identified from their 2,4-DNPH derivatives. Levels of mono- and dicarbonyl components of cigarette MSS were estimated by spectrophotometry of their 2,4-DNPH derivatives. The levels of low molecular weight aldehydes and ketones in cigarette MSS were estimated from their 2,4-DNPH derivatives. After removal of other oxidizable material, the glycerol content of tobacco could be estimated by oxidation of the glycerol and conversion of its oxidation product to its 2,4-DNPH derivative. Examination of 2,4-DNPH derivatives from tobacco and smoke revealed presence of several keto acids. Carbonyl components of cigar MSS were characterized by IR, UV, x-ray diffraction, and paper chromatography of their 2,4-DNPH derivatives. Examination of the 2,4-DNPH derivatives of tobacco smoke carbonyls revealed the presence of several dicarbonyl compounds. Identification of dicarbonyl components of tobacco smoke via their 2,4-DNPH derivatives. To aid in identification of aldehydes and ketones in tobacco smoke and in cellulose smoke, over 90 2,4-DNPH derivatives were prepared to serve as melting point and spectral standards. Carbonyl components in cigar MSS identified after 2,4-DNPH derivative formation, followed by exchange reaction of 2,4-DNPH derivatives with α-ketoglutaric acid. α-Ketoglutaric acid exchange procedure applied to identification of low molecular weight carbonyl components of tobacco. 2,4-DNPH derivatives of low molecular weight carbonyl components of tobacco smoke were separated by TLC. 2,4-DNPH derivatives previously prepared (1238) were used to characterize carbonyl components in cigarette smoke. Instead of α-ketoglutaric acid, oxalic acid and p-dimethylaminobenzaldehyde were used in exchange release of low molecular weight smoke carbonyl components from their 2,4-DNPH derivatives. 2,4-DNPH derivatives of cigarette smoke carbonyls separated by gas chromatography. Formaldehyde level of cigarette MSS estimated by HPLC of its 2,4-DNPH derivative. The levels of C1 through C4 aldehydes and ketones in cigarette MSS were estimated by HPLC of their 2,4-DNPH derivatives. 2,4-DNPH derivatives of acrolein (propenal) and acetone from tobacco smoke were separated by HPLC. The level of 5-hydroxymethyl-2-furaldehyde in tobacco and tobacco smoke were estimated via its 2,4-DNPH derivative. Volatile, low molecular weight carbonyl components of the headspace from tobacco and from MSS were quantitated through their 2,4-DNPH derivatives. Development of method to determine formaldehyde in cigarette sidestream smoke; method applicable to other low molecular weight carbonyl components of sidestream smoke. Low molecular weight carbonyl compounds in ETS were collected as their 2,4-DNPH derivatives. 3-Methylbenzothiazolone hydrazone hydrochloride Aliphatic aldehydes in MSS were estimated by derivative formation, followed by colorimetry. Aliphatic aldehydes in MSS were estimated by derivative formation, followed by colorimetry. Analysis refined to permit estimation of acrolein (propenal). Aldehyde and Ketone Derivatization Review of compounds used to derivatize aldehydes and ketones in tobacco smoke.

Reference

Seligman (3581) Resnik and Seligman (3108) Sakuma et al. (3396)

Jones et al. (1977a) Seligman (3581) Seligman and Edmonds (3582) Glock and Jensen (1312) Harrow et al. (1540) McRae and Mold (2525) Mold and McRae (2591) Martin et al. (2581) Glock (1310) Schepartz and Ogg (3438) Halter et al. (1491) Martin (2469) Fredrickson et al. (1238) Schepartz and McDowell (3436) Stephens et al. (3817) Lindsey et al. (2369) Frederickson et al. (1239) Jones and Monroe (1978a) Donzel (1049) Hodge and Mansfield (1670) Mansfield et al. (2456) Canon and Frank (591) Manning et al. (2452) Perini and Bell (2930) Brunnemann et al. (500) Bell et al. (243) DeLuca (929) Weaving (4155) Davis and Sneade (915)

Green and Rodgman (1373)

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The Chemical Components of Tobacco and Tobacco Smoke

Table III-3 Analysis of Cigarette Mainstream Smoke by Gas Chromatography Puffs/cig, avge

Cigarette Sample a Flue-cured, non-filtered Burley, non-filtered Oriental, non-filtered Tobacco blend, non-filtered Tobacco blend, carbon filtered a

Acetaldehyde µg/cig

Acetone µg/cig

Acrolein µg/cig

856 847 726 832 208

372 533 385 440 42

83 57 54 75 11

9.3 7.3 11.0 8.0 8.0

50-mm of 65-mm tobacco rod smoked during analysis

Because of the extreme differences between the levels of various components in cigarette smoke, levels that vary from milligrams per cigarette for nitrogen, carbon dioxide, and carbon monoxide to picograms per cigarette for several N-heterocyclic

TOTAL MAINSTREAM SMOKE

WET TOTAL PARTICULATE MATTER (WTPM) 22.5 mg [4.5%]b

3.5 mg [0.70%]b {15.6%}c

Water Nicotine “Tar”

1.4 mg [0.28%]b { 6.2%}c

17.6 mg [3.52%]b {78.2%}c

amines (Trp-P-1 and Trp-P-2), a logarithmic plot of the levels of specific MSS components was found to be a convenient way to compare their deliveries. In Figure III-2, a truncated form of the original logarithmic plot presented by Green and Rodgman 500 mga

VAPOR PHASE

477.5 mg [95.5%]

20.0 mg [4.0%]b

Waterd

295.0 mg [59.0%]b

Nitrogen

65.0 mg [13.0%]b

Oxygen Carbon dioxide Carbon monoxide Argon + helium + Neon + hydrogen

Alcoholse Acids Aldehydes and ketones Miscellaneous Alkanes Terpenoid hydrocarbons Smoke pigment Alkaloid derivatives Esters Phenols

Unidentifiedh Total weight =

3.5 mg [20.0%]f 2.9 mg [16.5%]f 2.5 mg [14.2%]f 2.3 mg [13.2%]f 1.1 mg [ 6.2%]f 1.1 mg [ 6.2%]f 0.9 mg [ 5.1%]f 0.8 mg [ 4.5%]f 0.8 mg [ 4.5%]f 0.8 mg [ 4.5%]f

62.5 mg [12.5%]b 20.0 mg [4.0%]b 7.5 mg [1.5%]b

“other components”

7.5 mg [1.5%]b

Hydrocarbons

3.8 mg [50.6%]g

Aldehydes + ketones Nitriles Miscellaneous Heterocyclics Alcohols Acids Esters

2.0 mg [26.7%]g 0.60 mg [8.0%]g 0.60 mg [8.0%]g 0.15 mg [2.0%]g 0.15 mg [2.0%]g 0.12 mg [1.6%]g 0.08 mg [1.1%]g

0.9 mg [ 5.1%]f 17.6 mg

Total weight = 7.50 mg

Note: The properties of the cigarette studied were as follows: 85-mm filtered cigarette; 68-mm, tobacco rod; 17-mm triacetin-plasticized cellulose acetate filter tip; cased commercial American blend a It is now estimated that over 5000 components have been identified in MSS from tobacco cigarettes. Some components such as water, the simple phenols, hydrogen cyanide, and the volatile N-nitrosamines are found in both the vapor and particulate phases of cigarette MSS. Hence the total of the number in the two phases appears to exceed the number in the whole. b Value in brackets represents percent of Total Mainstream Smoke weight, 500 mg. c Value in parentheses represents percent of WTPM, 22.5 mg. d Much of this water is contributed by the air drawn through the cigarette during puffing (35-ml puff, 1-sec duration, 1 puff/min, total puffs = 10) in a laboratory whose atmosphere is controlled to the specifications proposed by the FTC; namely, temperature = 25°C, relative humidity (RH) = 60%. e This class of compounds includes added humectants (glycerol, propylene glycol) transferred from the tobacco rod to the MSS. The transferred humectants constitute about 10 to 12% of the FTC “tar”. f Value in brackets represents percent of FTC “tar” weight, 17.6 mg. g Value in brackets represents percent of “Other Components” weight, 7.5 mg. h There have been various estimates of the number of unidentified components present in extremely small amounts in the FTC “tar”. Several investigators have estimated the number of unidentified components to range from five to twenty times the number of identified components, i.e., from about 20000 to 100000.

Figure III-1  Approximate composition of cigarette mainstream smoke.

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Aldehydes and Ketones

Vapor phase

Nitrogen

Mainstream smoke yield/cig

Particulate phase

400 mg 200

Oxygen, carbon dioxide

Water, carbon monoxide

100 mg 80 40 20

FTC “tar”

10 mg 8

4 2 Acetaldehyde Isoprene Acetone Limonene Nitric oxide HCN Acrolein 1, 3-Butadiene Formaldehyde 2-Furaldehyde Crotonaldehyde Benzene Acrylonitrile

1000 µg = 1 mg 800 400 200

Water

Humectants (glycerol, propylene glycol) Total alkanes Saturated aliphatic esters

100 µg 80

Solanesol Phytosterols

40

Solanesyl esters

Nicotine The acids: palmitic, stearic, oleic, linoleic, linolenic Catechol Total alkyl pyridines

20 10 µg 8

Phenol

o-Cresol Phytyl esters

4

α-Tocopherol Solanesyl acetate

Indole Indole, 3-methylAnabasine

Figure III-2  Cigarette mainstream smoke components: logarithmic plot.

(1373), shows the cigarette MSS yields of several of the most plentiful vapor-phase aldehydes and acetone. Table III-4, modified and updated from similar tables presented by Chortyk and Schlotzhauer (722) and by Baker (171a), summarizes the major precursor relationships proposed and/ or demonstrated to date between tobacco leaf components and tobacco smoke components. These proposals are based in part on the results of a great variety of pyrolysis studies. In some cases, the validation of the proposals is based on the results obtained by addition of leaf components to tobacco and assessing the effect on the levels of specific MSS components when the “spiked” tobacco is actually smoked in a

cigarette and its MSS composition is compared to that of the MSS from the control tobacco cigarette. In their quantitation (via their 4-nitrophenylhydrazone derivatives) of several aldehydes and ketones in the MSS from cigarettes made from flue-cured laminae and from fluecured midribs, Sakuma et al. (3396) reported no significant differences between the MSS yields of the compounds listed in Table III-5. However, many were much reduced when the cigarette was tipped with a charcoal filter. From their study of the pyrogenesis of acrolein (propenal) from glycerol, Doihara et al. (1023) and others deduced that a tobacco smoking product that contains glycerol as a

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The Chemical Components of Tobacco and Tobacco Smoke

Table III-4 Precursors in Tobacco of Aldehydes and Ketones in Tobacco Aldehydes and Ketones Formaldehyde, acetaldehyde, 2-propenal (acrolein), acetone, α,β-dicarbonyls, furaldehydes

Precursors sugars

polysaccharides (cellulose, starch, and/or pectin)

lignin pectins C1-C5 aldehydes C3-C4 ketones 2-Furancarboxaldehyde Acetaldehyde Propanal Propanal, 2-methyl- (isobutyraldehyde) 2-Propenal 2-Butenal (crotonaldehyde) 2-Furancarboxaldehyde 2-Furancarboxaldehyde, 5-methyl2-Butanone 3-Buten-2-one

pectin

References Gager et al. (1264, 1265) Higman et al. (1647) Houminer and Patai (1835) Johnson et al. (1960) Fredrickson (1228) Fredrickson et al. (1238) Newell and Best (2764) Zamorani et al. (4398c) Martin et al. (2468a) Scheijen and Boon (3428) Newell and Best (2764) Scheijen et al. (3429) Squire and Waymack (3779a)

cellulose

Kato et al. (2046) Sakuma et al. (3401, 3402, 3404, 3045) Wakeham and Silberman (4104) Yamazaki and Saito (4369)

triglycerides

Kitamura (2111a)

Formaldehyde Acetaldehyde Acetone 2-Propenal 2-Propenal

glycerol

Doihara et al. (1023, 1024)

glycerol

2-Propenal

polysaccharides lignin

Aromatic aldehydes: Benzaldehyde, 3,4-dihydroxy- (protocatechualdehyde), Benzaldehyde, 4-hydroxyBenzaldehyde, 4-hydroxy-3-methoxy- (vanillin), Benzaldehyde, 3,5-dimethoxy-4-hydroxy- (syringaldehyde)

lignin

Harbin and Laurene (1497) Kröller (2192, 2196) Kobashi et al. (2144) Wynder and Hoffmann (4337) Burton (535) Fagerson (1170a) Kaburaki et al. (2003) Kato (2042) Kato et al, (2043, 2046) Kato et al. (2043) Martin et al. (2468a) Yang and Wender (4378)

Direct transfer from tobacco; however, lignin is the most likely precursor of many aromatic aldehydes as well as many aromatic acids in tobacco.

humectant has an enhanced potential for the formation and release of acrolein (propenal) during smoking [see Wynder and Hoffmann (4337)]. In their study of the levels of acrolein, acetaldehyde, acetone, hydrogen cyanide, nitrogen oxides, nicotine, and total solids in pipe tobacco MSS, Harbin and Laurene (1497) reported

Wender and Yang (4163) Yang and Wender (4378, 4379)

that the acrolein delivery increased as the glycerol level was increased by addition but the acrolein delivery eventually leveled off when the glycerol addition exceeded 6%. From an examination of the structure of lignin [see Ball (176a)], it is obvious why its pyrolysis products include a variety of phenolic aldehydes and acids, many of which

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Aldehydes and Ketones

Table III-5 Aldehydes and Ketones in Mainstream Smoke from All Lamina and All-Midrib Cigarettes In Mainstream Smoke From Flue-Cured Tobacco, µg/cig Carbonyl Compound

Lamina

Midrib

Formaldehyde Acetaldehyde Propanal Propanal, 2-methylPropenal (acrolein) Butanal 2-Propanone (acetone) 2-Butanone

5 685 97 103 184 36 217 159

10 779 81 57 156 21 220 186

have been identified in cigarette MSS. Lignin is composed of coniferyl alcohol {I}, p-coumaryl alcohol {II}, and sinapyl alcohol {III} in a variety of ratios that are dependent on the plant species (Figure III-3).

The Assertion of Aldehydes and Ketones as Ciliastatic Tobacco Smoke Components The reports by Wynder et al. (4306a, 4306c) in the early 1950s that cigarette smoke tar or CSC was tumorigenic to mouse skin prompted an intense search for the responsible component(s). Initially, the PAHs were selected for investigation because of the wealth of chemical and biological data generated on a great number of them following the synthesis of DB[a,h]A in 1929 (760, 1184), the isolation and identification of B[a]P from coal tar in 1932 (796a, 797), and the demonstration of the potent tumorigenicity of both of them to mouse skin by the Kennaway group (194, 796a, 797, 2078). Almost immediately after the report by Wynder et al. (4306a) of the mouse skin-painting results with tobacco tar, the PAHs were proposed by some investigators to be the major tumor initiators in CSC. Because of its level in CSC and its potency in mouse-skin tumorigenesis, B[a]P was defined as the most significant of the PAHs in tobacco smoke. CH2=CH-CH2OH

We have demonstrated experimentally … that 0.0001 per cent or even 0.0005 per cent benzopyrene in acetone will not produce any tumors in the present experimental mouse or

CH2=CH-CH2OH

OCH3 OH I

However, it was soon recognized that neither the B[a] P content nor its tumorigenicity could explain the biological response observed in the mouse skin-painting bioassay. Similarly, neither the total content of the PAHs tumorigenic to mouse skin nor their summed tumorigenicities could explain the observed biological response. In fact, it was pointed out many times over the next several decades that the levels of B[a]P and other tumorigenic PAHs in tobacco smoke condensate accounted for less than 3% of the observed tumorigenicity [Wynder and Wright (4353, 4354), Wynder and Hoffmann (4307, 4308, 4312, 4316, 4317, 4319, 4332, 4342), Druckrey (1056), Roe (3310, 3311), USPHS (3999, 4005, 4009, 4010), Lazar et al. (2320), Stedman (3767), Selikoff et al. (3584a), Coultson (830)]. As early as the mid-1950s, Wynder and Wright (4353) noted that the concentration of B[a]P in CSC was insufficient to account for its observed carcinogenicity to mouse epidermis: “The concentration in which benzo[a]pyrene seems to be in cigarette tar is insufficient to account for the observed carcinogenic activity to mouse epidermis.” At the 1957 Blatnik Committee hearings, Wynder reported Wright’s opinion [Wright (4282a)] on the subject as well as his own [Wynder (4296)]. Wynder noted that much attention had been directed at the PAH B[a]P. So much in fact that, as Wynder stated, B[a]P had become an issue in itself because it was one of the known tumorigenic substances and everyone tried to blame everything on it alone. During his testimony, he also noted that his Sloan Kettering group had repeatedly stated that the amount of B[a]P in tobacco tar was insufficient to explain the animal results published by his group. He added that cigarette tar contained numerous other B[a] P-related compounds much more active than B[a]P and they most likely accounted for the majority of the activity, and it was more or less academic whether it was B[a]P or a dibenzopyrene or a dibenzanthracene or a substituted B[a]P because they were all formed in the same manner during the tobacco smoking process. That same year, Wynder and Wright (4354) wrote that, to that date, no carcinogens had been identified in large enough quantities in tobacco tar or its fractions to account for the observed activity in skin-painting studies:

CH2=CH-CH20H

H3CO OH II

OCH3 OH III

Figure III-3  Phenolic alcohol components of lignin.

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222 rabbit groups. Thus, there is conclusive proof that the animal results cannot be solely due to the benzopyrene content of tobacco [sic]. The benzpyrene content of the total tar as well as the active fractions is far too low to account alone for the positive results [in laboratory animal]. So far, no carcinogens have been identified in large enough quantity in tobacco tar or its fractions to account for the observed activity.

These Wynder-Wright 1957 results led to an intensive but unsuccessful eighteen-month search for a “supercarcinogenic” PAH. The absence of such a PAH was subsequently confirmed by the USDA group at Athens, Georgia, by their identification of over 500 PAHs in the PAH fraction from cigarette MSS, an identification procedure that completely accounted for the fraction in the cigarette smoke studied (3732, 3736, 3756–3759). In 1959, unable to explain the bioassay (mouse skin-painting) results with CSC on the basis of either its B[a]P content (less than 2% explainable) or its total PAH content (less than 3% explainable), Wynder and Hoffmann (4307) at the 1959 American Association for Cancer Research (AACR) meeting added the concept of promotion by low molecular weight phenols to the concept of tumor initiation by PAHs in an attempt (unsuccessful) to explain the bioassay results. They reiterated their view the following year at the 1960 AACR conference (4309): “The phenol fraction could be established as an important promoting portion of the tobacco smoke condensate.” A similar comment that the amount of tumorigenic PAHs found in CSC could not by themselves account for the total biological activity observed was included in a more detailed publication (4307) of their AACR presentation. They also stated (4308) that the higher PAHs played an important role in the carcinogenicity of CSC but when the various known concentrations of the carcinogenic PAHs as estimated in CSC were summed, it was obvious that they could not account for the established carcinogenicity of the CSC nor of its isolated PAH fraction. Several carcinogenic higher aromatic polycyclic hydrocarbons [are] present in tobacco smoke condensate. They include benzo[a]pyrene …, benzo[e]pyrene …, chrysene …, benz[a] anthracene …, dibenz[a,h]anthracene …, and dibenzo[a,i] pyrene … From the amount in which these materials have been found in tobacco smoke condensate it was evident that these, by themselves, could not account for the total biological activity observed.

In 1960, Van Duuren et al. (4027) reported the identification of several aza-arenes (dibenz[a,h]acridine, dibenz[a,j]acridine, dibenzo[c,g]carbazole) not only structurally similar to some of the known tumorigenic PAHs in CSC but also reported under certain conditions to be tumorigenic to mouse skin. Adding this class of tumorigenic cigarette smoke components to the assessment of the tumorigenicity of CSC failed to account for more than a few percent of the observed response. However, it should be noted that Candeli et al. (587) could not confirm the findings of Van Duuren et al. on the presence

The Chemical Components of Tobacco and Tobacco Smoke

of these three aza-arenes in cigarette MSS. During the next three decades, other research groups in Germany, Japan, and the United States were also unable to confirm the presence in cigarette MSS of dibenz[a,h]acridine, dibenz[a,j]acridine, and dibenzo[c,g]carbazole [3260, 3414, Table 12-7 in (172)]. Wynder and Hoffmann (4311) wrote that the PAHs in CSC accounted for not more than 3% of the total biological activity observed in mouse-skin bioassays: The polynuclear aromatic hydrocarbons are mainly formed during the combustion of tobacco. The tobacco of our standard cigarettes contains only very minute quantities of benzo(a)pyrene (0.02 ppm). A bioassay indicates that these polycyclic hydrocarbons of the condensate by themselves, however, can account for not more than 3 per cent of the total biological activity.

Wynder and Hoffmann (4312) also wrote that the established carcinogenicity of CSC to mouse epidermis could to a great extent be accounted for on the basis of initiating carcinogens, largely PAHs, and promoting substances, a major group of which was the phenols. This statement was not true in 1961, nor is it true now. In their lengthy 1964 review of tobacco carcinogenesis, Wynder and Hoffmann (4319) stated that no one could deny that tobacco products were tumorigenic even though no single component in tobacco smoke could by itself or jointly with other components account for the observed tumorigenic activity of such tobacco products to the skin of laboratory animals: “It is furthermore true that none of the agents is carcinogenic in the concentrations in which they are present in tobacco products.” Wynder and Hoffmann (4332) expressed similar views on the tumorigenicity of tobacco smoke components in their 1967 book, but they continued to maintain that the PAHs in cigarette smoke were important as tumor initiators: While BaP and other carcinogenic PAH can by themselves account for only a small portion of the total tumorigenic activity of cigarette smoke condensate, probably less than 2%, they are, nevertheless, of obligatory importance as tumor initiators.

The next year, Wynder and Hoffmann (4342) wrote: Carcinogenic polynuclear hydrocarbons in the concentrations present in tobacco “tar” clearly do not, by themselves, account for the observed carcinogenicity.

On several occasions, the U.S. Surgeon General in his periodic reports on smoking and health discussed the relationship between the levels of PAHs in cigarette smoke, their tumorigenic potency to mouse skin, and the observed biological response with CSC in mouse skin-painting bioassays. The results of a number of such assays [mouse skin-painting] present a puzzling anomaly: the total tar from cigarettes has about 40 times the carcinogenic potency of the benzo(a) pyrene present in the tar. The other carcinogens known

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Aldehydes and Ketones to be present in tobacco smoke are, with the exception of dibenzo(a,i)pyrene, much less potent than benzo(a)pyrene and they are present in smaller amounts. Apparently, therefore, the whole is greater than the sum of the known parts. (3999)

Unable to explain the observed tumorigenicity to mouse skin of cigarette smoke condensate in terms of its content of known tumorigenic PAHs and/or tumorigenic aza-arenes, Wynder and Hoffmann (4307, 4309–4313) added the concept of promotion to their arsenal with particular emphasis on this property of the nontumorigenic PAH and low molecular weight phenolic components in the CSC. Inclusion of the concepts of initiation, promotion, and cocarcinogenesis by cigarette smoke components could only account for a small percentage of the number of tumor-bearing animals in the mouse skin-painting studies. This inability to explain the results observed in laboratory animals was a major creditability problem in the attempt to relate the laboratory animal data with CSC to human smoking experience. In an attempt to offset their failure to explain the mouse skin-painting bioassay results with CSC on the basis of its content of tumorigenic PAHs and aza-arenes, promoting and/ or cocarcinogenic phenols, and promoting and/or cocarcinogenic nontumorigenic PAHs, Wynder and Hoffmann (4314, 4315) added the concept of ciliastasis in an attempt (unsuccessful) to explain cigarette smoke tumorigenicity in smokers’ lungs. It was proposed that impairment of ciliary action would result in prolonged exposure of the ciliated tissue to the inhaled particle and the tumorigens contained therein. Obviously, ciliastasis is not relevant to the initiation of tumors in the mouse skin-painting bioassay with CSC. Cilia are small, hair-like entities covering the surface of certain portions of the upper respiratory tract* and these beat rhythmically and synchronously to move a thin layer of mucus upward toward the mouth where it is swallowed or expectorated. Inhaled particles may be entrained in this mucus and thus removed from the respiratory tract by its cilia-induced movement. Impairment of ciliary activity results in a failure to clear particles from the respiratory tract. This impairment of ciliary activity, known as ciliastasis, may be produced by a variety of inhaled materials. A detailed definition of cilia and description of their action appear in Rivera (3184a). Many of the early laboratory investigations on ciliastasis produced by cigarette MSS and/or its components were studies involving ciliated tissue from clams, mussels, or extirpated lung tissue from rabbits, etc. Usually, Hilding (1652a) is credited with initiating the interest in respiratory tract ciliastasis produced by cigarette MSS. In 1956 and 1957, he reported the results of his studies of the effect of cigarette smoke on ciliated tissue in the lungs of cows. However, numerous reports on studies of the ciliastatic action of cigarette MSS had appeared in the literature during the preceding two decades. *

Other anatomical sites in the mammalian body possess ciliated tissue, but these have no relevance to the discussion of tobacco smoke inhalation.

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In the late 1930s, Mendenhall and Shreeve (2530a) and Proetz (2991a) described their studies on ciliastasis. Mendenhall and Shreeve (2530a) reported that nicotine in cigarette MSS did not appear to be a contributor to ciliastasis in extirpated bovine tracheal tissue exposed to cigarette MSS, but the difference they observed between the smokes from nonmentholated vs. mentholated cigarettes indicated that menthol had a ciliastatic effect. However, in 1952, Rakieten et al. (3072b) reported no difference between the MSSs from nonmentholated vs. mentholated cigarettes in the ciliastasis induced in ciliated tissue from humans, rabbits, or rats. Their findings conflicted with those reported by Mendenhall and Shreeve. Rakieten et al. (3072b) also reported that nicotine contributed only slightly to the observed ciliastatic effect of cigarette MSS. Representative studies on ciliastasis produced by cigarette MSS include those of Dalhamn (891a), Falk et al. (1175), Kotin and Falk (2179), and Ballenger (178). In all these studies, cigarette MSS was reported to be ciliastatic in in vitro systems. Falk et al. reported that nicotine was involved in the ciliastasis induced by cigarette smoke. However, Guillerm et al. (1451a) reported that neither nicotine nor hydrogen cyanide was a contributor to the ciliastasis produced by cigarette MSS when tested individually at the concentrations determined in cigarette MSS. They reported that all the aldehydes and ketones tested at their concentrations in cigarette MSS were ciliastatic and acetaldehyde and acrolein appeared to act synergistically in the ciliastatic action. In 1962, Wynder and Hoffmann (4314) combined the ciliastasis concept with the three tumorigenesis factors mentioned above: It was proposed that impairment of ciliary action would result in prolonged exposure of the ciliated tissue to the inhaled particle and the tumorigens contained therein. For the CSC, they reported low molecular weight phenols to be in vitro ciliastats and that cellulose acetate filters plasticized with triacetin substantially reduced the ciliastatic effect of phenols. The same year, Davis and George (911a) reported the effectiveness of triacetin-plasticized cellulose acetate in reducing the phenols level in cigarette MSS with the corresponding reduction of the observed ciliastasis. Because of the assertion that low molecular weight phenols were promoters for tumorigenic PAHs and thus played a role in CSC tumorigenesis and possibly in cancer causation in smokers, research was underway to find methods to reduce their levels in cigarette MSS, for example, the studies at Lorillard on selective phenols filtration by Spears (2399, 3765), at R.J. Reynolds Tobacco Co. (RJRT) by Laurene (2295) and Laurene et al. (2306), by Hoffmann and Wynder (1791), Mokhnachev et al. (2579), and Morie (2628, 2629, 2636) and on phenol precursors by Rodgman et al. (3251, 3277, 3305, 3306), and by Wynder and Hoffmann (4317) on the precursors in tobacco of the low molecular weight phenols in tobacco smoke. Obviously, the results of these studies were equally applicable to reducing levels of phenols because of their alleged ciliastatic action in the respiratory tract. Wynder and Hoffmann (4317) and Wynder et al. (4350) reported the results of their study of the ciliastatic components

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in cigarette smoke condensate: Nicotine was not a factor in the ciliastasis of CSC; the phenolic fraction and the acidic fraction were significant ciliastats. The same year, Kensler and Battista (2083, 2084) reported their findings on the ciliastatic activity of vapor-phase components of cigarette MSS and its reduction by activated carbon filters. Falk et al. (1173a, 1175) also described the effect of many of the same smoke components on mucus flow. Hydrogen cyanide, acrolein, formaldehyde, acetaldehyde, nitrogen oxides, ammonia, and phenol were considered important vapor-phase ciliastats.* The Kensler-Battista research on the effectiveness of carbon in reducing vapor-phase ciliastats in cigarette MSS was reported within a few months of the publication of the Reader’s Digest article on the effectiveness of carbon-containing filters in reducing ciliastats in cigarette MSS and the appearance in the marketplace of Liggett and Myers (L&M) Lark cigarette. Its filter included a chamber filled with a specially treated carbon based on a patent issued to Keith of L&M R&D. The Kensler-Battista study was performed at A.D. Little and was contracted by L&M (2083, 2084). Because of these reports on vapor-phase components of cigarette MSS, emphasis at RJRT R&D was shifted from attempts to reduce the levels of the phenols reported to be promoters or cocarcinogens to attempts to reduce the levels of vapor-phase components reported to be ciliastatic. These vapor-phase components included the simpler, volatile phenols which equilibrate between MSS vapor phase and particulate phase. From 1963 to 1972, a great variety of filter-tip additives were examined with respect to their ability to remove specific MSS components reported to be ciliastatic in in vitro experiments. After the Kensler-Battista publications, numerous publications appeared on the reduction of the delivery of ciliastatic components by filter tips (893a), on the ciliastatic action of nicotine (178), and on the ciliastatic activity of phenol (295). In a preliminary study, Rodgman et al. (3306) examined the removal of water-soluble vapor-phase ciliastatic components from cigarette MSS by saliva and mucous secretions in the upper respiratory tract. They reported that the levels of representative ciliastats such as the aldehydes and ketones were substantially reduced in the oral cavity, resulting in a diminution of the levels reaching the ciliated tissue in the lower respiratory tract. Rodgman et al. also emphasized that such oral cavity absorption of water-soluble ciliastats did not substantially affect the levels of ciliastatic components in the particulate phase. External impetus for this investigation was provided by comments in the Advisory Committee’s 1964 Report to the U.S. Surgeon General (3999) on the possible oral cavity removal of water-soluble ciliastats, by comments by Dalhamn *

Because of its vapor pressure properties, phenol is present in both the particulate phase and the vapor phase of cigarette MSS aerosol. Thus, it is amenable to removal from the vapor phase by selective filtration and to reduction of its level in the particulate phase by all the technologies whereby MSS particulate phase or “tar” delivery is reduced, for example, filtration efficiency, air dilution (increased paper porosity, filter-tip ventilation), and inclusion of expanded tobacco in the blend.

The Chemical Components of Tobacco and Tobacco Smoke

and his colleagues (893a, 894b) on the ciliastatic activity of filtered and nonfiltered cigarette MSS and by Wynder (4301). In 1965, Wynder et al. (4304) wrote: The principal volatile ciliatoxic components appear to be water-soluble … Important considerations are the temperature of the respiratory tract … and the nature of the overlying mucous coat, the layer that all ciliastatic components penetrate to act upon cilia …

In their study, Rodgman et al. (3306) showed that passage of cigarette MSS over moistened filter paper strips substantially reduced the levels of the vapor-phase ciliastats but did not produce much effect on the “tar” delivery. Rodgman and Cook (3289) examined a variety of carbon-containing filter tips and found that the delivery of several vapor-phase ciliastats (the aldehydes and ketones) could be reduced substantially by some of them. In some instances, the ciliastatic components adsorbed on the carbon were eluted from the carbon as the fire cone approached the filter tip and the filter tip temperature was increased. As a result, the levels of these components were inordinately increased in the last few puffs from the cigarette. RJRT was not the only U.S. tobacco company interested in the removal of water-soluble ciliastats from cigarette MSS. † Industrial Bio-Test Laboratories (3A12), under contract to RJRT, conducted a series of studies on in vitro ciliastasis of cigarette MSS from 1964 through 1967. Major findings included: (1) The theory of reduction of the levels of ciliastats in the smoke stream by moist surfaces was confirmed. (2) The ciliastatic activity of the MSS particulate phase was essentially unchanged by passage over moist surfaces. (3) The ciliastatic activity of cigarette MSS was substantially reduced by passage of the MSS through a carbon-containing filter tip. In 1966, Dalhamn (891a) and Dalhamn and Rylander (893c) reported on the effect of filtration on the delivery of ciliastatic compounds in MSS. They reported that in vitro ciliastats were present in both the vapor and particulate phases of MSS. In their 1964 lengthy review and 1967 book, Wynder and Hoffmann (4319, 4332) commented on ciliastasis induced by cigarette MSS: All studies reported to date have shown that cigarette smoke affects the metachronic activity of cilia, a motion that is necessary to propel the viscid mucoid mass. During inhalation, in the absence of effectively beating cilia, mucus flow slows down and perhaps stops. At that time, components in cigarette smoke may act upon the underlying cells, as can the entrapped particles. †

In 1965, American Tobacco marketed the Waterford cigarette whose filter contained encapsulated water. Prior to smoking the cigarette, the smoker would gently squeeze the filter tip, rupture the capsules to release the encapsulated water which would spread throughout the interstices between the filter-tip fibers. Water-soluble MSS vapor-phase components would be “scrubbed” from the smoke stream. The Waterford had a very short life in the marketplace.

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In their mid-1960s publications, Wynder and Hoffmann commented several times on the fact that most of the known ciliastatic components of MSS demonstrated to be ciliastatic in various in vitro systems were water soluble and this property would markedly influence their fate and behavior during and after inhalation. Wynder and Hoffmann (4330) noted: As far as human smoking habits are concerned, it remains also to be estimated to which extent volatile smoke components reach the bronchial tree. Preliminary studies indicate that a significant proportion of the gaseous components is being retained within the oral cavity.

Later, Wynder and Hoffmann [see p. 542 in (4332)] wrote: Water-soluble volatile components, which are primarily responsible for the results of the acute in vitro short-term cilia toxicity tests, are, to a large extent, removed when cigarette smoke contacts the saliva in the mouth and the abundant secretions of the trachea and main bronchi.

They added [see p. 646 in (4332)]: In man’s manner of smoking, however, volatile components are retained to a significant degree in the oral cavity and may, therefore, be far less important than when tested experimentally.

These words, perhaps prophetic, were shown to be true by Dalhamn et al. (892), who reported in 1968 that as much as 60% of the water-soluble (and ciliastatic) components of cigarette MSS were absorbed in the oral cavity of the human smoker, whereas the absorption of water-insoluble (and nonciliastatic) components such as isoprene was low (about 20%). They also reported that about 16% of the MSS particulate matter was retained in the mouth. Mouth absorption of acetaldehyde and acetone averaged about 57%. Earlier, Rodgman et al. (3306) had conducted a study similar to but much less elaborate than that of Dalhamn et al. (892). Rodgman et al. studied the mouth absorption of components of the MSS from five different brands: The total absorption of all vaporphase aldehydes and ketones averaged 53%; the absorption of isoprene averaged less than 10%. The more than a dozen cigarette brands tipped with carbon-containing filter tips were already losing market share by the time Dalhamn et al. reported the results of their study of the mouth absorption of water-soluble vapor-phase components (892). Their scientific communication, plus the consumer unacceptable “carbon-filter” off-taste, produced not only a further reduction of sales but also diminished interest, both within and outside of the tobacco industry, in vapor-phase ciliastats as participants in respiratory problems attributed to cigarette MSS. From 1968 through 1972, study continued not only at RJRT R&D but also throughout the tobacco industry on ways to reduce the levels of vapor-phase components, many of which were reported to be ciliastatic in in vitro systems. The major effort was aimed at reducing the level of hydrogen cyanide (a potent in vitro ciliastat) because of its level in cigarette

MSS (about 200 to 400 µg from a cigarette delivering 15 to 25 mg of FTC “tar”), its toxicity (other than ciliastasis) when examined alone, and the fact that consumers would be more familiar with the toxic properties of hydrogen cyanide (also known as hydrocyanic acid or “cyanide”) than with the toxic properties of MSS components such as acrolein or phenol. Most of the effort during this period dealt with filter-tip additives other than carbon. Thus, in the late 1960s it was known that in vitro ciliastatic components in the vapor phase of MSS were not reaching the ciliated areas of the respiratory tract in the concentrations first considered to be a problem and the levels of the ciliastatic components in the MSS particulate phase could be controlled by the filtration methods used to control “tar” delivery. Another technology to control the per cigarette deliveries of both vapor-phase and/or particulate-phase MSS components (whether they be ciliastatic or not) was air dilution via filter-tip ventilation. At RJRT R&D, basic research on this cigarette design technology, subsequently classified as significant in the generation of a “safer” or “less hazardous” cigarette, was pursued into the mid-1970s (3116a, 3119a, 3120). Dalhamn (891c) stated with regard to a “less hazardous” cigarette: If … one were to venture a reply to the question of what a less hazardous cigarette would be like, I cannot for the moment find a better one than that given by Rylander and myself [to the 1968 Consumer Subcommittee of the U.S. Senate Committee on Commerce]: Our belief, based upon the scientific knowledge available at present, is that the only way to guarantee a reduction in the harmful effects of inhaled smoke is to decrease the overall exposure. This can be done by reducing the number of cigarettes smoked or by using filter cigarettes, provided the reduction brought about by the filter will equal in all respects and for all potentially hazardous compounds the reduction in dose obtained if the number of cigarettes is reduced. Due to the limited amount of data and the difficulty of extrapolating from laboratory findings to man, we believe that a reduction of only selected components of cigarette smoke cannot be accompanied by a statement guaranteeing a reduction in the harmful effects of inhaled smoke.

The topic dealing with ciliastasis and MSS ciliastats (from testing in in vitro systems) is of particular interest with respect to the ETS situation because of the data showing:

1. The major ciliastatic components in tobacco smoke are water soluble. These include formaldehyde, acetaldehyde, crotonaldehyde, ethyl carbamate, and hydrazine:* all are water-soluble tobacco smoke components that appear as tumorigens

*

Other water-soluble tobacco smoke components categorized as ciliastats on the basis of in vitro test results include ammonia, hydrogen cyanide, acrolein, acetone, nitrogen dioxide, and low molecular weight phenols. The phenols are distributed between the particulate and vapor phases of tobacco smoke.

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Table III-6 In vitro Ciliary Activity, Cigarette Smoke Fractions, and Dose Level Smoke Fraction From Which Aqueous Extract was Obtained Phenolic fraction Acidic fraction c Neutral fraction “Insoluble” fraction Basic fraction

% Of Smokea

Immediate & Complete Ciliastasis at Dcb

  9.3 (16.0)d   2.2 (11.0) 47.2 (0.9) 14.0 (20.0)   8.7 (65.0)

Complete Ciliastasis in 10-40 min at D10

0.03 0.04 — 1.1 1.95

0.015 0.02 0.27 0.55 0.98

No Apparent Ciliastasis at Do

Dc/Do

0.002 0.007 0.034 0.055 0.08

15 6 8e 20 24

The unit for Dc, D10, and Do is g/100 ml. The values for each fraction as a percentage of total smoke condensate were previously described by Wynder and Hoffmann (4311, 4312) c Phenol-free. d Number in parentheses is percentage of smoke fraction that is soluble in water. e Value for D10/Do. a

b







on the various published lists of tumorigens in tobacco smoke (1727, 1740, 1741, 1743, 1744). 2. Dose reduction (effectively, dilution) of MSS or some of its “ciliastatic” components or ciliastatic fractions eventually results in a dose or concentration level at which no ciliastasis is produced in the in vitro systems used. 3. A large proportion of the inhaled MSS components categorized as ciliastats (and in some instances as tumorigens) does not reach the ciliated areas of the respiratory tract because of their removal from the smoke stream during passage over the moist tissues of the mouth and trachea [see Rodgman et al. (3306), Dalhamn et al. (892)]). 4. Ciliastatic compounds inhaled nasally are removed from the inhaled gas stream by “resorption.”

This raises the question as to how much formaldehyde or acetaldehyde or crotonaldehyde in ETS, an already extremely dilute system, will reach the lung whether inhaled orally or nasally! Are the levels of these tobacco smoke components in ETS sufficient for these compounds to be included on the Hoffmann and Hecht list (1727), the Occupational Safety and Health Administration (OSHA) list (2825), the Hoffmann and Hoffmann lists (1740, 1741, 1743), or the Hoffmann et al. list (1744)?

Ciliastasis Studies with Cigarette Smoke Condensate Fractions Wynder and Hoffmann (4314) and Wynder et al. (4350) in their study with mussels of the ciliastatic activity of aqueous extracts of various fractions of cigarette smoke condensate demonstrated that reduction of the applied dose of each of the fractions tested eventually changed the ciliastasis from “immediate and complete” to “none.” Their findings are summarized in Table III-6. Calculation of the ratio Dc/Do, where Dc is the dose producing “immediate and complete” ciliastasis and Do is the dose producing “zero” ciliastasis, gives values ranging from

6 to 24, that is, a 24-fold dilution of every mainstream cigarette smoke condensate fraction tested in this study resulted in or would result in a non-ciliastatic situation. The data in Table III-6 originally presented at the annual AACR meeting by Wynder and Hoffmann (4314) were subsequently published, but in less detail, by Wynder et al. (4350).

Ciliastasis Studies With Individual Cigarette Mainstream Smoke Components Examination of the in vitro ciliastasis produced by a variety of MSS components reveals that for all components studied there is a level below which no ciliastasis is observed. Guillerm et al. (1451a) reported the results of their study of the effect of various MSS components in the in vitro system, ciliated rat trachea. Concentrations less than those shown in Table III-7 produced no ciliastasis in ciliated rat trachea. All of the compounds listed in Table III-7 are primarily vaporphase components of MSS. Wynder et al. (4350) in their study of the phenolic components of cigarette smoke also reported that reduction of

Table III-7 Lowest Concentrations in Ringer Solution Leading to Ciliastasis in Ciliated Rat Trachea Compound Propenal Formaldehydea Acetaldehydea Propanal Propanal, 2-methyl2-Furaldehyde 2-Butanone 2-Propanone a

Concentration, µg/L 90 200 3000 3500 4500 7500 80000 100000

On various lists of tobacco smoke tumorigens (1727, 1740, 2825).

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the concentrations of solutions of the simple phenols (phenol, o-cresol, m-cresol, p-cresol, o-ethylphenol, and 2,4-dimethylphenol) from 1.0% to 0.05% (a 20:1 dilution) reduced the ciliary activity of each solution in an in vitro system (ciliated mussel tissue) to zero: At the highest concentration (1.0%), the phenol derivatives demonstrated greater ciliastatic effects than did phenol itself. At the lowest concentrations tested (0.05%), none of the phenols induced ciliastasis.

Nose Inhalation of Environmental Tobacco Smoke vs. Mouth Inhalation of Mainstream Smoke On several occasions, Rodgman (3255, 3255a, 3257) discussed the effect of water solubility of tobacco smoke components reported to be ciliastatic in in vitro systems on the ultimate exposure of the smoker’s lungs to MSS or the nonsmoker’s lungs to ETS. Early in the study of the effect of MSS components on ciliary activity in in vitro systems, it was realized that all of the MSS components (formaldehyde, acetaldehyde, acrolein, hydrogen cyanide, formic acid, acetic acid, etc.) that produced ciliastasis in the in vitro systems were water soluble. This observation led to proposals by Dalhamn and Sjoholm (894b), Dalhamn and Rylander (893a), Rodgman et al. (3306), Wynder (4301), USPHS (3999), Wynder et al. (4304, 4305), and Wynder and Hoffmann (4332, 4342) that this water solubility would result in removal of substantial amounts of the in vitro ciliastatic components from the MSS by their solution in the aqueous fluids coating the surfaces of the oral cavity and trachea during the time that the MSS was held in and/or traversed these portions of the respiratory tract. The levels of ciliastats reaching the ciliated areas in the smoker’s lower respiratory tract would produce insignificant ciliastasis, if any at all. This “scrubbing” of ciliastatic components from the inspired MSS stream was demonstrated in smokers by Rodgman et al. (3306) and Dalhamn et al. (892, 893). Nasally inhaled components are removed in the nasal cavity by “resorption,” a process similar to the “scrubbing” of water-soluble components from gas streams such as MSS vapor phase. Dalhamn, in his 1961 study of ciliastatic activity, demonstrated that sulfur dioxide was a powerful ciliastat in vitro at or below 100 ppm but did not produce ciliastasis in vivo at or below 100 ppm because much of the sulfur dioxide was removed in the nasal cavity (891a). Sulfur dioxide was subsequently identified as a minor tobacco smoke vapor-phase component (3882). Dalhamn (891a) found that in rabbits exposed to 300, 200, and 100 ppm of sulfur dioxide, the percentage showing cessation of ciliary activity within 45 min was 90, 60, and 0, respectively. Removal of inhaled components in the nasal cavity, termed “resorption,” is similar to the “scrubbing” of water-soluble components from gas streams, such as the MSS vapor phase. This nasal resorption is an important process not only from a ciliastasis-MSS component point of view but also from an ETS point of view

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since ETS, in contrast to MSS which is primarily inhaled via the mouth, is inhaled primarily through the nose. ETS vaporphase components that would be removed through resorption in the nasal cavity include formaldehyde, acetaldehyde, crotonaldehyde, hydrazine, and possibly ethyl carbamate, five MSS components listed by Hoffmann and Hecht (1727) as “tumorigens” in MSS. Thus, very little, if any, of these watersoluble components, already highly diluted in ETS, would reach the lungs and the ciliated tissue to be involved in lung cancer causation attributed to ETS by some authors. As noted by Aviado (126a), data from inhalation studies in animals indicate it is unlikely that either formaldehyde or hydrazine contribute to pulmonary carcinogenesis. In 1965, Dalhamn and Rylander (893b) commented on the possible differences in the effects produced by mouth inhalation vs. nose inhalation of tobacco smoke: The most important point is probably that the smoke is administered through the mouth. If smoke is administered through the nose quite different absorption conditions are present, and it is likely that the smoke which enters the lungs differs considerably from that inhaled through the mouth. This could also be one of the factors which explains why in animal experiments no tumor-producing effects have been found by tobacco smoke in inhalation studies where the smoke was administered through the nose.

In 1968, Dalhamn et al. published the results of their studies with humans on the mouth absorption (892) and lung retention (893) of various components of cigarette smoke. As noted earlier, the findings that a substantial percentage of the levels of MSS water-soluble components demonstrated to be ciliastatic in vitro is absorbed in the oral cavity lessened the interest in ciliastasis produced by MSS components. The data generated by Dalhamn et al. also served a second useful purpose in that they demonstrated: (1) the remarkable difference, albeit with respect to only a few MSS smoke components, between the compositions of inhaled and exhaled MSS, and (2) all of the few components measured in the inhaled MSS were found in the exhaled MSS, that is, none was 100% retained in the lungs, etc., nor 100% absorbed in the oral cavity. These data are summarized in Tables III-8 and III-9. It is obvious that mouth absorptions of such water-soluble ciliastats as acetaldehyde (60%) and acetone (56%) are substantial (Table III-8), whereas the mouth absorptions of the relatively water-insoluble components isoprene (20%), toluene (28%), and CO (3%) are much less. The data in Table III-9 are derived from those of Dalhamn et al. (892, 893). The change in the composition of the MSS delivered by the cigarette to the composition of the MSS exhaled by the smoker is readily seen from the ratios, for example, acetaldehyde is inhaled by the smoker at a ratio of 31.3 µg/mg total particulate matter but is exhaled at a ratio of 8.3 µg/mg total particulate matter; acetone is inhaled at a ratio of 19.0 µg/mg total particulate matter but exhaled at a ratio of 66.7 µg/mg total particulate matter. Similarly, the MSS composition is altered by holding the smoke in the mouth without

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The Chemical Components of Tobacco and Tobacco Smoke

Table III-8 Lung Retention and Mouth Absorption of Several Cigarette Mainstream Smoke Components Per Cigarette Mainstream Smoke Inhalation into Lungs Smoke Component Acetaldehyde, µg Acetone, µg Acetonitrile, µg Isoprene, µg Toluene, µg CO, mg TPM, mg a b

Delivery

Retention

%

940 570 320 560 250 30.0b 30.0

930 490 282 554 232 16.2 28.8

99 86 91 99 93 54 96

Held in Mouth for 2 sec Exhaled 10 80 28 6 18 13.8 1.2

Absorbed in Moutha 560 320 230 110 70 0.9 4.8

%

Exhaled

60 56 74 20 28 3 16

380 250 80 450 180 29.1 25.2

No inhalation Per cigarette CO yield assumed to be the same as per cigarette TPM yield.

inhalation. Since these exhaled smokes, whether originally inhaled, held in the mouth with no or minimal inhalation, or some blend of both (inhalation and mouth retention ultimately contribute to ETS), it is obvious that the contribution is not equivalent quantitatively to the MSS originally generated by the cigarette. The data presented by Dalhamn et al. (892, 893) on lung retention of MSS components were similar to data reported earlier by Laskowski (2267) and to data on lung retention and mouth absorption of ciliastats by Rodgman et al. (3306). The various sets of data are summarized in Table III-10. Each set of data indicates that exhaled MSS is substantially different quantitatively from the inhaled MSS. If cigarette MSS is mouth inhaled and held for any length of time (a few seconds) in the mouth prior to being drawn into the lungs, some of the MSS water-soluble vapor-phase components are “scrubbed” from the smoke stream and reach the ciliated areas at much reduced concentrations. This is also true to a lesser degree for water-soluble components of the particulate phase (see Tables III-8, III-9, and III-10).

The exposure of the lungs to “resorbed” entities alleged to be tumorigenic will be much less than some authors claim. Similarly, in nose inhalation of ETS, some of its water-soluble components (formaldehyde, acetaldehyde, crotonaldehyde, ethyl carbamate, hydrazine)—alleged to be tumorigenic at the levels in MSS—will be “resorbed” in the nasal cavity and reach ciliated areas at concentrations reduced not only by the “resorption” mechanism but also by the dilution inherent in ETS generation from exhaled MSS and sidestream smoke produced during inter- and intrapuff smoldering. The exposure of the lungs to these “tumorigens”’ will obviously be substantially less than some writers claim. Thus, these mechanisms—“scrubbing” and “resorption”— effective in substantially diminishing the amounts of MSS water-soluble in vitro ciliastats that reach the lung during active smoking will be operative during ETS inhalation, whether oral or nasal, and diminish the amounts of the same and similar ETS components that reach the lung. This diminution in amounts will be particularly pertinent in the case of the smoke components formaldehyde, acetaldehyde, crotonaldehyde,

Table III-9 Difference Between Composition of Inhaled and Exhaled Mainstream Smoke and Between Mouth-Held and Exhaled Mainstream Smoke Per Cigarette Ratios, µg/g TPM or µg/g TPM Smoke Component Acetaldehyde, µg Acetone, µg Acetonitrile, µg Isoprene, µg Toluene, µg CO, mg TPM, mg a b

Delivery Ratio

Inhalation into Lungs and Exhaled, Exhaled MSS Ratio

Held in Mouth for 2 seca and Exhaled, Exhaled MSS Ratio

31.3 19.0 10.3 18.7 8.3 1.0b 1.0

8.3 66.7 23.3 5.0 15.0 11.5 1.0

15.1 9.9 3.2 17.9 3.2 1.15 1.0

No inhalation Per cigarette CO yield assumed to be the same as per cigarette TPM yield

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Table III-10 Lung Retention and Mouth Absorption Data % Retention or Absorption Laskowski (2267)

Rodgman et al. (3306)

Dalhamn et al. (892, 893)

Smoke Component

LRa

MAa

LR

MA

LR

MA

Aldehydes & ketonesb Acetaldehyde Acetone Acetonitrile Isoprene Toluene TPM Nicotine Pyridine Ammonia Phenols Carboxylic acids CO

99 —c — — — — — 67 98 98 57 44 —

— — — — — — — — — 56 — — —

80–90 — — — 80–92 — 80–90 — — — — — —

40–67 — — — 5-10 — 10–15 — — — — — —

— 99 86 91 99 93 96 — — — — — 54

— 60 56 74 20 28 16 — — — — — 3

LR = percentage retained in lungs; MA = percentage absorbed in mouth About 70 to 75% of the volatile aldehydes and ketones in MSS is acetaldehyde plus acetone. For cigarettes in the 1950s and 1960s, the acetaldehyde:acetone ratio approximated 2:1. c — = not determined. a

b

ethyl carbamate, and hydrazine on the Hoffmann and Hoffmann “List of 60” (1740). The following paragraphs include comments about two of the much researched smoke components formaldehyde and acetaldehyde. Formaldehyde yields in cigarette range from 3.4 µg for filtered cigarettes to 283 µg in unfiltered cigarettes (2564, 3427). This compound is usually found in the vapor phase. The suggested formation mechanism for formaldehyde is destructive distillation and pyrolysis of celluloses, starch, pectins, lignin, and sugars [Burton (535), Chortyk and Schlotzhauer (722), Gager et al. (1264, 1265), Green (1351), Johnson et al. (1960), Stedman (3797)]. In both indoor and outdoor air in the United States, formaldehyde is usually present at the generally nonirritating level of approximately 0.06 ppm (1145a). In May 1992, OSHA ruled the exposure limit to formaldehyde be reduced from 3 ppm to 0.75 ppm (2683a). Although most significant exposure to formaldehyde is generally industrial, it also naturally occurs in food, for example, fruits and vegetables (2111b). Levels of formaldehyde in fruits and vegetables range from 3.3 µg/g in spinach to 17.3 µg/g in apples (3986a). Formaldehyde is tumorigenic and mutagenic only at doses many-fold higher than that seen in cigarette MSS. Whether formaldehyde is mutagenic at noncytotoxic doses remains controversial due to the small number of studies and the variability of results (1873a). Formaldehyde reportedly has been found to induce aneuploidy (2363a, 2868a). In addition, results from some studies have suggested that humans routinely exposed to formaldehyde display increases in chromosomal aberrations and sister chromatid exchanges in peripheral lymphocytes. However, rodents treated with formaldehyde in vivo

gave negative results for chromosomal aberrations and assays for lethal mutations. Additional rodent studies on DNA damage showed unconvincing results as well (1873a). The overall tumorigenicity of formaldehyde was tested in two strains of rats and one strain of mice. Significant increases in squamous cell carcinomas of the nasal cavity were observed in both rat strains after inhaling highly cytotoxic doses of formaldehyde. However, no carcinomas were observed in any of the mice inhaling the same dose (2086a). In other studies to evaluate formaldehyde tumorigenicity, mice and hamsters were exposed via inhalation, rats via subcutaneous injection, and rabbits via exposure in oral tanks. At the time, the results from these studies were considered inadequate to evaluate the tumorigenic risk to humans. Although formaldehyde was tumorigenic in rats when administered at very high dose levels (2610a, 3789b), the evidence of its tumorigenicity in humans was considered by the International Agency for Research on Cancer (IARC) to be inadequate, until 2005 (3A03). Recently, IARC reevaluated the evidence on formaldehyde and reclassified it as a Group 1 human carcinogen (3A16). As noted previously, the reported MSS yield of acetaldehyde ranged from 18 µg/cigarette (1853a) to 2815 µg/cigarette (2564) for nonfiltered cigarettes. However, a substantial difference exists between the analytically derived yields of acetaldehyde and other water-soluble vapor-phase components reported to be ciliastatic and the smoker’s exposure to them. Dalhamn et al. (892) described how a substantial percentage of water-soluble components such as acetaldehyde are removed from the vapor phase of the smoke stream by solution in the aqueous fluids coating the oral cavity, thus never reaching the upper or lower respiratory tract. The

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proposed mechanisms of formation for acetaldehyde are destructive distillation and pyrolysis and its major precursors are reported to be the celluloses, pectins, starch, lignin, and sugars [Burton (535), Chortyk and Schlotzhauer (722), Gager et al. (1264, 1265), Green (1351), Johnson et al. (1960), Stedman (3797)]. Additional complexities exist regarding the predictability of biological activity. For example, a significant amount of vapor-phase water-soluble components such as formaldehyde and acetaldehyde are “scrubbed” from the smoke stream into solution by the fluids coating the oral cavity and upper respiratory tract; thus they reach the lung at a diminished level (892, 893). Similarly, only a modest percentage of a waterinsoluble component such as isoprene is retained by the smoker because a significant portion of it is exhaled. In light of these phenomena and the fragmentary nature of the data on actual exposure and retention, the possible physiological effect of formaldehyde, acetaldehyde, and isoprene at the cited cigarette MSS delivery ranges cannot be extrapolated. Very few studies have been performed in which a smoking machine or system was modified to approximate the effect of oral cavity fluids on the retention of specific MSS components. It has been known since the early 1950s and confirmed

in the 1960s that different classes of smoke components are retained to different degrees by the smoker (892, 2267, 3255, 3257, 3306). Thus, the composition of the cigarette MSS retained by the smoker is significantly different from that exhaled by the smoker. Also, both the biologically retained and exhaled smokes are obviously different compositionally from the cigarette MSS retained and analyzed by the smoking machine-collection system. While much emphasis was placed on the aldehyde and ketone components in the vapor phase of cigarette MSS because of their in vitro ciliastatic activity, much research was also conducted after the mid-1950s to identify aldehyde and ketone components in the particulate phase of cigarette MSS primarily because many were found to contribute consumer acceptable flavor and aroma properties to the MSS. As noted by Rodgman (3266), many of the aldehydes and ketones used by the tobacco industry in its flavor formulations [see listing by Doull et al. (1053)] are known components of untreated tobacco and/or its smoke. Thus, such additives are not strangers to the tobacco and/or its smoke but their addition increases the consumer acceptable flavorants. Table III-11 lists some of the tobacco and/or tobacco smoke components that have been or are used in flavor formulations.

Table III-11 Tobacco and/or Tobacco Smoke Aldehydes and Ketones Used in Flavor Formulations CAS No.

Chemical Abstracts Nomenclature

As Listed by Doull et al. (1053)

Smoke

Tobacco

benzaldehyde p-ethoxybenzaldehyde salicylaldehyde vanillin veratraldehyde o-tolualdehyde m-tolualdehyde p-tolualdehyde cuminaldehyde phenylacetaldehyde 2-phenyl-2-butenal piperonal 2-methylbutyraldehyde 3-methylbutyraldehyde trans, trans-2,4-decadienal decanal hexanal 2-hexenal valeraldehyde isobutyraldehyde cinnamaldehyde 5-methyl-2-thiophenecarboxaldehyde 2-tridecenal

+ — + + — + + + + + + + + + + — + + + + + + —

+ — + + + + + + + + + + — + + + + + + + + + +

1,3-butanediol 2,3-butanedione

+ +

+ +

Aldehydes 100-52-7 10031-82-0 90-02-8 121-33-5 120-14-9 529-20-4 620-23-5 104-87-0 122-03-2 122-78-1 4411-89-6 120-57-0 96-17-3 590-86-3 25152-84-5 112-31-2 66-25-1 6728-26-3 110-62-3 78-84-2 104-55-2 13679-70-4 7774-82-5

Benzaldehyde Benzaldehyde, 4-ethoxyBenzaldehyde, 2-hydroxyBenzaldehyde, 4-hydroxy-3-methoxyBenzaldehyde, 3,4-dimethoxyBenzaldehyde, 2-methylBenzaldehyde, 3-methylBenzaldehyde, 4-methylBenzaldehyde, 4-(1-methylethyl)Benzeneacetaldehyde Benzeneacetaldehyde, α-ethylidene1,3-Benzodioxole-5-carboxaldehyde Butanal, 2-methylButanal, 3-methyl2,4-Decadienal Decanal {capraldehyde} Hexanal {caproic aldehyde} 2-Hexenal, (E) Pentanal Propanal, 2-methyl2-Propenal, 3-phenyl2-Thiophenecarboxaldehyde, 5-methyl2-Tridecenal

107-88-0 431-03-8

1,3-Butanediol 2,3-Butanedione {diacetyl}

Ketones

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Table III-11 (Continued) Tobacco and/or Tobacco Smoke Aldehydes and Ketones Used in Flavor Formulations CAS No. 78-93-3 513-86-0 5471-51-2 23696-85-7 35044-68-9 23726-92-3 623-15-4 122-57-6 127-41-3 14901-07-6 89-80-5 1125-21-9 13215-88-8 99-49-0 89-81-6 6091-50-5 13494-06-9 13494-07-0 80-71-7 100-06-1 98-86-2 32974-92-8 1193-79-9 122-00-9 1333-52-4 22047-25-2 1122-62-9 350-03-8 1072-83-9 24295-03-2 110-43-0 5166-53-0 119-61-9 1937-54-8 821-55-6 600-14-6 123-76-2 107-87-9 141-79-7 127-17-3 4940-11-8 118-71-8 593-08-8 3796-70-1 112-12-9

Chemical Abstracts Nomenclature

As Listed by Doull et al. (1053)

Smoke

Tobacco

2-Butanone 2-Butanone, 3-hydroxy2-Butanone, 4-(4-hydroxyphenyl)2-Buten-1-one, 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl){β-damascenone} 2-Buten-1-one, 1-(2,6,6-trimethylcyclohex-1-enyl)- {β-damascone} 3-Buten-2-one, 4-(2-furanyl)3-Buten-2-one, 4-phenyl3-Buten-2-one, 4-(2,6,6-trimethyl-2-cyclohexen-1-yl)3-Buten-2-one, 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)Cyclohexanone, 5-methyl-2-(1-methylethyl)2-Cyclohexene-1,4-dione, 2,6,6-trimethyl2-Cyclohexen-1-one, 4-(2--(2-butenylidene)-3,5,5trimethyl2-Cyclohexen-I-one, 2-methyl-5-(1-methylethyl)2-Cyclohexen-1-one, 3-methyl-6-(1methylethyl)1,2-Cyclopentanedione, 3,4-dimethyl1,2-Cyclopentanedione, 3,5-dimethyl2-Cyclopenten-1-one, 2-hydroxy-3-methylEthanone, 1-(4-methoxyphenyl)Ethanone, 1-phenylEthanone, 1-(5-ethylpyrazintl)Ethanone, 1-(2-furanyl 5-methyl)Ethanone, 1-(4-methylphenyl)Ethanone, 1-(naphthalenyl)Ethanone, 1-pyrazinylEthanone, 1-(2-pyridinyl)Ethanone, 1-(3-pyridinyl)Ethanone, 1-(1H-pyrrol-2-yl)Ethanone, 1-(2-thiazolyl)2-Heptanone 3-Hexen-2-one, 5-methylMethanone, diphenyl6,8-Nonadien-2-one, 8-methyl-5-(1-methylethyl)2-Nonanone 2,3-Pentanedione Pentanoic acid, 4-oxo2-Pentanone 3-Penten-2-one, 4-methyl- {mesityl oxide} Propanoic acid, 2-oxo4H-Pyran-4-one, 3-hydroxy-2-ethyl4H-Pyran-4-one, 3-hydroxy-2-methyl2-Tridecanone 5,9-Undecadien-2-one, 6,10-dimethyl- {geranylacetone} 2-Undecanone

2-butanone acetoin 4-(p-hydroxyphenyl)-2-butanone 4-(2,6,6-trimethylcyclohexa-1,3-dienyl)-but-2en-4-one 4-(2,6,6-trimethylcyclohex-2-enyl)-but-2-en-4one 4-(2-furyl)-3-buten-2-one 4-phenyl-3-buten-2-one α-ionone β-ionone l-menthone 2,6,6-trimethylcyclohex-2-ene-1,4-dione 4-(2-butylidene-3,5,5-trimethyl)-2-cyclohexen1-one l-carvone d-piperitone

+ + + +

+ + — +

+

+

+ + + + + + +

+ + + + + + +

+ —

+ +

3,4-dimethyl-1,2-cyclopentanedione 3,5-dimethyl-1,2-cyclopentanedione methylcyclopentenolone acetanisole acetophenone 2-acetyl-3-ethylpyrazine 2-acetyl-5-methylfuran 4-methylacetophenone methyl naphthyl ketone acetylpyrazine 2-acetylpyridine 3-acetylpyridine methyl 2-pyrrolyl ketone 2-acetylthiazole 2-heptanone 5-methyl-3-hexen-2-one benzophenone solanone 2-nonanone 2,3-pentanedione levulinic acid 2-pentanone 4-methyl-3-penten-2-one pyruvic acid ethylmaltol maltol 2-tridecanone 6,10-dimethyl-5,9-undecadien-2-one 2-undecanone

+ + + + + + + + + — + + + + + + + + + + + + + + + + — — +

— — + + + — + + — + + + + — + + — + + — + + + + — + + + +

Tables III-12 and III-13 list the aldehydes and ketones, respectively, reported as tobacco and/or tobacco smoke components. The aldehydes number 263, with 143 identified in tobacco smoke, 199 in tobacco, and 79 in both. The ketones

number 1090, of which 656 have been identified in smoke, 647 in tobacco, and 213 in both. Table III-14 depicts the chronology of many of the studies on aldehydes and ketones in tobacco and tobacco smoke.

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Table III-12 Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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237

Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-12 (Continued) Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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251

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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255

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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263

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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265

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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267

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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279

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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293

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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295

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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296

The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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297

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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298

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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299

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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300

The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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301

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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302

The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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304

The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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305

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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306

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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307

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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308

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Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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309

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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310

The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Aldehydes and Ketones

Table III-13 (Continued) Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

Table III-14 Chronology of Studies on Aldehydes and Ketones in Tobacco Smoke NOTE: While many of the following items deal with the identification and quantitation of formaldehyde in cigarette MSS, SSS, and ETS, the evidence for the presence of formaldehyde (H2C=O) per se is scant. Data indicate that formaldehyde is present as its hydrate, i.e., as dihydroxymethane [H2C(OH)2], which in most instances behaves chemically and biologically the same as formaldehyde. Year

Event

1843 1859 1867 1904 1909 1926 1927 1931

Acrolein (propenal) was first identified as a component in the destructive distillate from fat by Redtenbacher (3093b). Formaldehyde (methanal) was discovered by Butlerov (3A02). Formaldehyde was rediscovered by A.W. Von Hofmann (3A24). Thoms (3912) reported the presence of formaldehyde in cigarette smoke. From his toxicologic study of cigarette smoke, Lehmann (2343) reported the presence of formaldehyde in cigarette smoke. Neuberg and Kobel in their study of the aldehydes reported the presence of several aldehydes, including formaldehyde (2702a). Neuberg and Ottenstein (2706) report the presence of formaldehyde in tobacco smoke. Neuberg and Burkard (2701) reported the presence of formaldehyde, acetaldehyde, butyraldehyde (butanal), 3-hydroxybutyraldehyde (3-hydroxybutanal, aldol), benzaldehyde, 3-pentanone, and 4-heptanone in cigarette smoke. McNally (2524) reported the presence of formaldehyde and acrolein (propenal) in tobacco smoke. Pfyl (2937) confirmed the finding of Neuberg and Burkard (2701) on the presence of acetaldehyde in tobacco smoke. In his study of the irritant factors in cigarette smoke, Bogen (1936) classified formaldehyde, acetaldehyde, and acrolein (propenal) as “irritant factors” in cigarette smoke and rated formaldehyde as a major contributor to cigarette smoke irritation. Prentiss (2988a) reported that acrolein (propenal) was a powerful lachrymator; even at 3 ppm (7mg/m3) acrolein was reported to be highly irritating to the conjunctiva and to the respiratory tract. Proetz (2991a) attributed ciliastasis on upper respiratory tract mucosa of rabbits exposed to cigarette smoke to the aldehydes in the smoke. Ribeiro (3126) reported the presence of acrolein (propenal) in tobacco smoke. Wenusch (4202) reported 2-furaldehyde and acetone in cigarette smoke. Roffo (3324) reported 2-furaldehyde in cigarette smoke. Schmalfuss (3475) reported biacetyl (2,3-butanedione) in tobacco smoke. Smirnov et al. (3A19) listed 3-pentanone as a tobacco smoke component. In his catalog of the components of tobacco smoke reported to mid-1954, Kosak (2170) provided references to reports in tobacco smoke of the following aldehydes: Formaldehyde [Neuberg and Ottenstein (2706), Neuberg and Burkard (2702), McNally (2524)], acetaldehyde [Neuberg and Burkard (2702), Pfyl (2937)], butyraldehyde (butanal) [Neuberg and Burkard (2702)], acrolein (propenal) [McNally (2524)], benzaldehyde [Neuberg and Burkard (2702)], 2-furaldehyde [Wenusch (1939), Roffo (3324)].

1932 1933 1936 1937 1939 1939 1939 1939 1939 1940 1954

(Continued )

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Table III-14 (continued) Chronology of Studies on Aldehydes and Ketones in Tobacco Smoke Year

1955 1956 1959 1959

1961

1963

1963 1963 1963 1964

1964

1964

1965

1965 1965/1966

1966

1967

Event

Kosak also cataloged reports on the following ketones in tobacco smoke: 3-Pentanone (diethyl ketone) [Neuberg and Burkard (2702)], 4-heptanone (dipropyl ketone) [Neuberg and Burkard (2702)], 17-tritriacontanone (dipalmityl ketone) [Schürch and Winterstein (3562)], and 2,3-butanedione (biacetyl) [Schmalfuss (3475)]. In his study of the vapor phase of cigarette MSS, Laurene (2293) identified acrolein (propenal). Buyske et al. (564) reported butyraldehyde (butanal) and crotonaldehyde (2-butenal) in cigarette MSS. In their review of the components of tobacco and tobacco smoke, Johnstone and Plimmer (1971) listed 18 aldehydes and ketones in tobacco smoke. In anticipation of their possible utility in the identification of aldehydes and ketones that might be present in the MSS from an all-tobacco and/or an all-cellulose cigarette, Fredrickson et al. (1238) prepared over 90 2,4-dinitrophenylhydrazone derivatives for use as standards and cataloged their infrared spectra. The spectral data were used several years later by Fredrickson et al. to identify numerous aldehydes and ketones in tobacco smoke (1239). Guillerm et al. (1451a) reported the ciliastatic activity of acetaldehyde and acrolein (propenal) in liquid and in vapor form in an in vitro system. They also reported the synergistic ciliastatic activity of these two aldehydes in cigarette MSS exposure studies. Horton et al. (3A11) reported that exposure of mice via inhalation to formaldehyde induced hyperplasia and metaplasia in the lung and typical hyperplastic changes in the trachea but the tracheal tissue changes did not progress to invasive carcinoma. Kensler and Battista (2083, 2084) reported significant ciliatoxicity for formaldehyde and acrolein and their levels in cigarette MSS were reduced by passage of the smoke through a charcoal-containing filter. In a study with human ciliated tonsillar epithelium, George (3A09) reported not only was phenol a strong ciliastat but also that acrolein (propenal) was an even stronger ciliastat. Murphy et al. (3A17) reported that exposure of guinea pigs to low concentrations of acrolein (propenal) resulted in an increase in total respiratory flow resistance plus decreased respiratory rates and increased tidal volume. Even though the Advisory Committee to the U.S. Surgeon General (3999) reported that formaldehyde and acrolein (propenal) were two of the components of cigarette MSS considered to be inhibitors of ciliastatic transport activity, the Committee concluded: No one of these [ciliastatic components] occurs at levels high enough to produce the effect noted for smoke. Laurene et al. (2305) described an analytical method for the quantitative determination of acetaldehyde, acrolein (propenal), and acetone in cigarette MSS. Subsequently, an improvement in the analytical procedure for these three carbonyl components was reported by Laurene and Harbin (2302). From their study of the pyrogenesis of acrolein (propenal) from glycerol, Doihara et al. (1023) and others deduced that a tobacco smoking product that contains glycerol as a humectant has an enhanced potential for the formation and release of acrolein (propenal) during smoking [see Wynder and Hoffmann (4337)]. In testing the ciliatoxicity of cigarette MSS aldehydes to clam gill cilia, Wynder et al. (4330) reported that formaldehyde, acrolein (propenal), and crotonaldehyde (2-butenal) showed the highest toxicity. They also reported that acrolein was about twice as ciliatoxic as phenol in the clam gill cilia test [see also Wynder and Hoffmann (p. 253 in (4332)]. In addition to their aldehyde ciliatoxicity results, Wynder et al. (4330) also noted the serious error introduced into the results obtained in their study of the ciliatoxicity of low molecular weight acids in tobacco smoke. To quantitate the level of formaldehyde in cigarette MSS, Newsome et al. (2782) reported on a colorimetric method involving chromatropic acid. Walker and Kiefer (4109) examined the effect of cigarette MSS vapor phase on clam gill cilia. Removal of the acrolein region from the chromatographed vapor phase resulted in a significant reduction in the ciliastatic activity. Contrary toxicity results were reported for the same MSS in which the levels of acrolein (propenal) and acetaldehyde were reduced by 66% and 82%, respectively, by a “hydrazide” filter. The ciliastatic activity of the vapor phase of the “hydrazide” filtered MSS was, within experimental error, the same as that of the unfiltered smoke. Wynder and Hoffmann (4337) offer a possible explanation for these contradictory results: Acrolein administered alone is quite toxic but in the cigarette smoke vapor phase its effect is “masked” or “neutralized” by other smoke components (identity not specified). In their study of the levels of acrolein, acetaldehyde, acetone, hydrogen cyanide, nitrogen oxides, nicotine, and total solids in pipe tobacco MSS, Harbin and Laurene (1497) reported that the acrolein delivery increased as the glycerol level was increased by addition but the acrolein delivery leveled off when the glycerol addition exceeded 6%. Wynder and Hoffmann (4337) discussed the conversion of the glycerol, used as a humectant in tobacco smoking products, to acrolein (propenal) during the smoking process.

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Table III-14 (continued) Chronology of Studies on Aldehydes and Ketones in Tobacco Smoke Year

Event

1968

In their study of the ciliastatic components of cigarette smoke MSS vapor phase, Dalhamn et al. (892, 893) reported that the absorption of the vapor-phase ciliastats by the fluids coating the oral cavity resulted in significant reductions of acetaldehyde (60%) and acetone (56%), i.e., significant levels of these in vitro ciliastats failed to reach the ciliated lung tissue and thus were unable to exert the ciliatoxicity asserted by some investigators. In his review of the components of tobacco and tobacco smoke, Stedman (3797) listed references to some 46 aldehydes and ketones in tobacco smoke. Martin and Thacker (2478) described the quantitation of several aldehydes (piperonal, ethylvanillin, vanillin) used as flavorants in cigarette tobacco. Despite the reported findings of Dalhamn et al. (892, 893), the Royal College of Physicians (3363) noted that acrolein (propenal) was one of the most important ciliastatic components of tobacco smoke, possibly contributing to the causes of pulmonary disease by interfering with the self-cleansing mechanism of the lung and thereby allowing more prolonged contact between the lining of the bronchial tubes and the carcinogenic agents in the smoke. From their study of 85-mm nonfiltered cigarettes made from each of four varieties of flue-cured tobacco, Rathkamp et al. (3087, 3088) reported that the MSS acetaldehyde deliveries ranged from 800 to 1,280 µg/cig; the acrolein (propenal) deliveries ranged from 51 to 102 µg/cig. The U.S. Surgeon General (4003) classified formaldehyde as a suspected contributor to the health hazard of smoking snf acrolein (propenal) as a probable health hazard in cigarette smoke. Testa and Joigny (3885) reported that the per cigarette delivery of acrolein (propenal) from a cigarette made from black tobacco was 65.7 µg. Tsuchiya et al. (3986a) reported that the levels of formaldehyde in fruits and vegetables ranged from 3.4 µg/g in spinach to 17.3 µg/g in apples. Kitchen et al. (2111b) noted that the most significant exposure to formaldehyde is generally industrial but formaldehyde occurs naturally in many foodstuffs, e.g., fruits and vegetables. Osha standards for exposure to air contaminants require an employee’s exposure to acrolein (propenal) not exceed an 8-hr time-weighted average of 0.25 mg/m3 (0.1 ppm) in the workplace air, in any 8-hr shift, during a 40-hr work week. Extensive experimental smoking in an unventilated room provided index levels for acrolein (propenal) that accumulated during the cigarette smoking. The industrially permitted threshold limit value (TLV) for acrolein (0.1 ppm; 0.25 mg/m3) was only exceeded under experimental conditions where as large number of cigarettes were burned in a closed room [Weber et al. (3A25)] . In his discussion of the vapor phase of cigarette MSS, Norman (2799a) listed per cigarette deliveries of 1200 µg and 70 µg for acetaldehyde and acrolein (propenal), respectively. Mansfield et al. (2456) described an analytical method to quantitate formaldehyde in cigarette MSS. In their study of the effect of inhaled acrolein (propenal) on the tumorigenicity of benzo[a]pyrene or N-nitrosodiethylamine, Feron and Kruysse (3A08) conducted inhalation and intratracheal experiments with two groups of 18 male and 18 female 6-wk old Syrian hamsters. One group was exposed to 9.2 mg/m3 (4 ppm) of acrolein in air (7 hr/day, 5 d/wk, 52 wk). The other group was similarly exposed to acrolein via inhalation but received an intratracheal installation of 0.9% saline. All animals alive at 81 wk were sacrificed. Only one female had a tracheal papilloma. Tumors at other sites were not increased vs untreated controls. In its assessment of tobacco smoke components reported to be ciliastatic, the Royal College of Physicians (3364) reported that acrolein (propenal) appeared to be the most important. According to the Chemical Industrial Institute of Toxicology (CIIT) (3A04), data supporting the tumorigenicity of formaldehyde were first reported on 8 October, 1979 [see Battelle Institute (3A01)]. U.S. Surgeon General (4005) reported acrolein (propenal) to be one of the major toxic agents in the vapor phase of unaged cigarette MSS. Swenberg et al. (3A21) reported the induction of squamous cell carcinomas in the nasal cavities of rats exposed to cigarette MSS plus 15 ppm of formaldehyde in chambers, 30 hr/wk for 18 months. The authors noted that reported per cigarette deliveries for formaldehyde ranged from 20 to 90 µg; for acrolein (propenal), deliveries ranged from 10 to 40 µg. Swenberg et al. listed acrolein as a ciliatoxic agent in cigarette MSS. In its report, the Battelle Institute (3A01) described the induction of tumors in rats and mice exposed via inhalation to formaldehyde.

1968 1970 1971

1971/1973

1972 1972 1975 1976 1976 1976

1977 1977 1977

1977 1979 1979 1980

1981

(Continued )

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Table III-14 (continued) Chronology of Studies on Aldehydes and Ketones in Tobacco Smoke Year

Event

1981

According to Niosh, workers who smoke cigarettes are exposed to additional levels of formaldehyde since cigarette MSS contains as much as 40 ppm of formaldehyde by volume. It was deduced that an individual who smokes a pack a day (20 cigarettes) would inhaled 0.38 mg of formaldehyde whereas occupational exposure at 3 ppm could result in a daily intake of 29.0 mg (3A04). Dalbey (3A06) reported that 88 male Syrian hamsters exposed to 70 ppm of formaldehyde vapor (5 hr/d, 5 d/wk) for their lifetime showed no detectable respiratory tract tumors. No respiratory tract tumors were observed in a similar inhalation experiment involving male hamsters exposed to 30 ppm of formaldehyde (5 hr/d, 1d/wk) for their lifetime. In its assessment of the literature on formaldehyde, the IARC (3A13) reported that it considered the evidence sufficient that formaldehyde was carcinogenic to rats. However, the IARC also stated that the epidemiological data [to that time] did not provide adequate evidence to assess the carcinogenicity of formaldehyde in man. The U.S. Surgeon General (4010) reported that formaldehyde and acrolein (propenal) were “tumorigenic” and each was “a major toxic agent” in the vapor phase of cigarette MSS. In a discussion of low-delivered doses of alleged carcinogenic compounds, Starr (3789b) note: Even though formaldehyde has been demonstrated to be mutagenic/genotoxic in test systems of one kind or another, we do not know that is in the human case. Formaldehyde is a major chemical building block in our society. Its outright ban would cause dramatic changes in society [also see Starr in Clary et al. (3A05)]. At the Chemical Industrial Institute of Toxicology (CIIT) meeting, Fayerweather stated: When the epidemiological studies are viewed as a whole, the data suggest that formaldehyde has not been responsible for producing cancer in man [see Fayerweather in Clary et al. (3A05)]. Jenkins et al. (1932) at the Oak Ridge National Laboratory (ORNL) analyzed the MSS from 32 commercial brands of cigarettes marketed in the U.S. for their deliveries of specific smoke components. Included was acrolein (propenal) whose deliveries ranged from 33 to 141 µg/cig. Kerns et al. (2086b) reported significant increases in squamous-cell carcinomas of the nasal cavity were observed in both strains of rats after inhaling highly cytotoxic doses of formaldehyde. However, no carcinomas were observed in mice after inhaling the same dose. In other studies to evaluate the carcinogenicity of formaldehyde, mice and hamsters were exposed via inhalation, rats via subcutaneous injection and rabbits via exposure in oral tanks. The results from these studies have been considered inadequate to evaluate the carcinogenic risk to humans (3A06, 3A13). From its study of formaldehyde, the United States Department of Health and Human Services (USDHHS) (3A23) reported: The data are sparse and conflicting and do not yet provide persuasive evidence of a causal relation between exposure to formaldehyde and cancer in man. It concluded: Although some epidemiological studies noted that there may be an association between formaldehyde exposure and some forms of cancer, the data from these studies are not sufficient, at this time, for quantitative risk modeling. The Environmental Protection Agency (EPA) (3A07) noted: There may be a reasonable basis to conclude that certain exposures to formaldehyde present a significant risk of widespread harm to human beings. This statement contradicts a previous one by the EPA in 1982 that no significant risks to human were expected from formaldehyde! From their assessment of components of indoor air found to be tumorigenic in laboratory animals, Sterling and Arundel (3A20) suggested that formaldehyde was potentially carcinogenic to humans. Theiss et al. (3A22) reported a statistically significant increase in the number of lung adenomas in mice after inhaling air containing 15 ppm of formaldehyde for 18 weeks. Acetaldehyde deliveries ranged from 18 to 2815 µg/cig for nonfiltered cigarettes [Huynh et al. (1853a), Miyake and Shibamoto (2564)]. A proposal to lower the exposure limit of formaldehyde from 5 to 1 ppm was under consideration by OSHA (3A18). Although formaldehyde was reported by Starr and Gibson (3789b) to be carcinogenic in rats when administered at very high dose levels, IARC found the weight of evidence of its carcinogenicity in humans to be inadequate. The IARC (1870) listed the delivery range for acrolein (propenal) in cigarette MSS vapor phase as 10 to 110 µg/cig and classified it as a ciliatoxic component. Formaldehyde was reported in two studies to induce aneuploidy [Liang and Brinkley (2363a), Oshimura and Barrett (2868a)].

1982

1982

1982 1982

1982

1983

1983

1984

1984

1984 1984 1984 1985 1985 1986 1985/1986

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Table III-14 (continued) Chronology of Studies on Aldehydes and Ketones in Tobacco Smoke Year

Event

1986

Brunnemann et al. (500) determined several volatile aldehydes and ketones in tobacco headspace and tobacco smoke by derivatization with 2,4-dinitrophenylhydrazine. Tobacco smoke carbonyl components identified included: Formaldehyde, acetaldehyde (1000 µg/cig), propionaldehyde (propanal), acrolein (propenal), isobutyraldehyde (2-methylpropanal), crotonaldehyde (2-butenal), methacrolein (2-methylpropenal), benzaldehyde (1 µg/cig), and acetone. Bell et al. (243) used the formation of the 2,4-dinitrophenylhydrazone derivative of formaldehyde in SSS as the means to quantitate the level of formaldehyde in SSS. In its review of formaldehyde, the IARC noted that formaldehyde is carcinogenic and mutagenic only at doses far in excess of that seen in cigarette MSS. Whether formaldehyde is mutagenic at non-cytotoxic dose levels remains controversial because of the small number of studies and the variability of the results (3A14). The IARC (3A15) also noted that results from some studies suggest that humans routinely exposed to formaldehyde display increased chromosomal aberrations and sister chromatid exchanges in peripheral lymphocytes. Nevertheless, rodents treated with formaldehyde in vivo gave negative results for chromosomal aberrations and assays for lethal mutations; other rodent studies on DNA damage gave equivocal results. Deluca (929) described a 2,4-dinitrophenylhydrazine procedure for the collection of carbonyl compounds in ETS. Formaldehyde deliveries in MSS vapor phase range from 3.4 µg for filtered cigarettes to 283 µg in unfiltered cigarettes [Schaller et al. (3427), Miyake and Shibamoto (2564)]. Hoffmann and Hecht (1727) included formaldehyde, acetaldehyde, and crotonaldehyde (2-butenal) in their list of 43 tumorigenic components of tobacco and tobacco smoke. Their text accompanying the list plus the authors’ disregard of how the tumorigenicity of many of the 43 components was determined experimentally raises serious questions as to why many of the components were listed. The EPA (1148) cited the Hoffmann-Hecht list of 43 tumorigenic components in tobacco and tobacco MSS in their effort to indict ETS as a significant health hazard. In their treatise on ETS, Guerin et al. [(3A10), see p. 197 in (1446)] at ORNL discussed in detail the levels of formaldehyde in indoor and outdoor air. They noted: It might be expected that environmental tobacco smoke would be an important contributor to indoor air concentrations of formaldehyde because formaldehyde is known to be a constituent of cigarette smoke. Popular commercial cigarettes deliver approximately 20-90 micrograms of formaldehyde in their mainstream smoke and 1-2 milligrams of formaldehyde in their SSS. While this contribution may at first appear highly significant, it has generally been found to be very minor when compared with other sources. OSHA ruled that the exposure limit for formaldehyde should be reduced from 3 ppm to 0.75 ppm. OSHA (2825) in its list of 43 tumorigenic components of tobacco smoke included only formaldehyde and acetaldehyde but not crotonaldehyde (2-butenal). NCI (2683a) reported on the OSHA 1992 ruling that the exposure limit for formaldehyde should be reduced from 3 ppm to 0.75 ppm. Although formaldehyde was reported by Monticello and Morgan (2610a) to be carcinogenic in rats when administered at very high dose levels, IARC found the weight of evidence of its carcinogenicity in humans to be inadequate. Formaldehyde deliveries in MSS vapor phase range from 3.4 µg for filtered cigarettes to 283 µg in unfiltered cigarettes [Schaller et al. (3427), Miyake and Shibamoto (2564)]. Acetaldehyde deliveries ranged from 18 to 2815 µg/cig for nonfiltered cigarettes [Huynh et al. (1853a), Miyake and Shibamoto (2564)]. Green and Rodgman (1373) reviewed presentations during the first half century (1947-1996) of the TCRC on the subject of the identification and quantitation of aldehydes and ketones in cigarette MSS and SSS as well as in ETS. Hoffmann and Hoffmann (1740, 1741) in their lists of 60 tumorigenic components of tobacco and tobacco smoke included only two aldehydes - formaldehyde and acetaldehyde. Crotonaldehyde (2-butenal) include in the 1990 Hoffmann-Hecht list (1727) was omitted from the Hoffmann-Hoffmann (1740), an omission that paralleled the 1994 OSHA list (2825). According to information from the Environmental Health Center (EHC) (1145a), formaldehyde is usually present at the non-irritating level of about 0.06 ppm. Smith et al. discussed the IARC classification of the tobacco smoke vapor-phase components formaldehyde and acetaldehyde as IARC Group 2A [Smith et al. (3713)] and Group 2B [Smith et al. (3714)] carcinogens, respectively. In a discussion of the various lists of tumorigenic components in tobacco and tobacco smoke issued between 1986 and 2003, Rodgman and Green (3300) and Rodgman (3265) noted that formaldehyde, acetaldehyde, crotonaldehyde (2-butenal), and acrolein (propenal) were included in the majority of them (1217, 1740, 1741, 1743, 1744, 1808, 1870, 2825) IARC revaluated formaldehyde and classifies it as a Group 1 carcinogen (3A03, 3A16).

1987 1987

1988 1989 1990

1990 1992

1992 1994 1994 1994 1995

1996 1997/1998

1998 1999 2003

2006

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4

Carboxylic Acids

IV.A  The Carboxylic Acids Numerous organic acids have been identified in tobacco. These volatile, nonvolatile, and amino acids have been discussed in-depth by Tso [see Chapter 24 in (3973)]. The major nonvolatile acids are 2-hydroxy-1,2,3-propanetricarboxylic (citric), hydroxybutanedioic (malic), and ethanedioic (oxalic). The minor nonvolatile acids are hydroxyacetic (glycolic), butanedioic (succinic), propanedioic acid (malonic), butenedioic (E) (fumaric acid), and 2-oxopropanoic (pyruvic). The major volatile acids in tobacco are acetic and formic acid; minor volatile acids are propanoic, 2-furancarboxylic acid (2-furoic), benzoic, α-methylbutyric, β-methylvaleric, and numerous others. Over forty amino acids and related compounds have been identified in tobacco [Leffingwell (2337)]. The number of identified carboxylic acids in tobacco and tobacco smoke has escalated greatly since the publication in 1954 by Kosak (2170) of his list of identified components in tobacco smoke. The Kosak list included the following carboxylic acids in tobacco smoke: formic acid, acetic acid, butanoic acid, pentanoic acid (valeric acid), hexanoic acid (caproic acid), 7- and 8-carbon carboxylic acids, butanedioic acid (succinic acid), butenedioic acid (E) (fumaric acid), benzoic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid (citric acid), and phenolic acids. Kosak questioned the identification data of many of the acids listed. Johnstone and Plimmer (1971), in their 1959 catalog of tobacco and tobacco smoke components, listed fifty-two specific acids plus a range of saturated aliphatic acids. However, Johnstone and Plimmer listed tobacco and smoke amino acids in a different section of their report and included nicotinic acid and nicotinamide as amino acids [see Table 11 in (1971)]. Also, listed in a third section were such carboxylic acids as 3-[[3-(3,4-dihydroxyphenyl)-1oxo-2-propenyl]oxy]-1,4,5-trihydroxycyclohexanecarboxylic acid (chlorogenic acid), 1,3,4,5-tetrahydroxycyclohexanecarboxylic acid (quinic acid), and 3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid (shikimic acid) [see Table 9 in (1971)]. Similar separation problems are encountered on examination of the various assignments of carboxylic acids in the 1968 review by Stedman [see Tables IX, X, and XIV in (3797)]. In our report, any compound with a carboxyl group is cataloged in this chapter. Table IV.A-1 summarizes the numbers of carboxylic acids and amino acids identified to date in tobacco and tobacco smoke. Their listing and references are presented in subsequent tables. Despite the number of acids identified in tobacco and tobacco smoke, very few of the tobacco smoke acids have been indicted as toxicants. In 1964, Boyland et al. (4A01) described the induction of a bladder carcinoma in one of sixteen mice

(6.5%) implanted with a cholesterol pellet containing 3-(3,4dihydroxyphenyl)-2-propenoic acid (caffeic acid). However, the carcinogenicity could not be attributed to the acid when it was observed that five of the seventy-seven mice (6.5%) implanted with the cholesterol pellet alone developed bladder carcinomas. Although caffeic acid was not included in any of the pre-2001 listings by the International Agency for Research on Cancer (IARC) (1871), Hoffmann and Wynder (1808), Hoffmann and Hecht (1727), Hoffmann et al. (1773), Hoffmann and Hoffmann (1740, 1741, 1742), it was listed in the two 2001 publications by Hoffmann and Hoffmann (1743) and Hoffmann et al. (1744), primarily because of its phenolic nature. In the latter two articles, formic, acetic, and propanoic acids are listed as major mainstream smoke (MSS) vaporphase components [Table 5-1 in (1743), Table 2 in (1744)] and hexadecanoic acid (palmitic acid), octadecanoic acid (stearic acid), 9-octadecenoic acid (oleic acid), 9,12-octadecadienoic acid (linoleic acid), 9,12,15-octadecatrienoic acid (linolenic acid), and 2-hydroxypropanoic acid (lactic acid) are listed as major MSS particulate-phase components [Table 5-2 in (1743), Table 3 in (1744)].* By inclusion of per cigarette yields from the mid-1950s to the date of the publication, these long-chained saturated and unsaturated acids and lactic acid are listed as major particulate-phase components. No comment is made as to whether that statement about the per cigarette yields of the six acids is valid for cigarettes manufactured post-1995. The formic, acetic, and propanoic acids listed as major MSS vapor-phase components were defined as ciliastats by Wynder et al. (4304, 4350) in the mid-1960s [see summary graph, p. 254, Table VII-31 in (4332)]. However, Wynder and Hoffmann (4332) were among the first to comment on the fact that all vapor-phase ciliastats are water soluble and therefore may be removed from the smoke stream by solution in the fluids coating the oral cavity. In their 1967 book [see p. 646 in (4332)], they stated: In man’s manner of smoking, however, volatile components are retained to a significant degree in the oral cavity and may, therefore, be far less important than when tested experimentally.

The validity of their 1967 statement had been demonstrated by the results of studies in 1964 by Rodgman et al. (3306, 4A02) and subsequently in 1968 by Dalhamn et al. (892) on the removal of substantial amounts of water-soluble vaporphase ciliastats from inhaled MSS by the oral cavity fluids. *

From a comparison of the listings in (1743) and (1744), it should be noted that in the particulate-phase acids listed in (1744) stearic acid has been inadvertently omitted and its per cigarette MSS yield assigned to palmitic acid.

317

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-1 Acids Identified in Tobacco and Tobacco Smoke to Date Acid Category

Total

Smoke

Tobacco

Tobacco and Smoke

Carboxylic acids

52 745

37 354

43 614

29 223

Table 8 in (1971) Table IV.A-3

Amino acids

28 103

4 30

26 102

2 29

Table 11 in (1971) Table IV.B-7

It is interesting to note that all but two (formic acid, octadecanoic acid [stearic acid]) of the MSS vapor-phase and particulate-phase acids discussed above—whether identified in tobacco, tobacco smoke, or both—are listed by Doull et al. (1053) as compounds included in the flavor formulations added to a tobacco blend by U.S. cigarette manufacturers to enhance consumer acceptability of the product. Table IV.A-2 lists the tobacco and/or smoke carboxylic acids that, according to the Doull et al. listing (1053), are or have been used recently as components in flavor formulations for tobacco. It should also be noticed that the flavor ingredient additions in Table IV.A-2 include fifteen amino acids. Table IV.A-3 is a catalog of the carboxylic acids identified to date in tobacco, tobacco smoke, and tobacco substitute smoke. Of the 745 components listed, 354 have been identified in smoke, 614 in tobacco, and 223 in both. Because of the recent interest in several amino acid degradation products generated during the tobacco smoking process, a separate section (IV.B) is devoted to the amino acids and a discussion of their behavior during pyrolysis and the smoking process.

IV.B The Amino Acids and Related Compounds Amino acids, both as free acids and as acids bound within protein molecules, are present in all of the tobacco types (flue-cured, burley, Oriental, Maryland) used in the American tobacco blend. The diversity and levels of amino acids in various tobaccos have been presented by Gori [see Table 2 in (1329), Table  2 in (1330)] and Tso and Chaplin [see Table  8 in (3975)]. Leffingwell (2337), in his report on nitrogen components of leaf and their relationship to smoking quality, reported in 1976 that there were forty-three amino acids isolated from tobacco. Examples of amino acids occurring free and/or bound in tobaccos include α- and β-alanine, α-and γ-aminobutyric acid, arginine, aspartic acid, cysteic acid, cysteine, cystine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, norleucine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine (3983b). The presence in cigarette MSS of numerous free amino acids and amino acid-derived compounds was demonstrated in the mid-1950s. This occurred soon after the publication of the results of several cigarette smoke-related epidemiological

Reference

and biological studies led to a massive escalation in tobacco smoke composition studies; for example, Buyske et al. (562) reported the identification of glutamic acid and its derivative glutamine (glutamic acid 5-amide) in tobacco smoke. Other amino acids identified in tobacco smoke include alanine, aspartic acid (and asparagine), cysteine, glycine, leucine, ornithine, phenylalanine, proline, serine, threonine, and valine [Ishiguro and Sugawara (1884)]. In the early 1960s, pyrocoll (dipyrrolo[a,d]pyrazine-5,10dione) was identified in cigarette MSS by Mold et al. (2592), who proposed that the amino acid proline, either free or bound, was its precursor. During their study of the isolation and identification of N-heterocyclic components (the indoles and carbazoles) in cigarette MSS, Rodgman and Cook (3279) confirmed the presence of pyrocoll. Two decades earlier, Van Order and Linwall (4B01) had demonstrated that dry distillation of the amino acid tryptophan yielded indole and 3-methylindole (skatole), both of which were subsequently identified as tobacco smoke components by Rodgman and Cook (3279). Roberts [see citation in Rodgman and Cook (3279)] had also identified indole as a component of burley tobacco. By means of pyrolysis studies (850°C, nitrogen atmosphere) with the amino acids lysine, leucine, and tryptophan, Patterson et al. (2902) demonstrated that each of the three amino acids yielded the N-heterocyclic compounds indole, quinoline, isoquinoline, several nitriles, and a series of PAHs ranging in complexity from bicyclic to tetracyclic (their findings are summarized in Table IV.B-1). In their study, B[a] P was found only in the pyrolysate from leucine. From their own findings and from a previous report by Jarboe and Rosene (1923a) that quinoline and isoquinoline were components of a nicotine pyrolysate, Patterson et al. (2902) suggested that the precursors in tobacco of the aza-arenes quinoline and isoquinoline in tobacco smoke might be nicotine and/or the amino acids. They also reported that tryptophan, on a per mole pyrolyzed basis, yielded a phenol fraction whose weight was more than five times that generated from lysine and about thirty times that from leucine. In another series of experiments, Patterson et al. (2903) reported (1) the effect of the pyrolysis temperature on the composition of the pyrolysate from the amino acid phenylalanine with emphasis on the levels of PAHs generated and (2) the effect of other compounds (tryptophan or pyrrole) on the composition of the pyrolysate when mixtures of equimolar quantities of tryptophan and phenylalanine or pyrrole and

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Carboxylic Acids

Table IV.A-2 Tobacco and/or Tobacco Smoke Carboxylic Acids Used in Flavor Formulations Identified In CAS No.

Chemical Abstracts Nomenclature

As Listed by Doull et al. (1053)

64-19-7 107-95-9 74-79-3 5794-13-8 56-84-8 103-82-2 65-85-0 147-71-7 6915-15-7 107-92-6 116-53-0 503-74-2 13201-46-2 52-90-4 334-48-5 143-07-7 6899-05-4 6899-04-3 111-14-8 57-10-3 110-44-1 142-62-1 4536-23-6 1289-40-3 71-00-1 73-32-5 56-87-1 112-05-0 506-21-8 463-40-1 112-80-1 124-07-2 109-52-4 97-61-0 105-43-1 646-07-1 123-76-2 591-80-0 63-91-2 147-85-3 77-92-9 79-09-4 50-21-5 79-31-2 127-17-3 501-52-0 499-12-7 621-82-9 544-63-8 72-19-5 60-18-4 7004-03-7

Acetic acid β-Alanine L-Arginine L-Asparagine monohydrate L-Aspartic acid Benzeneacetic acid Benzoic acid Butanedioic acid, 2,3-dihydroxyButanedioic acid, hydroxylButanoic acid Butanoic acid, 2-methylButanoic acid, 3-methyl2-Butenoic acid, 2-methylL-Cysteine Decanoic acid Dodecanoic acid L-Glutamic acid L-Glutamine Heptanoic acid Hexadecanoic acid 2,4-Hexadienoic acida Hexanoic acid Hexanoic acid, 2-methyl2-Hexenoic acid L-Histidine DL-Isoleucine L-Lysine Nonanoic acid 9,12-Octadecadienoic acid 9,12,15-Octadecatrienoic acid 9-Octadecenoic acid Octanoic acid Pentanoic acid Pentanoic acid, 2-methylPentanoic acid, 3-methylPentanoic acid, 4-methylPentanoic acid, 4-oxo4-Pentenoic acid L-Phenylalanine L-Proline 1,2,3-Propanetricarboxylic acid, 2-hydroxyPropanoic acid Propanoic acid, 2-hydroxyPropanoic acid, 2-methylPropanoic acid, 2-oxoPropanoic acid, 3-phenyl1-Propene-1,2,3-tricarboxylic acid 2-Propenoic acid, 3-phenylTetradecanoic acid L-Threonine L-Tyrosine Valine

acetic acid β-alanine L-arginine asparagine l-aspartic acid phenylacetic acid benzoic acid tartaric acid malic acid butyric acid 2-methylbutyric acid isovaleric acid methyl-2-butenoic acid L-cysteine capric acid lauric acid L-glutamic acid L-glutamine enanthic acid palmitic acid sorbic acid a caproic acid 2-methylhexanoic acid 2-hexenoic acid L-histidine DL-isoleucine L-lysine nonanoic acid linoleic acid linolenic acid oleic acid caprylic acid valeric acid 2-methylvaleric acid 3-methylpentanoic acid 4-methylpentanoic acid levulinic acid 4-pentenoic acid L-phenylalanine L-proline citric acid propionic acid lactic acid isobutyric acid pyruvic acid 3-phenylpropionic acid aconitic acid cinnamic acid myristic acid L-threonine L-tyrosine valine

a

Smoke

Tobacco

+ + — + + + + — + + + + + + + + + + + + + + + + — — — + + + + + + + + + + + + + + + + + + + + + + + — +

+ + + + + + + + + + + + + + + + + + + + + + + — + + + + + + + + + + + + + + + + + + + + + + + + + + + +

2 ,4-Hexadienoic acid (sorbic acid) is not included in the Doull et al. list (1053) but is included in flavor formulations used by cigarette manufacturers outside of the U.S. [see Table 7A in (3266)].

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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Carboxylic Acids

321

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

323

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

325

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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326

The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

327

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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328

The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

329

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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330

The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

331

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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332

The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

333

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

335

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

337

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

339

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

341

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

343

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

345

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

347

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

349

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

351

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

353

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

355

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

357

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

359

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

361

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

363

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

Table IV.A-3 (Continued) Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

phenylalanine were pyrolyzed. The results from this study are summarized in Table IV.B-2. The difference between the pyrogenesis of PAHs from phenylalanine and the mixture of equimolar quantities of phenylalanine and the amino acid tryptophan prompted Patterson et al. (2903) to propose the addition of amino acids to tobacco as a possible means to control the PAH content of the CSC: These results suggest the possibility that aromatic hydrocarbon content of tobacco “tar” may be affected by the amino acid composition of the tobacco and that it might be possible to affect deliberately the amount of aromatics and bases formed by adding suitable additives, such as amino acids, to the tobacco.

Of course, in 1971 when Patterson et al. offered this suggestion, the presence in amino acid pyrolysates of the socalled “cooked food” mutagens and the inordinately high mutagenicity of several of them were unknown. Higman et al. (1647) also reported the generation of PAHs, phenols, pyridines, indole, quinoline, and other aromatic bases during the pyrolysis of amino acids and proteins from tobacco [see the review on pyrogenesis of smoke components by Chortyk and Schlotzhauer (722)]. The pyrolysis results reported by Higman et al. are summarized in Table IV.B-3.

Tryptophan was also found to be the precursor in tobacco of two other N-heterocyclic compounds, namely harman (1-methyl-9H-pyrido[3,4-b]indole) and norharman (9H-pyrido[3,4-b]indole), in tobacco smoke. These compounds were originally identified in tobacco and tobacco smoke by Philip Morris R&D personnel in 1961 and 1962 [Poindexter and Carpenter (2972)] and in 1963 [Poindexter et al. (2972)]. That tryptophan was indeed a precursor in tobacco of the two harmans in smoke was demonstrated by addition of radiolabeled tryptophan to cigarette tobacco and identification of radiolabeled harman and norharman in the MSS. In the mid-1970s, pyrolysis studies with several amino acids led to the isolation and identification of several additional polycyclic N-heterocyclic compounds which are reported not only to be tumorigenic to mouse skin but also to show inordinately high mutagenicity when tested in the Ames bioassay with Salmonella typhimurium. The impetus for these particular amino acid pyrolysis studies was not the attempt to define the relationship between tobacco leaf precursors and tobacco smoke components but the observation that the extracts of broiled, fried, or roasted foodstuffs (meat, fish, poultry, etc.) were highly mutagenic in the Ames bioassay (Salmonella typhimurium). These N-heterocyclic

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Table IV.B-1 Components in Pyrolysates from the Amino Acids Lysine, Leucine, and Tryptophan (2902) Yield, mg/mole of Amino Acid Pyrolyzed Pyrolysate Component

Lysine

a

Leucine

Tryptophan

Nitrogen Compounds Hydrogen cyanide Aniline Quinoline Isoquinoline Benzonitrile o-Tolunitrile m-Tolunitrile p-Tolunitrile Phenylacetonitrile Indole 1-Naphthonitrile 2-Naphthonitrile

+b 60 160 80 470 30 30 20 6 20 10 —

+ 5 8 6 40 + 30 + — + 30 —

+ — 17.7 2.4 1370 610 + + 400 610 350 170

5 10 2 40 210 10 10 20 30 10 30 10 10 2 10 10 + + —

20 30 — 70 620 40 50 — 19 80 250 90 110 20 30 50 + + 30

— + + — 1100 + — — 3 140 7900 210 270 — 150 110 + + —

Cyclic Hydrocarbons Styrene Biphenyl Bibenzyl Indene Naphthalene Naphthalene, 1-methylNaphthalene, 2-methylAcenaphthene Acenaphthylene Fluorene Anthracene/phenanthrene Fluoranthene Pyrene Pyrene, methylBenzofluorene Chrysene Triphenylene Benz[a]anthracene Benzopyrene a b

Pyrolyzed as lysine monohydrochloride + indicates the presence of compound; — indicates the absence of the compound.

compounds, all amines, derived from the amino acids and/ or proteins in heated foodstuffs, were often described as “cooked food” mutagens. Eventually they were defined as N-heterocyclic amines. In a later chapter, the N-heterocyclic amines will be discussed in greater detail. The studies in the 1970s on the tumorigenicity and mutagenicity of extracts of cooked foodstuffs were reminiscent of the studies in the 1920s by Kennaway (2074–2076, 2080), who reported the tumorigenicity of extracts of heated foodstuffs or pyrolysates from heated organic compounds such as cholesterol, and by Roffo (4A03–4A05), who reported the tumorigenicity of pyrolyzed cholesterol. Subsequently it was

shown that many of the foodstuff pyrolysates and the cholesterol pyrolysates contained a spectrum of PAHs, including B[a]P. Identification of the highly mutagenic N-heterocyclic compounds in amino acid pyrolysates was followed by identification of some of them not only in broiled or roasted meats but also in mainstream CSC. In 1977, Sugimura et al. (3829) reported the identification of the potent mutagens 3-amino-1-methyl-5H-pyrido[4,3-b] indole (coded Trp-P-2) and 3-amino-1,4-dimethyl-5Hpyrido[4,3-b]indole (coded Trp-P-1) in pyrolysates from tryptophan. The next year, Yamamota et al. (4365a) identified two additional highly mutagenic compounds in pyrolysates

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Table IV.B-2 Pyrolysis of Phenylalanine. A. Effect of Pyrolysis Temperature. B. Effect of Equimolar Addition of Tryptophan or Pyrrole (2903) Material Pyrolyzed Phe + Tryb

Phe + Pyrc

450°C

650°C

850°C

950°C

850°C

850°C

850°C

— 10300

1270 12000

10300 2550

4360 +

10300 2550

2980 —

2240 345

— 0.12 — — — — 0.42 4.12 — — – — —

0.36 1.45 + — 0.48 1.70 1.33 9.70 0.48 0.48 3.50 — 0.48

2.73 3.50 — — 1.94 2.55 4.50 20.00 1.94 1.27 3.20 3.20 2.55

— 1.27 — — <0.18 0.73 0.85 7.90 2.60 0.60 1.20 <0.60 1.58

2.73 3.50 — — 1.94 2.55 4.50 20.00 1.94 1.27 3.20 3.20 2.55

— 3.52 — 2.98 0.054 0.40 0.78 1.44 0.22 0.16 0.30 0.22 0.16

0.17 5.60 0.73 0.34 0.086 0.99 0.65 2.41 0.39 0.04 0.39 + 0.30

1.27 — — — – — — — —

0.85 0.36 0.06 0.18 1.40 1.40 2.30 1.80 3.00

7.88 2.85 — 0.18 — — 0.72 12.00 10.90

1.27 0.06 0.06 — — — — 0.30 0.18

7.88 2.85 — 0.18 — — 0.72 12.00 10.90

3.80 0.68 1.38 0.38 0.22 1.14 17.35 25.75 1.10

1.46 0.26 0.26 0.26 0.13 1.00 0.86 1.30 0.43

Phenylalanine (Phe) Pyrolyzed at Pyrolysate Component a

Phe

Monocyclic Aromatic Hydrocarbons Biphenyl Bibenzyl Polycyclic Aromatic Hydrocarbons Indene Naphthalene Naphthalene, 1-methylNaphthalene, 2-methylAcenaphthene Acenaphthylene Fluorene Phenanthrene/anthracene Benzofluorene Fluoranthene Pyrene Pyrene, methylChrysenes N-Containing Compounds Benzonitrile o-Tolunitrile m-Tolunitrile p-Tolunitrile Phenylacetonitrile 1-Naphthonitrile Indole Quinoline Isoquinoline

Yield of pyrolysis component in mg/g of compound or mixture pyrolyzed. Pyrolysis involved equimolar quantities of phenylalanine and tryptophan (total mol. wt. = 369). c Pyrolysis involved equimolar quantities of phenylalanine and pyrrole (total mol. wt. = 232). a

b

from glutamic acid: 2-aminodipyrido[1,2-a:’,2’-d]imidazole (coded Glu-P-2) and 2-amino-6-methyldipyrido[1,2-a:3’,2’-d] imidazole (coded Glu-P-1). Table IV.B-4 lists several polynuclear N-heterocyclic amines that exhibit extremely high mutagenicity levels in the Ames bioassay, are amino acid pyrolysis products, and have been identified in various broiled, fried, or roasted foodstuffs as well as in CSC [Sugimura (3828c)]. On a per microgram basis, B[a]P in the Ames bioassay with Salmonella typhimurium (Strain TA 98) shows about 200 revertants/µg. Several of the amino acid-derived compounds in Table IV.B-4 exceed the B[a]P effect with the TA 98 strain by factors ranging from about 10 to over 2100. Yoshida and Matsumoto (4388) reported the identification of two α-carbolines in CSC: 2-amino-9H-pyrido[2,3-b]indole

(coded AαC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (coded MeAαC). These and several other such compounds were reported in CSC by Yamashita et al. (4367, 4368). The quantitative levels of the possibly amino acid-derived, mutagenic N-heterocyclics in CSC are shown in Table IV.B-4. In their studies they emphasized in particular the identification and quantitation of 2-amino-3-methylimidazo[4,5-f]quinoline (coded IQ) because of its inordinately high mutagenicity (found to be 433000 and 490000 revertant/µg in several determinations) in the Ames bioassay with Salmonella typhimurium strain TA 98. Demonstration of the mutagenicity of the compounds listed in Table IV.B-4 was followed by demonstration of their tumorigenicity in various laboratory animals. Ohgaki et al. (2849b) demonstrated the tumorigenicity of 2-amino-3-methylimidazo[4,5-f]

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Table IV.B-3 Components in Pyrolysates from Amino Acids (Proline and Glycine) and Proteins (Casein and Collagen) (1647) Amino Acid or Protein Pyrolysate Component

a, b

Casein

Collagen

Proline

Glycine

Nitrogen Compounds Hydrogen cyanide Pyridine Pyridine, 2-methylPyridine, 3-methylPyridine, 4-methylPyridine, 3-vinylAniline Pyrrole Quinoline Isoquinoline Indole Benzonitrile o-Tolunitrile m-Tolunitrile

+ + + + + + + + + + + + + +

+ + + + + + + + + + + + + +

+ + + + + — + + + + + — + +

+ + + + + — — + — — — + — —

+ + + + + + +

+ + + + + + +

+ + — — — — —

— + + + + — —

+ + + + + +

+ — + + + +

— — — — — —

— — — — — —

Cyclic Hydrocarbons Benzene Toluene Styrene Xylenes Indene Naphthalene Fluorene Phenols Phenol o-Cresol m-Cresol p-Cresol Phenol, ethylXylenol

 indicates the presence of compound; — indicates the absence of the + compound. b In the publication by Higman et al., actual pyrolysis yield data are listed for each compound. a

quinoline (IQ) in mice. Takayama et al. (3862c) and Tanaka et al. (3865c) reported its tumorigenicity in rats. 3-Amino-1, 4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1methyl-5H-pyrido[4,3-b]indole (Trp-P-2) were reported to be tumorigenic in mice by Matsukura et al. (2491a) and in rats by Hosaka et al. (1835a) and Takayama et al. (3862d). Ohgaki et al. (2849b) reported that 2-amino-6-methyldipyrido[1,2-a:3′,2′-d]imidazole (Glu-P-1), 2-aminodipyrido

[1,2-a:3′,2′-d]-imidazole (Glu-P-2), 2-amino-9H-pyrido[2,3-b] indole (AαC), and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC) were tumorigenic in mice, and Takayama et al. (3862d) reported Glu-P-1 and Glu-P-2 to be tumorigenic in rats. In a 1989 manuscript that was subsequently published, Hoffmann and Hecht (1727) discussed amino acid-derived aromatic amines in cigarette MSS as follows: Of the known carcinogenic pyrolysis products of the amino acids, so far only 2-amino-3-methylimidazo(4,5-f)quinoline has been detected in trace amounts of 0.26 ng in the smoke of a Japanese filter cigarette [Yamashita et al. (4368)].

Apparently, Hoffmann and Hecht had overlooked not only the reports of the identification in CSC of several other known “carcinogenic” pyrolysis products of amino acids, for example, 2-amino-9H-pyrido[2,3-b]indole (AaC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC) (4388) or 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) (4367) but also the reports on the tumorigenicity of several other N-heterocyclic amines in different laboratory animals (1835a, 2491a, 2849, 2849a, 2849b, 3862b, 3862c, 3865c). Table IV.B-5 summarizes the reported MSS levels of the N-heterocyclic amines considered to be significant tumorigens by Hoffmann and Hoffmann (1740, 1741) plus the assessment of the IARC (1870) on their tumorigenicity in laboratory animals and humans. During tobacco growth, curing, aging, and/or the smoking process, the amino acids in tobacco may react with ammonia and/or amino acids to yield Amadori compounds which, when heated during the smoking process, will generate a variety of pyrazines [Green et al. (1376)]. Many of the pyrazines found in tobacco smoke are highly flavorful and contribute uniquely to the aroma and taste not only of tobacco smoke but also of a variety of consumer food products [Maga and Sizer, (2439)], such as coffee, tea, cocoa, roasted peanuts, and roasted, broiled, or fried meats, poultry, and fish. Table IV.B-6 lists the tobacco and/or smoke amino acids that, according to the Doull et al. listing (1053), are or have been used recently as components in flavor formulations for tobacco. In their tabulation of possible flavorants for tobacco smoking products, Leffingwell et al. (2341) listed the contributions to tobacco smoke taste and aroma of twenty-three amino acids added individually to cigarette tobacco filler. Table IV.B-7 lists the amino acids and related compounds identified in tobacco, tobacco smoke, and tobacco substitute smoke. In Table IV.B-7, a total of 103 such components are listed, of which 30 have been identified in smoke, 102 in tobacco, and 29 in both smoke and tobacco.

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Table IV.B-4 Amino Acid-Derived N-Heterocyclic Amines Compound Code IQ Trp-P-1 Trp-P-2 Glu-P-1 Glu-P-2 AaC MeAaC a b

Mutagenicitya, rev/µg

Level in CSC,

Name

TA 98

TA 100

ng/cigb

Imidazo[4,5-f]quinoline, 2-amino-3methyl5H-Pyrido[4,3-b]indole, 3-amino-1,4-dimethyl5H-Pyrido[4,3-b]indole, 3-amino-1-methylDipyrido[1,2-a:3’,2’-d]imidazole, 2-amino-6-methylDipyrido[1,2-a:3’,2’-d]imidazole, 2-amino9H-Pyrido[2,3-b]indole, 2-amino9H-Pyrido[2,3-b]indole, 2-amino-3-methyl-

433000 490000 39000 104200 49000 1900 300 200

7000

0.26

1700 1800 3200 1200 20 120

0.29–0.48 0.82–1.1 0.37–0.89 0.25–0.88 25–260 2–37

Salmonella typhimurium, strain TA 98 or TA 100, with S-9 mix. See Hoffmann and Hoffmann (1740, 1741).

Table IV.B-5 Summary of Lists of Tumorigenic N-Heterocyclic Amines in Tobacco Smoke IARC (1870) Evaluation of Evidence re Tumorigenicity In Component

Hoffmann and Hecht (1727)

OSHA (2825)

Hoffmann and Hoffmann (1740, 1741)

MSS Level wt/cig

Laboratory Animals

Humans

— — — — — — — — —

— — — — — — — — —

+ + + + + + + + +

0.37–0.89 ng 0.25–0.88 ng 0.29–0.48 ng 0.82–1.1 ng 25–260 ng 2–37 ng 0.26 ng 11–23 ng 0.26 ng

sufficient sufficient sufficient sufficient sufficient sufficient sufficient sufficient sufficient

— — — — — — probable possible probable

Glu-P-1 Glu-P-2 Trp-P-1 Trp-P-2 AaC MeAaC IQ PhIP IQ

Table IV.B-6 Tobacco and/or Tobacco Smoke Amino Acids Used in Flavor Formulations Identified In CAS No. 107-95-9 74-79-3 5794-13-8 56-84-8 52-90-4 6899-05-4 6899-04-3 71-00-1 73-32-5 56-87-1 63-91-2 147-85-3 72-19-5 60-18-4 7004-03-7

Chemical Abstracts Nomenclature β-Alanine L-Arginine L-Asparagine monohydrate L-Aspartic acid L-Cysteine L-Glutamic acid L-Glutamine L-Histidine DL-Isoleucine L-Lysine L-Phenylalanine L-Proline L-Threonine L-Tyrosine Valine

As Listed by Doull et al. (1053)

Smoke

Tobacco

β-alanine L-arginine asparagine l-aspartic acid L-cysteine L-glutamic acid L-glutamine L-histidine DL-isoleucine L-lysine L-phenylalanine L-proline L-threonine L-tyrosine valine

+ — + + + + + — — — + + + — +

+ + + + + + + + + + + + + + +

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Table IV.B-7 Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carboxylic Acids

371

Table IV.B-7 (Continued) Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.B-7 (Continued) Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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373

Table IV.B-7 (Continued) Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IV.B-7 (Continued) Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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375

Table IV.B-7 (Continued) Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table IV.B-7 (Continued) Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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377

Table IV.B-7 (Continued) Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table IV.B-7 (Continued) Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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379

Table IV.B-7 (Continued) Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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5

The Esters

While no esters were reported in tobacco smoke by Kosak (2170) in his 1954 compilation of reported tobacco smoke components, the number of esters in tobacco and its smoke has increased dramatically over the years and now exceeds 1000. In 1955, Latimer (2270) collated and reported component data from Chemical Abstracts and listed only one set of esters reported in tobacco and its smoke, the “glycerides.” In 1959, Johnstone and Plimmer (1971) listed sixteen identified esters from these two sources. Between the Johnstone and Plimmer review and that of Stedman (3797) in 1968, the number of identified esters in tobacco and/or smoke escalated to over 300. The research leading to the major part of the increase involved identification of the following classes of esters: (1) esters from long-chained aliphatic alcohols and saturated and unsaturated acids, (2) esters from solanesol and acetic acid and numerous saturated and unsaturated acids, (3) esters from several phytosterols and numerous saturated and unsaturated acids, and (4) β-amyrin and numerous saturated and unsaturated acids. One other significant finding that stimulated much subsequent research on sugar esters was the isolation, identification, and synthesis of a specific ester in Oriental tobacco by Schumacher (3535) in 1960 and its identification a year later in Oriental tobacco smoke by Rodgman and Cook (3278). The ester was 6-acetyl-2,3,4-tris-d-3-methylvaleryl-β-Dglucopyranoside, that is, glucose esterified with the two aliphatic acids, acetic and 4-methylpentanoic (β-methylvaleric). The Schumacher research leading to the identification of this ester was described in detail by Green and Rodgman (1373) during the Symposium of the 50th Tobacco Research Chemists’ Conference. In his 1968 review of tobacco and smoke components, Stedman [see p. 165 and Table VI in (3797)] discussed at some length the procedures used to identify 272 esters of long-chained aliphatic alcohols in tobacco smoke. However, Stedman not only failed to cite the source of his discussion, an article by Rodgman et al. (3294), but also omitted from his text and ester tabulation that an identical series of esters was identified by Rodgman et al. in an aliphatic ester fraction obtained from Rowland and Latimer, who had isolated the fraction from flue-cured tobacco (3358) during their 1958 study of the solanesyl esters in tobacco. The identification of the numerous esters in the aliphatic ester fraction from tobacco and smoke led to the identification of a series of solanesyl and phytosteryl esters of saturated and unsaturated aliphatic acids in tobacco and smoke (3296) and a similar series of β-amyrin esters in tobacco by Fredrickson (1230). As mentioned previously, the characterization of the glucose ester in tobacco by Schumacher (3535) and the discovery that it generated the flavorful acid, 4-methylpentanoic

(β-methylvaleric) during the smoking process, led many years later to a series of studies aimed at determining the structure of the sucrose esters in tobacco. Despite the numerous studies, seldom was the precise structure of a sucrose ester defined. The various studies included those of Rivers (3185) in the early 1980s and of Severson et al. (3606), Schlotzhauer et al. (3473), Wahlberg et al. (4102), and Danehower (896) in the mid- to late 1980s. Several studies on tobacco and tobacco smoke composition, including studies of the long-chained aliphatic ester fraction, ultimately led to an interesting extrapolation by Green and Rodgman [see endnote 39 in (1373)] on the number of smoke components. Because of the limitations of analytical technology at the time of the Rodgman et al. study (3294) on the long-chained aliphatic ester fraction from tobacco and smoke, the higher molecular weight esters could neither be determined nor characterized. However, it was noted that qualitatively the tobacco ester fraction and the smoke ester fraction were similar. Every ester identified by Rodgman et al. in the smoke ester fraction was found in the tobacco ester fraction. Minor quantitative differences between the levels of individual esters in the two fractions were observed. With much improved analytical technology in the late 1980s, Arrendale et al. (103), in their study on the long-chained aliphatic ester fraction in tobacco, were able to identify not only many of the esters identified earlier in tobacco and smoke by Rodgman et al. but also many more higher molecular weight esters. Logic would dictate that if every ester identified in the Rodgman et al. study was present in both tobacco and smoke then every ester identified by Arrendale et al. (103) in tobacco would also be in smoke. Inclusion of the esters newly identified by Arrendale et al. in the smoke list results in a substantial increase in the number of smoke components. Examination of the esters listed in Table V-3 indicates that most of the esters identified in tobacco smoke are found in the particulate phase. An ester that exists predominantly in the vapor phase of tobacco smoke and was identified in cigarette MSS vapor phase by Laurene (2310) in 1959 and Grob (1413) in 1962 was the methyl ester of acetic acid. Since then, acetic acid methyl ester has been identified in cigarette MSS vapor phase in over fifty different studies. Because many esters have an aroma or taste acceptable to the consumer, the list of individual compounds used as tobacco ingredients by U.S. tobacco manufacturers contains numerous esters. Such a list was prepared by Doull et al. (1053) from information provided by the U.S. tobacco product manufacturers. A detailed examination of the Doull et al. list by Rodgman (3266) revealed that many of the added ingredients had been identified in additive-free tobacco and/or its smoke. 381

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As Rodgman noted, the compounds added as ingredients to cigarette tobacco may fall into one of the following categories: • It is a component of one or more of the tobacco types (flue-cured, Oriental, burley, Maryland) commonly used in cigarette blends. • It is a component of cigarette MSS. • It is a component of both tobacco and tobacco smoke. • It is not a component of either the tobaccos or their smoke. An ingredient compositionally similar to but not identical with a tobacco leaf or smoke component may be categorized in two ways: It is either an isomer or a homolog of a compound identified in natural tobacco leaf and/or its smoke. As noted, there are compounds used as cigarette ingredients that do not fall into any of the first three categories listed. In the broad spectrum of chemistry, biochemistry, and biology, cases exist where the properties of one homolog vary significantly from those of another or where the properties of one isomer differ significantly from those of another. For example, whether classified as a “Group 2A carcinogen” by the International Agency for Research on Cancer (IARC) (1868a), or a significant carcinogen in cigarette MSS (1727), or overall as a borderline carcinogen by others (983), the specific tumorigenicity of mouse skin-painted or subcutaneously injected benz[a]anthracene (B[a]A) is insignificant compared to that of its homolog, 7,12-dimethylbenz[a]anthracene (DMB[a]A), one of the four most potent tumorigenic polycyclic aromatic hydrocarbons (PAHs) known (983). The isomeric C20H12 PAHs benzo[e]pyrene (B[e]P) and benzo[a]pyrene (B[a]P) differ markedly in their specific tumorigenicities in studies involving mouse skin painting or subcutaneous injection (983). B[e]P under the usual laboratory test conditions is found to be essentially nontumorigenic on skin painting or subcutaneous

The Chemical Components of Tobacco and Tobacco Smoke

injection, whereas the isomeric B[a]P under the same conditions is one of the most potent tumorigens known. Of the 460 individual ingredients listed by Doull et al. [1053, see Table 1 in (3266)], 117 (25%) are esters (Table V-1) and all have been approved for use by the U.S. Food and Drug Administration or by the Flavor and Extract Manufacturers Association (FEMA). Of the 117 esters listed by Doull et al., 46 (39%) have been identified in untreated cigarette tobacco and/or its smoke (indicated by + in Table V-1) and 18 are either an homolog (indicated by H in Table V-1) or an isomer (indicated by I in Table V-1) of a known tobacco and/or smoke component. Doull et al. (1053) also listed 146 mixtures reportedly used by U.S. manufacturers as flavoring ingredients in tobacco products [see Table 2 in (3266)]. Many of these mixtures are obviously multicomponent items and detailed analyses of several of them (cardamom, cocoa, coffee, davana, licorice) indicated the presence of esters [see Table 3 in (3266)] listed by Doull et al. (1053). A similar situation exists with regard to flavorful mixtures used on tobacco products by non-U.S. manufacturers. Some thirty-four such mixtures are used on tobacco products by non-U.S. manufacturers [172a, 174a, 174b, 174c, see Table 7B in (3266)]. Compounds (forty-eight in number) other than those in the Doull et al. list are used in tobacco products by manufacturers in countries other than the United States [172a, 174a, 174b, 174c, see Table 7A in (3266)]. Among the fortyeight esters, are nineteen (21%) that have been identified in untreated cigarette tobacco and/or its smoke (indicated by + in Table V-2).* Table V-3 lists the esters identified to date in tobacco and/ or tobacco smoke.

*

Inadvertently, two esters (methyl anthranilate and methyl 2-octynate) already included in Table 1 in (3266) were included in Table 7A in (3266).

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383

The Esters

Table V-1 Esters Used as Tobacco Ingredients by U.S. Tobacco Product Manufacturers (1053) Identified In CAS No. 123-86-4 151-05-3 115-95-7 105-87-3 141-78-6 112-06-1 3681-71-8 142-92-7 123-92-2 80-26-2 89-48-5 140-39-6 110-19-0 143-13-5 2442-10-6 24851-98-7 93-92-5 103-45-7 103-54-8 122-72-5 76-49-3 125-12-2 141-97-9 122-43-0 101-97-3 102-22-7 5421-17-0 101-41-7 102-19-2 101-94-0 102-13-6 102-20-5 104-21-2 122-91-8 102-17-0 93-89-0 93-58-3 120-51-4 134-20-3 118-61-6 119-36-8 87-19-4 118-55-8 118-58-1 121-98-2 94-46-2 106-65-0 109-21-7 10094-34-5 106-29-6 141-16-2 105-54-4 106-27-4 540-18-1 103-52-6 103-37-7

Chemical Abstracts Nomenclature

Smoke

Tobacco

Acetic acid, butyl ester Acetic acid, 1,1-dimethyl-2-phenylethyl ester Acetic acid, 3,7-dimethyl-1,6-octadien-6-yl ester Acetic acid, 3,7-dimethyl-2,6-octadien-1-yl ester Acetic acid, ethyl ester Acetic acid, heptyl ester Acetic acid, 3-hexen-1-yl ester Acetic acid, hexyl ester Acetic acid, 3-methylbutyl ester Acetic acid, 2-(4-methyl-3-cyclohex-1-yl)-2-propyl ester Acetic acid, 5-methyl-2-(1-methylethyl)-cyclohexanyl ester Acetic acid, 4-methylphenyl ester Acetic acid, 2-methylpropyl ester Acetic acid, nonyl ester Acetic acid, 1-octen-3-yl ester Acetic acid, 2-pentyl-3-oxo-1-cyclopentyl-, methyl ester Acetic acid, 1-phenethyl ester Acetic acid, 2-phenethyl ester Acetic acid, 3-phenyl-2-propenyl ester Acetic acid, 3-phenylpropyl ester Acetic acid, endo-1,7,7-trimethylbicyclo[2,2,1]heptan-2-yl ester Acetic acid, exo-1,7,7,-trimethylbicyclo[2,2,1]heptan-2-yl ester Acetoacetic acid, ethyl ester Benzeneacetic acid, butyl ester Benzeneacetic acid, ethyl ester Benzeneacetic acid, 3,7-dimethyl-2,6-octadieny-1-yl ester Benzeneacetic acid, hexyl ester Benzeneacetic acid, methyl ester Benzeneacetic acid, 3-methylbutyl ester Benzeneacetic acid, 4-methylphenyl ester Benzeneacetic acid, 2-methylpropyl ester Benzeneacetic acid, phenylethyl ester; Benzenemethanol, 4-methoxy-, acetate Benzenemethanol, 4-methoxy-, formate Benzenemethanol, 4-methoxy-, phenylacetate Benzoic acid, ethyl ester Benzoic acid, methyl ester Benzoic acid, phenylmethyl ester Benzoic acid, 2-amino-, methyl ester Benzoic acid, 2-hydroxy-, ethyl ester Benzoic acid, 2-hydroxy-, methyl ester Benzoic acid, 2-hydroxy-, 2-methylpropyl ester Benzoic acid, 2-hydroxy-, phenyl ester Benzoic acid, 2-hydroxy-, phenylmethyl ester Benzoic acid, 4-methoxy-, methyl ester Benzoic acid, 3-methylbutyl ester Butanedioic acid, dimethyl ester Butanoic acid, butyl ester Butanoic acid, 1,1-dimethyl-2-phenylethyl ester Butanoic acid, 3,7-dimethyl-2,6-octadien-1-yl ester Butanoic acid, 3,7-dimethyl-6-octenyl ester Butanoic acid, ethyl ester Butanoic acid, 3-methylbutyl ester Butanoic acid, pentyl ester Butanoic acid, phenylethyl ester Butanoic acid, phenylmethyl ester

+ — — — + H — — — + — — — — — — — + — — — — — H — — — + — — — — + — — + + + — — — — — — — — + H — — — + — — H +

+ — + — + Ha — + — + — — — H — — + + — — — — — H + — — + — — — H — — — + + + + + + — — + — + — H — — — + — — H + (Continued)

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384

The Chemical Components of Tobacco and Tobacco Smoke

Table V-1 (Continued) Esters Used as Tobacco Ingredients by U.S. Tobacco Product Manufacturers (1053) Identified In CAS No. 7452-79-1 10032-15-2 109-19-3 1009-20-6 108-64-5 556-24-1 659-70-1 55066-56-3 140-26-1 140-27-2 10544-63-5 110-40-7 110-38-3 106-33-2 77-83-8 105-86-2 33467-73-1 110-45-2 638-49-3 614-99-3 611-13-2 126-14-7 106-30-9 628-97-7 123-66-0 2198-61-0 123-68-2 123-29-5 112-63-0 111-61-5 301-00-8 111-62-6 106-32-1 2035-99-6 638-25-5 111-12-6 539-82-2 539-88-8 102-76-1 105-53-3 105-37-3 122-63-4 103-56-0 7492-70-8 97-64-3 97-89-2 65416-14-0 103-93-5 109-15-9 103-48-0 103-36-6 103-26-4 7779-65-9 122-67-8 103-53-7

Chemical Abstracts Nomenclature

Smoke

Tobacco

Butanoic acid, 2-methyl-, ethyl ester Butanoic acid, 2-methyl-, hexyl ester Butanoic acid, 3-methyl-, butyl ester Butanoic acid, 3-methyl-, 3,7-dimethyl-2,6-octadieny-1-yl ester Butanoic acid, 3-methyl-, ethyl ester Butanoic acid, 3-methyl-, methyl ester Butanoic acid, 3-methyl-, 3-methylbutyl ester Butanoic acid, 3-methyl-, 4-methyylphenyl ester Butanoic acid, 3-methyl-, phenethyl ester Butanoic acid, 3-methyl-, 3-phenyl-2-propenyl ester 2-Butenoic acid, ethyl ester Decanedioic acid, diethyl ester Decanoic acid, ethyl ester Dodecanoic acid, ethyl ester Ethyl methylphenylglycidate Formic acid, 3,7-dimethyl-2,6-octadien-1-yl ester Formic acid, 3-hexenyl ester Formic acid, 3-methylbutyl ester Formic acid, pentyl ester 2-Furancarboxylic acid, ethyl ester 2-Furancarboxylic acid, methyl ester α-D-Glucopyranoside, β-D-fructofuranosyl-, octaacetate Heptanoic acid, ethyl ester Hexadecanoic acid, ethyl ester Hexanoic acid, ethyl ester Hexanoic acid, 3-methylbutyl ester Hexanoic acid, 2-propenyl ester Nonanoic acid, ethyl ester 9,12-Octadecadienoic acid (Z,Z), methyl ester Octadecanoic acid, ethyl ester 9,12,15-Octadecatrienoic acid, methyl ester 9-Octadecenoic acid, ethyl ester Octanoic acid, ethyl ester Octanoic acid, 3-methylbutyl ester Octanoic acid, pentyl ester 2-Octynoic acid, methyl ester Pentanoic acid, ethyl ester Pentanoic acid, 4-oxo-, ethyl ester 1,2,3-Propanetriol, triacetate Propanedioic acid, diethyl ester Propanoic acid, ethyl ester Propanoic acid, phenylmethyl ester Propanoic acid, 3-phenyl-2-propenyl ester Propanoic acid, 2-butoxy-, butyl ester Propanoic acid, 2-hydroxy-, ethyl ester Propanoic acid, 2-methyl-, 3,7-dimethyl-6-octenyl ester Propanoic acid, 2-methyl-, 2-methyl-4-oxo-4H-pyran-3-yl ester Propanoic acid, 2-methyl-, 4-methylphenyl ester Propanoic acid, 2-methyl-, octyl ester Propanoic acid, 2-methyl-, phenylethyl ester 2-Propenoic acid, 3-phenyl-, ethyl ester 2-Propenoic acid, 3-phenyl-, methyl ester 2-Propenoic acid, 3-phenyl-, 3-methylbutyl ester 2-Propenoic acid, 3-phenyl-, 2-methylpropyl ester 2-Propenoic acid, 3-phenyl-, phenylethyl ester

I — H — + — — — — — — — — — — — — — — H + — — + + — — — + — + — — — — — + — + H + — — — + — — — — H + H H H H

Ib — H + + — — + — H — + + — — + — — — + — + + + — — + + + + + + — — — + H — H + — — — — — — — — H — — — — —

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385

The Esters

Table V-1 (Continued) Esters Used as Tobacco Ingredients by U.S. Tobacco Product Manufacturers (1053) Identified In CAS No. 103-41-3 122-69-0 122-68-9 93-60-7 124-06-1 10580-24-2

Chemical Abstracts Nomenclature 2-Propenoic acid, 3-phenyl-, phenylmethyl ester 2-Propenoic acid, 3-phenyl-, 3-phenyl-2-propenyl ester 2-Propenoic acid, 3-phenyl-, 3-phenylpropyl ester 3-Pyridinecarboxylic acid, methyl ester Tetradecanoic acid, ethyl ester Undecanoic acid, butyl ester

a

H = a homolog of an identified tobacco and/or smoke component

b

I = an isomer of an identified tobacco and/or smoke component

Smoke

Tobacco

+ + — + — —

— — — + + H

Table V-2 Esters Used as Tobacco Ingredients by Tobacco Product Manufacturers Outside of the U.S. Identified In CAS No. 141-12-8 150-84-5 2497-18-9 126-64-7 87-20-7 539-90-2 76-50-6 103-38-8 16409-46-4 104-57-4 540-07-8 591-68-4 7549-33-9 105-68-0 103-28-6 78-35-3 97-62-1 103-59-3 110-27-0

Chemical Abstracts Nomenclature Acetic acid, 3,7-dimethyl-2,8-octadien-1-yl ester Acetic acid, 3,7-dimethyl-6-octen-1-yl ester Acetic acid, 2-hexen-1-yl ester Benzoic acid, 3,7-dimethyl-1,6-octadien-6-yl ester Benzoic acid, 2-hydroxy-, 3-methylbutyl ester Butanoic acid, 2-methylpropyl ester Butanoic acid, 3-methyl-, endo-1,7,7-trimethylbicyclo[2,2,1]heptan-2-yl ester Butanoic acid, 3-methyl-, phenylmethyl ester Butanoic acid, 3-methyl-, 5-methyl-2-(1-methylethyl)-cyclohexanyl ester, Formic acid, phenylmethyl ester Hexanoic acid, pentyl ester Pentanoic acid, butyl ester Propanoic acid, anisyl ester Propanoic acid, 3-methylbutyl ester Propanoic acid, 2-methyl-, phenylmethyl ester Propanoic acid, 2-methyl-, 3,7-dimethyl-1,6-octadien-6-yl ester Propanoic acid, 2-methyl-, ethyl ester Propanoic acid, 2-methyl-, 3-phenyl-2-propen-1-yl ester Tetradecanoic acid, 1-methylethyl ester

Smoke

Tobacco

— — — — — — — — — — — — — — — — — — —

— — + — + — + + — + — — — — + — — — —

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386

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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The Esters

387

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:15:26 PM

388

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C005.indd 388

11/13/08 5:15:28 PM

The Esters

389

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:15:29 PM

390

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C005.indd 390

11/13/08 5:15:31 PM

The Esters

391

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:15:33 PM

392

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:15:34 PM

The Esters

393

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:15:37 PM

394

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:15:38 PM

The Esters

395

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:15:42 PM

396

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C005.indd 396

11/13/08 5:15:43 PM

The Esters

397

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:15:46 PM

398

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C005.indd 398

11/13/08 5:15:54 PM

The Esters

399

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:15:59 PM

400

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:16:01 PM

The Esters

401

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:16:03 PM

402

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C005.indd 402

11/13/08 5:16:06 PM

The Esters

403

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:16:08 PM

404

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C005.indd 404

11/13/08 5:16:10 PM

The Esters

405

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:16:13 PM

406

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:16:15 PM

The Esters

407

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:16:17 PM

408

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:16:20 PM

The Esters

409

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:16:22 PM

410

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:16:25 PM

The Esters

411

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:16:27 PM

412

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:16:29 PM

The Esters

413

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:16:32 PM

414

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:16:34 PM

The Esters

415

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:16:36 PM

416

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:16:39 PM

The Esters

417

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:16:41 PM

418

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:16:43 PM

The Esters

419

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:16:46 PM

420

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:16:48 PM

The Esters

421

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:16:52 PM

422

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:16:54 PM

The Esters

423

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:16:57 PM

424

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:16:59 PM

The Esters

425

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:17:02 PM

426

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C005.indd 426

11/13/08 5:17:04 PM

The Esters

427

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:17:06 PM

428

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C005.indd 428

11/13/08 5:17:08 PM

The Esters

429

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:17:16 PM

430

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C005.indd 430

11/13/08 5:17:17 PM

The Esters

431

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:17:19 PM

432

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:17:22 PM

The Esters

433

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:17:24 PM

434

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:17:26 PM

The Esters

435

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:17:29 PM

436

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:17:31 PM

The Esters

437

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:17:34 PM

438

The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued) Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:17:36 PM

6

The Lactones

At various periods during the past fifty years, lactones in tobacco and tobacco smoke, particularly those in tobacco smoke, were discussed with regard to their toxicity, tumorigenicity, and genotoxicity. However, examination of the numerous lists of tobacco and tobacco smoke components classified as toxic, tumorigenic, and/or genotoxic reveals that seldom is a lactone included. The first significant list, derived from the 1986 International Agency for Research on Cancer (IARC) monograph on tobacco smoke (1870), was published in 1986 by Hoffmann and Wynder (1808). Over the next two decades, the Hoffmann-Wynder list was followed by successive similar but not identical lists by Hoffmann and Hecht (1727) in 1990, Hoffmann et al. (1773) in 1993, the Occupational Safety and Health Administration (OSHA) (2825) in 1994, Hoffmann and Hoffmann (1740, 1741, 1743) in 1997, 1998, and 2001, and Fowles and Bates (1217) in 2001 [see a summary of all these lists in Table 2 in Rodgman (3265)]. Based on its February 1985 meeting on tobacco smoking, the IARC Working Group wrote in 1986 [see p. 107 in (1870)]: About 80 lactones have been identified in tobacco smoke. These compounds, especially the γ-butyrolactones, and others, have alkylating potential and some have been reported to be carcinogenic in laboratory animals [Lawley (6A12)]. [see also Appendix 2, pp. 387–394) in (1870)]. Quantitatively, about half the lactones in the smoke consist of γ-butyrolactone [IARC (6A10)] (about 10 μg/cigarette) and its derivatives; δ-valerolactone and some alkylated and unsaturated δ-valerolactones, as well as coumarin [see pp. 427–430 in Wynder and Hoffmann (4332)], 6-methylcoumarin, and 3,4dihydrocoumarin have also been isolated [Schumacher et al. (3553)]. The occurrence of coumarin derivatives in smoke could be due to pyrolysis of polyphenols with a coumarin structure … or of plant extracts added to tobacco to enhance flavour [see pp. 427–430 in Wynder and Hoffmann (4332)]. Coumarin itself is carcinogenic to rats after oral administration [IARC (6A10)].

In its monograph, IARC made no comment on the ten lactones, including coumarin, that Lawley listed as inactive in oncogenesis tests [see Table XXVII in (6A12)], citing the 1965 study on coumarin by Dickens and Jones (6A06). IARC also failed to mention the 1984 listing by Slaga and DiGiovanni (3685) of the report by Wattenberg et al. (4149d), who described the anticarcinogenicity of coumarin towards the potent tumorigenic polycyclic aromatic hydrocarbons (PAHs) benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a] anthracene (DMB[a]A). At the time of the writing of the IARC 1986 monograph on tobacco smoking, over 100 lactones had been identified in tobacco smoke.

The information on pages 387–394 in Appendix 2 in (1870), particularly the information provided by the IARC Working Group on lactones on page 391, is:

Compound

Degree of Evidence in Animals (and Humans)

5. Lactones Coumarin γ-Butyrolactone

Limited evidence No evidence

In the cited Figure 5 [see page 93 in (1870)], only the following five lactones (substituted coumarins) of the nearly two dozen identified in tobacco and/or tobacco smoke were depicted, namely, scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one), scopolin [7-(β-D-glucopyranosyloxy)-6-methoxy-2H-1-benzopyran-2-one], esculetin (6,7-dihydroxy-2H-1benzopyran-2-one), cichoriin [7-(β-D-glucopyranosy-loxy)6-hydroxy-2H-1-benzopyran-2-one], and scopoletin-β-gentiobioside. Two lactones that received some attention with regard to tobacco and smoke were aflatoxins, B1 and B2, primarily aflatoxin B1, the more toxic of the two. In 1970, Kaminski et al. (2024) examined the butts, ashes, and mainstream smoke (MSS) vapor phase and particulate phase from machinesmoked commercial nonfilter cigarettes treated with aflatoxin B1. In six separate smoking experiments, no trace of aflatoxin B1 was detected in any of the fractions examined. In their 1967 examination of several samples of leaf tobacco, including three types of good-grade tobaccos and heavily molded flue-cured tobacco, and of cigarette smoke condensate (CSC), Tso and Sorokin (3986) failed to detect aflatoxin B1. They also reported that no aflatoxin B1 was found in the CSC from cigarettes enriched with authentic aflatoxin B1 prior to smoking. They concluded that the added aflatoxin B1 was changed or decomposed during the smoking process. Later, Tso (3970) again reported the results of this aflatoxin B1 study at the 1967 World Conference on Smoking and Health. In his 2000 review of scientific publications on aflatoxin B, tobacco, and tobacco smoke, Massey (2484) concluded that aflatoxin B was not a contamination issue on tobaccos and, even if present, would decompose in the burning cigarette and would not transfer to smoke. As noted in the quotation from the 1986 IARC monograph, orally administered coumarin (2H-1-benzopyran-2one) had been reported as carcinogenic in rats. The results reported from several studies on the tumorigenicity of coumarin eventually resulted in coumarin being removed from

439

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440

The Chemical Components of Tobacco and Tobacco Smoke

OH 6 7

5

8

4

H2 C

3

O

O

O

OO

I

OH

O

II

OH

HO

O V

O

O

IV

O

O

O

COOH

III

OH

O

O

OH COOH OH

OH COOH

Figure VI-1  Relationships between coumarin, its derivatives, and dicumarol.

the flavor formulations used throughout the tobacco industry on cigarette and pipe tobacco. Coumarin was considered by the consumer as a significantly acceptable contribution to tobacco smoke. Coumarin was identified by Schumacher and Vestal as a minor component of untreated Oriental tobacco in the early 1960s (3560). The initial concern in the early 1960s about the addition of coumarin {I} to tobacco products was whether or not it was converted during the smoking process to dicumarol (3,3’-methylenebis[4-hydroxy-2H-1-benzopyran-2-one]) {II} (Figure VI-1). Dicumarol is a powerful anticoagulant that had been identified in sweet clover hay (6A21). In previous metabolic studies, it had been reported that coumarin was not a precursor of dicumarol {II} (6A03, 6A15) or of o-coumaric acid [3-(2-hydroxyphenyl)-2-propenoic acid] {III} (6A21). {III} was known to be a precursor of dicumarol via 4-hydroxycoumarin {IV}. Laboratory animals (rats, rabbits) fed coumarin excreted 4-hydroxycoumarin {IV} (6A04). Between 70% and 90% of coumarin administered to humans resulted in excretion of 7-hydroxycoumarin {V} (6A17), a coumarin derivative never indicted as dangerous to any species or proposed as a dicumarol precursor.

Newell reported in 1963 that (1) inclusion in cigarette tobacco of 3-14C-coumarin {I} gave no dicumarol {II} in either the MSS or the sidestream smoke (SSS) and (2) inclusion in cigarette tobacco of unlabeled dicumarol gave no dicumarol {II} in either the MSS or the SSS (2757). Of the 3-14C-coumarin applied to the tobacco blend, Newell reported that 60% appeared unchanged in the MSS and SSS. To assess the claims of the possible adverse effect of including coumarin in flavor formulations, several reports and memoranda were written in the late 1970s about the coumarin situation in an obvious attempt to put the issue in perspective. In 1978, Buchner (6A05) listed several of the authorities that incorrectly cited negative tumorigenicity results as positive, for example, in 1976, the National Institute for Occupational Safety and Health (NIOSH) (6A16) incorrectly cited results published in 1955 by Roe and Salaman (6A20). Much weight was given to the reported findings of Griepentrog (6A02, 6A07), the only findings on the induction of bile duct carcinomas in coumarin-fed rats. Buchner (6A05) summarized many of the results of studies that raised questions about the classification of coumarin as a carcinogen, for example, the negative tumorigenicity results reported by

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The Lactones

Hagan et al. (6A08) and Hazleton et al. (6A09). He also cited several genotoxicity studies in which coumarin was found to be inactive against human chromosomes (6A22) and against Salmonella typhimurium strains TA 1535, TA 1537, TA 98, and TA 100 in the Ames test [Buchner, private communication, see Reference 26 in (6A22)]. Paralleling the report by Buchner were several memoranda on coumarin by Rodgman in 1978 (6A18) and 1982 (6A19) in which the problems of misinterpretation of data and contrary data pertinent to coumarin were presented. Included in the memoranda were the negative mutagenicity results obtained in Ames tests with five strains (TA 1535, TA 1537, TA 1538, TA 98, TA 100) of Salmonella typhimurium on coumarin conducted in-house by Lee (6A13) at R.J. Reynolds Research and Development. His results were confirmed on a coded coumarin sample among a set of coded samples tested at a contract laboratory (6A14). Despite the controversies over the tumorigenicity of coumarin, its use in tobacco flavor formulations was subsequently discontinued throughout the tobacco industry worldwide. In its 2000 evaluation of the tumorigenicity of coumarin (2H-1-benzopyran-2-one), IARC (6A11) noted the following as of 21 August, 2000: Coumarin is a natural product occurring in the essential oils of a large number of plants, such as cinnamon, cassia, lavender and woodruff. It is used for its fragrance in many personal care products (perfumes, deodorants, soaps) and in tobacco, in household and industrial products to mask unpleasant odours and, in some countries, as a flavouring agent in food and beverages. It has also been used to treat several medical conditions. Exposure to coumarin may occur from its

441 production, its natural presence in many plants and essential oils, and its several industrial, medical and consumer uses.

According to IARC, no data were available to its Working Group on the carcinogenicity of coumarin in humans. After assessment of various studies in which coumarin was administered to laboratory animals, IARC concluded that the evidence was limited in laboratory animals on the carcinogenicity of coumarin. IARC described its overall evaluation of coumarin as a carcinogen as follows: “Coumarin is not classifiable as to its carcinogenicity to humans.” In 1998, Abbott (6A01) described the results of the examination of numerous food additives by the World Health Organization. The food additives in this particular study comprised a series of so-called aliphatic lactones. Among the lactones discussed were several that not only are used as foodstuff additives but also occur in tobacco and/or its smoke and several that are used as tobacco additives. The results of several toxicological studies (acute toxicity, shortand long-term toxicity, carcinogenicity) and genotoxic studies on the lactones were described in detail by Abbott. Table VI-1 presents the results listed by Abbott on those lactones that are used in tobacco products. Table VI-2 lists the tobacco and/or smoke lactones that, according to the Doull et al. listing (1053), are or have been used recently as components in flavor formulations for tobacco. The number of lactones identified to date in tobacco and/ or tobacco smoke is 304. Of these, 162 have been identified in tobacco smoke, 201 in tobacco, and 59 in both tobacco and tobacco smoke. Table VI-3 lists the lactones identified in tobacco and tobacco smoke to date.

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442

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Table VI-1 Some Biological Properties of Lactones Used as Additives in Foodstuffs as Well as in Tobacco Products (6A01) Lactone CAS No.

CAS Nomenclature

104-50-7 96-48-0

2(3H)-Furanone, 5-butyldihydro2(3H)-Furanone, dihydro-

Common Name γ-octalactone γ-butyrolactone

Smoke or Tobacco Component

Flavor Formulation Additive

+ +

+ +

Genotoxicity a

negative

Acute Toxicity, LD50, mg/kg >5000 (rat)c 1245 (mouse)

Short-term Toxicity, NOELb, mg/kg/day 300 (rat) 175 (mouse)

2(3H)-Furanone, dihydro-5-ethyl2(3H)-Furanone, dihydro-5-heptyl-

γ-hexalactone γ-undecalactone

+ -

+ +

706-14-9 108-29-2 2305-05-7 104-61-0

2(3H)-Furanone, dihydro-5-hexyl2(3H)-Furanone, dihydro-5-methyl2(3H)-Furanone, dihydro-5-octyl2(3H)-Furanone, dihydro-5-pentyl-

γ-decalactone} γ-valerolactone} γ-dodecalactone} γ-nonalactone}

+ + +

+ + + +

105-21-5 28664-35-9 698-10-2 591-12-8 7779-50-2 106-02-5 27593-23-3 3301-94-8 713-95-1 710-04-3 823-22-3 705-86-2 698-76-0

2(3H)-Furanone, dihydro-5-propyl2(5H)-Furanone, 3-hydroxy-4,5-dimethyl2(5H)-Furanone, 5-ethyl-3-hydroxy-4-methyl2(3H)-Furanone, 5-methylOxacycloheptadec-7-en-2-one Oxacyclohexadecan-2-one 2H-Pyran-2-one, 6-pentyl2H-Pyran-2-one, tetrahydro-6-butyl2H-Pyran-2-one, tetrahydro-6-heptyl2H-Pyran-2-one, tetrahydro-6-hexyl2H-Pyran-2-one, tetrahydro-6-methyl2H-Pyran-2-one, tetrahydro-6-pentyl2H-Pyran-2-one, tetrahydro-6-propyl-

γ-heptalactone

+ + ‑ + + +

+ + + + + + + + + + + +

α-angelica lactone ω-pentadecalactone 6-amyl-α-pyrone δ-nonalactone} δ-dodecalactone δ-undecalactone} δ-hexalactone δ-decalactone} δ-octalactone}

a

References to the various genotoxicity systems used may be found in Abbott [see Table 6 in (6A01)].

b

NOEL = no observed effect level

c

References to procedures used may be found in Abbott [see Table 3 in (6A01)]

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6 negative 2 positive

3 negative 3 positive negative

>5000 (rat) 18500 (rat) >5000 (rat) >5000 (rat) >5000 (rat) 9780 (rat) 3440 (guinea pig) >5000 (rat)

2800 (mouse) 2 negative

>5000 (rat) >5000

>14 (rat)

>50 (rat) >72 (rat)

>1.3 (rat) >17 (rat)

The Chemical Components of Tobacco and Tobacco Smoke

695-06-7 104-67-6

443

The Lactones

Table VI-2 Tobacco and/or Smoke Lactones Used in Flavor Formulations Identified In CAS No.

Chemical Abstracts Nomenclature

50-81-7 96-48-0 104-50-7 695-06-7 104-67-6 706-14-9 108-29-2 2305-05-7 104-61-0 105-21-5 591-12-8 27538-09-6

L-Ascorbic acid {L-gulofuranolactone, 3-oxo-} 2(3H)-Furanone, dihydro2(3H)-Furanone, dihydro-5-butyl2(3H)-Furanone, dihydro-5-ethyl2(3H)-Furanone, dihydro-5-heptyl2(3H)-Furanone, dihydro-5-hexyl2(3H)-Furanone, dihydro-5-methyl2(3H)-Furanone, dihydro-5-octyl2(3H)-Furanone, dihydro-5-pentyl2(3H)-Furanone, dihydro-5-propyl2(3H)-Furanone, 5-methyl3(2H)-Furanone, 3-ethyl-4-hydroxy-5-methyl- b

551-08-6 564-20-5 7779-50-2 106-02-5 3301-94-8 713-95-1 710-04-3 2721-22-4 705-86-2 698-76-0

1(3H)-Isobenzofuranone, 3-butylideneNaphtho[2,1-b]furan-2(1H)-one, decahydro-3a,6,6,9a-tetramethylOxacycloheptadec-7-en-2-one Oxacyclohexadecan-2-one 2H-Pyran-2-one, tetrahydro-6-butyl- b 2H-Pyran-2-one, tetrahydro-6-heptyl2H-Pyran-2-one, tetrahydro-6-hexyl2H-Pyran-2-one, tetrahydro-6-nonyl- b 2H-Pyran-2-one, tetrahydro-6-pentyl2H-Pyran-2-one, tetrahydro-6-propyl-

a

As Listed by Doull et al. (1053) ascorbic acid 4-hydroxybutanoic acid lactone γ-octalactone γ-hexalactone γ-undecalactone γ-decalactone γ-valerolactone γ-dodecalactone γ-nonalactone γ-heptalactone 4-hydroxy-3-pentenoic acid lactone 3-ethyl-4-hydroxy-5-methyl-3(2H)furanoneb 3-butylidenephthalide sclareolide ω-6-hexadecenlactone ω-pentadecalactone δ-nonalactoneb δ-dodecalactone δ-undecalactone tetradecalactoneb δ-decalactone δ-octalactone

Smoke

Tobacco

+ + + – + -

+ + + + Ha + + H + + + -

+ -

H + H + H H H H + +

H = homolog of an identified tobacco and/or smoke component This lactone is not included in the Doull et al. list (1053) but is included in flavor formulations used by cigarette manufacturers outside of the U.S. [see Table 7A in (3266)]

b

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444

The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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445

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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446

The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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447

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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448

The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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449

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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450

The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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451

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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452

The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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453

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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454

The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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455

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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456

The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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The Lactones

457

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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458

The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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459

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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460

The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued) Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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7

Anhydrides

The number of anhydrides identified in tobacco and tobacco smoke is small. In 1988, Roberts (3215) reported that there were only ten anhydrides identified in tobacco, ten identified in tobacco smoke, and four in both tobacco and tobacco smoke. The number of anhydrides in tobacco and tobacco smoke has not changed substantially since that time. There are presently thirteen anhydrides identified in tobacco, thirteen in tobacco smoke, and six in both tobacco and tobacco smoke. In his 1984 review of the carcinogenesis induced by alkylating agents, Lawley (Table XXV, p. 434 in 7A04) tabulated the findings of Dickens and Jones on a study of the tumorigenicity (sarcogenicity) of maleic anhydride (7A01) and 2,3dimethylmaleic anhydride and succinic anhydride (7A02) administered by subcutaneous injection to Wistar rats. In its 1986 monograph, the International Agency for Research on Cancer (IARC) wrote very little on the few anhydrides in tobacco smoke [see p. 107 in (1870)]. IARC commented: At least eight acid anhydrides have been found in cigarette smoke, including maleic anhydride and succinic anhydride and their alkylated derivatives [Schumacher et al. (3553), Newell et al. (2769)]. These smoke constituents are of particular concern because of their alkylating potential. Maleic anhydride, 2,3-dimethylmaleic anhydride and succinic anhydride have produced local tumours in one experiment in rats [Dickens and Jones (7A01, 7A02), IARC (7A03)].

An inserted comment in the IARC monograph referred the reader to Appendix 2, pages 389–394 in (1870), which listed the components in tobacco smoke that had been evaluated for carcinogenicity in the IARC monograph series. The tumorigenicity of succinic anhydride was listed as:

Compound

It is obvious from the review by Lawley (7A04) and the data in the Dickens and Jones reports (7A01, 7A02) that the anhydrides are sarcogens, not carcinogens, that is, they do not fit the definition of a carcinogen, a factor that induces a carcinoma. At R.J. Reynolds Tobacco Co. (RJRT) R&D, two anhydrides, 3,4-diethyldihydro-2,4-furandione (diethylsucccinic anhydride) and 3,4-dimethyldihydro-2,4-furandione (dimethylsucccinic anhydride) were identified by Jones and Latimer during their research on Oriental tobacco composition. The two anhydrides were listed in their 1943 report on the Oriental tobacco components they identified through the end of 1942 (1980). In a subsequent RJRT research effort in 1963 and 1964, several anhydrides (see Table VII-1) were isolated from tobacco smoke and identified by Fredrickson (1233, 1235) during his study of the composition of burley tobacco smoke condensate. Two decades later, several additional anhydrides (see Table VII-1) were identified as components of Oriental tobacco by Schumacher (3543). Table VII-1 lists the twenty anhydrides identified to date in tobacco and/or tobacco smoke. None of the anhydrides listed in Table VII-1 was included in any of the many publications issued between 1986 and 2001 in which the toxicants in tobacco and/or tobacco smoke were listed (1217, 1727, 1740, 1741, 1743, 1744, 1773, 1808, 2825). No anhydride was included in the 1994 Doull et al. list (1053) on compounds in flavor formulations used on tobacco products by members of the U.S. tobacco industry.

Degree of Evidence in Animals (and Humans)

7. Agricultural chemicals and derivatives Succinic anhydride Limited evidence

461

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The Chemical Components of Tobacco and Tobacco Smoke

Table VII-1 Anhydrides in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Anhydrides

463

Table VII-1 (CONTINUED) Anhydrides in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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8

Carbohydrates and Their Derivatives

The four macromolecules that have been called the “building blocks of life” are carbohydrates, proteins, lipids, and nucleic acids. Tso (3873) estimated that as much as 75% of all the carbon from CO2 that is reduced by plants enters into some form of carbohydrate for at least a brief period of time. Via numerous metabolic pathways these carbohydrates are converted into hundreds of functional molecules necessary to sustain life. There are 279 components in tobacco and/or tobacco smoke that may be considered either as a complete carbohydrate or one in which a carbohydrate is linked to another structure, such as a glycoside. This number is greater than the 156 listed by Tso in his 1990 book [see Table 1.38 in (3873)] because of our inclusion of the carbohydrate-combined components. The following indicates the difference in numbers:

Tso Carbohydrates

Reference

Total

Smoke

Tobacco

Tobacco and Smoke

Table 1.38 in (3873) Table VIII-3

156 279

30 35

138 271

12 27

A great number of carbohydrate-linked components, mostly in tobacco, involve the linkage of a carbohydrate to a 2H-1-benzopyran-2-one or 4H-1-benzopyran-4-one, which may not only be hydroxylated, for example, 6-(β-D-glucopyranosyloxy)-7-hydroxy-2H-1-benzopyran-2-one (esculin), but also may have one or more hydroxyphenyl links, for example, 3-[(6-deoxy-α-L-mannopyranosyl)oxy]-2-(3,4-dihydroxyphenyl)5,7-dihydroxy-4H-1-benzopyran-4-one (quercitrin), 3-[[6O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyl] oxy]-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one (rutin), and 3-(β-D-glucopyranosyloxy)-5,7dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one (kaempferol glycoside). Components such as these were classified as polyphenols. Tobacco components such as the latter three may be the precursors of part of the phenols yield in tobacco smoke. Snook et al. (8A08) determined the levels of rutin and kaempferol glycoside in sixty-two different species of Nicotiana. Their levels ranged from <0.005 to 1.6% for rutin and <0.005 to 0.16% for the kaempferol glycoside. There are, of course, in tobacco several carbohydrate-linked benzopyranones that lack an hydroxyphenyl group, for example, 6-(β-D-glucopyranosyloxy)-7-hydroxy-2H-1-benzopyran-2one (esculin) and 7-(β-D-glucopyranosyloxy)-6-methoxy2H-1-benzopyran-2-one (scopolin).

As indicated in Table VIII-1, only a few tobacco and/or tobacco smoke carbohydrates are used in the flavor formulations used by cigarette manufacturers in the United States (1053) and in other countries (3266). None of those used in that way is linked to a noncarbohydrate entity. The use of tobacco containing various carbohydrate additives, such as the various sugars listed in Table VIII-1, has been the subject of much discussion recently in attempts to link such additives to medical problems induced by cigarette smoke. The major concern was the generation of carbonyl compounds such as formaldehyde and acetaldehyde. Although Baker (8A02), in his letter to the editor of Food and Chemical Toxicology, agrees with the statements of Talhout et al. (3865b) that addition of sugars to tobacco results in increased yields of formaldehyde in the mainstream smoke (MSS), he also provided numerous references [Baker (8A01), Baker and Bishop (172a, 172b), Baker et al. (172c, 174a, 174b, 174c, 8A03), Baker and Smith (174e), Gori (1332), Massey (2484a), Rodgman (3264), Rustemeier et al. (3370), Seeman et al. (3579, 8A06), Thornton and Massey (3913), Zilkey et al. (4418)] and much discussion to counter the assertions by Talhout et al. (3865b) that sugar addition had an adverse effect on the biological properties of the MSS. Not included in Baker were the facts that (1) Doull et al. (1053), in their detailed 1994 assessment of 599 additives used by members of the U.S. tobacco industry in cigarette manufacture, reported no significant biological problem from the use of sugars in the flavor formulations and (2) Dalhamn et al. (892) had reported in 1968 that a significant percentage of water-soluble MSS vapor-phase components, such as formaldehyde, acetaldehyde, and other carbonyls, never reached the respiratory tract cilia of the smoker because of their solution in the fluids coating the oral cavity. The findings of Dalhamn et al. (892) were a confirmation of those by Rodgman et al. (3306), Industrial Bio-Test Laboratories, an independent contract laboratory (8A04), and the repeated assertions by Wynder and Hoffmann that such would be the case with water-soluble ciliastats (4330, 4332). In their mid-1960s publications, Wynder and Hoffmann commented several times on the fact that most of the known ciliastatic components of MSS demonstrated to be ciliastatic in various in vitro systems were water soluble and this property would markedly influence their fate and behavior during and after inhalation. Wynder and Hoffmann (4330) noted: As far as human smoking habits are concerned, it remains also to be estimated to which extent volatile smoke components reach the bronchial tree. Preliminary studies indicate that a significant proportion of the gaseous components is being retained within the oral cavity. 465

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Table VIII-1 Tobacco and/or Smoke Carbohydrates Used in Flavor Formulations Identified in CAS No.

Chemical Abstracts Nomenclature

57-48-7 59-23-4 50-99-7 57-50-1 50-99-7 31103-86-3 50-70-4

D-Fructose D-Galactose α-D-Glucose α-D-Glucopyranoside, β-D-fructofuranosyl- {sucrose} α-D-Glucose Mannose Sorbitola

a

As Listed by Doull et al. (1053)

Smoke

Tobacco

sugars sugars sugars sugars sugars sugars glucitol

+ + + + + + -

+ + + + + + +

 orbitol (glucitol)) is not included in the Doull et al. list (1053) but is included in flavor formulations used by cigarette manufacturers S outside of the U.S. [see Table 7A in (3266)].

As noted by Baker (8A02), Talhout et al. (3865b) commented on the effect on MSS carbonyl component yields produced by additions to tobacco of 12% of three sugars but they did not describe the effect of the additions of 4% of each sugar, an addition level that more closely resembled that used commercially. Table VIII-2 lists the changes reported by Shelar et al. (8A07) in per cigarette MSS yield of formaldehyde, acetaldehyde, acetone, and acrolein by addition of 4% fructose, glucose, or sucrose to two different burley samples. Not discussed by either Baker (8A02) or Talhout et al. (3865b) was a 1970 study by Best (297) in which a flue-cured tobacco sample was treated with sugar to raise its level from 12.6% to 21.0%. Even though the sugar addition to the flue-cured tobacco represented a 66% increase, the MSS yields of carbonyl components increased: Formaldehyde from 35.4 μg/cigarette to 48.8 μg/cigarette, a 37.8% increase; acetaldehyde from 998 μg/ cigarette to 1020 μg/cigarette, a 2.2% increase; acrolein from 124 μg/cigarette to 131 μg/cigarette, a 5.6% increase. In his review of the genotoxicity of tobacco smoke and tobacco smoke condensate, DeMarini (933) described in detail the 1979 findings of Mizusaki et al. (2568) on the effect of the cigarette smoke condensate (CSC) from high-sugar tobacco (20% to 30%) vs. the CSC from low-sugar tobacco

Later, Wynder and Hoffmann [see p. 542 in (4332)] wrote: Water-soluble volatile components, which are primarily responsible for the results of the acute in vitro short-term cilia toxicity tests, are, to a large extent, removed when cigarette smoke contacts the saliva in the mouth and the abundant secretions of the trachea and main bronchi.

They added [see p. 646 in (4332)]: In man’s manner of smoking, however, volatile components are retained to a significant degree in the oral cavity and may, therefore, be far less important than when tested experimentally.

Baker (8A02), in the letter to the editor of Food and Chemical Toxicology in which he responded to the assertions of Talhout et al. (3865b), noted several early studies cited by Talhout et al., those of Thornton and Massey (3913) and Shelar et al. (8A07) in which high levels of a carbohydrate (sugar) were added to the tobacco, resulting in a significant increase in the MSS yield of several carbonyl compounds, namely formaldehyde, acetaldehyde, and acrolein. However, the added carbohydrate greatly exceeded the amount usually added in an industrial situation.

Table VIII-2 Effect of Sugars Added to Burley Tobacco on Mainstream Smoke Aldehyde and Ketone Yields (8A07) Per Cigarette MSS Yield Formaldehyde

Acetaldehyde

Acetone

Acrolein

Burley 1 + 4% fructose + 4% glucose + 4% sucrose

16.0 18.2 (13.8%) 15.7 (-2%) 20.4 (27.5%)

507 591 (16.6%) 553 (9.1%) 574 (13.2%)

269 333 (23.8%) 335 (24.5%) 364 (35.3%)

118 135 (14.4%) 123 (4.2%) 139 (17.8%)

Burley 2 + 4% fructose + 4% glucose + 4% sucrose

11.2 12.0 (7.1%) 18.6 (66.1%) 18.2 (62.5%)

578 652 (12.8%) 567 (-2%) 561 (-3%)

306 330 (7.8%) 216 (-29.5%) 270 (-12%)

118 130 (10.2%) 93 (-21.2%) 109 (-7.7%)

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Carbohydrates and Their Derivatives

(5%) in the Ames test (Salmonella typhimurium strain TA 1538). The high-sugar tobacco CSC was much less mutagenic than the low-sugar tobacco CSC. DeMarini (933) also summarized the results of a study by Sato et al. (8A05) in which various sugars were added to the tobacco in high-“tar” and low-“tar” cigarettes, the CSCs collected, and tested for mutagenicity in the Ames test with Salmonella typhimurium TA 98 and TA 100, with and without activation. The sugars tested included glucose, fructose, galactose, lactose, sucrose, and sorbitol. The mutagenicity of the CSC from the sugartreated high-“tar” cigarettes was reduced 35% from the mutagenicity observed for the CSC from the untreated tobacco cigarette. The mutagenicity of the CSC from the low-“tar” cigarettes was reduced 36% from mutagenicity of the CSC from the untreated tobacco cigarette. In the National Cancer Institute study of the third set of cigarettes, Gori (1332) reported the effect of adding invert sugar at a level approximating that used commercially to the Standard Experimental Blend III (SEB III) [see Table 8, p. 99, cigarette 81 in (1332)] on the per cigarette MSS yields of numerous smoke components, including formaldehyde, acetaldehyde, and acrolein [see Table 8, p. 59 in (1332)]. The

467

multiple samples of SEB III yielded an average of 33.8 μg/ cigarette of formaldehyde, 1212 μg/cigarette of acetaldehyde, and 110 μg/cigarette of acrolein. Cigarette 81, fabricated from SEB III with added invert sugar, yielded 32.3 μg/cigarette of formaldehyde, 1090 μg/cigarette of acetaldehyde, and 113 μg/cigarette of acrolein. Dermal assays were initiated with 100 ICR Swiss female mice in each group. Multiple samples of CSC from SEB III at 12.5 mg and 25.0 mg doses produced twenty-seven and forty-seven tumor-bearing animals (TBA), respectively [see Table 2, p. 86 in (1332)], whereas the CSC from the invert sugar-treated SEB III at 12.5 mg and 25.0 mg doses produced nineteen and forty-one TBA, respectively [see Table 3, p. 87, cigarette 81 in (1332)]. However, the CSCs studied would be devoid of formaldehyde, acetaldehyde, and acrolein because of their vaporization during the collection, solution preparation, and administration of the CSCs. Table VIII-3 lists the carbohydrates and their derivatives identified to date in tobacco, tobacco smoke, and tobacco substitute smoke. Of the 279 identified carbohydrates listed, most of them are tobacco components: 271 have been identified in tobacco vs. only 35 in smoke; 27 have been identified in both tobacco and smoke.

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Table VIII-3 Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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469

Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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471

Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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473

Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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474

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Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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475

Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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477

Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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479

Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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481

Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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482

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Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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483

Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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485

Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table VIII-3 (continued) Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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9

Phenols and Quinones

IX.A Phenols Examination of the extensive literature on the composition of tobacco smoke reveals that considerable effort was expended in the early 1960s in defining the nature of the phenolic components of tobacco smoke. Subsequently, even though the identity of many phenols in tobacco smoke are now known, research has indicated their number identified in tobacco smoke is much fewer than the number of identified polynuclear aromatic hydrocarbons (PAHs). With the tremendous effort expended on the identification of PAHs and some of their nitrogen analogs in tobacco smoke, what series of events triggered the interest in and the emphasis on phenols in tobacco smoke in the early 1960s? The reports by Wynder et al. (4306a, 4306c) in the early 1950s that cigarette smoke “tar” or cigarette smoke condensate (CSC) was tumorigenic to mouse skin prompted an intense search for the responsible component(s). Initially, the PAHs were selected for investigation because of the wealth of chemical and biological data generated on a great number of them following the synthesis of dibenz[a,h]anthracene (DB[a,h]A) in 1929 (760, 1184), the isolation of benzo[a]pyrene (B[a]P) from coal tar in 1932 (796a, 797), and the demonstration of the potent tumorigenicity of both of them to mouse skin (194, 2078). Almost immediately after the report by Wynder et al. (4306a) of the mouse skin-painting results with tobacco “tar,” the PAHs were proposed by some investigators to be the major tumor initiators in CSC. Because of its level in CSC and its potency in mouse-skin tumorigenesis, B[a]P was defined as the most significant of the PAHs in tobacco smoke. However, it was soon recognized that neither the B[a] P content nor its tumorigenicity could explain the biological response observed in the mouse skin-painting bioassay. Similarly, neither the total content of the PAHs tumorigenic to mouse skin nor their summed tumorigenicities could explain the observed biological response. In fact, it was pointed out repeatedly over the next several decades that the levels of B[a]P and other tumorigenic PAHs in CSC accounted for less than 3% of the observed tumorigenicity [Wynder and Wright (4353, 4354), Wynder and Hoffmann (4307, 4308, 4312, 4317, 4319, 4332, 4342), Druckrey (1056), Roe (3310, 3311), USPHS (3999, 4005, 4009, 4010), Lazar et al. (2320), Stedman (3797), Selikoff et al. (3584a), Coultson (830)]. As early as the mid-1950s, Wynder and Wright (4353) noted that the concentration of B[a]P in cigarette tar was insufficient to account for its observed carcinogenicity to mouse epidermis: “The concentration in which benzo[a] pyrene seems to be in cigarette tar is insufficient to account for the observed carcinogenic activity to mouse epidermis.” At the 1957 Blatnik Committee hearings, Wynder reported Wright’s opinion (4282a) on the subject as well as his own

(4296). Wynder noted that much attention had been directed at the PAH B[a]P. So much in fact that, as he stated, B[a] P had become an issue in itself because it was one of the known tumorigenic substances and everyone tried to blame everything on it alone. During his testimony, he also noted that his Sloan Kettering group had repeatedly stated that the amount of B[a]P in tobacco “tar” was insufficient to explain the animal results published by his group. He added that cigarette “tar” contained numerous other B[a]P-related compounds much more active than B[a]P and they most likely accounted for the majority of the activity, and it was more or less academic whether it was B[a]P or a dibenzopyrene or a dibenzanthracene or a substituted B[a]P because they were all formed in the same manner during the tobacco smoking process. That same year, Wynder and Wright (4354) wrote that, to that date, no carcinogens had been identified in large enough quantities in tobacco “tar” or its fractions to account for the observed activity in mouse skin-painting studies: We have demonstrated experimentally … that 0.0001 per cent or even 0.0005 per cent benzopyrene in acetone will not produce any tumors in the present experimental mouse or rabbit groups. Thus, there is conclusive proof that the animal results cannot be solely due to the benzopyrene content of tobacco . The benzopyrene content of the total tar as well as the active fractions is far too low to account alone for the positive results [in laboratory animal]. So far, no carcinogens have been identified in large enough quantity in tobacco tar or its fractions to account for the observed activity.

These Wynder-Wright results led to an intensive but unsuccessful eighteen-month search for a “supercarcinogenic” PAH by Wright. The absence of such a PAH was subsequently confirmed by the USDA group at Athens, Georgia [Snook (3732), Snook et al. (3756–3758)] by their identification of over 500 PAHs in the PAH fraction from cigarette mainstream smoke (MSS), an identification procedure that completely accounted for the fraction in the cigarette smoke studied. In 1959, unable to explain the bioassay (mouse skin-painting) results with CSC on the basis of either its B[a]P content (less than 2% explainable) or its total tumorigenic PAH content (less than 3% explainable), Wynder and Hoffmann (4307) added the concept of promotion by low molecular weight phenols to the concept of tumor initiation by PAHs in an attempt (unsuccessful) to explain the bioassay results. A similar comment that the amount of tumorigenic PAHs found in CSC could not by themselves account for the total biological activity observed was included in a more detailed publication (4307). They also stated (4308) that the higher PAHs played an important role in the carcinogenicity of CSC but when the various known concentrations of the 487

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carcinogenic PAHs, as estimated in CSC, were summed, it was obvious that they could not account for the established carcinogenicity of the CSC nor of its isolated PAH fraction. Several carcinogenic higher aromatic polycyclic hydrocarbons [are] present in tobacco smoke condensate. They include benzo[a]pyrene …, benzo[e]pyrene …, chrysene …, benz[a] anthracene …, dibenz[a,h]anthracene …, and dibenzo[a,i] pyrene … From the amount in which these materials have been found in tobacco smoke condensate it was evident that these, by themselves, could not account for the total biological activity observed.

In 1960, Van Duuren et al. (4027) reported the identification of several aza-arenes (dibenz[a,h]acridine, dibenz[a,j]acridine, dibenzo[c,g]carbazole) not only structurally similar to some of the known tumorigenic PAHs in CSC but also reported to be tumorigenic under certain conditions to mouse skin. Adding this class of tumorigenic cigarette smoke components to the assessment of the tumorigenicity of CSC failed to account for more than a few percent of the observed response. However, it should be noted that Candeli et al. (587) could not confirm the findings of Van Duuren et al. on the presence of these three aza-arenes in cigarette MSS. During the next three decades, other research groups, as shown in Table IX.A-1, in Germany, Japan, and the United States were also unable to confirm the presence in cigarette MSS of dibenz[a,h] acridine, dibenz[a,j]acridine, and dibenzo[c,g]carbazole. Wynder and Hoffmann (4312) wrote that the PAHs in CSC accounted for not more than 3% of the total biological activity observed in mouse-skin bioassays:

The polynuclear aromatic hydrocarbons are mainly formed during the combustion of tobacco. The tobacco of our standard cigarettes contains only very minute quantities of benzo(a)pyrene (0.02 ppm). A bioassay indicates that these polycyclic hydrocarbons of the condensate by themselves, however, can account for not more than 3 per cent of the total biological activity.

They also wrote (4313) that the established carcinogenicity of CSC to mouse epidermis could to a great extent be accounted for on the basis of initiating carcinogens, largely PAHs, and promoting substances, a major group of which was the phenols. This statement was not true in 1961, nor is it true now. Wynder and Hoffmann (4314), unable to explain the mouse skin-painting bioassay results with CSC on the basis of its content of tumorigenic PAHs and aza-arenes, promoting and/or cocarcinogenic phenols, and promoting and/or cocarcinogenic nontumorigenic PAHs, added the concept of ciliastasis in an attempt (unsuccessful) to explain cigarette smoke tumorigenicity in smokers’ lungs. In their lengthy 1964 review of tobacco carcinogenesis, Wynder and Hoffmann (4319) stated that no one could deny that tobacco products were tumorigenic even though no single component in tobacco smoke could by itself or jointly with other components account for the observed tumorigenic activity of such tobacco products to the skin of laboratory animals: It is furthermore true that none of the agents is carcinogenic in the concentrations in which they are present in tobacco products.

Table IX.A-1 Dibenz[a,h]acridine (I), Dibenz[a,j]acridine (II), and 7H-dibenzo[c,g]carbazole (III) in Nicotine Pyrolysates (Pyr) and Mainstream Cigarette Smoke Condensate Dibenz[a,h]acridine

Dibenz[a,j]acridine

7H-Dibenzo[c,g]carbazole

Investigators

Pyr

CSC

Pyr

CSC

Pyr

CSC

Van Duuren et al. (4027) Candeli et al. (587), Wynder and Hoffmann (4319, 4332) Kaburaki et al. (2006) Schmeltz et al. (3499) Schmeltz et al. (3512) Snook (3733) Snook et al. (3750) Grimmer et al. (1409) Kamata et al. (2021) Sasaki and Moldoveanu (3414) Rustemeier et al. (3370)

yes NE no no no NE NE NE NE NE NE

yes no NE NE no no no no no no no

yes NE no no no NE NE NE NE NE NE

yes yes NE NE no no no no no no yes

no NE NE no no NE NE NE NE NE NE

yes NE NE NE no no no no NE NE NE

yes = Compound identified. no = Compound not found or identified. NE = Substrate not examined for compound in question. Examination of these results indicates that Van Duuren et al. (4027) reported the identification of the three N-heterocyclic compounds (I, II, and III) in MSS CSC and two of them (I and II) in a nicotine pyrolysate; whereas, Candeli et al. (587) failed to identify I but did identify II in MSS CSC. The 1963 Candeli et al. findings on II in MSS CSC were not confirmed in 1979 by investigators (3512) from the same laboratory: Hoffmann was a participant in both the 1963 and 1979 studies. Two studies (3499, 3512) confirmed the 1960 report by Van Duuren et al. that 7H-dibenzo[c,g] carbazole (III) was not present in a nicotine pyrolysate.

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Wynder and Hoffmann (4332) expressed similar views on the tumorigenicity of tobacco smoke components in their 1967 book, but they continued to maintain that the PAHs in cigarette smoke were important as tumor initiators: While BaP and other carcinogenic PAH can by themselves account for only a small portion of the total tumorigenic activity of cigarette smoke condensate, probably less than 2%, they are, nevertheless, of obligatory importance as tumor initiators.

The next year, Wynder and Hoffmann (4342) wrote, “Carcinogenic polynuclear hydrocarbons in the concentrations present in tobacco ‘tar’ clearly do not, by themselves, account for the observed carcinogenicity.” On several occasions, the U.S. Surgeon General in his periodic reports on smoking and health discussed the relationship between the levels of PAHs in cigarette smoke, their tumorigenic potency to mouse skin, and the observed biological response with CSC in mouse skin-painting bioassays. The results of a number of such assays [mouse skin-painting] present a puzzling anomaly: the total tar from cigarettes has about 40 times the carcinogenic potency of the benzo(a) pyrene present in the tar. The other carcinogens known to be present in tobacco smoke are, with the exception of dibenzo(a,i)pyrene, much less potent than benzo(a)pyrene and they are present in smaller amounts. Apparently, therefore, the whole is greater than the sum of the known parts. [see p. 58 in (3999)] Benzo(a)pyrene is present in much larger concentrations than is any other carcinogenic polycyclic hydrocarbon. The inability to account for the carcinogenicity of the tobacco products, except to a very minor degree, by the amount of benzo(a)pyrene present was unanticipated. Both Druckrey (1056) and Wynder (4300) emphasized that the benzo(a)pyrene concentration of various tobacco and smoke preparations is only sufficient to account for a very small part of the carcinogenicity of these materials [see pp. 144–145 in (3999)]. PAH alone, however, account for only a small portion of the carcinogenicity of tobacco “tar” … The levels of carcinogenic PAH in tobacco smoke are well below their practical threshold as complete mouse skin carcinogens … (see 4005). The contribution of BaP or PAH in general to mouse skin carcinogenesis by cigarette smoke condensate cannot be fully measured at this time. Wynder and Hoffmann [4332] found a correlation between BaP levels and carcinogenicity of smoke condensates from several types of cigarettes. A much larger series of experimental cigarettes was studied in the smoking and health program of the National Cancer Institute. No significant dependence of carcinogenic potency on BaP content was observed [Gori (1329, 1330, 1332, 1333), National Cancer Institute (2683)]. [See (4009).]

The carcinogenic activity of the particulate matter of tobacco smoke in epithelial tissues of laboratory animals is greater than the sum of the effects of the known carcinogens present [(see 4010); and the comment in the 1964 Advisory Committee Report to the Surgeon General: “Apparently, therefore, the whole is greater than the sum of the known parts” (3999)].

489

In 1980, Coultson (830) commented on the decades of attention on B[a]P in cigarette MSS and its supposed relevance in cigarette smoke-induced cancers: Whether it’s benzo[a]pyrene or not, nobody really knows. More work has been done on benzo[a]pyrene to prove it to be the causative agent in cigarette smoking than I think on any other chemical for any disease that I know. And yet the point is, you can’t prove it.

The failure of PAHs to explain no more than a few percent of the tumorigenicity of CSC led to the inclusion of the concept of promotion in the overall equation. As noted previously, Wynder and Hoffmann (4313) asserted that the established carcinogenicity of CSC on mouse epidermis could to a great extent be accounted for on the basis of initiating carcinogens, largely PAHs, and promoting substances, a major group of which was the phenols. Their assertion was incorrect in 1961, and it is incorrect today. In his listing of reported identified tobacco smoke components (Table IX.A-2), Kosak (2170) listed published reports on two simple phenols, the early reports on phenol by Wenusch (4202) and Ikeda (1857) and on catechol (1,2-benzenediol) by Kissling (2107) and Wenusch (4202), but he questioned the identification of phenol. Kosak also cited earlier reports by Thoms (3912) and McNally (2524) who mentioned the presence of “phenols” in tobacco smoke and Roffo (3324) who mentioned the presence of phenolic acids. However, it should be remembered that Roffo’s 1939 studies dealt with a destructive distillate from tobacco, not with tobacco smoke generated in a tobacco smoking process simulating that used by human smokers. Table IX.A-3 summarizes 1954 listing by Kosak of phenolic components reported in tobacco smoke, the year of the report, and the investigators involved. However, critical examination of the chronology of the pre-1954 investigations of phenolic compounds in tobacco smoke reveals that Kosak’s 1954 publication suffers from several deficiencies with regard to reports on this class of tobacco smoke components. The examination indicates that his manuscript was submitted to the journal Experientia in September 1953, accepted for publication shortly thereafter, and appeared in a February 1954 issue of the journal. One of the significant omissions was the report by Rayburn and his colleagues at the Research Department of the American Tobacco Company: At the 6th Tobacco Chemists’ Research Conference (TCRC) in December 1952, Rayburn (3089) described the unequivocal identification of four low molecular weight phenols in the MSSs from a series of cigarettes, each member of the series fabricated from one of the four major tobacco types (flue-cured, burley, Maryland, Oriental). The phenols identified were phenol, guaiacol (2-methoxyphenol), o-cresol (2-methylphenol), and m-cresol (3-methylphenol). The next year, these results were published by Rayburn et al. in the journal Analytical Chemistry (3090). In Table IX.A-4 literature references are listed for phenolic components in tobacco smoke cited by Kosak (2170) plus several pertinent references not included in his publication.

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Table IX.A-2 Tobacco Smoke Components Listed by Kosak (2170) Class

Component

Class

Component

Class

Component

Hydrocarbons

Hentriacontane (?) Acetylene “Unsaturated hydrocarbons” Azulene Phenanthrene (?) Anthracene (?) Benzopyrene (?) “Condensed aromatics” (?)

Ketones

3-Pentanone 4-Heptanone 17-Tritriacontanone (?) 2,3-Butanedione “Higher” ketones (?)

Acids

Formic acid Acetic acid Butyric acid Valeric acid Caproic acid C7 and C8 aliphatic acids (?) Succinic acid (?) Fumaric acid (?) Citric acid (?) Benzoic acid (?) Phenolic acids (?)

Alcohols and Phenols

Methanol Glycerol Diethylene glycola Ethylene glycola Phenol (?) Catechol (?)

Alkaloids

Nicotine Pyridyl ethyl ketone Myosmine Nicotyrine α-Socratinec β-Socratinec γ-Socratinec Obelinc Lohitamc Anodminc Lathraeinc Poikilinec Gudhamc

Miscellaneous Components

Levoglucosand “Phytosterol” (?) C10H14O (a furan ?) “Resins” (?) “Resin acids” (?)

Aldehydes

Formaldehyde Acetaldehyde Butyraldehyde Acrolein (?) Benzaldehyde 2-Furaldehyde (?) b

Other N-containing components

Pyrrole (?) “Pyrroles” (?) “N-Methylpyrrolidines” (?) Pyridine “Picoline” (?) “Lutidine” (?) “Collidine” (?) “Pyridine bases” (?) Methylamine (?) “Chlorophyll degradation products” (?) “Uric acids” (?)

Inorganic Components

Ammonia Carbon monoxide Carbon dioxide Hydrogen cyanide Hydrogen sulfide Thiocyanic acid (?) Oxygen Arsenic e “Acetates” (?) “Chlorides” (?) “Cyanides” (?) “Nitrates” (?)

a b c

d e

In smoke because of transfer of an humectant added to tobacco. The question mark indicates that Kosak did not consider the evidence in the literature to be definitive proof of the identity of the component. Subsequent study demonstrated this component was not a well-defined compound but an artifact, a mixture, or an ammonium salt [see discussion by Johnstone and Plimmer (1971)]. 1,6-Anhydro-β-D-glucopyranose. Probably present as As2O3..

The report of the possible presence of phenol-like compounds in Oriental tobacco by Jones and Latimer (1980) at RJRT R&D eventually prompted a research project to synthesize a series of phenols in an attempt to find one or more that would impart a pleasant leather-like aroma to cigarette smoke (3235a, 3240a). Some twenty phenols were synthesized. However, none was ever used commercially as a tobacco flavorant or in any extensive in-house panel tests, for the following reasons.

During the course of his initial research project (3235a, 3240a) at RJRT R&D, Rodgman suggested the possibility of the conversion of several of the phenols to a quinone during the smoking process. This suggestion, coupled with the reports by Takizawa (3865a) that several simple quinones such as p-benzoquinone (2,5-cyclohexadiene-4-dione), 1,2-naphthoquinone (1,2-naphthalenedione), and 1,4-naphthoquinone (1,4-naphthalenedione) were tumorigenic to mouse skin, raised serious questions about the addition of phenols to the tobacco blend.

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OH

Table IX.A-3 Phenolic Components of Tobacco Smoke Listed by Kosak (2170) Year

Investigator

Component

1904 1919 1932 1939 1939 1939 1947

Thoms (3912) Kissling (2107) McNally (2524) Roffo (3324) Wenusch (4202) Wenusch (4202) Ikeda (1857)

“phenols” catechol “phenols” phenolic acids catechol phenol phenol

The biological findings on p-benzoquinone were subsequently confirmed by Tiedemann (3916a). Takizawa (3865a) reported that neither of the higher molecular weight quinones 9,10-anthraquinone (9,10-anthracenedione) or 9,10-phenanthrenequinone (9,10-phenanthrenedione) was tumorigenic to mouse skin. Rodgman also communicated to management the substance of the early reports by Boutwell et al. (414), subsequently amplified by Boutwell and Bosch (414), that when certain low molecular weight phenols were applied to mouse skin in sequence with a level of a tumorigenic PAH such as B[a]P either insufficient to induce tumors or sufficient to induce tumors in only a small percentage of the treated animals the phenols enhanced (or promoted) the tumorigenic effect of the PAH, that is, the percent tumor-bearing animals (% TBA) was much higher than that anticipated on the basis of the PAH dose administered. The effectiveness of the promotion of the tumorigenicity of a tumorigenic PAH by a phenol is dependent on the substituents R2 and R6 on the C2 and C6 carbons, the carbon atoms adjacent to the carbon to which the hydroxyl group is attached (Figure IX.A-1). If R2 = H or R6 = H or if R2 = R6 = H, then the phenol will exert a promoting effect, the effect being greatest when both substituents R2 = R6 = H.

R6

R2

R3

R5 R4

Figure IX.A-1  A substituted phenol.

If neither R2 nor R6 is hydrogen, that is, when R2 ≠ H and R6 ≠ H, no promoting effect is observed. The coupling of the findings reported by Boutwell et al. (414) on the promoting effects of low molecular weight phenols on PAHs in the mouse skin-painting bioassay with the failure to explain the tumorigenicity of CSC on the basis of its PAH content subsequently triggered extensive research both within and outside of the tobacco industry on several aspects of the phenols in tobacco smoke.



1. Identification and quantitation of phenols in cigarette MSS: To date, the number of phenols identified in tobacco smoke exceeds 400 (see Table IX.A-22). While the number of phenols identified is significantly fewer than the number of PAHs identified in cigarette MSS, the number of identified tobacco smoke phenols is much greater than that identified in any other consumer product such as tea, coffee, or cocoa, again a reflection of the intense scrutiny directed at tobacco smoke vs. that directed at any other consumer product. 2. Bioassays to determine contribution of phenols to CSC tumorigenicity: Determination of the biological relationship, if any, between the phenol fraction from cigarette MSS or its individual components and the PAH fraction from cigarette MSS or its individual components needed to be conducted. Was the biological relationship between phenol and

Table IX.A-4 Studies of Phenolic Components of Tobacco Smoke Omitted from the 1954 Listing by Kosak (2170) Year

Investigator

Component

1871 1876 1904 1919 1932 1939 1939 1947 1950 1952 1953 1954

Vohl and Eulenberg (4065) Ludwig (2408) Thoms (3912) Kissling (2107) McNally (2524) Roffo (3324) Wenusch (4202) Ikeda (1857) Molinari (2605) Rayburn (3089) Rayburn et al. (3090) Kosak (2170)

phenol phenol “phenols” 1,2-dihydroxybenzene (catechol) “phenols” phenolic acids phenol, 1,2-dihydroxybenzene (catechol) phenol phenol, 1,2-dihydroxybenzene (catechol) phenol, 2-methoxyphenol (guaiacol), 2-methylphenol (o-cresol), 3-methylphenol (m-cresol) phenol, 2-methoxyphenol (guaiacol), 2-methylphenol (o-cresol), 3-methylphenol (m-cresol) list of tobacco smoke components

Note: Entries in bold print refer to items included by Kosak (2170).

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the tumorigenic PAHs one of promotion, cocarcinogenesis, inhibition, or anticarcinogenesis? 3. Determination of the nature of the precursors in tobacco of the phenols in cigarette MSS: The studies in the mid-1960s to identify the major precursors in tobacco of the phenols in tobacco smoke paralleled the studies in the late 1950s and early 1960s on the precursors in tobacco of the PAHs in tobacco smoke. 4. The effect of cigarette design parameters on delivery of MSS phenols: Determinations of which cigarette design parameters enabled significant control of the levels of phenols in MSS needed to be conducted.

In the following paragraphs, each of the topics listed above is discussed in considerable detail with an attempt to put in perspective the relationships between isolation/identification, precursor definition, bioassay results, and delivery control pertinent to the phenols in cigarette MSS.

IX.A.1 Identification and Quantitation of Phenols in Cigarette MSS In their reviews of phenolic components of tobacco smoke, Wynder and Hoffmann (4319, 4332) concluded their report on the first successful isolation of phenols from tobacco smoke by Vohl and Eulenberg (4065) and Ludwig (2408) with the comment: “Since that time, publications have dealt sporadically with smoke phenols.” From the early 1950s through 1967, over 110 reports dealing with phenols in smoke were presented at scientific meetings and/or published in peer-reviewed journals. Such a number can hardly be considered as sporadic! Many of the studies in the 1950s dealt with the identification and quantitation of various low molecular weight phenols in cigarette MSS [see the studies on phenol, the methylphenols (the cresols), 2-methoxyphenol (guaiacol), the dimethylphenols (the xylenols) by Rayburn (3089), Rayburn et al. (3090), Commins and Lindsey (786–789, 789a), Izawa et al. (1906), and on scopoletin by Yang et al. (4373–4375)]. Not only was a variety of separation techniques employed to obtain the phenols but also a variety of analytical techniques was employed for the quantitation. Examples of these methods follow.

Diazotization with p-nitroaniline, paper chromatography, UV absorption spectrophotometry Methylation, paper chromatography, UV absorption spectrophotometry Formation of 2,4-dinitrobenzoates Formation of phenylazobenzene sulfonic acid derivatives Methylation, gas chromatography Gas chromatography, internal standard addition

Rayburn et al. (3090)

Commins and Lindsey (786)

Izawa et al. (1906) Izawa et al. (1906) Carruthers and Johnstone (615) Hoffmann and Wynder (1789), Crouse et al. (851), Spears (3764)

Gas chromatography 4-Aminoantipyrine treatment, colorimetry Glass capillary gas chromatography Diazotization with p-nitroaniline, colorimetry Thin layer chromatography Derivatization, colorimetry

Oakley et al. (2820) Lorentzen and Neurath (2397) Smith and King (3716) Smith and King (3717, 3718) Smith and Sullivan (3719) Knoop and Rosene (2142a)

In 1959, Johnstone and Plimmer (1971) cataloged the sixteen tobacco smoke phenols listed in Table IX.A-5. Examination of the chronology of the published reports on phenols in tobacco smoke reveals the escalation (see Table IX.A-6) of the scientific publications/presentations between 1952 and 1964, the year of the Advisory Committee’s Report on Smoking and Health to the U.S. Surgeon General (3999). This escalation was similar to but not as extensive as the increase from 1953 to 1964 in the number of presentations/publications pertinent to PAH in tobacco smoke. In January 1964, the Advisory Committee on Smoking and Health submitted its report to the U.S. Surgeon General (3999). Because of the widespread dissemination of the contents of this report, its January 1964 publication provides an appropriate point in time to assess the situation with regards to prior research publications on phenolic compounds in tobacco smoke. Table IX.A-6 summarizes chronologically some of the various reports issued between 1952 and 1964 on tobacco smoke phenols. Of the eighty-two reports cited in Table IX.A-6 from 1952 through 1964, eighty were issued from 1955 through 1964. If, because of the early 1964 issuance of the Advisory Committee’s Report, the publications on tobacco smoke phenols in 1964 are omitted from the listing, the number from 1953 through 1963 becomes sixty-five. As noted previously in the discussion of the early studies of PAHs, a similar assessment of publications on PAHs in tobacco smoke indicated that some 213 reports were issued from 1953 through 1964. If the publications on tobacco smoke PAHs in 1964 are omitted, the number from 1953 through 1963 becomes 200. During the first decade of research on tobacco smoke, effort was divided between the identifications of the various phenolic compounds and improvements of their quantitation in cigarette MSS. Less than a decade after the 1959 review by Johnstone and Plimmer, Stedman (3797) tabulated the reports in which the identifications of fifty-four phenols in tobacco smoke were described (Table IX.A-7). In their 1980 review, Ishiguro and Sugawara (1884) listed over 150 phenolic compounds that had been identified as tobacco smoke components. By the mid-1990s, over 270 completely identified phenolic compounds were reported as tobacco smoke components (Table IX.A-22). It should be noted that, despite repeated criticisms of the publication policy of the R.J. Reynolds Tobacco Company on tobacco smoke composition, seventy of the phenolic compounds listed in Table IX.A-22 were first

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Table IX.A-5 Tobacco Smoke Phenols Cataloged by Johnstone and Plimmer (1971) Phenol

References

1,2-Benzenediol {catechol} 1,3-Benzenediol {resorcinol} 1,4-Benzenediol {hydroquinone} 2H-Benzopyran-6-one, 7-hydroxy6-methoxy- {scopoletin} Ethanone, 1-(3-hydroxyphenyl){3’-hydroxyacetophenone} Ethanone, 1-(4-hydroxyphenyl){4’-hydroxyacetophenone} 1-Naphthalenol {1-naphthol} 2-Naphthalenol {2-naphthol} Phenol Phenol, 2,4-dimethyl- {2,4-xylenol} Phenol, 3,5-dimethyl- {3,5-xylenol} Phenol, 2-dimethoxy- {guaiacol} Phenol, 2-methyl- {o-cresol} Phenol, 3-methyl- {m-cresol} Phenol, 4-methyl- {p-cresol} Phenol. 2,4,6-trimethyl- {mesitol}

Molinari (2605, 2607), Bonnet and Neukomm (396), Carruthers and Johnstone (615) Commins and Lindsey (789, 789a) Bonnet and Neukomm (396) Yang et al. (4373-4375) Carruthers and Johnstone (615) Carruthers and Johnstone (615) Commins and Lindsey (789, 789a) Commins and Lindsey (789, 789a) Vohl and Eulenberg (4065), Ludwig (2408), Rayburn (3089), Rayburn et al. (3090), Commins and Lindsey (789, 789a), Bonnet and Neukomm (396), Carruthers and Johnstone (615) Wynder and Wright (4354) Carruthers et al. (616), Clemo (765) Rayburn (3089), Rayburn et al. (3090) Rayburn (3089), Rayburn et al. (3090), Commins and Lindsey (789, 789a), Carruthers and Johnstone (615) Rayburn et al. (3089), Commins and Lindsey (789, 789a), Carruthers and Johnstone (615) Commins and Lindsey (789, 789a), Carruthers and Johnstone (615) Bonnet and Neukomm (396)

Table IX.A-6 Publications/Presentations (1952–1964) Pertinent to Identification of Phenolic Components of Tobacco Smoke Number Year

In Year

Accumulated

Investigator(s)

1952

1

1

Rayburn (3089)

1953

1

2

Rayburn et al. (3090)

1955

1

3

Wright and Wynder (4353)

1956

5

8

Commins and Lindsey (786–789, 789a)

1957

3

11

Bonnet and Neukomm (396), Landahl and Tracewell (2261), Wynder and Wright (4354)

1958

11

22

Bonnet (392), Carruthers et al. (616), Clemo (765), Rowland (3347), Weaving (4156), Wender et al. (4164), Yang et al. (4373–4375)

1959

8

29

Dieterman et al. (969), Doll (1025), Izawa et al. (1906), Onishi (2858), Reid (3096), Rodgman and Cook (3271), Roe et al. (3314)

1960

3

33

Carruthers and Johnstone (615), Rodgman and Cook (3280, 3286), Weaving (4158), Yang et al. (4376)

1961

8

41

Cundiff (859), Herrmann (1625), Hoffmann and Wynder (1789), Latimer (2274), Rodgman and Cook (3286), Wynder and Hoffmann (4311–4313)

1962

7

48

Kato and Shibayama (2044), P. Lorillard Co. R&D (2399), Rodgman and Cook (3286), Schmeltz et al. (3488), Wynder and Hoffmann (4314), Yang and Wender (4377, 4378)

1963

17

65

Crouse et al. (851), Hoffmann et al. (1766), Hoffmann and Wynder (1791), Kato et al. (2045), Laurene (2295, 2295a), Laurene et al. (2311, 2312), Lorentzen and Neurath (2397), Osman et al. (2876), Rodgman and Cook (3286), Rodgman and Mims (3305), Spears (3764, 3765), Unghvary et al. (3995), Wender and Yang (4163), Wynder and Hoffmann (4317)

1964

17

82

Ehmke and Neurath (1115), Elmenhorst (1129), Esterle and Campbell (1164), Knoop and Rosene (2142a), Mann et al. (2451), Oakley et al. (2820), Pyriki and Moldenauer (3043), Rodgman and Cook (3286), Seehofer et al. (3574), Smith and King (3716, 3717)

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Table IX.A-7 Tobacco Smoke Phenols Cataloged by Stedman (3797) 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17 18. 19. 20. 21. 22. 23.

24.

25. 26. 27.

Acetic acid, 2-hydroxyphenylAcetic acid, 3-hydroxyphenylAcetic acid, 4-hydroxyphenylBenzaldehyde, 3,4-dihydroxyBenzaldehyde, 3,5-dimethoxy4-hydroxyBenzaldehyde, 2-hydroxyBenzaldehyde, 3-hydroxyBenzaldehyde, 4-hydroxyBenzaldehyde, 4-hydroxy3-methoxy1,2-Benzenediol 1,3-Benzenediol 1,4-Benzenediol Benzoic acid, 3,4-dihydroxyBenzoic acid, 3,5-dimethoxy4-hydroxyBenzoic acid, 2-hydroxyBenzoic acid, 3-hydroxyBenzoic acid, 4-hydroxyBenzoic acid, 3-hydroxy4-methoxyBenzoic acid, 4-hydroxy3-methoxy2H-1-Benzopyran-6-one, 6,7dihydroxy2H-1-Benzopyran-6-one, 7-hydroxy6-methoxyCinnamic acid, 3,4-dihydroxyCinnamic acid, 3,4-dihydroxy-, 3-ester with 1,3,4,5-tetrahydroxycy clohexanecarboxylic acid Cinnamic acid, 3,4-dihydroxy-, 5-ester with 1,3,4,5tetrahydroxycyclohexanecarboxylic acid Cinnamic acid, 3,5-dimethoxy4-hydroxyCinnamic acid, 4-hydroxyCinnamic acid, 4-hydroxy3-methoxy-

28. 29. 30. 31. 32.

Ethanone, 1-(2-hydroxyphenyl)Ethanone, 1-(3-hydroxyphenyl)Ethanone, 1-(4-hydroxyphenyl)1-Naphthalenol 2-Naphthalenol

acetophenone, 2’-hydroxyacetophenone, 3’-hydroxyacetophenone, 4’-hydroxy1-naphthol 2-naphthol

vanillin

33. 34. 35. 36.

Phenol Phenol, 2,6-dimethoxyPhenol, 2,3-dimethylPhenol, 2,4-dimethyl-

2,3-xylenol 2,4-xylenol

catechol resorcinol hydroquinone protocatechuic acid syringic acid

37 . 38. 39. 40. 41.

Phenol, 2,5-dimethylPhenol, 2,6-dimethylPhenol, 3,4-dimethylPhenol, 3,5-dimethylPhenol, 2-ethyl-

salicylic acid

isovanillic acid

42. 43. 44. 45.

Phenol, 3-ethylPhenol, 4-ethylPhenol, 2-methoxyPhenol, 2-methoxy-

vanillic acid

46. Phenol, 4-methoxy-

esculetin

47. Phenol, 2-methoxy-4-(1-propenyl)-

isoeugenol

scopoletin

48. Phenol, 2-methoxy-4-(2-propenyl)-

eugenol

caffeic acid chlorogenic acid

49. Phenol, 2-methyl50. Phenol, 3-methyl-

o-cresol m-cresol

neochlorogenic acid

51. Phenol, 4-methyl-

p-cresol

sinapic acid

52. Phenol, 5-methyl-2-(1-methylethyl)-

thymol

coumaric acid ferulic acid

53. Phenol, 2,4,6-trimethyl54. Propanoic acid, 3-hydroxyphenyl-

mesitol

protocatechualdehyde syringaldehyde salicaldehyde

2,5-xylenol 2,6-xylenol 3,4-xylenol 3,5-xylenol

guaiacol

55. Propanoic acid, 4-hydroxyphenyl-

reported as tobacco smoke components by R.J. Reynolds Tobacco Company R&D personnel and the identities of an additional twenty-five phenolic smoke components reported by others were confirmed. As shown by the citations included in Table IX.A-8, the Tobacco Chemists’ Research Conference over the years has been a significant forum for the dissemination of new and meaningful information pertinent to phenolic components in tobacco smoke. While the nature and levels of the low molecular weight phenols in tobacco smoke were being defined in the late 1950s and early 1960s, additional research permitted the identification of several more complex phenolic components of tobacco smoke, for example, the naphthalenols by

Commins and Lindsey (789, 789a), hydroxybenzopyranones such as scopoletin by Yang et al. (4373–4375) and Wender et al. (4164), esculetin by Dietermann et al. (969), α-tocopherol by Rodgman and Cook (3271), hydroxycinnamic acids by Yang and Wender (4376), hydroxyphenylacetic acids by Yang and Wender (4377) and Wender and Yang (4163), and several hydroxybenzaldehydes by Yang and Wender (4379). In contrast to the low molecular weight phenols, many of these more complex phenols are also present at more than trace amounts in tobacco. A series of low molecular weight, volatile phenols were identified in the tobacco type Latakia by Irvine and Saxby (1876, 1877a) at much greater levels than volatile phenols are found in other tobacco types such as fluecured and burley.

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Table IX.A-8 Presentations at Tobacco Chemists’ Research (TCRC) and Tobacco Science Research Conferences (TSRC) on Phenolic Components of Tobacco Products TCRC

Investigator(s)

TCRC

Investigator(s)

• Isolation, Identification, Quantitation of Phenols in Tobacco Products 6th 12th 16th 16th 17th 18th 18th 18th 18th 18th 19th 19th 20th 20th 21st 22nd 22nd 23rd 24th 25th 27th 28th 29th 29th 29th 30th 30th 31st 31st 32nd 32nd 32nd 32nd 33rd

Rayburn (3089) Rowland (3347) Davis and George (911a) Schmeltz et al. (3488) Burdick et al. (526) Ayres and Thornton (127) Esterle and Campbell (1164) Knoop and Rosene (2142a) Mann et al. (2451) Rodgman and Cook (3280) Ayres and Thornton (128) Spears et al. (3767) Kallianos et al. (2016) Schlotzhauer et al. (3468) Kallianos et al. (2017) Benner et al. (276) Leach and Alford (2321) Benner et al. (275) Miller et al. (2554) Singer and Hoffmann (3674) Thacker and Martin (3894) Guerin et al. (1450) Newell et al. (2769) Roberts and Watts (3228) Schumacher et al. (3553) Chamberlain et al. (664) Kallianos (2614) Hecht et al. (1561) Schlotzhauer et al. (3474) Cornell et al. (828) Heckman and Best (1587) Snook et al. (3744) Snook et al. (3746) Snook et al. (3751)

34th 34th 35th 36th 36th 37th 39th 40th 42nd 42nd 42nd 43rd 45th 46th 46th 48th 50th 50th 51st 51st 52nd 53rd 54th 55th 55th 56th 56th 57th 57th 58th 58th 58th 58th 59th

Carmella et al. (600) Schlotzhauer et al. (3462) Carmella et al. (598) Lee et al. (2329) Snook and Chortyk (3737) Carmella et al. (599) Adams et al. (30) McWilliams et al. (2526) Nanni et al. (2681a) Risner and Cash (3172) Snook et al. (3754) Risner and Cash (3174) Lee et al. (2330a) Prakasch and Ireland (2983) Risner (3166) Wilson (4268) Green and Rodgman (1373) Risner (3170) Risner and Nelson (3170) Zhangyu et al. (4412) Risner and Cash (3174) Forehand et al. (1213) Wooten et al. (4279) Li et al. (2361) Purkis et al. (3007) Honglin et al. (1825) Reffick et al. (3093) Volgger et al. (4067) Warren (4137) Hwang et al. (1854) Little et al. (2379) Loureau et al. (2400a) Sheng et al. (3646) Hwang et al. (1853a)

• Precursor, Biological, and Other Studies on Phenols in Tobacco Products 19th 19th 22nd 23rd 23rd 23rd 23rd 25th 26th 28th

Chortyk et al. (725a) Spears et al. (3767) Bell et al. (246) Benner et al. (275) Burton et al. (539) Colucci et al. (783b) Lakritz et al. (2253) Rathkamp et al. (3087) Artho et al. (105) Baggett and Morie (156)

Eventually, several hydroxyphenyl alcohols and hydroxybenzyl alcohols were identified in tobacco and tobacco smoke by Hecht et al. (1561). These identifications were soon followed by the identification of a series of phenolic acids from tobacco by Snook et al. (3749, 3751). Table IX.A-5 summarizes the studies on phenols in tobacco smoke up to 1964. In Table IX.A-9, studies on phenols in tobacco smoke from 1964 to date are summarized.

28th 29th 31st 37th 48th 50th 52nd 54th 59th 59th

Hecht et al. (1582) Brunnemann et al. (496) Hardy and Hobbs (1501) Brunnemann et al. (499) Wilson (4268) Hu (1840a) Leffingwell and Alford (2339) Doolittle et al. (1051) Dyakonov et al. (1077a) Hwang et al. (1853a)

IX.A.2 Bioassays to Determine the Contribution of Phenols to Cigarette Smoke Condensate Tumorigenicity At several scientific meetings in the mid-1950s, Boutwell et al. (414) described their preliminary findings on the promoting effect of phenol on the specific tumorigenicity of 7,12dimethylbenz[a]anthracene (DMB[a]A) when the application

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Table IX.A-9 Reports of Research Pertinent to Phenolic Compounds in Tobacco and Tobacco Smoke, 1964 to 2005 Year

Investigator(s)

1964

Ehmke and Neurath (1115), Elmenhorst (1129), Esterle and Campbell (1164), Knoop and Rosene (2142a), Mann et al. (2451), Oakley et al. (2820), Pyriki and Moldenauer (3043), Rodgman (3251), Rodgman and Cook (3286), Seehofer et al. (3574), Smith and King (3716, 3717), Smith and Sullivan (3719), Testa et al. (3890), USPHS (3999), Wynder and Hoffmann (4319)

1965

Bock et al. (358), Chortyk et al. (725a), Cuzin et al. (884), Kaburaki et al. (1996, 1997), Kato et al. (2043, 2046), LeRoux (2351), Lipp (2374, 2376, 2377), Rodgman and Cook (3286), SEITA (3602), Smith and King (3718), Spears et al. (3767), Steck and Wender (3792), Steck et al. (3793), Testa et al. (3891), Waltz and Häusermann (4121), Waltz et al. (4123, 4124), Wynder and Hoffmann (4330)

1966

Bell et al. (248), Chortyk et al. (726), Kallianos et al. (2016), Mokhnachev and Latayeva (2577), Mold et al. (2594), Müller and Moldenhauer (2653), Schlotzhauer et al. (3468), Shamberger (3625), Touey and Kiefer (3937), Van Duuren et al. (4037)

1967

Hoffmann and Wynder (1797), Kallianos et al. (2017), Lyerly and Gilleland (2413a), Mokhnachev and Latayeva (2578), Müller and Moldenhauer (2653), Schlotzhauer et al. (3468), Schmeltz et al. (3486), Wynder and Hoffmann (4332)

1968

Avetyam et al. (125), Bell et al. (246), Benner et al. (274), Chamberlain and Stedman (666), Colucci and Sizemore (783a), Dalhamn (891a), Hoffmann and Wynder (1798), Irvine and Saxby (1876), Kaburaki et al. (1994, 1995), Kallianos et al. (2016), Leach and Alford (2321), Schmeltz and Schlotzhauer (3497), Stedman (3797), Van Duuren et al. (4036), Wynder and Hoffmann (4342, 4346)

1969

Benner et al. (275, 276), Burton et al. (539), Colucci et al. (783b), Georgiev (1284a), Green et al. (1377, 1378), Grob and Völlmin (1427), Irvine and Saxby (1877a), Lakritz et al. (2253), Leach et al. (2322), Wynder and Hoffmann (4344, 4346)

1970

Green et al. (1377), Grob and Völlmin (1426), Kaburaki et al. (2006), Kushnir et al. (2245), Laurene et al. (2306), Martin and Thacker (2478), Miller et al. (2554), Reynolds (3111), Testa (3884), Viart (4050), Wynder and Hoffmann (4346a)

1971

Green and Schumacher (1375), Hoffmann and Wynder (1800), Kaburaki et al. (2005), Miller et al. (2554), Rathkamp et al. (3087), Royal College of Physicians (3363), Shigematsu et al. (3650), Singer and Hoffmann (3674), Van Duuren et al. (4035)

1972

Artho et al. (105), Bock (352), Elmenhorst (1132), Hoffmann and Wynder (1802, 1803), Klimisch and Reese (2125), Schmeltz et al. (3499), Schumacher et al. (3557), USPHS (4003)

1973

Baggett and Morie (155), Benner et al. (278), Derreux et al. (952), Diffee (970), Morie and Sloan (2635), Rathkamp et al. (3088), Thacker and Martin (3894), Van Duuren et al. (4029)

1974

Akin and Chamberlain (39a), Baggett and Morie (156), Green and Best (1356), Guerin et al. (1449), Hecht et al. (1582), Heckman (1586), Klus and Kuhn (2137), Lloyd and Miller (2387, 2388), Newell et al. (2767), Schmeltz et al. (3484), Schumacher et al. (3553)

1975

Baggett and Morie (156), Brunnemann et al. (496), Hecht et al. (1583), Malaterre et al. (2447), Newell et al. (2769, 2777), Roberts and Watts (3228), Schmeltz et al. (3484), Schumacher et al. (3553)

1976

Best et al. (312), Brunnemann et al. (497), Chamberlain et al. (664), Green et al. (1375b), Hoffmann et al. (1780), Ishiguro et al. (1878a, 1879, 1886), Kallianos (2014), Kensler (2082), Mauldin (2506), Miller et al. (2543), Moates (2570), Newell et al. (2761, 2762, 2765, 2766), Patterson et al. (2904), Sakuma et al. (3395), Testa and Hys (3892), Van Duuren and Goldschmidt (4028)

1977

Brunnemann et al. (514), Hardy and Hobbs (1501), Harrell (1530), Hecht et al. (1561), Schlotzhauer et al. (3474), Schmeltz and Hoffmann (3491), Schmeltz et al. (3512), Schumacher et al. (3553), Walters (4113)

1978

Chamberlain et al. (663), Cornell et al. (828), Green et al. (1371), Hecht et al. (1561), Heckman and Best (1587), Ishiguro and Sugawara (1881–1883), Newell et al. (2769), Schlotzhauer (3447), Schlotzhauer et al. (3474), Snook et al. (3744, 3746, 3753), Van Duuren et al. (4038)

1979

Chamberlain et al. (652), Green et al. (1367), Schmeltz et al. (3512), Snook and Fortson (3745), Snook et al. (3751), USPHS (4005)

1980

Ishiguro and Sugawara (1884), Martin and Gilleland (2476), Mokhnachev and Mironenko (2579), Sakuma et al. (3402), Schlotzhauer et al. (3452), Snook et al. (3747), Van Duuren (4026), Wattenberg et al. (4149c)

1981

Hecht et al. (1562), Heckman and Best (1587), Morée-Testa (2615), Schlotzhauer and Chortyk (3453), Shelar and Colby (3641–3643), Snook et al. (3748, 3749), USPHS (4009)

1982

Hwang et al. (1854a), Sakuma et al. (3400), Schlotzhauer et al. (3462), Snook and Chortyk (3737, 3738), USPHS (4010)

1983

Brunnemann et al. (499), Hoffmann et al. (1736), Yoshida and Fukuhara (4386)

1984

Adams et al. (28), Jeanty et al. (1926)

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Table IX.A-9 (Continued) Reports of Research Pertinent to Phenolic Compounds in Tobacco and Tobacco Smoke, 1964 to 2005 Year

Investigator(s)

1985

Adams et al. (30), Eaker and Hutcherson (1091), Eble et al. (1105), Sakuma et al. (3392), Snook et al. (3743)

1986

Grimmer et al. (1409), IARC (1871), LaVoie et al. (2314a, 2314b), McWilliams et al. (2526), Risner (3159)

1987

Adams et al. (31), Grimmer et al. (1409), Melikian et al. (2527f)

1988

Nanni et al. (2681), Risner (3161), Risner and Cash (3171, 3172)

1989

Melikian et al. (2527c, 2527d), Risner and Cash (3173, 3174), Schmidt and Hecker (3519a), Snook et al. (3754)

1990

Martin et al. (2480), Melikian et al. (2527g), Nanni et al. (2681), Risner and Cash (3173)

1991

Risner (3165)

1992

Prakash and Ireland (2983), Risner (3166), Zhao and Zhou (4414)

1994

Risner et al. (3168), Wilson (4268)

1996

Green and Rodgman (1373), Hu (1840a), Risner (3170)

1997

Borgerding et al. (420), Risner and Nelson (1970), Zhangyu et al. (4412)

1998

Hecht et al. (1572), Hoffmann and Hoffmann (1741), Leffingwell (2339), Nelson et al. (2691)

1999

Baker (172), Forehand et al. (1213), Hirose et al. (1656a), Leffingwell (2338), Omori et al. (2857),

2000

Fowles et al. (1217), Hajaligol and Fisher (1485), Wooten et al. (4279)

2001

Hoffmann and Hoffmann (1743), Li et al. (2361), Wooten et al. (4277)

2002

Carmines (603), Lauterbach (2313a), Reddick et al. (3093), Smith et al. (3712)

2003

Chen and Moldoveanu (688), Dagnon and Edreva (890), Volgger et al. (4067), Warren (4137)

2004

Gregg et al. (1386), Hwang et al. (1854), Little et al. (2379), Loureau et al. (2400a), Zha and Moldoveanu (4407)

2005

Little et al. (2379a), Uchii and Sato (3990a)

2006

Larkins (2262a)

of the PAH to mouse skin was followed by an application of phenol. Subsequently, Boutwell and Bosch (414) reported that phenol and many substituted phenols enhanced or promoted the specific tumorigenicity of PAHs. However, they reported that 1,2-benzenediol (catechol) exhibited no tumorpromoting activity. Later, 1,2-benzenediol (catechol) was found to be the most plentiful low molecular weight phenol in cigarette MSS [Kallianos et al. (2016), Schlotzhauer et al. (3462), Schlotzhauer and Chortyk (3453), Morée-Testa (2615), Risner and Cash (3171–3174), Risner (3165),] and was reported [Van Duuren et al. (4029)] to be a cocarcinogen for PAHs, not a promoter. Coincident with the phenol studies of Boutwell et al. (414) and during the time that much effort was being expended to resolve the question about the presence of PAHs in tobacco smoke, Gwynn and Salaman (1463b) reported the promoting effect of CSC. Two years later, Gellhorn (1281) reported that whole CSC acted as a promoting agent for several tumorigenic PAHs applied to mouse skin.

The next year, Roe et al. (3314) reported that the phenolic fraction from CSC exerted a significant promoting effect on the specific tumorigenicity of PAHs. They theorized: Cigarette smoke condensate may be richer in tumour-promoting substances than in tumour-initiating substances. Phenolic compounds may be responsible for much of its promoting activity.

As noted previously, Wynder and Hoffmann (4307), unable to explain the bioassay (skin painting) results with CSC on the basis of either its B[a]P content (less than 2% tumor-bearing animals explainable) or its total tumorigenic PAH content (less than 3% tumor-bearing animals explainable), added the concept of promotion, particularly that attributed to low molecular weight phenols, in an attempt (unsuccessful) to explain the bioassay results in laboratory animals. They amplified their theory in a more detailed publication (4307). They also stated (4308) that the higher molecular weight PAHs played an important role in the carcinogenicity to mouse skin of CSC but when the various known concentrations of the carcinogenic PAHs as

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estimated in CSC were summed, it was obvious that these smoke components acting either individually or in concert could not account for the established carcinogenicity to mouse skin of the CSC nor of its isolated PAH fraction. Because of the inability to explain the mouse skin-painting bioassay results with CSC on the basis of its PAH content and because of the presumed biological relationship between the phenol fraction and/or its individual components and the PAH fraction and/or its individual components, the findings reported by Boutwell et al. (414), Gwynn and Salaman (1463b), Gellhorn (1281), and Roe et al. (3314) stimulated extensive research on the nature and levels of the phenols in cigarette MSS in the late 1950s to early 1960s. Over the next few years, the results from different laboratories of the bioassays involving tobacco smoke phenols varied considerably. The variations raised the question as to whether the relationship between the tobacco smoke phenols and PAHs was one of promotion, cocarcinogenesis, inhibition, or anticarcinogenesis. From the results of their studies on the administration of B[a]P plus phenol and the administration of DMB[a]A plus phenol, Wynder and Hoffmann (4313) concluded: [Our results] show that promoting substances present in tobacco smoke can increase and accelerate the tumor yield of

carcinogenic polynuclear hydrocarbons that by themselves are not present in sufficient concentration to yield any tumors or yield them only after a prolonged latent period.

In 1958, Wynder et al. (4355) proposed the use of the level of B[a]P in CSC as an “indicator” or “marker” of the specific tumorigenicity (mouse skin) of CSC as well as an “indicator” or “marker” of its levels of tumorigenic PAHs with four or more rings. When the low molecular weight phenols in tobacco smoke attracted considerable attention because of their claimed contribution to the specific tumorigenicity of CSC, Hoffmann et al. (1766) and Wynder and Hoffmann (4317) extended the “indicator” concept to phenol, designating it as an “indicator” or “marker” for the promoting low molecular weight volatile phenols in cigarette MSS. Just as the concept of B[a]P as an “indicator” or “marker” of CSC specific tumorigenicity and tumorigenic higher PAHs content was subsequently shown to be incorrect, so was the concept of phenol as an “indicator” or “marker” of phenols-induced promoting activity of CSC and promoting phenols content shown to be incorrect. The phenol “indicator” situation is discussed below. Table IX.A-10 summarizes some of the diversity observed in the bioassay results on the properties pertinent to the tumorigenicity of PAHs of several phenol components of tobacco

Table IX.A-10 Variation in Bioassay Results with Phenols or Phenol-Containing Materials Effect on Specific Tumorigenicity of Polycyclic Aromatic Hydrocarbons Phenol

Promotion

CSC

yes: Gwynn and Salaman, (1463b), Gellhorn (1281) yes: Roe et al. (3314)

a

Phenolic fraction from CSC a

Phenols Phenol

1,2-Benzenediol {catechol}

1H-1-Benzopyran-6-ol, 3,4dihydro-2,5,7,8-tetramethyl-2(4,8,12-trimethyltridecyl){α-tocopherol}

a

yes: Boutwell et al. (414) yes: Wynder and Hoffmann, (4313, 4317), Hoffmann and Wynder (1791), Hoffmann et al. (1736) no: Van Duuren and Goldschmitt (4028)

Cocarcinogenicity

Inhibition or Anticarcinogenesis

no: Van Duuren et al. (4029)

yes: Van Duuren et al. (4029, 4035)

yes: Van Duuren et al. (4029), Van Duuren and Goldschmitt (4028), Hecht et al. (1562), Hoffmann et al. (1736)

yes: Shamberger (3625), Slaga and Bracken (3684), Viaje et al. (4049a), Shklar (3655a), Weerapradist and Shklar (4159a), Toth and Patil (3927a), Mirvish (2559b)

CSC = cigarette smoke condensate

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smoke (phenol, catechol, and α-tocopherol), the phenolic fraction from CSC, and CSC itself. Although much attention and effort were devoted to the supposed deleterious effects of various tobacco smoke components such as the PAHs, the aza-arenes, and the low molecular weight phenols, very little was reported about the tobacco smoke components with properties that offset the supposed tumorigenicity or promoting effects of the compound classes mentioned. One of the first examples of cigarette MSS components inhibiting the action of a “tumorigen” was described by Wynder and Hoffmann (4311). This finding was an outgrowth of their studies on the effect of organic solvent extraction of tobacco on the PAH content of the extracted tobacco smoke. Lam (2255) and Wynder (4294) in the mid-1950s proposed that the precursors in tobacco of PAHs in cigarette MSS were the saturated aliphatic hydrocarbons; Wright (4282a) and Wynder et al. (4355, 4356) proposed the phytosterols as the PAH precursors, and Wright (4282) also proposed the terpenoid compounds as major PAH precursors. These compounds are removable almost totally or to a substantial degree by extraction of tobacco with organic solvents such as hexane or pentane. Cigarettes fabricated from the extracted tobacco yielded lower quantities in MSS of PAHs such as B[a]P that were known under certain laboratory conditions to produce tumors on the shaved backs of susceptible strains of mice. Skin-painting studies with mainstream CSC collected by smoking cigarettes made with the control and extracted tobaccos gave a lower percentage of TBA in the extracted tobacco CSC group. However, the decrease in % TBA was much less than the percent decrease in the level in the CSC of tumorigenic PAHs such as B[a]P (4282, 4294, 4307, 4355, 4356). One explanation for this difference was that the solvent extraction removed nearly all the aliphatic saturated hydrocarbons from the tobacco and, thus, they were either absent from the MSS from the extracted-tobacco cigarettes or present at extremely low levels. Wynder and Hoffmann [see pp. 330– 331 in (4319) and pp. 370–371 in (4332)] reported that this aliphatic saturated hydrocarbon fraction (constituting about 3% of the mainstream CSC) inhibited the activity of tumorigenic PAHs, including B[a]P. The components in the aliphatic hydrocarbon fraction ranged from pentadecane (C15) to pentatriacontane (C35). Each hydrocarbon was present as the normal, iso, and anteiso isomers. The C27 to C33 hydrocarbons constituted about 80% of the saturated hydrocarbon fraction; with C31 (n-hentriacontane) and C33 (n-tritriacontane) hydrocarbons usually being the most plentiful components in the fraction. Subsequent study with improved analytical methodology demonstrated the presence of trace amounts of additional isomeric aliphatic saturated hydrocarbons with as many as forty carbons. Studies with B[a]P and the C31 and C35 saturated hydrocarbons (SHC), where the SHC:B[a]P ratio was 200:1 and 100:1, showed that both saturated hydrocarbons exerted a significant inhibiting effect at both levels on the specific tumorigenicity of B[a]P in mouse skin-painting experiments [4311, 4314, see also pp. 330–331 in (4319) and pp. 370–371 in (4332)].

499

When the saturated hydrocarbon content (normally about 3% of the particulate phase) of mainstream CSC was increased from 3% to 4% (an overall 33% increase) by addition of the saturated hydrocarbon fraction isolated from CSC, the specific tumorigenicity of the CSC decreased, the % TBA decreased from 40% to 24%. The MSS of a cigarette delivering 20 mg of CSC contains about 0.6 mg (600,000 ng) of this saturated hydrocarbon fraction and 10 ng of B[a]P, an SHC: B[a]P ratio of 60,000:1, far in excess of the 200:1 or 100:1 SHC: B[a]P ratio that produced the significant inhibition of the specific tumorigenicity of B[a]P reported in the mouse skin-painting bioassay (4314, 4319, 4332). Other MSS components may have also influenced the PAH and mouse skin-painting results obtained with control tobacco CSC vs. the CSC from organic solvent-extracted tobacco. The extraction of tobacco with a solvent such as hexane not only removed the saturated aliphatic hydrocarbon inhibitors from the tobacco, thus making impossible their transfer to MSS when such tobacco is smoked, but also removed other components such as β-sitosterol (4356), α-tocopherol (vitamin E) (3271, 3347), indole (3279), and α- and β-4,8,13-duvane-1,3diol (3221, 3361, 3389), thus preventing their transfer to MSS during the smoking process. Subsequently, these tobacco components, now known to transfer from the tobacco rod to MSS during the smoking process and presumably to sidestream smoke (SSS) during cigarette smolder, have been shown to behave as anticarcinogens for several of the reported tobacco smoke “tumorigens,” such as the PAHs, the N-nitrosamines, and ethyl carbamate. Neither the presence of several of these tobacco and MSS components nor their anticarcinogenic or inhibitory activity vs. known tumorigens was known in the late 1950s or early 1960s. Despite the emphasis on the contribution of CSC components to its specific tumorigenicity when administered to laboratory animals via skin painting, the inhibition of tumorigenesis by CSC and several of its components was not completely ignored during the 1960s. In addition to the role of saturated aliphatic hydrocarbons in the inhibition of the specific tumorigenicity of CSC reported by Wynder and Hoffmann [4311, 4314, see also pp. 330–331 in (4319) and pp. 370–371 in (4332)], other studies pertinent to the antitumorigenicity of tobacco smoke included an earlier one in 1958 by Hoffman and Griffin (1672a) plus later ones in the mid-1960s by Homburger and his colleagues (1823, 1823b, 1824) as well as one reported in the late 1970s by Chamberlain et al. (663) at the USDA. Comparison of the list of the 5200 or so identified components in tobacco smoke with extensive lists presented by Fay et al. (1177a) and Slaga and DiGiovanni (3685) of compounds and elements reported to possess inhibitory or anticarcinogenic action in carcinogenesis-type experiments in laboratory animals reveals not only that tobacco smoke contains numerous anticarcinogens but also that the levels in tobacco smoke of many of them far exceed those of the levels of the reported tobacco smoke “tumorigens” (3255a). The levels of many of the anticarcinogens in tobacco smoke vs. those of the reported smoke “tumorigens” are far in excess of the ratio needed for the anticarcinogenicity to be effective. Table IX.A-11, adapted

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Table IX.A-11 Inhibitors and Anticarcinogens in Tobacco Smoke Tobacco Smoke Component Class (examples)

Tumorigen Suppressed

Hydrocarbons, saturated (e.g., C31H64, C35H72) Hydrocarbons, unsaturated (D-limonene) Hydrocarbons, monocyclic aromatic (benzene) Hydrocarbons, aromatic, polycyclic (naphthalene, anthracene, phenanthrene, fluoranthene, pyrene, benzo[e]pyrene, benzo[b]triphenylene) Lactones (coumarin, α-angelica lactone) Alcohols (ethanol, n-butanol, tert-butanol, cholesterol, β-sitosterol, α- and β-4,8,13-duvane-1,3-diol Purines (caffeine, theobromine) Indoles (indole, indole-3-acetonitrile) Miscellaneous components (maleic anhydride, aconitic acid, selenium, carbon disulfide) Phenols (phenol, caffeic acid, ferulic acid, gallic acid; 2-hydroxycinnamic acid; 4-methoxyphenol; α-tocopherol) (see Table IX.A-9)

B[a]P NNKa, dibenzo[a,i]pyrene B[a]P, DB[a,h]A B[a]P, DB[a,h]A, DMB[a]A

a b

B[a]P, DMB[a]A NNNb, DMB[a]A ethyl carbamate, N-nitrosamines, DMB[a]A B[a]P B[a]P, DMB[a]A, 1,2-dimethylhydrazine B[a]P, N-nitrosamines, 1,2-dimethylhydrazine, DMB[a]A, 1,2-dihydro3-methylbenz[e]aceanthrylene (3-methylcholanthrene)

NNK = 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone NNN = N’-nitrosonornicotine

from Rodgman (3255a), lists tobacco smoke components reported to be inhibitory or anticarcinogenic to several of the “tumorigens” reported to be present in tobacco smoke. Hoffmann et al. (1766) reported that the results from their study of the levels of several selected components in the MSSs from different tobacco products gave suggestive support to the hypothesis that B[a]P and phenol may serve as “indicators” of the specific tumorigenic activities (initiation, promotion) of tobacco “tars.” During the next decade, the hypothesis that phenol was an “indicator” of the low molecular weight, promoting phenols was reiterated numerous times by Wynder and Hoffmann (4319, 4330, 4332, 4342, 4344, 4346, 4346a). However, as research on the biological effects of phenols in tobacco smoke escalated, it became obvious that the promoting effect of the low molecular weight phenols on the specific tumorigenicity of PAHs in tobacco smoke was not as definitive as Wynder and Hoffmann and other investigators asserted. The discovery that a large percentage of the volatile phenols are removed from MSS by the plasticized filter tip led to differences of opinion on the promoting action of the volatile phenols. Numerous statements in Hoffmann-Wynder presentations and publications described their conclusions with respect to volatile phenols removal vs. tumorigenicity of the phenolsdepleted CSC. Examples of their statements follow. In their 1967 book, Wynder and Hoffmann [(4340), see p. 626 in (4332)] stated: It should be noted, however, that a reduction of phenols in tobacco smoke condensate has not led to a concomitant reduction of tumorigenicity in the corresponding “tars.”

In 1968, Wynder and Hoffmann (4342) again discussed phenols as promoters:

Volatile phenols represent one type of tumor promoter in tobacco smoke. In mouse-skin carcinogenesis, however, they evidently do not play an essential role as such, since a significant reduction of phenols in the smoke condensate is not accompanied by a similar reduction in carcinogenic activity of the “tar” [4332].

A year later, Wynder and Hoffmann [see p. 298 in (4344)] wrote: The only known group of promoters in tobacco smoke are the volatile phenols. Their reduction of up to 80% by selective filtration, however, did not lead to a reduction of tumor promoting activity.

In the same article, they added [p. 299 in (4344)]: A reduction of phenol in tobacco smoke through the use of filters, however, does not alter the complete tumorigenic activity of “tar” obtained from such cigarettes. This infers that a selected reduction of volatile phenols will not reduce the tumor-promoting activity of such “tar.”

In the written introduction to their presentation at the 28th TCRC in 1974, Hecht et al. (1582) stated the following and cited Wynder and Hoffmann (4332) as their source: Phenol and some substituted phenols are weak promoters, but they alone contribute only a small part of the promoting activity, since selective filtration of phenol does not change significantly the biological activity of the resulting condensate.

In their discussion of tumor promoters and the complexity of CSC, Van Duuren et al. (4035) reported: Phenol, which is a weak tumor-promoting agent, is indeed an inhibitor of tumorigenesis when applied simultaneously with benzo[a]pyrene.

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Table IX.A-12 Tobacco Smoke Phenols with Anticarcinogenic or Antipromoting Properties Phenolic Smoke Component

Reference to Identification in Tobacco Smoke

Benzoic acid, 3,4,5-trihydroxy- {gallic acid} 1H-1-Benzopyran-6-ol, 3,4-dihydro-2,5,7,8tetramethyl-2-(4,8,12trimethyltridecyl)- {α-tocopherol}

Kröller (2195) Rodgman and Cook (3271, 3286), Rodgman (3251)

Phenol

Vohl and Eulenberg (4065), Ludwig (2408), Ikeda (1857) Spears (3764) Yang et al. (4376), Yang and Wender (4377), Wender and Yang (4163) Yang et al. (4376), Yang and Wender (4377), Wender and Yang (4163) Yang and Wender (4377)

Phenol, 4-methoxy2-Propenoic acid, 3-(3,4-dihydroxyphenyl)-, cis-{cis-caffeic acid} 2-Propenoic acid, 3-(3,4-dihydroxyphenyl)-, trans-{trans-caffeic acid} 2-Propenoic acid, 3-hydroxy-4-methoxyphenyl)-, trans- {ferulic acid}

Van Duuren et al. also noted that rutin, a tobacco component, also inhibited B[a]P carcinogenesis in the mouse skin-painting bioassay. From the results of their biological experiments on cocarcinogenesis (simultaneous and repeated application of an agent, in this case 1,2-benzenediol [catechol]), with B[a]P, Van Duuren et al. (4029) deduced that 1,2benzenediol (catechol) showed remarkable cocarcinogenic activity with B[a]P. They reported: Phenol has been regarded as an important “tumor promoter” in cigarette smoke condensate … [but our] work indicates it is inactive in cocarcinogenesis and, indeed, has a slightly inhibitory effect on benzo[a]pyrene carcinogenesis.

Later, Van Duuren and Goldschmidt (4028) demonstrated the cocarcinogenicity of 1,2-benzenediol (catechol) when applied as a 2% solution to mouse skin three times weekly with a solution of 0.005% B[a]P. They contrasted the remarkable cocarcinogenic activity of 1,2-benzenediol (catechol) with its inactivity as a tumor promoter for B[a]P. Hecht et al. (1562) described the importance of 1,2-benzenediol (catechol) as a tobacco smoke cocarcinogen. They also noted that the levels of 1,2-benzenediol (catechol) in MSS was reduced by prior extraction of the tobacco with hexane-ethanol or by inclusion of reconstituted tobacco sheet (RTS) in the tobacco blend. While Wynder and Hoffmann wrote at length about the promoting effect of low molecular weight phenols and the phenol fraction of CSC on PAH tumorigenicity, it is interesting to note their change in emphasis in 1986. In a 1986 article (1808), the Hoffmann-Wynder discussion dealt primarily with the nature of tumor initiators (PAHs) and cocarcinogens (catechols), with no mention of the phenolic promoters they had discussed repeatedly for more than two decades since the

Reference to Anticarcinogenesis (AC) or Antipromotion (AP) (AC) Mirvish et al. (2559c) (AC) Shamberger (3625), Slaga and Bracken (3684), Viaje et al. (4049a), Shklar (3655a), Weerapradist and Shklar (4159a), Toth and Patil (3927a), Mirvish (2559b) (AP) Van Duuren et al. (4035) (AC) Wattenberg et al. (4149c) (AC) Wattenberg et al. (4149c), Wattenberg (4149b) (AC) Wattenberg et al. (4149c), Wattenberg (4149b) (AC) Wattenberg (4149b)

early 1960s! In that same year, the IARC published its monograph on tobacco smoking to which Wynder and Hoffmann had contributed substantial information on tobacco smoke chemistry. In its monograph, IARC defined the phenols as a major group of promoting agents in tobacco smoke (1870), but IARC made no mention of the Wynder-Hoffmann observation of a lack of effect on specific tumorigenicity of the almost complete removal of the phenols from MSS. Although much was written during the 1950s, 1960s, and 1970s about the supposed adverse effect, that is, the promoting effect of phenolic compounds in tobacco smoke on its specific tumorigenicity in laboratory animals, significant properties, for example, their anticarcinogenicity and/or antipromoting effects, of several specific tobacco smoke phenols have generally been overlooked. Phenolic compounds in tobacco smoke known to possess either of these properties are listed in Table IX.A-12. In addition to the known antitumorigenic and antipromoting effects of CSC and several specific components in it, it has also been shown by Lee et al. (2327a, 2327b, 2337c) that cigarette MSS possesses antimutagenic properties that offset the mutagenicity in the Ames test (Salmonella typhimurium) of several N-nitrosamines and several of the N-heterocyclic amines defined as “cooked food” mutagens.

IX.A.3 Determination of the Nature of the Precursors in Tobacco of the Phenols in Mainstream Smoke Resolution of the question of the presence of tetracyclic and higher PAHs, particularly B[a]P, in tobacco smoke was followed chronologically by studies to determine the source of the PAHs in tobacco smoke. When the PAH-containing

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environmental pollutants from lighting sources (matches, hydrocarbon-fueled cigarette lighters, etc.) were discarded in the early 1950s as significant contributors to the PAHs in tobacco smoke, particularly cigarette MSS, the contribution of tobacco itself to the PAHs in smoke was questioned: What were the components in tobacco that, during the smoking process, could act as significant precursors of the PAHs in its smoke? The investigation sequence was essentially the same with the reported tumorigenic aza-arenes in tobacco smoke. Initially, the identifications of the azaarenes were resolved. Subsequently, studies were conducted to define the precursors in tobacco of the aza-arenes identified in tobacco smoke. As noted previously, however (see Table IX.A-1 and accompanying text), the results reported on numerous studies between 1963 and 1992 have raised other serious questions concerning the presence of the aza-arenes dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole in tobacco smoke and their supposed generation from nicotine. The difference in the levels of simple phenols in tobacco smoke vs. their levels in the major tobacco types (flue-cured, burley, Maryland tobaccos), which collectively constitute the major proportion of American cigarette tobacco blends, suggested that the simple phenols in cigarette MSS were present not as a result of their significant direct transfer per se from the tobacco but as a result of their pyrosynthesis from precursors comprising one or more tobacco components. Long before the concern expressed that the simple phenols possessed promoting activity that enhanced the tumorigenicity of tumorigenic PAHs (414) and the concern expressed by Roe et al. (3314) and Wynder and Hoffmann (4307) about the presence of the simple phenols in tobacco smoke, Wenusch (4202) had suggested that the major sources in tobacco of the tobacco smoke phenols were its lignin and complex carbohydrate and polyphenol components. In contrast to flue-cured, burley, and Maryland tobaccos, highly aromatic tobaccos such as Latakia were reported to contain significant levels of free simple phenols (1876, 1877a). As the complexity of the phenols increased, the likelihood of their presence in tobacco increased and many were found in smoke as a result of direct transfer, for example, the high molecular weight phenol, 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-1H-1-benzopyran-6-ol (α-tocopherol), first identified as a tobacco leaf component by Rowland (3347) and as a tobacco smoke component by Rodgman and Cook (3271), 6,7-dihydroxy-2H-1-benzopyran-6-one (esculetin) identified in tobacco and its smoke by Dieterman et al. (969). In the early 1960s, Herrmann (1625, 1626) reviewed various studies on the phenols, phenolic acids, and related compounds identified in tobacco and tobacco smoke. Examination of the chronology of the investigation of phenolic components of tobacco smoke reveals an interesting situation. In the early 1960s, substantial research was

The Chemical Components of Tobacco and Tobacco Smoke

conducted on the phenols in tobacco smoke, their identification, their quantitation, and their major precursors in tobacco. When the promoting effect of the low molecular weight monohydric phenols was seriously questioned, the effort on phenols waned for some years but accelerated again when the claims on the co-carcinogenicity of the dihydric phenols, particularly 1,2-benzenediol (catechol), surfaced. This situation triggered examination of the levels of the benzenediols in tobacco smoke and their possible precursors in tobacco. Table IX.A-13 summarizes some of the studies conducted to define the nature of the major precursors in tobacco of the phenolic components of tobacco smoke. Zane and Wender (4403) described their pyrolysis (pyrolysis temperature that of a Bunsen burner flame) of the tobacco components rutin, quercitin, and chlorogenic acid. In addition to nonphenolic compounds, each pyrolysate was reported to contain 1,2-benzenediol (catechol) with lesser amounts of 4-methyl-1,2-benzenediol, 1,3-benzenediol (resorcinol). The amounts of phenol and 4-methylphenol (p-cresol) in the pyrolysates obtained under various conditions from several major tobacco components (cellulose, pectin, and lignin), a tobacco additive (invert sugar), several individual tobacco types (flue-cured tobacco, cased burley tobacco, Maryland tobacco), and a tobacco substitute (spinach) were reported by Rodgman and Mims (3305) and Rodgman and Cook (3286). Table IX.A-14 summarizes the results. Spears et al. (3767) and Bell et al. (248) determined the generation of phenol when flue-cured and burley tobaccos and various tobacco components (glucose, sucrose, starch, cellulose, and pectin) were pyrolyzed at various temperatures in an air or nitrogen atmosphere. In each instance, phenol was generated. In their study of tobacco lignin as a phenols precursor, Kato et al. (2043) examined the residue resulting from heating tobacco stalk lignin at 450 to 500°C for two hours. They identified the following phenols: phenol, 2-methoxyphenol (guaiacol), 2-methylphenol (o-cresol), 3-methylphenol (m-cresol), 4-methylphenol (p-cresol). Kato et al. (2046) also conducted a comparative thermal analysis of tobacco stalk-derived cellulose, holocellulose, and lignin subjected to similar heating. In a continuation of the pyrolysis study by Chortyk et al. (725a, 726) on the possible contribution of the tobacco pigment to the PAH content of tobacco smoke composition, Schlotzhauer et al. (3468) examined the pyrogenesis of phenols from high molecular weight components of tobacco, specifically the tobacco pigment and the biopolymers lignin, cellulose, and pectin. They (3468) reported that the phenol amounts (phenol, 3- and 4-methylphenol [m- and p-cresol]) found in the pyrolysates from Oriental tobacco and the high molecular weight tobacco components (pigment, lignin, pectin, and cellulose) pyrolyzed at 700°C/nitrogen atmosphere were generated in the following sequence: Oriental tobacco > pigment > lignin ≥ pectin >> cellulose

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Table IX.A-13 Precursors in Tobacco of Phenols in Tobacco Smoke Tobacco Smoke Phenol

Phenol Methylphenols {cresols}

Dimethylphenols {xylenols} Benzenediols {catechol, resorcinol, hydroquinone}

Tobacco Leaf Precursor

References

   

lignin

Rodgman and Mims (3305), Kato et al. (2043, 2046), Schlotzhauer et al. (3456, 3462, 3468), Higman et al. (1647), Carmella et al. (598)

   

sugars

Spears et al. (3767), Bell et al. (248), Higman et al. (1647), Carmella et al. (598, 602), Schlotzhauer et al. (3462)

polysaccharides (cellulose, starch, pectin)

Kato et al. (2043, 2046), Spears et al. (3767), Bell et al. (248), Schlotzhauer et al. (3456, 3462, 3468), Higman et al. (1647), Brunnemann et al. (496, 497), 1975, 1976, Carmella et al. (598, 601, 602)

protein

Higman et al. (1647)

amino acids

Higman et al. (1647)

extracted tobacco

Rodgman and Cook (3277), Rodgman and Mims (3305), Severson et al. (3616), Carmella et al. (600), Schlotzhauer et al. (3453, 3462)

tobacco pigment

Schlotzhauer et al. (3468)

tobacco extracts

Schlotzhauer et al. (3456), Severson et al. (3616)

rutin

Zane and Wender (4403), Spears et al. (3767), Bell et al. (248), Brunnemann et al. (496, 497), Carmella et al. (598), Schlotzhauer et al. (3462)

     

                   

  quinic acid a   chlorogenic acid

Ayres and Thornton (127a) Zane and Wender (4403), Brunnemann et al. (496, 497), Carmella et al. (598, 600, 602), Schlotzhauer et al. (3462)

a

Quinic acid = 1,3,4,5-tetrahydroxycyclohexanecarboxylic acid

b

Chlorogenic acid = 3-(3,4-dihydroxyphenyl)-2-propenoic acid, 3-ester with 1,3,4,5-tetrahydroxycyclohexanecarboxylic acid

In a study of the effect of steady-state pyrolysis of tobacco vs. pulsed pyrolysis simulating the puffing sequence in a smoked cigarette, Patterson et al. (2904) reported that the pulsed pyrolysis procedure gave much higher levels of the low molecular weight phenols (phenol, 2-, 3-, and 4-methylphenol [o-, m-,and

p-cresol], 2-, 3-, and 4-ethylphenol, 2,4-, and 2,5-dimethylphenol [2,4- and 2,5-xylenol], and 2-methoxyphenol [guaiacol]) in the pyrolysate than did the steady-state pyrolysis. The report of the significant cocarcinogenicity of 1,2-benzenediol (catechol) by Van Duuren and Goldschmidt (4028)

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Table IX.A-14 Pyrolysis of Tobacco, Tobacco Components, and Spinach: Phenol Content of Pyrolysate Phenol, µg/g Pyrolyzed Material Pyrolyzed

Atmosphere

T°C

Phenol

4-Methylphenol (p-Cresol)

Individual Component Cellulose Cellulose Pectin Lignin Lignin Invert sugar

nitrogen nitrogen nitrogen nitrogen air nitrogen

550 650 550 550 550 550

460 350 310 2370 440 140

215 110 130 2330 460 50

Tobaccos and Spinach Flue-cured Burley, cased Maryland Spinach

nitrogen nitrogen nitrogen nitrogen

550 550 550 550

730 620 470 360

310 390 150 280

and the subsequent confirmation of its cocarcinogenicity by Hecht et al. (1562) triggered considerable interest in the source in tobacco of 1,2-benzenediol (catechol) in tobacco smoke. In the early 1980s, Schlotzhauer et al. (3462) and Schlotzhauer and Chortyk (3453) at the USDA, in their study of the precursors in tobacco of phenols in tobacco smoke, investigated the pyrolysis of various solvent-extracted fractions from tobacco plus the tobacco residue after extraction. The extracted tobacco residue, the ethanol extract, and the methanol extract were the major sources of benzenediols (catechol, resorcinol, and hydroquinone). From these results, it was proposed that chlorogenic acid in tobacco was a major precursor of the benzenediols, particularly 1,2-benzenediol (catechol), in tobacco smoke. The extracted tobacco residue was also reported as the major source of the monohydric phenols (phenol, cresols, xylenols, and guaiacols). Figure IX.A-2 illustrates the possible relationship between 1,2-benzenediol (catechol) and several complex tobacco phenols subsequently studied as its precursor. In a continuation of their study of the conversion of various tobacco components to catechol, Schlotzhauer et al. (3462) examined the phenols formed during the pyrolysis of a variety of tobacco components, including chlorogenic and caffeic acids, rutin and quercetin, cellulose and lignin, and fructose and sucrose (Table IX.A-15). They reported that chlorogenic acid, usually the most abundant polyphenol in tobacco, produced the highest levels of 1,2-benzenediol (catechol) and 4-ethyl-1,2-benzenediol (4-ethylcatechol) during pyrolysis. In addition, the tobacco biopolymer lignin was also reported to be a significant source of 1,2-benzenediol (catechol). Their examination of the phenols generation by pyrolysis of several different flue-cured and burley tobaccos indicated that the flue-cured tobaccos produced significantly higher levels of

the phenols than did the burley tobaccos. A similar situation is obtained when the MSS phenols from cigarettes fabricated from all flue-cured and all burley tobaccos are compared on a milligram of phenol per milligram of CSC basis [Wynder and Hoffmann (4317, 4332)]. Because they considered 1,2-benzenediol (catechol) a “major constituent of tobacco smoke,” a component they considered an important contributor to the biological properties of smoke, Hoffmann and his colleagues at the American Health Foundation conducted an extensive study in the early 1980s on the pyrosynthesis of 1,2-benzenediol (catechol) during the tobacco smoking process. The goal of the study was to determine the major precursor(s) in tobacco of the 1,2-benzenediol (catechol) in MSS. Initial experiments by Carmella et al. (600) involved the sequential extraction of tobacco with hexane, chloroform, benzene, and methanol, followed by pyrolysis of the material extracted by each solvent and determination of the 1,2-benzenediol (catechol) in the pyrolysate. Only the pyrolysates from the methanol extract and the residual extracted tobacco indicated the presence of 1,2-benzenediol (catechol) precursors. From the results of a study in which Kentucky reference 1R1 cigarettes were “spiked” with increasing levels of chlorogenic acid (the 3-ester of 3,4-dihydroxycinnamic acid with 1,3,4,5-tetrahydroxycyclohexane-carboxylic acid), smoked under standard conditions, and the MSS analyzed for 1,2benzenediol (catechol), Carmella et al. (598) concluded that, under their experimental conditions, chlorogenic acid was not a major precursor in tobacco of 1,2-benzenediol (catechol) in tobacco smoke. This finding was the opposite of that reported by Schlotzhauer et al. (3453, 3462). In a subsequent study by Carmella et al. (602), tobacco was extracted sequentially with hexane then aqueous methanol.

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Phenols and Quinones

O OH

O HOOC

2 1

3

4 5

OH

OH HO

OH

OH

Chlorogenic acid; 3-O-caffeoylquinic acid CAS No. 327-97-9 Cyclohexanecarboxylic acid, 3-[[3-(3,4dihydroxyphenyl)-1-oxo-2-propenyl]oxy]1,4,5-trihydroxy-\

trans-Caffeic acid CAS No. 4361-87-9 2-Propenoic acid, 3-(3,4-dihydroxyphenyl)-

HO

HO O

HO ruffinose

COOH

HO

OH

OH

O

HO

O

HO O

O OH Rutin CAS No. 153-18-4 4H-1-Benzopyran-4-one, 3-[[6-O-(6-deoxy-αL-mannopyranosyl)-β-D-glucopyranosyl]oxy]2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-

OH

Quercitin CAS No. 117-39-5 4H-1-Benzopyran-4-one, 2-(3,4dihydroxyphenyl)-3,5,7-trihydroxy-

Figure IX.A-2  Potential precursors in tobacco of 1,2-benzenediol (catechol) in tobacco smoke.

The major components of the aqueous methanol extract were identified as fructose, glucose, sucrose, and chlorogenic acid. Contributions of each of these tobacco components plus the contributions of the tobacco components cellulose and rutin to the 1,2-benzenediol (catechol) level in cigarette MSS were determined in a “spiking” experiment in which cigarettes were “spiked” with each of the components mentioned, two of which were radiolabeled (fructose and cellulose). The

minimum contributions of these components to the 1,2benzenediol (catechol) level in MSS were: cellulose, 7% to 12%; total of the sugars, glucose, fructose, and sucrose, 4%; chlorogenic acid, 13%; rutin, less than 1%. Carmella et al. considered that a significant portion of the unaccounted for 1,2-benzenediol (catechol) was formed from the other biopolymers, pectin, starch, and hemicellulose. It would appear that these 1984 results on the involvement of chlorogenic acid as a

Table IX.A-15 Pyrolysis of Tobacco Components: Generation of Phenols Tobacco Component Pyrolyzed Phenol

Chlorogenic

Caffeic Acid

Rutin

Quercetin

Lignin

Cellulose

Fructose

Sucrose

× — —

— — —

— — —

— — —

× × ×

— — —

— — —

— — —

× —

× —

× ×

× ×

× ×

— —

— —

— —

×

—

×

—

—

—

—

—

—

—

×

—

—

—

—

—

×

—

…

—

—

×

×

×

Phenol Phenol, 2-methoxy- a Phenol, 2-methoxy4-(1- propenyl)-b 1,2-Benzenediol c 1,2-Benzenediol, 4-methyl1,2-Benzenediol, 4-ethyl1,2-Benzenediol, 4-propylFurfuralsd

Guaiacol Isoeugenol c Catechol d Furfural and/or 5-(hydroxymethyl)furfural a

b

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1,2-benzenediol (catechol) precursor differed from those presented previously by the same investigators [Carmella et al. (602) vs. Carmella et al. (598) who earlier stated in 1981: The results under these experimental conditions [a “spiking” experiment] suggest that chlorogenic acid is not a major precursor of catechol in cigarette smoke.

Carmella et al. (601) reported that cellulose in tobacco was a major precursor of 1,2-benzenediol (catechol) in tobacco smoke. Comparison of the pyrogenesis of 1,2-benzenediol (catechol) from cellulose and carboxymethylcellulose suggested that the 1,2-benzenediol (catechol) level in tobacco smoke might be reduced by modification of the tobacco cellulose. Subsequently, Carmella et al. (599) reported that carboxymethylation of the cellulose in tobacco reduced the 1,2-benzenediol (catechol) in the MSS from 252 to 162 µg/ cigarette, a 36% reduction. In addition to investigations of the possible precursors in tobacco of phenols in cigarette MSS, the contribution of several tobacco additives to phenols in MSS was studied. Many years before the advent of the use of expanded tobacco and filter-tip perforations in the design of low- to medium“tar” cigarettes, Kato and Shibayama (2044) reported that vanillin (4-hydroxy-3-methoxybenzaldehyde) incorporated in the tobacco blend by many manufacturers as a flavorant was converted to phenol during the smoking process and therefore should not be used as a cigarette tobacco flavorant. Contradictory results were reported in a subsequent study at RJRT R&D by Eble et al. (1105) with radiolabeled vanillin. They reported that no radiolabeled phenol was detected in the cigarette MSS and concluded that vanillin did not generated phenol during the smoking process. The difference between the Kato and Shibayama 1962 results and the Eble et al. 1985 results was readily explained by the difference in the experimental conditions used in the two studies: Kato and Shibayama (2044) used continuous draw in their smoking regime, that is, no alternating puff and smoldering period, whereas Eble et al. (1105) used the intermittent-puff regime and smoking procedure defined in the U.S. FTC “tar” and nicotine procedure (35-ml puff-volume, 2-sec puff-duration, 1 puff/min, 25°C, 60% relative humidity, etc.). Many flavoring materials have been proposed for use as flavoring materials in tobacco smoking products. Leffingwell et al. (2341) reported that these range from individual chemical compounds to a variety of natural herbs, essential oils, and extracts. Many of the proposed flavoring additives for tobacco smoking products have been included in commercial

products, but many have not. Among the naturally occurring mixtures used historically were deer tongue, tonka bean, and vanilla extract (2341). In the early 1970s, Higman et al. (1649) investigated the pyrolysis of these three historically used tobacco additives to determine their possible contributions to the composition of cigarette smoke. In addition to numerous monocyclic and PAHs and their monocyclic and polycyclic nitrogen analogs, all three pyrolysates contained phenol, cresols, and xylenols. The deer tongue and tonka bean pyrolysates also contained naphthols and coumarin. With regard to the use of these three materials as tobacco additives, the authors noted: The contribution of such additives [tonka bean, deer tongue, vanilla extract] to the chemical and biological effects of cigarette smoke would be in proportion to the amounts of such additives used and also to the pyrolytic-distillation pattern to which the additive is subjected in the thermal flow environment of the burning cigarette.

The report by Gori (1332) and the National Cancer Institute (2683) on the results obtained in the NCI Smoking and Health Program on “less hazardous” cigarettes (1329, 1330, 1332, 1333, 2683) led to an initial concern about the contribution of cocoa added to tobacco to the chemical and biological properties of the smoke from cigarettes containing cocoa-treated tobacco. Subsequent examination of the biological data indicated that the initial concern was unfounded. Schlotzhauer (3447) at the USDA research center in Athens, Georgia, reported the results of his analysis of the pyrolysis of cocoa powder and its possible contribution to the phenols content of smoke from cigarettes made with cocoa-treated tobacco. Pyrolysis of cocoa at various temperatures (350°, 450°, 550°, 650°, and 750°C) yielded phenol, the three dimethylphenols (o-, m-, and p-cresol), several dimethylphenols (xylenols), and 1,2-benzenediol (catechol). From his results, Schlotzhauer concluded: Addition of cocoa powder to tobacco products in the quantities normally utilized for flavoring purposes would not … be expected to significantly enhance the phenolic content of tobacco smoke. Results of the study indicate that the levels of phenols derived from pyrolysis of cocoa should not significantly enhance the phenol content of tobacco smoke …

As shown in Table IX.A-16, comparison of the MSS phenol data from the NCI study on cocoa-free (Sample Code 83) vs. cocoa-treated (Sample Code 82) (1332, 2683) confirms the view expressed by Schlotzhauer (3447).

Table IX.A-16 Smoke Chemistry Data: NCI Study of Cocoa Addition (1332) Relative to “dry” Condensate, µg/g Code No.

Filler

Phenol

o-Cresol

m- and p-Cresol

83 82

SEB III SEB III + 1% cocoa

4.33 4.46

0.68 0.75

1.98 2.02

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Phenols and Quinones

Over a decade later in 1990, Roemer and Hackenberg (3314a) reported the results of mouse skin-painting bioassays in which the CSCs from cigarettes containing various levels of cocoa were tested. The CSCs from cigarettes containing different levels of cocoa (0, 1%, and 3%) were studied for their specific tumorigenicity. Their results contradicted those reported by Gori (1332) for the NCI less hazardous cigarette study. The 1% and 3% addition levels of cocoa were equivalent to and three times, respectively, the level of cocoa usually added to commercial cigarettes. Roemer and Hackenberg noted: We found no evidence for indicating an enhancement of the biological activity of cigarette smoke condensates derived from cigarettes to which 1 and 3% cocoa was added.

Additional details pertinent to cocoa are summarized by Rodgman (3264).

IX.A.4 The Effect of Cigarette Design Parameters on Yield of Mainstream Smoke Phenols Despite the controversy over the biological properties of the phenols in tobacco smoke, that is, were they promoters of the tumorigenicity of the PAHs in the mouse skin-painting bioassay or cocarcinogens for the PAHs in that bioassay? Or were they noncontributors or minor contributors to the bioassay results? The next step after identification, refinement of quantitation procedures, and resolution of the question of precursors was the determination of which cigarette design parameters would permit control of the levels of phenols in MSS. Of course, the first method discovered to control the MSS levels of phenols was their selective filtration by the plasticized cellulose acetate filter tip. The extensive research on phenols in tobacco smoke eventually led to the resolution of the question of whether selective filtration of a particular component or class of components in cigarette MSS was possible. Despite listing effective filtration as an important means to reduce cigarette MSS particulate matter, Wynder and Hoffmann in 1961 (4311) categorized “selective filtration” of a particular component or class of components in cigarette MSS as an impossibility. However, the next year, because of their findings with low molecular weight phenols in the MSS of filter-tipped cigarettes, Wynder and Hoffmann (4314) reversed their previously expressed assertion on the impossibility of “selective filtration.” They reported that the levels of MSS low molecular weight phenols were significantly reduced (75% to 90%) by the plasticized cellulose acetate filter tip. It was determined by numerous investigators that highly volatile, low molecular weight phenols such as phenol and the isomeric methylphenols (the cresols) were selectively filtered from cigarette MSS. That the filter-tip plasticizer (usually triacetin) played a significant role in the selective filtration was demonstrated in the early 1960s by Lorillard (2399), Laurene (2295, 2295a, 2298), Laurene et al. (2311, 2312), Spears (3765), and Hoffmann and Wynder (1791). Brown and Williamson patented the use of Carbowax® as an alternative filter-tip additive for selective filtration of low molecular

507

weight phenols. Low molecular weight phenol levels in MSS were reduced 75% to 90% by the selective filtration of triacetin- or Carbowax®-treated cellulose acetate. Because of the volatility of the low molecular weight phenols, an equilibrium exists between these components of the tobacco smoke aerosol vapor phase and of the tobacco smoke aerosol particulate phase. Thus, these components are substantially partitioned between the particulate phase and vapor phase of cigarette MSS aerosol. The selective filtration (75% to 90%) occurs by removal from the smoke stream of significant amounts of low molecular weight phenols in the aerosol vapor phase. During the brief time of the MSS transit through the plasticized filter tip, removal of the phenols from the vapor phase results in vaporization of the phenols from the particles in attempt to reestablish the original particulate phase-vapor phase equilibrium. Subsequently, it was determined by Fredrickson (1236) in the mid-1960s and by Morie and Sloan (2635) and Brunnemann et al. (514) in the 1970s that similar selective filtration occurred with volatile N-nitrosamines such as N-dimethylnitrosamine and N-diethylnitrosamine with 70% to 80% of the volatile N-nitrosamines being removed from MSS by a plasticized cellulose acetate filter tip. The discovery in the early 1960s of the selective filtration of the low molecular weight phenols from cigarette MSS was subsequently confirmed by numerous investigators throughout the world. As shown by the citations in Table IX.A-17, the selective filtration of phenols from cigarette MSS was extensively studied from the early 1960s to the mid-1970s. A few additional studies have been described from the mid-1970s to date. From these studies, it was also reported by Laurene et al. (2311, 2312) that the effectiveness of the selective filtration of plasticized filter-tip cigarettes decreased during the shelf life of the cigarette. Discovery of the extensive partitioning of low molecular weight phenols between the particulate and vapor phases of cigarette MSS necessitated modifications to the methods for determining them. Although several low molecular weight PAHs such as naphthalene (mol wt 128) and its alkyl derivatives also show some partitioning between the particulate and vapor phases, the high molecular weight PAHs [anthracene and phenanthrene (mol wt 178), B[a]A (mol wt 228), DB[a,h] A (mol wt 278), B[a]P (mol wt 252)] exist almost exclusively in the particulate phase. Before the extent of this partitioning and the selective filtration of low molecular weight phenols had been determined, most early studies dealt with analysis for the per cigarette yield of the low molecular weight phenols in the particulate phase. Thus, the relationships between the per cigarette levels of the tumorigenic PAHs and these phenols in mainstream CSC and the proposed promotion of the specific tumorigenicity of the PAHs by the phenols required reassessment. This research observation-based comment raises the question about the repeated assertion of the importance of the promoting activity of phenol and other low molecular weight phenols, particularly in their supposed enhancement of the

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Table IX.A-17 Studies on the Selective Filtration of Phenolic Compounds in Cigarette Mainstream Smoke Year

Investigator(s)

Year

Investigator(s)

1962

Davis and George (911a) Lorillard (2399)

1967

George and Keith (1284) Müller and Moldenhauer (2653) Waltz et al. (4122)

1963

Hoffmann and Wynder (1791) Laurene (2295, 2295a) Laurene et al. (2311, 2312) Spears (3765) Waltz and Häusermann (4118)

1968

George (1283) Kallianos et al. (2016)

1969

Georgiev (1284a, 1284b)

1970

Reynolds (3111)

1972

Artho et al. (105)

1974

Baggett and Morie (156)

1975

Baggett and Morie (156) Brunnemann et al. (496)

1976

Brunnemann et al. (497) Kensler (2082)

1980

Mokhnachev and Mironenko (2579)

1994

Wilson (4268)

1964

1965

1966

Esterle and Campbell (1164) Pyriki and Moldenhauer (3043) Seehofer et al. (3574) Testa et al. (3890) Cuzin et al. (884) George (1282a) Kaburaki et al. (1996) Laurene (2298) LeRoux (2351) Lipp (2376, 2377) SEITA (3602) Waltz and Häusermann (4121) Kallianos et al. (2016) Müller and Moldenhauer (2653) Touey and Kiefer (3937)

specific tumorigenicity of PAHs. What kind of tobacco smoke promoter is it that exerts so little effect that, in its absence, the specific tumorigenicity in the mouse skin-painting bioassay of the CSC remains essentially unaltered? Table IX.A-18 illustrates the effect of several tobacco expansion procedures and inclusion of the expanded tobacco in the cigarette blend on the MSS phenol yield. Brunnemann et al. (496, 497) confirmed the previous finding of Waltz et al. (4123) that 1,2-benzenediol (catechol) was the phenol usually present at the highest yield in cigarette MSS. Brunnemann et al. determined that the level of 1,2benzenediol (catechol) in the MSS of a nonfiltered cigarette varied from 160 to 500 µg/cigarette. The level of 1,2-benzenediol (catechol) in the MSS from a filter-tipped cigarette varied from 60 to 200 µg/cigarette. They also reported that 1,2-benzenediol (catechol) and its derivatives were not selectively reduced by commercial cigarette filter tips as were many low molecular weight monohydric (one hydroxyl group) phenols. In 1953, when reconstituted tobacco sheet (RTS) was introduced into its cigarette products by R.J. Reynolds Tobacco Company as a cigarette design technology, little was known about either the nature or yields of phenols in cigarette MSS (see Table IX.A-4). Also, the promoting activity of low molecular weight phenols to the specific tumorigenicity of PAHs had not been reported by Boutwell et al. (414). Until the early to mid-1960s, the contribution of RTS to MSS

composition dealt primarily with the decrease in the yields of the MSS PAHs, particularly B[a]P, and the decrease in the specific tumorigenicity (mouse skin) of the CSC as the percent inclusion of the RTS in the blend was increased [see pp. 531–532 in (4332)]. Reports presented during the “less hazardous” cigarette workshop held at the 1967 World Conference on Smoking and Health were published the next year as an NCI monograph edited by Wynder and Hoffmann (4343). Moshy and Halter presented data on the effect of inclusion of experimental RTS in a blend. They wrote (2647a): It is apparent from the data [presented] that selective reductions of up to 45% for benzo[a]pyrene and up to 87% for phenol were achieved with some of the experimental tobacco leaves.

At the same conference, Hoffmann and Wynder (1798) also discussed the percent reduction of the PAH content, specifically the B[a]P content, of the cigarette CSC by inclusion of RTS in the cigarette tobacco blend. Although analytical data on the decrease in TPM, B[a]P, and phenol yields were presented graphically, they had no comment on the significant percent reduction in the phenol content of the MSS, a percent reduction that exceeded that of the B[a]P content. In the NCI Smoking and Health Program on the “less hazardous” cigarette, the substantial lowering of the yields of phenol and the 2-, 3-, and 4-methylphenols (o-, m-, and

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Table IX.A-18 Effect of Tobacco Expansion on Levels of Mainstream Smoke Phenols RJRT-Expanded Tobacco Study (3254) Tobacco Blend Composition

Mainstream Smoke Level

% RJRT-Expanded Blend

µg/cig

100 90 75 50 0

0 10 25 50 100

117 106 (9) c 95 (19) 72 (38) 45 (62)

% Flue-Cured

% RJRT-Expanded Flue-Cured 0 100

% Control Blend

b

100 0

126 70 (44) d

mg/g WTPM a 3.36 3.73 (-11) 3.36 (0) 2.76 (18) 2.16 (36)

3.09 2.99 (3)

NCI “Less Hazardous” Cigarette Study (1330, 2683) Mainstream Smoke Level, mg/g WTPMa Tobacco

Code No.

Phenol

o-Cresol

m- + p-Cresol

SEBII b SEBII SEBII SEBII SEBII

42 42 44 45 Avg

3.83 3.66 3.90 3.81 3.80

0.62 0.55 0.63 0.59 0.60

2.04 1.78 1.56 1.65 1.76

48 49 50

2.56 (33) c 2.93 (23) 3.47 (9)

0.36 (40) 0.40 (33) 0.49 (18)

1.10 (40) 1.37 (26) 1.61 (13)

RJRT-expanded SEBII PM-expanded SEBII NCSU-freeze dried SEBII

WTPM = wet total particulate matter SEBII = the Standard Experimental Blend used in the second phase of the NCI “Less Hazardous” Cigarette Study. c The number in parenthesis is the % decrease of the MSS yield of phenols in the MSS from the expanded or freeze-dried SEBII vs. that in the MSS from the control SEBII. a

b

p-cresols) in the MSS from RTS (paper process) cigarettes vs. the tobacco blend (SEBI) was recorded (1329). At RJRT R&D, Newell et al. (2765) reported the results of a detailed study of the effect of increasing the level of RTS (G7) on the composition of cigarette MSS. Decreased MSS yields of the PAHs, nicotine, and phenols plus increased yields in carbon monoxide, aldehydes, ketones, and low molecular weight acids were observed. In 1979, the U.S. Surgeon General (4005) reported the beneficial effects of inclusion of RTS on the MSS composition (B[a]P, phenols, specific tumorigenicity): Cigarette fillers low in wax layer components, either by use of tobacco stems, reconstituted tobacco sheet, or tobacco extracted with a hexane-ethanol mixture, delivered smoke significantly reduced in catechols … Although it has not been directly established that a selective reduction in catechol leads to a significant reduction of the tumorigenic potential of cigarette smoke, it is of interest that all those tars or whole smokes of cigarettes which are low in catechol also have a significant lower tumorigenic activity [Gori (1329, 1330, 1332)].

These comments on the relationship between RTS and the 1,2-benzenediol (catechol) yield in MSS are of interest

because examination of the MSS data from the four sets of experimental cigarettes [Gori (1329, 1330, 1332, 1333), NCI (2683)] reveal that no analysis for 1,2-benzenediol (catechol) was conducted on any of the cigarette samples in the study, that is, the 100 or so experimental cigarettes or the standard SEBI, SEBII, SEBIII, or SEBIV cigarettes and the Kentucky 1R1 reference cigarette. In the late 1950s and the 1960s, one of the methods studied to control the pyrosynthesis of PAHs from tobacco during the smoking process was the addition of various materials (inorganic or organic) to the tobacco in attempts to control its combustion and lower the per cigarette PAHs yields, particularly the B[a]P yield, in the tobacco smoke [Alvord and Cardon (56, 57), Lindsey et al. (2370), Rodgman (3246, 3254), Bentley and Burgan (286), Candeli et al. (589), Wynder and Hoffmann (4311, 4317, 4319, 4332), Cuzin et al. (885), deSouza and Scherbak (953), Pyriki et al. (3046), Hoffmann and Wynder (1797, 1798)]. The most effective additives in PAHs reduction were the nitrates. The following explanation of their effectiveness was offered. When heated, the nitrates generate nitric oxide (NO), an odd-electron compound, capable of “scavenging” free radicals thermally generated from tobacco components

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during the smoking process, thus interrupting the free radical reactions postulated as contributing to one of the mechanisms important in the generation of PAHs in tobacco smoke [see Badger and Spotswood (152), Badger (139a, 140), Badger et al. (141, 142, 147)]. However, in addition to lowering the levels of PAHs in tobacco smoke, addition of nitrates or the use of high-nitrate tobacco affected MSS yield and composition in other ways. In the 1950s and early 1960s, the reductions in the MSS yields of “tar,” nicotine, and PAHs in general and B[a]P in particular were viewed as desirable achievements. When concern was expressed about the supposed promoting action of the low molecular weight phenols, the reduction of their levels in MSS by nitrate addition to the tobacco was also viewed positively. These decreases were, however, accompanied by an increase in the level of NO in the smoke. Subsequently, two reported observations did much to dampen the enthusiasm for nitrate addition to the tobacco and/or the use of highnitrate tobaccos in the blend: • The identification of various volatile and tobaccospecific N-nitrosamines in tobacco and its smoke and the positive dependence of their levels in both tobacco and smoke on the nitrate level of the tobacco [Morie and Sloan (2635), Tso et al. (3985), Brunnemann et al. (499)]. • The identification of a series of nitrophenols, many of which are known to be highly toxic, in the MSS from cigarettes fabricated with nitrate-treated tobacco and/ or with high-nitrate tobaccos in the blend [Kallianos et al. (2016), Klus and Kuhn (2137)]. Table IX.A-19 summarizes some of the studies on the use of nitrate addition to tobacco and/or use of high-nitrate tobacco to reduce the yields of PAHs in cigarette MSS. Also noted in Table IX.A-19 are some of the other compositional changes observed in MSS yield and composition. In most instances, the yields of MSS PAHs in general and B[a]P were reduced although an occasional exception was observed, for example, in the NCI Smoking and Health Program on “less hazardous” cigarettes the MSS B[a]P yield increased with nitrate addition but the B[a]A yield decreased (1329). Benner et al. (274) reported that a comparison of the low molecular weight phenols in the MSS from high- and low-nitrate tobaccos showed little difference in the yields of phenol per milligram total particulate matter (TPM) but significant decreases in the yields of the methylphenols (the cresols) per milligram TPM. Benner et al. (276, 277) also reported that treatment of tobacco with an alternative combustion modifier (3:7 boric acid:sodium tetraborate decahydrate) increased the levels of low molecular weight phenols in cigarette MSS, an increase that was paralleled by the increase in low molecular weight phenols in the pyrolysates from cellulose or lignin treated with the same boric acid-tetraborate modifier. In the mid-1970s, Brunnemann et al. (497) described an improved method for the quantitation of 1,2-benzenediol (catechol) in tobacco smoke and a possible way to reduce its MSS level. The procedure they described involved extraction of

tobacco with a hexane-ethanol azeotrope which removed from the tobacco what Brunnemann et al. defined as “waxes.” They noted: Compared to the corresponding control cigarette, the dry TPM [from a cigarette filled with reconstituted tobacco from which the “wax” layer had been removed by hexane-ethanol azeotrope extraction] had been reduced by 44%, the nicotine by 47% and catechol by 85%. This demonstrates a strong, selective reduction of catechols in the smoke by the removal of the “wax” layer.

Additional impetus to study the level and source of 1,2benzenediol (catechol) in tobacco smoke was provided by Hecht et al. (1562), who asserted that 1,2-benzenediol (catechol) was an important tobacco smoke cocarcinogen. They also noted that the levels of 1,2-benzenediol (catechol) in cigarette MSS were reduced by prior extraction of the tobacco with a hexane-ethanol azeotrope or by inclusion of RTS in the tobacco blend. From the results of their study of cellulose vs. carboxymethylcellulose as a precursor of 1,2-benzenediol (catechol) in tobacco smoke, Carmella et al. (599, 601) reported that the carboxymethylation of tobacco cellulose significantly reduced the level of 1,2-benzenediol (catechol) in tobacco smoke. Wynder and Hoffmann asserted that cigarette MSS yield and composition were controllable in a beneficial way by increasing the number of cuts per inch in the tobacco blend filler. Results obtained in the NCI program on the “less hazardous” cigarette and reported in 1976 by Gori (1329) and 1980 by NCI (2683) were contradictory to the unpublished results obtained in 1963 by Hoffmann and Wynder and later reported by Wynder and Hoffmann [see p. 318 in (4319), pp. 529–531 in (4332), (4330)]. In the NCI study, important analytes such as B[a]P, B[a]A, phenol, and the three methylphenols (cresols) showed no consistent relationship between their MSS yields and width of cut of the cigarette tobacco filler. The mouse skin-painting bioassay also showed no consistency between % TBA and the CSCs generated from cigarettes with fillers of different cut widths. In their report of the results of an unpublished study by Hoffmann and Wynder of the effect of width of cut of the cigarette filler, Wynder and Hoffmann reported that increasing the number of cuts per inch (decreasing the cut width) decreased the per cigarette MSS yield of TPM and B[a]P. They did not report on the effect of cut width on phenols delivery. However, they did report that the specific tumorigenicity of the CSCs from cigarette fabricated with tobacco at 20, 30, and 50 cuts per inch decreased as the number of cuts per inch increased [see p. 318 in (4319), pp. 529–531 in (4332), (4330)]. Subsequently, Wynder and Hecht (4306d) tabulated the effect on chemical and biological properties of change in cut width as: “insignificant” for the change in per cigarette MSS yields of carbon monoxide, “tar,” nicotine, and B[a]P, as “insignificant” for the change in MSS ciliatoxicity, as “insignificant” for the change in specific tumorigenicity (mouse skin) of the CSC, and “unknown” for the changes in tumor promoting effect. Their table was used essentially unchanged by the Surgeon General in his 1979 report on smoking and health (4009).

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Table IX.A-19 Studies Involving Nitrate Addition to Tobacco Nitrate Identity

Change in CSC

Amount Added, %

B[a]P Level

Tumorigenicity

Comments

References

5.0 2.0 2.0

decrease decrease decrease

 Rodgman and Cook (3269) 

NaNO3

2.0 4.0 5.0 2.5 1.0 5.0

decrease decrease decrease decrease decrease decrease

  Bentley and Burgan (286)   

Cu (NO3)2.5 H2O Cu (NO3)2.5 H2O

5.0 5.0

decrease decrease

Mg (NO3)2.6H2O Al (NO3)3.9H2O KNO3 Cu (NO3)2

Cu (NO3)2.5 H2O

decrease decrease

Wynder and Hoffmann (4312) Wynder and Hoffmann (4317)

decrease

Pyriki et al. (3046)

KNO3

NaNO3

8.3

decrease

decrease

NaNO3

3.0 8.3 2.5

decrease decrease decrease

decrease decrease decrease

KNO3

0.1% vs. 1.66% nitrate tobacco

decrease

MSS 1,2-benzenediol (catechol) yield/cig inversely related to tobacco nitrate level, 4-nitro-1,2-benzenediol yield/cig related to tobacco nitrate level

Kallianos et al. (2016)

TPM/cig decreased, phenol/cig yield decreased, phenol/mg of CSC decreased, no N-nitrosamines detected in nitrate-enhanced tobacco cigarettes

Hoffmann and Wynder (4332)

  Hoffmann and Wynder (1798)  methylphenols (cresols) yields/mg TPM inversely related to tobacco nitrate level; little difference in phenol/mg TPM delivery

Benner et al. (274)

Klus and Kuhn (2137)

KNO3

1.3

ND

ND

yields of a series of nitrophenols identified in MSS from nitratetreated and high-nitrate tobacco cigarettes directly proportional to nitrate content of filler

KNO3

2.8

increase

decrease

increased nitrate gave Gori (1329) decreased phenol/mg TPM and methylphenols (cresols) levels/mg TPM, NO increased relative to TPM

2.3

decrease

decrease (Continued)

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Table IX.A-19 (Continued) Studies Involving Nitrate Addition to Tobacco Nitrate Identity

B[a]P level

Tumorigenicity

Comments

References

NO3 addition

decrease

decrease

nitrate addition and/or use of high-nitrate tobacco classified as “only of academic interest” because of undesirable N-nitrosamine-nitrate relationship.

Wynder and Hecht (4306d)

NO3 addition

decrease

decrease

Surgeon General reiterated Wynder-Hecht (4306d) comment.

USPHS (4005)

decrease

decrease

despite decreases in TPM, B[a]P, phenols, CSC tumorigenicity, use of low-nitrate tobacco or nitrate removal recommended because of undesirable N-nitrosamine-nitrate relationship.

Brunnemann and Hoffmann (480, 486)

decrease

decrease

MSS 1,2-benzenediol (catechol) level inversely related to nitrate content of filler; MSS volatile and tobacco-specific N-nitrosamine levels proportional to nitrate content of filler

Adams et al. (28)

NaNO3

Amount Added, %

Change in CSC

0.7 to 2.5

In the NCI Smoking and Health Program on “less hazardous” cigarettes [Gori (1329), NCI (2683)] the effects of cut width on cigarette smoke properties (chemical composition, biological properties) were not as pronounced as the effects reported in Wynder and Hoffmann [see p. 318 in (4319), pp. 529–531 in (4332), (4330)]. Examination of the summary of these studies in Table IX.A-20 reveals the lack of confirmation of the Hoffmann-Wynder results. In fact, the proposal that cut width would be a significant technology in the design of a “less hazardous” cigarette was similar to many of the proposals from the so-called cigarette design experts not associated with the tobacco industry. Of the numerous technologies proposed during the decade-long NCI study, only those eight technologies proposed by U.S. tobacco company and/or tobacco supplier R&D personnel were eventually classified as significant by the NCI (2683), Gori (1332, 1333), the U.S. Surgeon General (4005, 4009), and other anti-tobaccosmoking investigators such as Hoffmann and Hoffmann (1740).

The effectiveness of the various methods proposed to control the yield of the supposed promoting low molecular phenols may be summarized as: Tobacco extraction with wax-dissolving nonpolar organic solvents (hexane, pentane) to remove PAH precursors does indeed result in reduced levels of PAHs, including B[a]P, in cigarette MSS. However, the solution of what was considered by some as a possible PAH problem is accompanied by the creation of two alternative problems, both of which might be criticized from a scientific point of view. For example, extractive removal of the nonpolar organic solvent-soluble material results in an increase in the percentage of the organic solvent-insoluble biopolymers (the major phenols precursors cellulose, pectins, starch, and lignin) in the extracted tobacco residue. Smoking of the extracted residue in cigarette form yields higher levels of low molecular weight phenols in the MSS (3277, 3305). In addition, nitrates in the tobacco are not removed by solution in nonpolar organic solvents, so their percentages in the extracted tobacco residue increase.

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Table IX.A-20 Effect of Cut Width on Mainstream Smoke Properties PAHa, µg/g. Tobacco, cuts/in

Condensate, mg/cig

B[a]P

Phenol, mg/g

B[a]A

Phenol

2-Methylphenolb

3- and 4-Methylphenolb

% TBA

Hoffmann and Wynder [see p. 318 in (4319), pp. 529–531 in (4332), (4330)] 8 20 30 50 60

29.1 27.3 25.4 24.4 23.0

1.27 1.25 1.30 0.94 0.91

20

32.6

0.91

1.40

4.35

0.78

1.85

32

30.2

0.72

1.20

3.95

0.72

1.83

60

29.6

0.86

1.31

4.17

0.63

1.92

27 16 13

Gori (1329), NCI (2683)

a

b c d

46c 33d 44.6c 45.0d 39c 39d

PAH = polycyclic aromatic hydrocarbon, B[a]P = benzo[a]pyrene; B[a]A = benz[a]anthracene, % TBA = % tumor-bearing animals 2-Methylphenol, 3-methylphenol, 4-methylphenol = o-, m-, and p-cresol, respectively Painting dose = 50 mg of cigarette smoke condensate/day Painting dose = 25 mg of cigarette smoke condensate/day

Experimental results reported by Morie and Sloan (2635), Tso et al. (3985), and Brunnemann et al. (499) indicated that smoking of this increased-nitrate-level extracted residue in cigarette form would yield higher levels of N-nitrosamines in the MSS. Tobacco extraction with a hexane-ethanol azeotrope selectively reduced the levels of 1,2-benzenediols (catechols) in the cigarette MSS. Tobacco extraction with a polar organic solvent system (aqueous ethanol or aqueous methanol) removes chlorogenic acid, a known major precursor of 1,2-benzenediol (catechol), a phenol categorized as a cocarcinogen. Because nitrate addition to tobacco resulted in reduction of the cigarette MSS deliveries of “tar,” nicotine, PAHs including B[a]P, and the low molecular weight phenols, nitrate addition and/or use of high-nitrate tobacco was considered to be the way to introduce the most effective combustion modifier. However, while apparently solving several problems concerning MSS yield and composition, nitrate addition caused several alternate problems. Once the levels of N-nitrosamines and nitrogen oxides (NO) in tobacco smoke were shown to be positively correlated to the nitrate content of the tobacco filler, nitrate addition and the use of high-nitrate tobaccos were eventually viewed as undesirable technologies. In addition, higher nitrate tobacco fillers, whether a result of nitrate addition or inclusion of high-nitrate tobaccos, generated a series of nitrophenols, many of which are known to be highly toxic. From a comparison of the pyrogenesis of 1,2-benzenediol (catechol) from cellulose vs. carboxymethylcellulose, it was reported that the carboxymethylation of tobacco cellulose significantly reduced the level of 1,2-benzenediol (catechol) in tobacco smoke (599, 601).

Of the various technologies proposed to control the levels of phenols in cigarette MSS, selective filtration appears to be the most effective and most efficient. A significant portion (65% to 75%) of the low molecular weight monohydric phenols in cigarette MSS is removed from the smoke stream by a cellulose acetate filter tip plasticized with triacetin. As the cigarette ages, the plasticizer is slowly absorbed by the cellulose acetate fiber and the effectiveness of the selective filtration gradually decreases with time. The one drawback with selective filtration is that it does not occur with dihydric phenols such as 1,2-benzenediol (catechol) in the MSS, that is, 1,2-benzenediol and its homologs are not selectively removed from MSS by a plasticized filter tip. Many of the complex tobacco-only phenolic components have interesting structures in that they contain a cyclohexanecarboxylic acid moiety linked to one of the following: (1) a 4-hydroxyphenyl group, for example, p-coumaroylquinic acid, (2) a 3,4-dihydroxyphenyl group, for example, chlorogenic acid, or (3)) a 3-methoxy-4-hydroxyphenyl group, for example, 3-O-feruloylquinic acid. In each case, one can theorize that during the tobacco smoking process the complex tobacco phenol could sequentially yield a substituted 2-propenoic acid, a substituted benzaldehyde, a substituted benzoic acid, and a simple phenol. Table IX.A-21 summarizes the possible sequence of the pyrogenesis of such components. Each of the compounds listed as tobacco smoke components in Table IX.A-21 has been identified in cigarette MSS. A similar situation exists with a series of components in which a variously substituted 4H-1-benzopyranone is linked to a 4-hydroxyphenyl group, such as, kaempferol, or a 3,4-dihydroxyphenyl group, for example, quercitin, quercitrin, and rutin.

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The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-21 Theoretical Relationship between Phenols in Tobacco and Several Phenols in Tobacco Smoke Phenols

In Table IX.A-22, the various phenolic components of tobacco and tobacco smoke are listed, with appropriate references to the identifications for each. Many of the references cited contain additional references pertinent to the phenolic component in question. The many references cited in Table IX.A-22 include a variety of topics pertinent to the particular phenol. They cover the following topics:

1. The isolation and/or identification of the phenol from tobacco and/or smoke 2. Methods to quantitate the phenolic component in tobacco and/or smoke



3. Determination of the precursors in tobacco of the phenolic compound in smoke 4. Cigarette design technologies to decrease the per cigarette MSS yield of the phenolic compound 5. The biological properties of the phenolic compound 6. Discussions by personnel from governmental agencies, medical institutions, etc., on the biological problems pertinent to a given phenolic compound

While 558 phenolic components have been completely or partially identified in tobacco and tobacco smoke, 244

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515

Table IX.A-22 Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Phenols and Quinones

517

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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518

The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Phenols and Quinones

519

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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520

The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Phenols and Quinones

521

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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522

The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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523

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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524

The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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525

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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526

The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Phenols and Quinones

527

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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528

The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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529

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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530

The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Phenols and Quinones

531

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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533

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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535

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Phenols and Quinones

537

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Phenols and Quinones

539

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Phenols and Quinones

541

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Phenols and Quinones

543

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Phenols and Quinones

545

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued) Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Phenols and Quinones

were identified in tobacco only, 444 in tobacco smoke only, and 130 were identified in both tobacco and smoke. For the tobacco smoke components partially identified, the nature and/or position of an alkyl substitute was not defined by the investigator.

IX.B  Quinones Even in the mid-1950s when knowledge of the composition of tobacco smoke was extremely limited and only a few phenols were known to be present in tobacco smoke, it was suggested that several of the phenols might be converted to the corresponding quinone during the smoking process. This suggestion, coupled with the mouse skin-painting bioassay results reported by Takizawa (3865a) that several simple quinones such as 2,5-cyclohexadiene-1,4-dione (p-benzoquinone), 1,2-naphthalenedione (1,2-naphthoquinone), and 1,4-naphthalenedione (1,4-naphthoquinone) were tumorigenic to mouse skin, raised serious questions about the desirability of adding phenols to the tobacco blend to enhance the odor and flavor of its smoke. Despite the many studies in which benzene was used as the solvent for testing of the tumorigenicity of PAHs, benzene seldom induced tumors in

the skin-painted solvent-control group of laboratory animals [Hartwell (1543, 1544), Shubik and Hartwell (3664, 3665), Thompson et al. (3908)]. Similarly, naphthalene was found to be nontumorigenic in skin-painting studies. The mouse skin-painting bioassay results with 2,5-cyclohexadiene-1,4-dione (p-benzoquinone) were subsequently confirmed by Tiedemann (3916a). Neither of the higher molecular weight tricyclic quinones 9,10-anthracenedione (9,10-anthraquinone) (3865a) or 9,10-phenanthrenedione (9, 10-phenanthrenequinone) (3865a) was reported to be tumorigenic to mouse skin. In the early days of the studies on the specific tumorigenicity of various classes of compounds to mouse skin, investigators were intrigued by the activities exhibited by aromatic hydrocarbons, their dihydric phenols, and the quinones corresponding to the dihydric phenols. The results of mouse skin-painting bioassays with various aromatic hydrocarbons ranging in complexity from monocyclic to hexacyclic, their dihydric phenols, and the corresponding quinones are summarized in Table IX.B-1. From the studies on the chemical relationship between aromatic hydrocarbons and their quinones, the theory of the oxidation-reduction potential of quinones was proposed.

Table IX.B-1 Comparison of the Tumorigenicities of Aromatic Hydrocarbons, their Diols (Phenols), and their Diones (Quinones) Hydrocarbon Benzene

Diol

Dione

–

1,4-benzenediol (hydroquinone)

–

2,5-cyclohexadiene-1,4-dione (p-benzoquinone)

+

–

1,2-benzenediol (catechol)

–

3,5-cyclohexadiene-1,2-dione (o-benzoquinone)

?

(1,2-naphthoquinone)

–

1,2-naphthalenediol 1,2-naphthalenedione

+

1,4-naphthalenediol

–

1,4-naphthalenedione (1,4-naphthoquinone)

+

9,10-anthracenedione (9,10-anthraquinone)

–

(9,10-phenanthraquinone) 9,10-phenanthrenedione

– –

Naphthalene

Anthracene

–

9,10-anthracenediol

–

Phenanthrene

–

9,10-phenanthrenediol

–

5,6-chrysenediol

–

5,6-chrysenedione (5,6-chrysenequinone) 6,12-chrysenedione 7,12-benz[a]anthracenedione

Chrysene

Benz[a]anthracene

±

6,12-chrysenediol 7,12-benz[a]anthracenediol

– –

Dibenz[a,h]anthracene

±

7,14-dibenz[a,h]anthracenediol

–

Benzo[a]pyrene Dibenzo[b,def]chrysene

–

(7,12-benz[a]anthraquinone) 7,14-dibenz[a,h]anthracenedione (7,14-dibenz[a,h]anthraquinone)

–

+

benzo[a]pyroquinone

–

+

7,14-dibenzo[b,def]chrysenedione

–

– = negative response in mouse skin-painting bioassay + = positive response in mouse skin-painting bioassay ± = equivocal response in mouse skin-painting bioassay

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A prime proponent of this theory was Fieser (1180b), who reported the reduction potentials of the following quinones: • Several anthracenediones other than 9,10-anthracenedione [Conant and Fieser (790b), Fieser (1180a-1)]. • 9,10-Phenanthrenedione (9,10-phenanthraquinone) [Fieser (1180a-2)]. • 2,5-Cyclohexadiene-1,4-dione ( p-benzoquinone) [Fieser (1180a-3)]. • Several naphthalenediones other than the 1,2- and 1,4-naphthalenediones [Fieser (1180a-4)]. • 7,12-Benz[a]anthracenedione (7,12-benz[a]anthraquinone), 7,14-dibenz[a,h]anthracenedione (7,14benz[a,h]anthraquinone), 5,6-chrysenedione (5,6-chrysenequinone), 6,12-chrysenedione (6,12chrysenequinone) [Fieser and Dietz (1180a-5)]. • 3,5-Cyclohexadiene-1,2-dione (o-benzoquinone) and 1,2-naphthalenedione (1,2-naphthoquinone [Fieser and Peters (1180a-6)]. • 9,10-Anthracenedione (9,10-anthraquinone) [Fieser and Peters (1180a-7)] • 1,4-Naphthalenedione (1,4-naphthoquinone) [Fieser and Fieser (1180a-8)]. After the first demonstrations by Kennaway and Hieger (2078) of the tumorigenicity to mouse skin of DB[a,h]A, a PAH synthesized by Fieser and Dietz (1184), and of B[a]P by Barry et al. (194), the coal tar component isolated from coal tar and subsequently synthesized by Cook et al. (796a, 797), the tumorigenicity of a great number of PAHs and their derivatives was studied. Soon observed was the pronounced contrast between the gradation in specific tumorigenicities in the mouse skinpainting bioassay from the nontumorigenicity of the monoand bicyclic aromatic hydrocarbons benzene and naphthalene, respectively, to the potent tumorigenicities of the pentacyclic aromatic hydrocarbons DB[a,h]A and B[a]P vs. the tumorigenicities of the quinones 2,5-cyclohexadien-1,4-dione (p-benzoquinone), 1,2-naphthalenedione (1,2-naphthoquinone), and 1,4-naphthalenedione (1,4-naphthoquinone) and the nontumorigenicities of dibenzanthraquinone and benzopyroquinone. Neither the tricyclic aromatic hydrocarbons anthracene and phenanthrene nor their corresponding quinones have elicited tumors in the mouse skin-painting bioassay. The tumorigenicities of the tetracyclic hydrocarbons benz[a]anthracene and chrysene have been classified as extremely weak or equivocal. None of their quinones has shown tumorigenicity in the mouse skin-painting bioassay (see Table IX.B-1). Initially it was found that the higher the tumorigenic potency of the quinones, particularly the benzoquinones and the naphthoquinones, the higher was the reduction potential of the quinone. In essence, the oxidation-reduction potential theory was eventually used in an attempt to relate the oxidation-reduction potential of the hydrocarbon-quinone system to the specific tumorigenicity observed in the mouse skin-painting bioassays for PAHs and their quinones.

Although none of the diols (phenols) listed in Table IX.B-1 was found to be tumorigenic, in subsequent research dealing with the metabolism of tumorigenic PAHs, it was found that some of the dihydrodiols and dihydrodiol epoxides were tumorigenic to mouse skin [see review by Dipple et al. (983)]. However, it is obvious from examination of the structures of the dihydrodiols and dihydrodiol epoxides that none of these metabolites is a phenol. As the laboratory data and understanding of chemical carcinogenesis increased dramatically pre- and post-World War II, exceptions to the theory of oxidation-reduction potential resulted in its being supplanted by other more meaningful theories, for example, the relationship between electronic configuration, the activity of the so-called K region, and the inactivity of the so-called L region in aromatic compounds, particularly PAHs, and their tumorigenicity [see reviews by Coulson (829), Pullman and Pullman (3003)]. The interest in the theory of the electronic configuration-tumorigenesis relationship of PAHs was such that the 1953 review by Coulson was selected as the introductory chapter in Volume 1 of the newly instituted publication, Advances in Cancer Research. It is interesting to note that even in the early 1950s, the idea of the involvement of a hydroxylated PAH metabolite in tumorigenesis was already being discussed. For example, Pullman and Pullman (3003) wrote: It is nevertheless generally admitted that [dihydro]diols are probably intermediates in the metabolism of aromatic hydrocarbons

Although their speculation as to the precise nature of its involvement was somewhat in error, the Pullmans (3003) did propose that a dihydroepoxide might also be involved in the metabolism of PAHs, the metabolite-cellular component interaction, and the tumorigenicity attributed to some of the PAHs. The oxidation-reduction potential of the aromatic hydrocarbon-quinone system and its possible involvement in cigarette smoke was revisited some years later. Schmeltz et al. (3510) reported that cigarette smoke condensate (CSC) possessed reducing properties sufficient to reduce 2,5-cyclohexadiene-1,4dione (1,4-benzoquinone; p-benzoquinone) to 1,4-benzenediol (hydroquinone). This CSC-induced reduction apparently did not occur with 9,10-anthracenedione (9,10-anthraquinone). Compared to the number of polycyclic aromatic hydrocarbons (PAHs) and phenols identified in tobacco smoke, the number if quinones identified is low despite the fact that many of the phenols after their pyrogenesis during the smoking process could realistically yield quinones. Table IX.B-2 lists the forty-eight quinones identified to date in tobacco and tobacco smoke. Of the forty-eight, thirty-three were identified in smoke, twenty-one in tobacco, and only six in both. In his 1954 review of tobacco smoke components identified to that date, Kosak (2170) listed no quinone. In view of tobacco smoke composition findings after the mid-1950s, the suggestion in the late 1950s by Rodgman that phenols were inappropriate additives for cigarette smoke flavor

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Phenols and Quinones

enhancement might have been an example of excessive caution. His suggestion was based on two factors, the promoting effect of phenols reported in 1955, 1956, and 1959 by Boutwell and his colleagues (414) plus the possible conversion during the smoking process of substituted phenols to corresponding quinones, several of which had been reported to be tumorigenic by Takizawa (3865a) and Tiedemann (3916a). Obviously, the latter situation occurred infrequently. The great discrepancy between the large number of phenols and the small number

of quinones identified in tobacco smoke suggests that the phenol-quinone conversion does not occur in many instances or, if it does occur, the conversion results in the generation of extremely low levels of the quinone. As noted elsewhere, it has been estimated from examination of the many peaks and shoulders in the detailed glass capillary gas chromatograms from tobacco smoke and/or its fractions that the number of tobacco smoke components exceeds the number of identified tobacco smoke components by factors ranging from 10 to 25,

Table IX.B-2 Quinones Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table IX.B-2 (continued) Quinones Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Phenols and Quinones

551

Table IX.B-2 (continued) Quinones Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table IX.B-3 Chronology of Identification of Quinones in Tobacco and/or Smoke Year

Event

1924–1934

Fieser and his colleagues investigated the reduction of quinones and generated the theory of the oxidation-reduction potential of quinones. The reduction of the following quinones was studied: Several anthracenediones other than 9,10-anthracenedione [Conant and Fieser (790b), Fieser (1180a)], 9,10-phenanthrenedione (9,10-phenanthraquinone) (1180a), 2,5-cyclohexadiene-1,4-dione (p-benzoquinone) [Fieser (1180a)], several naphthalenediones other than the 1,2- and 1,4-naphthalenediones [Fieser (1180a)], 3,5-cyclohexadiene-1,2-dione (o-benzoquinone) and 1,2naphthalenedione (1,2-naphthoquinone) [Fieser and Peters (1180a)], 9,10-anthracenedione (9,10-anthraquinone) [Fieser and Peters (1180a)], 1,4-naphthalenedione (1,4-naphthoquinone) [Fieser and Fieser (1180a)] 7,12-benz[a]anthracenedione (7,12-benz[a]anthraquinone), 7,14-dibenz[a,h]anthracenedione (7,14-benz[a,h]anthraquinone), 5,6-chrysenedione (5,6-chrysene-quinone), 6,12-chrysenedione (6,12-chrysenequinone) [Fieser and Dietz (1180a)]. Later, the theory of the oxidation-reduction potential of quinones was advanced to explain the differences in tumorigenicity of the various quinones and their aromatic hydrocarbons sources.

1940–1941

Takizawa (3865a) reported that several simple quinones [2,5-cyclohexadiene-1,4-dione (p-benzoquinone), 1,2naphthalenedione (1,2-naphthoquinone), 1,4-naphthalenedione (1,4-naphthoquinone)] were tumorigenic in mouse skin-painting experiments.

1942

Fieser (1180b) reviewed the theory of the oxidation-reduction potential of quinones. Because some nontumorigenic aromatic hydrocarbons (benzene, naphthalene) yielded tumorigenic quinones, some nontumorigenic aromatic hydrocarbons yielded nontumorigenic quinones, and some tumorigenic aromatic hydrocarbons (dibenz[a,h] anthracene) yielded nontumorigenic quinones, attempts were made to correlate the relationship between aromatic hydrocarbons, their quinones, the reduction potential of quinones, and the tumorigenicities (mouse skin) of the aromatic hydrocarbons vs. the tumorigenicities of their quinones.

1953

Tiedemann (3916a) confirmed the finding of Takizawa on the tumorigenicity of 2,5-cyclohexadiene-1,4-dione (p-benzoquinone) to mouse skin.

1953–1955

The theory of oxidation-reduction potential of quinones was supplanted by other more meaningful theories, e.g., the relationship between electronic configuration, the activity of the so-called K region, and the inactivity of the so-called L region in aromatic compounds, particularly PAHs, and their tumorigenicity [see reviews by Coulson (829) and Pullman and Pullman (3003)].

1954

Kosak (2170) in his compilation of tobacco smoke components reported in the literature did not list a quinone.

1957

Bonnet and Neukomm (396) suspected the presence of 2,5-cyclohexadiene-1,4-dione (p-benzoquinone) in cigarette mainstream smoke because of the identification of 1,4-benzenediol (hydroquinone) when the smoke was collected under reducing conditions. Under similar reducing conditions, they were unable to identify 1,4-napthalenediol, concluding that 1,4-napthalenedione (1,4-naphthoquinone) was not present in the smoke.

1959

Bentley and Berry (282) in their compilation of identified tobacco smoke components listed the report of 2,5cyclohexadiene-1,4-dione (p-benzoquinone) by Bonnet and Neukomm (396).

1959

In their review of tobacco and tobacco smoke composition, Johnstone and Plimmer (1971) listed no quinone in tobacco or tobacco smoke.

1961

Onishi et al. (2860) reported the presence of 9,10-anthracenedione (9,10-anthraquinone) in tobacco smoke.

1965

Kröller (2195) reported the presence of 9,10-anthracenedione (9,10-anthraquinone) and 9,10-phenanthrenedione (9,10-phenanthraquinone) in tobacco smoke.

1965

To estimate the 1,4-benzenediol (hydroquinone) in tobacco smoke, Testa et al. (3891) used air oxidation to convert the 1,4-benzenediol (hydroquinone) to 2,5-cyclohexadiene-1,4-dione (p-benzoquinone) which was subsequently derivatized and estimated. No effort was made to determine whether any 2,5-cyclohexadiene-1,4-dione (p-benzoquinone) was already present in the smoke prior to the air oxidation.

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Table IX.B-3 (continued) Chronology of Identification of Quinones in Tobacco and/or Smoke Year

Event

1968

In his review of tobacco and tobacco smoke composition, Stedman (3797) listed only two quinones, 9,10anthracenedione (9,10-anthraquinone) in tobacco and 2,3,6-trimethyl-1,3-naphthalenedione (2,3,6-trimethyl-1,4naphthoquinone) in tobacco smoke. He discussed the Bonnet and Neukomm (396) report. Because of the uncertainty of the Bonnet and Neukomm data and additional data from Testa et al. (3891), Stedman did not include 2,5cyclohexadiene-1,4-dione (p-benzoquinone) as a tobacco smoke component. He also did not include the reports of the presence of 9,10-anthracenedione (9,10-anthraquinone) [Onishi et al. (2960), Kröller (2195)] or 9,10phenanthrenedione (9,10-phenanthraquinone) (2195) in tobacco smoke

1968–1969

Bell et al. (246, 247) reported the presence of several alkylated 9,10-anthracenediones in tobacco smoke.

1969–1978

RJRT R&D personnel identified numerous previously unidentified alkylated 2,5-cyclohexadiene-1,4-diones and 9,10-anthracenediones in tobacco smoke [Green et al. (1360, 1378), Schumacher et al. (3553), Heckman (1586), Newell et al. (2769)].

1976–1977

Schmeltz et al. (3510) identified several previously unidentified alkylated 2,5-cyclohexadiene-1,4-diones and 9,10-anthracenediones in tobacco smoke.

1978–1980

Snook et al. (3747, 3748) identified a series of alkyl-, dialkyl-, trialkyl-, and tetraalkyl-1,4-naphthalenediones.in tobacco smoke.

for example, see Wakeham (4103). It is possible that quinones contribute to some of the extremely minor chromatographic peaks representing components as yet unidentified. Table IX.B-3 lists the chronology of some of the major events pertinent to the identification of quinones in tobacco smoke. It is obvious that the number of significant events

for these quinones is substantially less than those cataloged for the PAHs, the aza-arenes, the phenols, and the N-nitrosamines. More than likely, the difference is a direct reflection of the concern expressed relative to the tumorigenicity in laboratory animals of the various classes of compounds.

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10

The Ethers

Assessment of the chronology of the number of ethers identified in tobacco and tobacco smoke provides another excellent example of the effect of the advancements in analytical technology on our ability to identify components in a complex mixture. In his 1954 review of the components identified to that date in tobacco smoke, Kosak (2170) lists only two ethers, 2-furancarboxaldehyde (furfural) and 1,6-anhydro-β-Dglucopyranose (levoglucosan). Johnstone and Plimmer (1971) did not list ethers as a specific class of components in tobacco or tobacco smoke but did mention the identification of several under different headings in their 1959 review, for example, furan, 2-methylfuran, 2-furancarboxaldehyde (furfural) and two of its derivatives, 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8, 12-trimethyltridecyl)-2H-1-benzopyran-6-ol (α-tocopherol) and 3,4-dihydro-2,7,8-trimethyl-2-(4,8,12,16,20,24,28,32-octamethyl-3,7,11,15,19,23,27,31-tritriacontaoctaenyl)-2H-1-benzopyran-6-ol (solanachromene), the monosaccharides glucose and fructose, the disaccharide sucrose, the trisaccharides raffinose and planteose, and the tetrasaccharide stachyose. Overall, fewer than thirty ethers are listed by Johnstone and Plimmer (1971). From 1959 to date the number of ethers identified in tobacco and tobacco smoke has increased over 30-fold to 992, 506 of which have been identified in tobacco smoke, 659 in tobacco, and 173 in both tobacco and tobacco smoke. In his 1968 review, Stedman (3797) tabulated the presence of five cyclic ethers in tobacco smoke, that is, furan, methylfuran, 2,5-dimethylfuran, tetrahydrofuran, and tetrahydropyran. Currently, the identified ethers with a furan nucleus exceed 275, those with a pyran nucleus exceed 225. The methoxy and ethoxy ethers number over 260, phenoxy ethers number 20.

One of the types of ethers that received considerable attention were the ethers derived from the cyclotetradecanols (see Figure X-1). Because of their unusual structure, none of them was counted in the furan or pyran nucleus group. Over twenty-five of these ethers have been identified in tobacco and tobacco smoke (9, 12, 3351, 3352, 3360, 3361, 4089–4091). As noted by Rodgman (3266), many components, including a number of ethers, used by the tobacco industry in its flavor formulations [see listing by Doull et al. (1053)] are known components of additive-free tobacco and/or its smoke. Thus, such additives are not strangers to tobacco and/or its smoke but their addition increases the consumer acceptable flavor. Table X-1 lists some of the tobacco and/or tobacco smoke ether components that have been or are used in flavor formulations. In Table X-2 are listed the various ethers identified to date in tobacco, tobacco smoke, and tobacco substitute smoke. Of the 992 ethers identified to date, 506 have been reported in smoke, 659 in tobacco, and 173 in both.

Overall Summary of Oxygen-Containing Components of Tobacco and/or Smoke: Chapters 2 through 10 Table X-3 summarizes the distribution in our catalogs in Chapters 2 through 10 of the O-containing components identified in tobacco and/or tobacco smoke. As we have noted in the introductions to each of the nine chapters, the numbers for the various classes of O-containing components have escalated tremendously since the last published review by Stedman (3797) in 1968 on tobacco and tobacco smoke components identified to that date.

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The Chemical Components of Tobacco and Tobacco Smoke

CH3

H 3C H 3C

10 11

9

8 1

6

H3C OH 5

7 2 3

4

CH3 CH3

O

13

14 1 2

CH3

O 1,5,11-Trimethyl-8-(1methylethyl)-15oxabicyclo[10.2.1]pentadeca2,6,10-trien-5-ol,

CH3

9 12 11 10 3

4

5

CH3

6

8 7

CH3

H3C

CH3

H3C

10 11

OH HO

12

8

5

7 2

1

OH

3

4

CH3

CH3

O

8-Hydroxy-4,8,14-trimethyl-11-(1methylethyl)-15oxabicyclo[12.1.0]pentadeca-4,9dien-6-one

9 O

6

1,5,11-Trimethyl-8-(1methylethyl)-15oxabicyclo[9.3.1]pentadeca-2,6diene-5,12-diol,

Figure X-1  Cembranoid ethers identified in tobacco and/or tobacco smoke.

Table X-1 Tobacco and/or Smoke Ethers Used in Flavor Formulations Identified In CAS No.

Chemical Abstracts Nomenclature

As Listed by Doull et al. (1053)

120-14-9 121-32-4 10031-82-0 121-33-5 123-11-5 151-10-0 150-78-7 104-46-1 1076-56-8 105-13-5 104-21-2 104-93-8 104-45-0 623-15-4 100-06-1 1193-79-9 611-13-2 93-18-5 470-82-6 91-10-1 7786-61-0 123-07-9 90-05-1 93-51-6 122-84-9

Benzaldehyde, 3,4-dimethoxy-; Benzaldehyde, 3-ethoxy-4-hydroxyBenzaldehyde, 4-ethoxyBenzaldehyde, 4-hydroxy-3-methoxyBenzaldehyde, 4-methoxy Benzene, 1,3-dimethoxyBenzene, 1,4-dimethoxyBenzene, 1-methoxy-4-(1-propenyl)Benzene, 3-methoxy-1-methyl-4-(1-methylethyl)Benzenemethanol, 4-methoxyBenzenemethanol, 4-methoxy-, acetate Benzene, 1-methoxy-4-methylBenzene, 1-methoxy-4-propyl3-Buten-2-one, 4-(2-furanyl)Ethanone, 1-(4-methoxyphenyl)Ethanone, 1-(2-furanyl 5-methyl)2-Furancarboxylic acid, methyl ester Naphthalene, 2-ethoxy2-Oxabicyclo[2.2.2]octane, 1,3,3-trimethylPhenol, 2,6-dimethoxyPhenol, 4-ethenyl-2-methoxyPhenol, 4-ethylPhenol, 2-methoxyPhenol, 2-methoxy-4-methyl2-Propanone, 1-(4-methoxyphenyl)-

veratraldehyde ethylvanillin p-ethoxybenzaldehyde vanillin p-methoxybenzaldehyde m-dimethoxybenzene p-dimethoxybenzene anethole 4-isopropyl-3-methoxy-1-methylbenzene anisyl alcohol anisyl acetate p-methylanisole dihydroanethole 4-(2-furyl)-3-buten-2-one acetanisole 2-acetyl-5-methylfuran methyl 2-furoate β-naphthyl ethyl ether eucalyptol 2,6-dimethoxyphenol 2-methoxy-4-vinylphenol p-ethylphenol guaiacol 2-methoxy-4-methylphenol 1-(p-methoxyphenyl)-2-propanone

a b

Smoke

Tobacco

Ia + Hb + + I

I + H + + I

+ ‑ ‑ + + H + + + + ‑ + + + + + + I

+ + + + ‑ ‑ + + + + + + + + + + + ‑

I = compound is an isomer of an identified component H = compound is a homolog of an identified component

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11/13/08 5:25:00 PM

557

The Ethers

Table X-2 Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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11/13/08 5:25:01 PM

558

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C010.indd 558

11/13/08 5:25:02 PM

The Ethers

559

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C010.indd 559

11/13/08 5:25:03 PM

560

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:25:05 PM

The Ethers

561

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:25:07 PM

562

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C010.indd 562

11/13/08 5:25:08 PM

The Ethers

563

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:25:16 PM

564

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:25:18 PM

The Ethers

565

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:25:19 PM

566

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:25:23 PM

The Ethers

567

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:25:24 PM

568

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:25:27 PM

The Ethers

569

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:25:28 PM

570

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:25:32 PM

The Ethers

571

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:25:33 PM

572

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:25:37 PM

The Ethers

573

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:25:38 PM

574

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:25:41 PM

The Ethers

575

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:25:42 PM

576

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:25:46 PM

The Ethers

577

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:25:47 PM

578

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C010.indd 578

11/13/08 5:25:50 PM

The Ethers

579

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:25:52 PM

580

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:25:55 PM

The Ethers

581

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:25:56 PM

582

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C010.indd 582

11/13/08 5:26:00 PM

The Ethers

583

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C010.indd 583

11/13/08 5:26:01 PM

584

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C010.indd 584

11/13/08 5:26:04 PM

The Ethers

585

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C010.indd 585

11/13/08 5:26:06 PM

586

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C010.indd 586

11/13/08 5:26:09 PM

The Ethers

587

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:26:10 PM

588

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C010.indd 588

11/13/08 5:26:14 PM

The Ethers

589

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:26:15 PM

590

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:26:18 PM

The Ethers

591

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:26:19 PM

592

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:26:22 PM

The Ethers

593

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:26:24 PM

594

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:26:27 PM

The Ethers

595

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:26:28 PM

596

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:26:32 PM

The Ethers

597

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:26:33 PM

598

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:26:36 PM

The Ethers

599

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:26:37 PM

600

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:26:41 PM

The Ethers

601

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:26:42 PM

602

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:26:46 PM

The Ethers

603

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:26:53 PM

604

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:26:55 PM

The Ethers

605

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:26:56 PM

606

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:27:00 PM

The Ethers

607

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:27:01 PM

608

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:27:04 PM

The Ethers

609

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:27:05 PM

610

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:27:09 PM

The Ethers

611

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:27:10 PM

612

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:27:13 PM

The Ethers

613

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:27:14 PM

614

The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued) Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

Table X-3 Distribution of Identified Oxygen-Containing Components between Tobacco and Tobacco Smoke Component Alcohols Phytosterols and derivatives Aldehydes Ketones Carboxylic acids Amino acids Esters Lactones Anhydrides Carbohydrates Phenols Quinones Ethers Totals a

Table Table II.A-5 Table II.B-2 Table III-12 Table III-13 Table IV.A-3 Table IV.B-7 Table V-3 Table VI-2 Table VII-1 Table VIII-3 Table IX.A-22 Table IX.B-2 Table X-2

Totala

Smoke

Tobacco

Smoke and Tobacco

1462 111 263 1090 745 103 1030 304 20 279 558 48 992

531 44 143 656 354 30 617 162 13 35 444 33 506

1152 102 199 647 614 102 924 201 13 271 244 21 659

221 35 79 213 223 29 511 59 6 27 130 6 173

7005

3568

5149

1712

 olyfunctional O-containing compounds are counted in each functional group, e.g., propanoic acid, 2-hydroxy- (lactic P acid) appears in the alcohol catalog and the acid catalog; benzoic acid, 4-hydroxy-3-methoxy- (vanillic acid) appears in the acid catalog, the phenol catalog, and the ether catalog.

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11

Nitriles

The nitriles in tobacco and tobacco smoke provide another excellent example of the escalation of the number of identified components. From the listing in 1954 by Kosak (2170) who recorded only the simplest nitrile, that is, hydrogen cyanide (HCN), in tobacco smoke to those cataloged in Table XI-2 which includes the simplest “nitrile,” hydrocyanic acid (HCN) plus 140 nitriles identified to date in tobacco and/or tobacco smoke. HCN was first identified in tobacco smoke in 1828 by Vogler (4062). Examination of Table XI-2 indicates the listing of seven partially identified nitrile isomers plus thirteen cyano group-containing pesticides used in tobacco agronomy. In the latter case, many were identified in tobacco only but several identified in tobacco were also found to transfer intact to smoke, for example, Cypermethrin® (52315-07-8). In their 1959 review of tobacco and tobacco smoke components, Johnstone and Plimmer (1971) listed the following four components containing a –C≡N group: hydrogen cyanide, cyanogen, thiocyanic acid, and thiocyanogen. No alkyl nitriles were listed. With the advent of gas chromatography, Grob used his gas chromatographic knowledge and skill to identify a series of nitriles in tobacco smoke in 1962 (1413) and 1965 (1416, 1417). His 1965 findings were accompanied by similar findings reported in 1965 by Newsome et al. (2782). Many of the nitriles identified in their studies were discussed by Wynder and Hoffmann in their 1967 book [see pp. 450–451 in (4332)]. They also discussed the reports by Campbell et al. (582) and McKee et al. (2519b) on the indication that acetonitrile in the body fluids was indicative of exposure to tobacco smoke because no other respiratory exposure was known. Table XI-1 lists some of the nitriles identified in the early 1960s. In his 1968 review on tobacco and tobacco smoke composition, Stedman (3797) listed fifteen nitriles, including HCN, as chemical components of tobacco smoke. Many of the nitriles listed were those identified by Grob (1412, 1413, 1416, 1416a, 1419) in his gas chromatographic studies of tobacco smoke. Stedman also listed 2-pyridinecarbonitrile and 3-pyridinecarbonitrile (nicotinonitrile) as pyrolysis products of various alkaloids. In addition to HCN, cyanogen, thiocyanic acid, and thiocyanogen, Schmeltz and Hoffmann, in their 1977 review of N-containing components of tobacco and tobacco smoke, listed thirty-one nitriles [see Table IX in (3491)]. Ishiguro and Sugawara, in their 1980 catalog (1884) of the chemical

components of tobacco smoke, listed thirty nitriles in addition to HCN, cyanogen, thiocyanogen, and thiocyanic acid. In its 1986 monograph on tobacco smoking, the International Agency for Research on Cancer (IARC) wrote very little about nitriles in tobacco smoke. IARC categorized HCN as one of the most toxic agents in the vapor phase of tobacco smoke and noted its presence in smoke was dependent on the level of nitrate, proteins, and amino acids in tobacco [see p. 96 in (1870)]. IARC also listed cyanogen as a tobacco smoke component. In its summary of its evaluation for carcinogenicity of chemical components identified in tobacco smoke, IARC did classify 2-propenenitrile (acrylonitrile) with sufficient evidence for carcinogenicity in animals but limited evidence in humans [see p. 392 in (1870)]. The per cigarette MSS yield of 2-propenenitrile (acrylonitrile) was listed at 3.2 to 15 μg, based on data provided by Wynder and Hoffmann from their 1982 publication (4348a). In a publication issued shortly after the IARC 1986 monograph on tobacco smoking, Hoffmann and Wynder estimated the number of tobacco smoke components to be approximately 3900, of which the number of nitriles was listed at 105 [see Table 1 in (1808)]. They listed HCN as a major toxic agent in nonfiltered cigarette smoke [see Table  2 in (1808)] and 2-propenenitrile (acrylonitrile) as a biologically active agent in MSS [see Table 13 in (1808)]. It is interesting to note that despite the considerable contribution of Wynder and Hoffmann to the subject of smoke components and their biological properties in the IARC 1986 monograph on tobacco smoking that only HCN, cyanogen, and 2-propenenitrile (acrylonitrile) of the 105 nitriles noted by Hoffmann and Wynder (1808) appeared in the IARC monograph (1870). In many of the publications issued between 1990 and 2001 in which various tumorigens in tobacco smoke, particularly cigarette smoke, were listed, 2-propenenitrile (acrylonitrile) was included [Hoffmann and co-authors (1727, 1740, 1741, 1743, 1744, 1783), Fowles and Bates (1217), OSHA (2825)]. In 2003, these lists were discussed in detail by Rodgman (3265). HCN and cyanogen, while not listed as tumorigens, were listed in many instances as biologically active toxicants. In many cases, acetonitrile was listed as a vapor-phase component of tobacco smoke. For example, in their 1997 and 2001 articles, Hoffmann and Hoffmann (1740, 1743) and Hoffmann et al. (1744) listed HCN, acetonitrile, 2-propenenitrile (acrylonitrile), and ten unnamed nitriles as

615

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616

The Chemical Components of Tobacco and Tobacco Smoke

Table XI-1 Nitriles Identified and/or Discussed in Tobacco Smoke by the Mid-1960s CAS No.

Nitrile

75-05-8 140-29-4 100-47-0 109-74-0 625-28-5 4786-20-3 628-73-9 107-12-0 78-82-0 107-13-1 126-98-7 110-59-8 542-54-1 100-54-9

Acetonitrile Benzeneacetonitrile {α-tolunitrile} Benzonitrile Butanenitrile Butanenitrile, 3-methyl- {isovaleronitrile} 2-Butenenitrile {crotononitrile} Hexanenitrile {capronitrile} Propanenitrile Propanenitrile, 2-methyl- {isobutyronitrile} 2-Propenenitrile {acrylonitrile} 2-Propenenitrile, 2-methyl- {methacrylonitrile} Pentanenitrile {valeronitrile} Pentanenitrile, 4-methyl- {isocapronitrile} 3-Pyridinecarbonitrile {nicotinonitrile}

References by Mid-1960s Grob (1413, 1416), Newsome et al. (2782), Wynder and Hoffmann (4319, 4332) Grob (1427) Grob (1426) Grob (1416, 1417, 1422), Wynder and Hoffmann (4332) Grob (1416, 1417), Wynder and Hoffmann (4332) Newsome et al. (2782), Wynder and Hoffmann (4332) Grob (1416, 1417, 1422), Wynder and Hoffmann (4332) Grob (1413, 1416, 1422), Newsome et al. (2782), Wynder and Hoffmann (4319, 4332) Grob (1413, 1416, 1422), Newsome et al. (2782), Wynder and Hoffmann (4319, 4332) Grob (1413, 1416, 1422), Newsome et al. (2782), Wynder and Hoffmann (4319, 4332) Grob (1413, 1416, 1422), Newsome et al. (2782), Wynder and Hoffmann (4319, 4332) Grob (1416, 1417, 1422), Wynder and Hoffmann (4332) Grob (1416, 1417), Wynder and Hoffmann (4332) Grob (1426)

cigarette MSS vapor-phase components but they listed only 2-propenenitrile (acrylonitrile) as a carcinogen. HCN was listed as a major toxic agent in cigarette smoke in their 2001 article (1743). Because of its inclusion in so many of the Hoffmann coauthored lists, 2-propenenitrile (acrylonitrile) was among the forty or so smoke components that subsequently became classified as a “Hoffmann analyte.” While it did not use the term “Hoffmann analyte” in its 2000 report, the Department of Health (Canada) proposed that analytical data on over forty components from tobacco smoke should be a requirement

to enable the department to assess the health hazard of a cigarette product marketed in Canada (11A01). In its list, the Department of Health (Canada) included 2-propenenitrile (acrylonitrile) and HCN. Examination of the Department of Health (Canada) list reveals that most of its components appear in the biologically active component lists in the publications co-authored by Hoffmann (1727, 1773, 1808, 1740, 1741, 1743, 1744). Table XI-2 lists the 141 nitriles identified to date in tobacco products. Of the 141, 131 have been identified in smoke, 23 in tobacco, and 13 in both.

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617

Nitriles

Table XI-2 Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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11/13/08 5:28:31 PM

618

The Chemical Components of Tobacco and Tobacco Smoke

Table XI-2 (CONTINUED) Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:28:32 PM

Nitriles

619

Table XI-2 (CONTINUED) Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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620

The Chemical Components of Tobacco and Tobacco Smoke

Table XI-2 (CONTINUED) Nitriles in Tobacco,Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:28:35 PM

Nitriles

621

Table XI-2 (CONTINUED) Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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622

The Chemical Components of Tobacco and Tobacco Smoke

Table XI-2 (CONTINUED) Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:28:40 PM

Nitriles

623

Table XI-2 (CONTINUED) Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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11/13/08 5:28:42 PM

624

The Chemical Components of Tobacco and Tobacco Smoke

Table XI-2 (CONTINUED) Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:28:44 PM

Nitriles

625

Table XI-2 (CONTINUED) Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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11/13/08 5:28:45 PM

12

Acyclic Amines

The great diversity and number of the N-containing components in tobacco and tobacco smoke make it difficult to categorize them and catalog the members in each category. Examination of past reviews indicates that their authors had the same problems even when the numbers of components in the various categories were much fewer than they are now. The categorization used herein is an attempt to present a simplified but complete system for the reader. Because of its nature, tobacco and its smoke contain a multitude of N-containing components distributed among various categories. The simplest categories, of course, are the nitriles and the acyclic or aliphatic amines. The latter category also includes individual amino acids and their complexes (proteins, polypeptides), many of which possess a nonsubstituted amino group. More complex are the pentacyclic and hexacyclic N-containing components plus those that are combinations of more than one of each type, that is, linked pentacyclic structures (porphyrin), linked hexacyclic structures (2,3′-bipyridine), or a linked pentacyclic and hexacyclic structure [3-(1-methyl-2-pyrrolidinyl)pyridine (nicotine)]. Even more complex are those structures in which two or more cyclic units are fused with at least one containing N in its cycle, that is, the aza-arenes. Also pertinent to tobacco smoke chemistry are the components possessing a combination of an amino group with an aza-arene structure such as occurs in the N-heterocyclic amines. All categories mentioned, except the amino acids, include components comprising carbon, hydrogen, and nitrogen. However, several other categories, like the amino acids and the N-nitrosamines, include oxygen in the molecule, for example, the amides {I}, imides {II}, and lactams {III} (Figure XII-1). Herein, the amines will be discussed and cataloged. Subsequently, the other categories mentioned will be discussed and cataloged, that is, amides, imides, and lactams, components with five-membered N-containing rings, six-membered N-containing rings, and combinations of them, the aza-arenes, and the N-heterocyclic amines. The amino acids were discussed and cataloged previously. Other components, similar to the N-heterocyclic amines in which an amino group is attached to a fused N-containing system, have been identified in tobacco and/or smoke, for example, 1H-purin-6-amine (adenine). Because of the multitude of nicotine-related alkaloids, amino acids, and proteins in tobacco, diligent research eventually led to the identification of a host of alkyl amines in tobacco and smoke. In addition to ammonia, the only alkylamine listed as a tobacco smoke component in 1954 by Kosak (2170) was methylamine, but he questioned its identification even though he cited the 1904 report by Thoms (3912) and the 1930 report by Koperina (2161) on its identification.

A similar Koperina report (2162) appeared in a 1931 monograph edited by Shmuk on tobacco research (3655c). In their 1959 review, Johnstone and Plimmer (1971) listed ammonia and trimethylamine as identified tobacco and smoke components and methylamine, dimethylamine, and ethylamine as identified tobacco smoke components. Nearly a decade later, in addition to the amino acids, Stedman listed over forty components with either a free or substituted amino group [see Table XI in (3797)]. In their 1977 tabulations of aliphatic and aromatic amines, Schmeltz and Hoffmann listed nearly eighty components almost equally divided between aliphatic and aromatic amines [see Tables I and II in (3491)]. Many of those they listed were identified in tobacco in the late 1960s by Irvine and Saxby (1877) and in tobacco smoke by Pailer et al. (2882, 2883, 2889). Ishiguro and Sugawara (1884) had a few more amines than those listed in the Schmeltz-Hoffmann compilation because they included as aliphatic amines several cyclic amines and their alkyl derivatives, such as pyrrolidine and piperidine. However, this need not be considered a discrepancy. Examination of the structures of N-ethylethanamine (diethylamine) {IV} vs. pyrrolidine {V} or N-(1-methylethyl)-2propanamine {VI} vs. 2,5-dimethylpyrrolidine {VII} reveals the structural similarities (Figure XII-2). While Tso (3973) in his 1990 book listed numerous nicotine alkaloid-related amines as identified tobacco components, his list also included ammonia but very few alkylamines and no aromatic aniline-related amines in tobacco [see Table 27-1, Part IV in (3973)]. In addition to the simplest amine of all, ammonia, included in Table XII-1 for the sake of completeness are hydroxylamine and hydrazine and several alkylhydrazine derivatives. The source of many of the amines, including the alkylamines in tobacco and/or its smoke, is the disintegration of various proteins, individual amino acids, and nicotine-related alkaloids (2001, 3477, 4275a) during tobacco growth or the smoking process (3972). Obviously, a portion of those amines identified in both tobacco and tobacco smoke occur in the smoke because of their transfer from the tobacco during the smoking process. The various benzenamine (aniline)-related components in tobacco are considered to arise from enzymatic or microbial disintegration of the amino acids phenylalanine or tyrosine (3491). Schmeltz et al. (3499) reported that the benzenamine-related amines were not generated from nicotine during the tobacco smoking process. In its 1986 monograph on tobacco smoking, the International Agency for Research on Cancer (IARC) [see pp. 107–109 in (1870)] noted that about 200 amines had been identified in tobacco smoke, based on its citation of the

627

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628

The Chemical Components of Tobacco and Tobacco Smoke

R

R1 N

O

O

N R

R2 I

O

N R

O

III

II

Figure XII-1  Oxygenated N-containing components of tobacco and tobacco smoke.

N H IV Ethanamine, N-ethyl109-89-7

N H V Pyrrolidine 123-75-1

N H VI 2-Propanamine, N-(1methylethyl)108-18-9

N H VII Pyrrolidine, 2,5-dimethyl3378-71-0

Figure XII-2  Structural similarities of alkylamines and pyrrolidines.

1977 review by Schmeltz and Hoffmann (3491), the 1982 review by Dube and Green (1067), and the report by Heckman and Best (1587). IARC described the per cigarette smoke yield of several alkylamines, noting that the most plentiful was methylamine. Citing the data presented by Patrianakos and Hoffmann (2900), IARC also discussed the per cigarette mainstream and sidestream smoke yields of several aromatic amines including eleven benzenamines, the 1-and 2-naphthalenamines, and the [1,1’-biphenyl]-2-, 3-, and 4-amines (the aminobiphenyls). IARC noted that it had previously evaluated the carcinogenicity of several tobacco smoke aromatic amines, namely, 1- and 2-naphthalenamine, [1,1’-biphenyl]4-amine, benzenamine (aniline), 2-methylbenzenamine

(o-toluidine), N-phenyl-2-naphthalenamine, and 2-methoxybenzeneamine (o-anisidine). Table XII-1 summarizes the IARC categorization of several amines, including hydrazine and 1,1-dimethylhydrazine, identified in tobacco smoke [see Appendix 2 in (1870)]. The IARC monograph (1870) is based on the findings of its 1985 Working Group. Despite its review of the literature to 1985, the IARC had no comment about the numerous reports (1835a, 2491a, 2492, 2849, 2849a, 2949b, 3829a, 3862b, 3862c, 3862d, 3865b, 4365a, 4388) issued from 1975 to 1985 on the isolation initially from cooked food and subsequently from tobacco smoke of the tumorigenic and highly mutagenic N-heterocyclic amines.

Table XII-1 IARC Evaluation of Carcinogenicity of Various Aromatic Amines in Tobacco Smoke (1870) Degree of Evidence in CAS No.

Amine

62-53-3 95-53-4

302-01-2 57-14-7 134-32-7 91-59-8

Benzenamine {aniline} Benzenamine, 2-methyl {o-toluidine; 2-toluidine} Benzenamine, 4-methoxy- {p-anisidine} [1,1’-Biphenyl]-4-amine {4-aminobiphenyl} Hydrazine Hydrazine, 1,1-dimethyl1-Naphthalenamine 2-Naphthalenamine

135-88-6

2-Naphthalenamine, N-phenyl-

104-94-9 92-67-1

Yield, ng/cig

Animals

102, 364 a 30-337b 32, 162a present 2-5.6 c 2.4, 4.6 a 24-43 b present b 4.3, 2.5 a 1-334 b 1.0, 1.7 a present

Limited evidence

—

Humans

Sufficient evidence Sufficient evidence Sufficient evidence

Inadequate evidence — Sufficient evidence

Sufficient evidence Sufficient evidence Inadequate evidence Sufficient evidence

Inadequate evidence — Inadequate evidence Inadequate evidence

Inadequate evidence

Inadequate evidence

a

Data cited by IARC (1870) from Patrianakos and Hoffmann (2900); first value is for a U.S. 85-mm non-filtered cigarette, second value is for a French 70-mm non-filtered cigarette.

b

Data cited by Hoffmann and Hoffmann (1741, 1743, 1744).

c

Data cited by Hoffmann and Hoffmann (1743, 1744).

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629

Acyclic Amines

There are several interesting aspects to the 1984 American Chemical Society monograph on chemical carcinogens edited by Searle (3568): • Despite a voluminous review by Dipple et al. (983) on PAHs and the tumorigenicity of many of them, no mention was made of a tumorigenic or carcinogenic PAH in tobacco smoke. • The only significantly tumorigenic, carcinogenic, or biologically active tobacco and tobacco smoke components discussed in the 1400-page monograph were the N-nitrosamines [see pp. 839–844 in Preussmann and Eisenbrand (2990)]. Much of the data cited by Dipple et al. were those previously presented by Hoffmann and his colleagues (514, 1680, 1685). • In two chapters on the tumorigenicity of aromatic amines, neither Garner et al. (1275a) nor Parkes and Evans (12A02) mention the presence in tobacco smoke of the aromatic amines categorized as significant tumorigens or carcinogens, namely, 2-naphthalenamine, [1,1’-biphenyl]-4-amine, and 2-methylbenzenamine (o-toluene). Garner et al. [see Table I in (1275a)] tabulated the tumorigenicity results of studies on many substituted benzenamines (anilines). The data indicated that several appeared to be as tumorigenic as or even more tumorigenic than 2-methylbenzenamine (o-toluidine), a tobacco smoke component listed as a significant tumorigen (1217, 1727, 1740, 1741, 1743, 1744, 1773, 1808, 2825). Each of them has been identified as a tobacco smoke component, for example, 3-methylbenzeneamine (m-toluidine), 4-methylbenzeneamine (p-toluidine), and 2,4,6-trimethylbenzenamine (mesitylamine), but none was listed as a significant tumorigen. • Despite the number of reports issued after 1975 on N-heterocyclic amines, Garner et al. (1275a) did not mention their presence in tobacco smoke. They commented, “A multitude of new aromatic amine or heterocyclic amino compounds will most

likely be discovered in the foreseeable future, such as those found in cooked foods” [Yamazoe et al. (4370a), Takeda et al. (12A03)]. Several of the components listed in Table XII-1 have been included in many of the lists of carcinogens, tumorigens, or biologically active components in cigarette smoke presented by Fowles and Bates (1217), Hoffmann and colleagues (1727, 1740, 1741, 1743, 1744, 1773, 1808), and OSHA (the Occupational Safety and Health Administration) (2825). Based on these lists, the per cigarette yields proposed by some authorities, such as the Department of Health (Canada) (12A01), to be determined of the “Hoffmann analytes” among the amines include 1-naphthalenamine, 2-naphthalenamine, [1,1’-biphenyl]-3-amine, [1,1’-biphenyl]-4-amine, 2-methylbenzenamine (o-toluidine), and ammonia. The primary goal in Table XII-2 is the listing of those tobacco and/or smoke components that are acyclic amines. In some cases, an amino group, either unsubstituted (-NH2) or substituted {VIII}, may be linked to a cyclic N-containing structure, -N

R1 R

2 VIII

for example, 2-pyridinamine, 2-amino-1,7-dihydro-6H-purin-6 -one (guanine), but the reason for inclusion of the component in Table XII-2 is that part of the molecule is an acyclic amine. For the sake of completeness, several components have been included in Table XII-2 because they possess the amine function (-NH 2) but are not linked to a carbon atom, for example, ammonia, hydrazine, and hydroxylamine. None of them fits the definition of an amide, imide, or lactam. Other components included in Table XII-2 for the sake of completeness are the amino acids with acyclic unsubstituted or substituted amine groups, the acyclic N-nitrosamines, and the N-heterocyclic amines. With the inclusion in Table XII-2 of the various items just mentioned, the number of acyclic amines and their derivatives total 469, with 259 identified in smoke, 316 in tobacco, and 106 in both tobacco and smoke.

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630

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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Acyclic Amines

631

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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632

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

633

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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634

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

635

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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636

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

637

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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638

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

639

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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640

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

641

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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642

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

643

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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644

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

645

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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646

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

647

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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648

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

649

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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650

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

651

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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652

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

653

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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654

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

655

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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656

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

657

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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658

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

659

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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660

The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Acyclic Amines

661

Table XII-2 (continued) Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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13

Amides

In his 1954 compilation of smoke components, Kosak (2170) listed no amide identified to that date. In their 1959 review of tobacco and tobacco smoke components, Johnstone and Plimmer (1971) described the identification of asparagine and glutamine in tobacco and glutamine and nicotinamide in tobacco smoke. The latter were identified in smoke by Buyske et al. (562). In its 1963 monograph on tobacco and smoke components, Philip Morris (2939) listed the amides, asparagine, glutamine, citrulline, and nicotinamide, as tobacco components but only glutamine and nicotinamide as smoke components. Stedman (3797) in his 1968 review of tobacco and smoke components listed asparagine, citrulline, and glutamine as amino-acid related components, not as amides [see Table XIV in (3797)]. Nicotinamide and N-methylnicotinamide were not listed specifically as amides but as alkaloid derivatives [see Table XI in (3797)]. Cotinine was also listed in the same table. Ishiguro and Sugawara (1884) in their 1980 monograph on tobacco smoke components listed a total of seventy-two amides, imides, and lactams (forty-nine amides, seven imides, sixteen lactams) [see Table I-15 in (1884)]. The reference for all but two of the compounds listed (formamide, urethane) was Schumacher et al. (3553). Several amides, imides, and lactams were listed by Ishiguro and Sugawara in other tables, for example, asparagine and glutamine under amino acids [Table I-19 in (1884)], cotinine and norcotinine under alkaloids, caffeine under N-polycyclics (excluding alkaloids). Citing publications by Schmeltz and Hoffmann (3491), Schumacher et al. (3553), and Heckman and Best (1587), the International Agency for Research on Cancer (IARC) in its 1986 monograph on tobacco smoking stated [see p. 109 in (1870)] that there was a large spectrum of amides, imides, and lactams in tobacco smoke (including some fifty aliphatic amides). While the IARC commented on the Johnston et al. 1973 report on the per cigarette yields of formamide, acetamide, and propanamide, it did not mention that Johnston et al., in their 1973 report (1965), had noted that only three amides, glutamine, asparagine, and nicotinamide, had been identified in tobacco smoke at that time. The IARC expressed concern about the twenty-four secondary amides identified in smoke, particularly N-methylformamide, N-methylacetamide, N-methylpropanamide, and N-methylnicotinamide, because of their propensity to generate tumorigenic nitrosamides. Despite the fact that these secondary amides have been identified in tobacco smoke and are known to readily form N-nitrosamides, no such N-nitroso compound has been identified to date in tobacco smoke [Rodgman and Green (3300)].

IARC also mentioned the two lactams N-methyl-2pyrrolidone and N-methyl-2-piperidone and the urethanes, but made no textual comment about their biological effect. Of the fifty-three amides identified in tobacco smoke by Schumacher et al. (3553), thirty-two were new to tobacco smoke composition. Their contribution in this regard was the result of the use of an analytical technology that permitted the fractionation and identification of many components in the water-soluble portion of cigarette smoke condensate. In his study of the composition of smoke from an allburley tobacco cigarette, Heckman (1586) identified sixteen amides, ranging in complexity from acetamide to N′-formylnornicotine. Although 186 amides are cataloged in Table XIII-1, it should be realized that the number of amides in tobacco far exceed the number of amides listed for tobacco and tobacco smoke. Each of the many thousands of enzymes, proteins, and proteinaceous components in tobacco possesses many amido linkages. Nearly 500 of the well-characterized enzymes and proteins are cataloged in Table XXII-2 in Chapter XXII, but that number is only a small fraction of the great number of such components in tobacco. IARC had little to say about the possible ill effects of any of the amides in tobacco smoke. However, it did note in an appendix to its monograph [Appendix 2, pp. 389–394 in (1870)] that sufficient evidence existed for the initiating and cocarcinogenic activity in animals of urethane (ethyl carbamate) and the evidence was limited for acetamide. IARC listed the per cigarette yields of acetamide and urethane. In the first listing of tumorigens, carcinogens, and toxicants in tobacco smoke, by Hoffmann and Wynder in 1986 (1808), only urethane was included. Urethane was included in several subsequent lists, those by Hoffmann and Hecht (1727), Hoffmann et al. (1773), and Hoffmann and Hoffmann (1740). In their 1997 list (1740), Hoffmann and Hoffmann added acrylamide (2-propenamide) as present in cigarette smoke but no per cigarette yield was included. In their next three lists of tumorigens, carcinogens, and toxicants in tobacco smoke issued between 1998 and 2001, Hoffmann and Hoffmann (1741, 1743, 1744) listed per cigarette yields of acetamide and urethane and the presence of acrylamide. Other listings of tumorigens, carcinogens, and toxicants in tobacco and tobacco smoke by the Occupational Safety and Health Administration (OSHA) (2825) in 1994 and Fowles and Bates (1217) in 2001 included urethane but not acetamide or acrylamide. The various degrees of inclusion in the many lists issued between 1986 and 2001 were summarized by Rodgman (3265).

663

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664

Acetamide, acrylamide, and urethane were not included in most of the requirements for “Hoffmann analyte” data as an indication of cigarette smoke hazard, for example, the Department of Health (Canada) proposal in 2000 (25A06). One other aspect of interest concerning amides is that several (asparagine, glutamine, and urea) appear on the Doull et al. list of individual compounds used in cigarette manufacture by U.S. companies (1053). The Doull et al. list also includes the imide 3,7-dihydro-1,3,7-trimethyl-1H-purine-2, 6-dione (caffeine). Although they are on the borderline of the definition of an amide, urethane plus urea and several of its derivatives have been included in Table XIII-1. Because each possesses structure I, each was included as an amide for the sake of completeness, for example, urea is H2N-CO-NH2 and ethyl

The Chemical Components of Tobacco and Tobacco Smoke

urethane is H2N-COO-C2H5. Several of the urea derivatives are compounds used in tobacco agronomy. H N O I

R1

R2

The number of compounds in Table XIII-1 totals 212, of which 191 are amides. The remaining components include urethane plus urea and several of its derivatives. Of the 212 compounds, 127 were identified in tobacco, 118 in tobacco smoke, and 33 were identified in both tobacco and smoke.

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Amides

665

Table XIII-1 Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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666

The Chemical Components of Tobacco and Tobacco Smoke

Table XIII-1 (continued) Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Amides

667

Table XIII-1 (continued) Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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668

The Chemical Components of Tobacco and Tobacco Smoke

Table XIII-1 (continued) Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Amides

669

Table XIII-1 (continued) Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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670

The Chemical Components of Tobacco and Tobacco Smoke

Table XIII-1 (continued) Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Amides

671

Table XIII-1 (continued) Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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672

The Chemical Components of Tobacco and Tobacco Smoke

Table XIII-1 (continued) Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Amides

673

Table XIII-1 (continued) Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table XIII-1 (continued) Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Amides

675

Table XIII-1 (continued) Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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676

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Table XIII-1 (continued) Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Amides

677

Table XIII-1 (continued) Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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14

Imides et al., Newell et al. (2769) identified five imides. In his earlier study of the composition of smoke from an all-burley tobacco cigarette, Heckman (1586) identified fifteen imides. Examination of the structures of several of the CSC components indicates that the decision of their categorization is somewhat difficult. In Figure XIV-IA, representative structures for an amide, an imide, and a lactam are presented. To which of these categories—amide, imide, or lactam—should the smoke component 1-acetyl-3-ethyl-1,5-dihydro-4-methyl2H-pyrrol-2-one {I} be assigned? Its structure is depicted in Figure XIV-IB. In Structure {II} of Figure XIV.B, the amide configuration is shown. Structures {III} and {IV} show the imide and lactam configurations, respectively. This same situation is present with several other smoke components. Although there may be some disagreement on the preciseness of our selection, for completeness sake such components are listed in each chapter in its major catalog table. As a result, the total number of components in each of the major catalog tables may be slightly inflated. In addition to several amides (asparagine, glutamine, urea), Doull et al. lists the imide 3,7-dihydro-1,3,7-trimethyl1H-purine-2,6-dione (caffeine) among individual compounds used in cigarette manufacture by U.S. companies (1053). The seventy-nine imides identified in tobacco and tobacco smoke are cataloged in Table XIV-1. Of the seventy-nine imides reported, thirty-nine have been identified in tobacco, fifty-nine in tobacco smoke, and nineteen in both tobacco and smoke.

In his 1954 compilation of tobacco smoke components, Kosak (2170) listed no imide identified in tobacco smoke to that date. Ishiguro and Sugawara, in their 1980 monograph on tobacco smoke components, listed a total of seventy-two amides, imides, and lactams, including seven imides [see Table I-15 in (1884)]. Their reference for all the imides listed was that of Schumacher et al. (3553). Ishiguro and Sugawara did not list caffeine as an imide but listed it under N-polycyclics (excluding alkaloids) [see Table I-14 in (1884)]. In its 1986 monograph on tobacco smoking, the International Agency for Research on Cancer (IARC) stated that there was a large spectrum of amides, imides, and lactams in tobacco smoke (including some fifty aliphatic amides) [see p. 109 in (1870)]. The basis for the IARC comments were the 1977 review of N-containing components in tobacco and tobacco smoke by Schmeltz and Hoffmann (3491) and the smoke composition publication in 1977 of Schumacher et al. (3553) and in 1981 by Heckman and Best (1587). Of the twenty-four imides identified in tobacco smoke by Schumacher et al. (3553), six were new to tobacco smoke composition. Many of the previously identified imides were derivatives of 1H-pyrrole-2,5-dione (maleimide), 2,5-pyrrolidinedione (succinimide), and 1H-isoindole-1,3(2H)-dione (phthalimide). The use of a recently developed analytical technology that permitted the fractionation and identification of components in the water-soluble portion of cigarette smoke condensate (CSC) was a key factor in their mid-1977 study. In a detailed study of the ether-soluble portion from the same CSC studied by Schumacher R1

R2

N

N H

O

O

N H

O

R

O

Imide configuration

Amide configuration

Lactam configuration

Figure XIV-1A  The amide, imide, and lactam configurations. H3C

C2H5

O

N O

H3C

CH3

C2H5

O

N O

H3C

CH3

C2H5

O

N H 3C

I II III 2H-Pyrrol-2-one, 1-acetyl-3-ethyl-1,5-dihydro-4-methyl(CAS No. 61892-80-6)

H3C

O

C2H5

N

O CH3

O IV

Figure XIV-1B  The amide {II}, imide {III}, and lactam {IV} configurations in 1-acetyl-3-ethyl-1,5-dihydro-4-methyl-2H-pyrrol-2-one {I}. 679

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Table XIV-1 Imides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Imides

681

Table XIV-1 (continued) Imides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table XIV-1 (continued) Imides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Imides

683

Table XIV-1 (continued) Imides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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684

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Table XIV-1 (continued) Imides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Imides

685

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15

N-Nitrosamines

The introduction to this chapter on N-nitrosamines (NNAs) in tobacco and tobacco smoke is a considerably abbreviated but updated version of the lengthy unpublished 1993 memorandum by Rodgman (3256). Omitted from this outline are several sections covered in detail in (3256). These include much of the discussion on the early studies of the biological properties of NNAs [see pp. 117–178 in (3256)] and studies on alternate sources of exposure to NNAs [see pp. 107–116 in (3257)]. The numerous publications during the past two decades on the identification, quantitation, and bioassay of NNAs, particularly those found in tobacco-related entities [tobacco, mainstream smoke (MSS), sidestream cigarette smoke (SSS), and environmental tobacco smoke (ETS)] raise the question as to why this class of tobacco/tobacco smoke components has received such emphasis. Since the early 1950s, several classes of compounds in tobacco smoke have been proposed as prime contributors to cancer of the respiratory tract in smokers. The events that triggered detailed examination of the composition of cigarette MSS included:



1. The results of retrospective studies that were interpreted as indicating an association between cigarette smoking and carcinoma of the lung in smokers [Levin et al. (2355), Mills and Porter (2556), Schrek et al. (3529), Wynder and Graham (4306b), Doll and Hill (1027), McConnell et al. (2525), Sadowky et al. (3375a)]. Subsequently, the results from additional retrospective studies and several prospective studies on smoking and respiratory tract cancer bolstered the evidence for this association. 2. Bioassay results from studies (4306a, 4306c) in which carcinomas were produced in susceptible mouse strains at the site of repeated skin painting with massive doses of cigarette smoke condensate (CSC) prepared in a manner supposedly simulating the human smoking process (the puff frequency used was a 2-sec puff each 20 sec vs. the usually accepted routine of a 2-sec puff each 60 sec). Between 1953 and late 1966, the major skin-painting studies involving CSC administered to various laboratory animal species numbered about sixty (4332).

Despite numerous statements to the contrary—that the data from mouse skin-painting experiments with CSC were not extrapolable from mouse skin to the human lung, some authorities continued to imply that such data were meaningful

in terms of respiratory tract cancer in smokers. For example, Wynder (4292) wrote: The mouse skin test cannot give definitive proof for a human carcinogen, although it has long been used as a reliable tool for testing of carcinogenic materials … The animal data must be considered, not as a proof for the human experience, but as a tool with which to work toward the isolation and identification of carcinogenic agent(s). At this time we can only assume, on the basis of the combined human and animal data, that these carcinogens are the same for man and for mice.

In 1956, Wynder (4295) stated: We believe that no animal data can be used to establish a causative role in cancer in man. Such proof can come only from human epidemiologic data … animal evidence by itself can never establish a human carcinogen nor can it ever disprove it … For example, if we suspect tobacco as a carcinogen to man, animal experimentation can determine the specific parts of tobacco which are carcinogenic to animals. Once identified, we can only assume that the specific carcinogens are the same to which man also responds and introduce preventive measures accordingly.

Despite comments such as these and additional ones in later publications, animal experimentation, particularly mouse skin-painting studies, constituted a substantial part of the bioassays on tobacco smoke. Such bioassays are not only expensive but also extremely time consuming (18 to 24 months). Because of the absence of a positive response in studies of tobacco smoke inhalation by laboratory animals, mouse skin-painting with CSC was selected as the bioassay of choice in the massive decade-long (1970–1980) study conducted by the National Cancer Institute (NCI) on “less hazardous” cigarettes, a study that involved nearly 100 test cigarettes and 30 standard or reference cigarettes (1329, 1330, 1332, 1333, 2683). Successively after the late 1950s, various classes of smoke components were proposed as either the cause of (as tumor initiators) or contributors to (as promoters, cocarcinogens, ciliastats) lung cancer in smokers:

1. Polycyclic aromatic hydrocarbons (PAHs) 2. Their polycyclic nitrogen analogs, the aza-arenes, reported to be carcinogenic to mouse skin 3. Low molecular weight phenols reported to be promoters of tumorigenic PAHs 4. Aldehydes and ketones reported to be ciliastatic in in vitro ciliated systems

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5. Aromatic amines 6. Metallic items (210Po, Ni) 7. Other miscellaneous compounds, such as ethyl urethan

One by one the claims for involvement of each of these classes of compounds were either discounted or seriously questioned [Rodgman (3255, 3257), Rodgman et al. (3307)]. PAHs were described as the only major tumor initiators in mouse skin carcinogenesis [Wynder and Hoffmann (4332)]: The many detailed data obtained in studies of tobacco carcinogenesis on mouse skin exclude with some certainty the major tumor initiators other than the PAH type play a role in this assay system.

Benzo[a]pyrene (B[a]P), because of its potency in skintumor carcinogenesis and per cigarette MSS yield, was considered the major PAH of concern in tobacco smoke. In 1981, the Surgeon General commented on PAHs [see p. 36 in (4009)]: BaP appears to be the most important single member of this class of compounds, taking into consideration both its concentration and its relative carcinogenic potency.

The Chemical Components of Tobacco and Tobacco Smoke



The failure of several groups of investigators [Candeli et al. (587), Kaburaki et al. (2006), Schmeltz et al. (3499, 3512), Snook (3733), Snook et al. (3750), Grimmer et al. (1409), Kamata et al. (2021), Sasaki and Moldoveanu (3414), Rustemeier et al. (3370)] to reproduce the findings of Van Duuren et al. (4027) on the presence and/or levels of the aza-arenes dibenz[a,h] acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole in tobacco smoke was discussed by Rodgman [3255, 3260, see Table 4 in (3265)] and Baker (172). The failure to explain the observed tumorigenicity of CSC in the mouse-skin bioassay by consideration of the following tobacco smoke systems led to the inclusion of ciliastasis by various water-soluble vapor-phase (VP) tobacco smoke components in an attempt to explain the causation of respiratory tract cancer in smokers:

It was obvious that additional mechanisms were needed to explain the observed biological effect since (1) B[a]P in CSC acting alone accounted for less than 2% of the observed biological response in mouse skin-painting studies, (2) the total PAH fraction accounted for less than 3% of the observed biological response in mouse skin-painting studies, (3) no “supercarcinogenic” PAH was found in CSC (3756–3758, 4282), and (4) inclusion of tumorigenic aza-arenes in CSC explained very little more of the unexplained tumorigenicity. The first additional explanation of the observed effect in skin-painting studies with CSC involved the mechanisms of promotion and cocarcinogenesis of tobacco smoke components. The smoke components first classified as promoters were the low molecular weight phenols because of their known promotion of such potent tumorigenic PAHs as B[a]P and dibenz[a,h]anthracene (DB[a,h]A) (414). However, the significance of the promoting/cocarcinogenic effect of tobacco smoke phenols on PAH tumorigenicity [Wynder and Hoffmann (4309, 4317, 4344)] was offset by the following observations:



1. Removal of a substantial amount (70% to 85%) of the low molecular weight phenols from CSC by selective filtration of the MSS did “not change significantly the biological activity of the resulting condensate” [Wynder and Hoffmann, see p. 626 in (4332), Hecht et al., see p. 2 in presentation manuscript (1582, 1583)]. 2. Low molecular weight phenols inhibited the tumorigenicity of B[a]P [Van Duuren et al. (4029, 4035)].

3. Inclusion of known initiators, promoters, and cocarcinogens in tobacco smoke in the calculation of its tumorigenicity explained less than 5% of the observed biological effect in skin-painting studies.





1. The levels in CSC of mouse-skin tumorigenic PAHs, acting individually or in concert, could not account for the response in CSC-painted animals. 2. The CSC levels of mouse-skin tumorigenic PAHs plus the promoting/cocarcinogenic phenols, acting individually or in concert, could not account for the observed response in CSC-painted animals. 3. The CSC levels of mouse-skin tumorigenic PAHs plus promoting/cocarcinogenic phenols and nontumorigenic PAHs, acting individually or in concert, could not account for the observed response in CSC-painted animals. 4. Inclusion of tumorigenic aza-arenes in the calculation could not account for the observed biological response.

In fact, when the levels of the known tumorigenic, promoting, and cocarcinogenic components of tobacco smoke and their activity toward mouse skin are included in the assessment, less than 5% of the observed biological response in the CSC-painted animals can be explained! To circumvent this failure to explain the observations with CSC-treated laboratory animals and attempt to explain the epidemiological findings in human smokers, ciliastasis was introduced as an additional mechanism involved in the causation of smokers’ lung cancer. In a variety of in vitro systems, ciliastasis was produced by cigarette MSS VP and by individual MSS VP components (hydrogen cyanide, formaldehyde, acetaldehyde, acetone, phenol). It was proposed that ciliastasis occurred in the smokers’ respiratory tract and significantly diminished the lung clearance mechanism of the cilia, thus permitting tobacco smoke particulate-phase particles (and their included “tumorigens”) to remain on the lung surface and initiate the cellular changes required for tumor development. However, this proposal was seriously

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compromised by the demonstration in intact animals as well as in human smokers that a large proportion (60% to 75%) of the in vitro ciliastats (all water-soluble) in the inhaled smoke failed to reach the ciliated tissue in the respiratory tract because of solution in the aqueous secretions coating the oral cavity tissues [Rodgman et al. (3306), Dalhamn et al. (892, 893)]. Prior to the emphasis on NNAs, the class of tobacco smoke components subjected to the most study was the PAHs, with particular emphasis on the CSC compound considered the most potent, B[a]P. Although the NNAs identified in tobacco and/or tobacco smoke number fewer than sixty, the number of PAHs either identified or partially identified* exceeds 500 [Severson et al. (3619), Snook et al. (3756-3758), Rodgman and Perfetti (3306a)]. The role played by the PAHs, particularly B[a]P, in induction of skin carcinoma in skin-painted laboratory animals was seriously questioned because of the demonstrations by Roe (3310, 3311) that a 10-fold increase and by Lazar et al. (2320) that a 30-fold increase in the B[a]P level of CSC failed to produce an increase in its tumorigenicity to mouse skin. This lack of correlation between levels of PAHs [B[a] P, benz[a]anthracene (B[a]A)] in CSC and percent tumorbearing animals was demonstrated in the NCI “less hazardous” cigarette study [Gori (3329, 3230, 3232, 3233), National Cancer Institute (2683)]. The results were acknowledged in the U.S. Surgeon General’s 1981 report [see p. 36 in (4009)]: The contribution of BaP or PAH in general to mouse skin carcinogenesis by cigarette smoke condensate cannot be fully measured at this time. Wynder and Hoffmann (4332) found a correlation between BaP levels and carcinogenic activity of smoke condensates from several types of cigarettes. A much larger series of experimental cigarettes was studied in the smoking and health program of the National Cancer Institute. No significant dependence of carcinogenic potency on BaP was observed [Gori (3329, 3230, 3232, 3233), NCI (2683)].

It should be noted that in the NCI “less hazardous” cigarette study, neither the tobaccos used in the nearly 100 experimental cigarettes and thirty standard and reference cigarettes nor the MSSs generated from them were analyzed for NNAs. Despite observations that NNAs in CSC or NNAs individually induce few, if any, tumors at the application site in mouse skin-painting studies with CSC, they are one of the two classes of tobacco product components to which the prohealth forces continue to devote their major efforts. In 1990, Hoffmann and Hecht (1727) noted: Mouse skin is particularly responsive to PAH tumorigenesis. It is not equally responsive to other important classes of carcinogens such as N-nitrosamines …

*

The partial identification of a PAH refers to the instances where the positions of alkyl substituents and/or their precise identity are uncertain, for example, a trimethyl vs. an ethylmethyl derivative.

689

As noted in 1984 by Hoffmann et al. (1696), three types of NNAs are formed in tobacco processing and during the tobacco smoking process: volatile N-nitrosamines (VNAs), tobacco-specific N-nitrosamines (TSNAs), and nonvolatile N-nitrosamines. The latter include N-nitrosodiethanolamine (NDELA) and N-nitrosoproline (NPRO). Recently, several N-nitrosamino acids were identified in tobacco. The major NNAs identified in tobacco and/or tobacco smoke are listed in Table XV-1. In the mid-1960s, Fredrickson (1236), using a laboratory procedure that precluded artifactual formation of NNAs, identified several volatile NNAs in cigarette MSS. He also reported that volatile NNAs, like the low molecular weight phenols, are selectively removed from MSS by plasticized (triacetin) cellulose acetate filters. Per cigarette MSS volatile NNA yields are reduced by 75% to 80% in this manner, a value similar to that observed with the selective filtration of low molecular weight phenols. This diminution of volatile NNA yields was confirmed several years later by Morie and Sloan (2635) and Brunnemann et al. (514). TSNAs, because of their low volatility, occur predominantly in the MSS particulate phase and behave similarly to other particulate-phase components such as the PAHs, that is, they are not selectively reduced by filtration with plasticized cellulose acetate. However, Hoffmann et al. (1685) noted that MSS TSNA yields are reduced by any technology designed to reduce the MSS particulate phase, such as increased filtration efficiency, increased air dilution (filter-tip perforation, paper porosity), and tobacco expansion. The precursors in tobacco of the NNAs in tobacco smoke have been studied extensively. Tobacco protein is reported by Brunnemann et al. (511) to be the major precursor of the volatile NNAs and N-nitrosoproline (NPRO). Based on these findings, Hoffmann et al. (1696) wrote: The protein fraction of tobacco appears to represent the major precursor group of the carcinogenic volatile nitrosamines in smoke. In addition, Tso et al. (3985) had previously reported that the volatile NNAs in smoke are proportional to the nitrate content of the tobacco filler, an observation also made by Morie and Sloan (2635).

Precursors of TSNAs in tobacco and smoke are nicotine, nornicotine, anabasine, and anatabine [Hecht et al. (1564), Adams et al. (29)]. Both nicotine and nornicotine are considered precursors of N’-nitrosonornicotine (NNN). Direct transfer of TSNAs from tobacco to the smoke accounts for about 40% of NNN and 30% of 4-(N-methylnitrosamino)-1(3-pyridinyl)-1-butanone (NNK) in MSS. The remainder of these two TSNAs in the MSS is formed during the smoking process [Hoffmann et al. (1734), Hecht et al. (1564)]. Like the levels of the volatile NNAs in MSS, the yields of the TSNAs in MSS are proportional to the nitrate content of the tobacco filler (3985). PAHs are ubiquitous. They are present in the atmosphere as components of a variety of dusts, soots, tars, oils, engine exhaust gases; in water; in many commonly consumed foodstuffs, particularly those that are heated, roasted, or broiled

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Table XV-1 Major N-Nitrosamines in Tobacco and/or Tobacco Smoke Chemical Name

Abbreviation

Common Name

Volatile N-nitrosamines 1-Butanamine, N-butyl-N-nitroso1-Butanamine, N-methyl-N-nitrosoEthanamine, N,1-dimethyl-N-nitrosoEthanamine, N-ethyl-N-nitrosoEthanamine, N-methyl-N-nitrosoMethanamine, N-methyl-N-nitrosoMorpholine, 4-nitrosoPiperidine, 1-nitrosoPropanal, 3-(methylnitrosamino)1-Propanamine, N,2-dimethyl-N-nitroso-

NDBA NBMA

N-nitrosodibutylamine N-nitrosobutylmethylamine N-nitrosoisopropylmethylamine N-nitrosodiethylamine N-nitrosoethylmethylamine N-nitrosodimethylamine N-nitrosomorpholine N-nitrosopiperidine 3-(methylnitrosamino)propionaldehyde N-nitrosoisobutylmethylamine; N-nitrosomethyl(2-methylpropyl)amine N-nitrosoethylisobutylamine; N-nitrosoethyl(2-methylpropyl)amine N-nitrosoethylpropylamine N-nitrosomethylpropylamine N-nitrosodipropylamine 3-(methylnitrosamino)propionitrile, N-nitrosopyrrolidine

NDEA NEMA NDMA NMOR NPIP

1-Propanamine, N-ethyl-2-methyl-N-nitroso1-Propanamine, N-ethyl-N-nitroso1-Propanamine, N-methyl-N-nitroso 1-Propanamine, N-nitroso-N-propylPropionitrile, 3-(methylnitrosamino)Pyrrolidine, 1-nitroso-

NDPA NPYR

Nonvolatile N-nitrosamines Diethanolamine, N-nitroso2-Pyrrolidinecarboxylic acid, 1-nitroso-

NDELA NPRO

N-nitrosodiethanolamine N-nitrosoproline; 2-pyrrolidinecarboxylic acid, 1-nitroso-

NAT iso-NNAC NNAL iso-NNAL NNK NAB NNN

N’-nitrosoanatabine 4-(N-methylnitrosamino)-4-(3-pyridinyl)-butanal 4-(N-methylnitrosamino)-4-(3-pyridinyl)- butanoic acid 4-(N-methylnitrosamino)-1-(3-pyridinyl)-butanol 4-(N-methylnitrosamino)-4-(3-pyridinyl)- butanol 4-(N-methylnitrosamino)-1-(3-pyridinyl)-butanone N’-nitrosoanabasine N’-nitrosonornicotine

NSAR

N-nitrosarcosine; N-methyl-N-nitrosoglycine

NMBA

4-(methylnitrosamino)butanoic acid 4-(methylnitrosamino)butanoic acid, methyl ester 2,6-di-(methylnitrosamino)hexanoic acid 2,5-di-(methylnitrosamino)pentanoic acid 1-nitroso-2-piperidinecarboxylic acid 3-(methylnitrosamino)propanoic acid; N-methyl-N-nitroso-β-alanine 3-(methylnitrosamino)propanoic acid, methyl ester 2-(methylnitrosamino)-3-phenylpropanoic acid 1-nitroso-2-pyrrolidinecarboxylic acid, methyl ester; N-nitrosoproline, methyl ester

Tobacco-Specific N-nitrosamines 2,3’-Bipyridine, 1-nitroso-1,2,3,6-tetrahydroButanal, 4-(N-methylnitrosamino)-4-(3-pyridinyl)Butanoic acid, 4-(N-methylnitrosamino)-4-(3-pyridinyl)1-Butanol, 4-(N-methylnitrosamino)-1-(3-pyridinyl)1-Butanol, 4-(N-methylnitrosamino)-4-(3-pyridinyl)1-Butanone, 4-(N-methylnitrosamino)-1-(3-pyridinyl)Pyridine, 3-(1-nitroso-2-piperidinyl)Pyridine, 3-(1-nitroso-2-pyrrolidinyl)N-Nitrosamino Acids, Esters, Nitriles Acetic acid, 2-(methylnitrosamino)Acetic acid, 2-(methylnitrosamino)-, methyl ester Butanoic acid, 4-(methylnitrosamino)Butanoic acid, 4-(methylnitrosamino)-, methyl ester Hexanoic acid, 2,6-di-(methylnitrosamino)Pentanoic acid, 2,5-di-(methylnitrosamino)2-Piperidinecarboxylic acid, 1-nitrosoPropanoic acid, 3-(methylnitrosamino)-

NMPA

Propanoic acid, 3-(methylnitrosamino)-, methyl ester Propanoic acid, 2-(methylnitrosamino)-3-phenyl2-Pyrrolidinecarboxylic acid, 1-nitroso-, methyl ester

[Rodgman (15A48), Grasso (1345), Maga (2438)] and in ETS. Similarly, exposure to NNAs is widespread. Volatile NNAs are not only components of MSS, SSS, and ETS, they are also present in a variety of foodstuffs and beverages. Sen et al. (15A52) noted: Nitrosopyrrolidine , which is a potent liver carcinogen [in laboratory animals], has been shown to be formed during the [a]

frying of bacon, and to be present in sausage, corned beef, luncheon meat, fried pig liver, cooked and uncooked cod fish and finned herring. [a]As noted previously, NPYR is a tobacco smoke component.

The magnitude of the occurrence of NDMA in beer was studied by Spiegelhalder (15A54) in a survey of many German beers: 70% of the sample showed NDMA at a mean

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concentration of 2.7 ppb with a maximum of 68 ppb. Barley malt was considered the NNA source. In 1988, Maga (2438) reviewed some forty publications on NNAs in common foodstuffs, beverages, and spices. The generation of NNAs by the reaction of ingested nitrates with body chemical components was discussed in a survey by the Office of Technology Assessment (15A38): Nitrate and nitrate salts naturally occur in vegetable, fish and meats, are in food for their preservative properties and are present in pesticide and drug residues in food. They react with other chemicals in the body to produce NNAs and N-nitrosamides.

In their 1990 list of forty-three “tumorigenic agents in tobacco and tobacco smoke,” a list cited frequently in reports issued by various governmental agencies (EPA, USPHS), Hoffmann and Hecht (1727) included five volatile NNAs (NDMA, NDEA, NEMA, NPYR, and NMOR), one nonvolatile NNA (NDELA), and three TSNAs (NNN, NNK, and NAB). Repeatedly since the mid-1980s, Hoffmann and his colleagues have published detailed reviews on NNAs, particularly TSNAs, their levels in tobacco, MSS, SSS, and ETS, and their supposed involvement in cancer induction in tobacco users plus many reports on other aspects of NNAs [Hecht et al. (15A18), Hoffmann et al. (1688, 1698, 1731, 1745, 1746, 1750, 1770–1772, 1774–1776), Hecht and Hoffmann (1571, 1571a, 15A19, 15A20), Hoffmann and Hecht (1725, 1727), Brunnemann et al. (459, 477), Brunnemann and Hoffmann (483, 484, 486, 487), Djordjevic et al. (977, 1013, 1015–1017), Andersen et al. (76), Rivenson et al. (3182), Prokopczyk et al. (2994, 2997)]. In addition to the studies by Hoffmann et al., a great number of conference presentations and journal publications on NNAs, particularly TSNAs, have been provided by other investigators. A representative sample includes the contributions by Brown et al. (437), Bush et al. (557), d’Andres et al. (895), de Roton et al. (951), Katsuya et al. (2050–2052), Moldoveanu et al. (2599), Nestor et al. (2700), Peele et al. (2917), Risner et al. (3176a), Risner and Wendelboe (3177), Tricker (3953), and Tricker et al. (3944–3948). Finally, with regard to NNAs it should be noted that CSCs from tobaccos grown under high-nitrate fertilization regimes produce fewer tumor-bearing animals than do the CSCs from tobaccos grown under low-nitrate fertilization regimes even though high-nitrate tobaccos usually show higher levels of both volatile NNAs and TSNAs and their smokes contain higher levels of these compounds than do low-nitrate tobaccos. The responses observed in mutagenicity testing (Ames test with Salmonella typhimurium) are the opposite of those observed in mouse skin-painting studies. Nitrate addition, use of high-nitrate tobacco, and/or use of tobacco stems, which are generally much higher in nitrate than laminae, result in reduced levels of MSS total particulate matter (and “tar”) and in mainstream CSCs with reduced levels of phenols and PAHs, including B[a]P, plus increased levels of NNAs [Wynder and Hoffmann (4312, 4317), Hoffmann and Wynder

(1797, 1798, 1801, 1802), Rathkamp and Hoffmann (3081, 3082), Hoffmann et al. (1783), Brunnemann and Hoffmann (480), Adams et al. (28)].

XV.A Volatile N-Nitrosamines The volatile NNAs in tobacco smoke, usually reported as tobacco smoke components that contribute to the health problems related to smoking, particularly the cigarette smokerespiratory tract cancer problem, are the first seven listed in Table XV-2. Table XV-3 summarizes much of the early research on the volatile N-nitrosamines. Almost a decade after the proposal by Boyland et al. (422, 423, 15A00) that the TSNAs NNN and NAB might be present in tobacco and tobacco smoke, NNN was identified in cigarette MSS by Klus and Kuhn (2136). This and subsequent identification of other TSNAs in tobacco and smoke resulted in a gradual decrease in the research effort on volatile NNAs and a significant increase in the research effort on TSNAs.

XV.B Nonvolatile N-Nitrosamines As noted in Table XV-1, N-nitrosodiethanolamine (NDELA) and N-nitrosoproline (NPRO) are classified as nonvolatile NNAs in tobacco and tobacco smoke. In bioassays in laboratory animals, N-nitrosoproline (NPRO) is the only tobacco/ tobacco smoke NNA to give negative responses. The one considered the more controversial of the two is NDELA. Prior to its identification in tobacco in 1977 and smoke in 1981, its biological properties in laboratory animals and other test systems had been studied for over a decade. Druckrey et al. (1058) reported that NDELA was an hepatic carcinogen in rats. In its review of biological data generated in NNA studies, the IARC (1866) reported that this compound induced tracheal carcinomas in the hamster. Lijinsky et al. (15A35) reported that NDELA induced carcinoma of the liver and kidney in rats. McMahon et al. (2521) reported that NDELA was mutagenic when tested in modifications of the Ames test with Salmonella typhimurium. In 1977, Schmeltz et al. (3480) isolated NDELA from tobacco and identified it. In 1981, Brunnemann and Hoffmann (479) reported that cigarettes fabricated from tobaccos treated with the diethanolamine salt of maleic hydrazide delivered 10 to 40 ng/cigarette of NDELA in the MSS. These two studies were conducted when it was permissible to treat tobacco with the diethanolamine salt of maleic hydrazide, a sucker growth inhibitor. Previously reported findings on the tumorigenicity in laboratory animals of NDELA and its level in cigarette MSS eventually led to the banning by the Environmental Protection Agency (EPA) (1147) of the use on tobacco of maleic hydrazide-diethanolamine salt in the United States and acceptance of the maleic hydrazide-potassium salt as replacement for the maleic hydrazide-diethanolamine salt. In his response to the Environmental Protection Agency’s draft document (1148) on ETS, Rodgman (3255) criticized the inclusion by EPA of NDELA as a tumorigenic agent

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Table XV-2 Summary of Lists of Tumorigenic N-Nitrosamines in Tobacco and Tobacco Smoke Mainstream Smoke Delivery/Cigarette Reported by 1986 Hoffmann & Wynder (1808)

1990, 1993 Hoffmann & Hecht (1727), Hoffmann et al. (1773)

N-Nitrosamine

IARC (1870)

N-Nitrosodimethylamine N-Nitrosoethylmethylamine N-Nitrosodiethylamine N-Nitrosodi-n-propylamine N-Nitrosodi-n-butylamine N-Nitrosopyrrolidine N-Nitrosopiperidine N-Nitrosodiethanolamine b N-Nitrososarcosine N’-Nitrosonornicotine 4-(N-Methylnitrosamino)1-(3-pyridyl)-1-butanone N’-Nitrosoanabasine N’-Nitrosoanatabine N-Nitrosomorpholine

1-200 ng 0.1-10 ng ND-10 nga ND-1 ng ND-3 ng 2-42 ng ND-9 ng ND-90 ng NL c 0.13-2.5 µg 0.08-0.77 µg

1-180 ng 1-40 ng 0.1-28 ng NL NL 2-110 ng ND-9 ng ND-40 ng NL 0.12-3.7 µgd 0.12-0.95 µg

ND-200 ng ND-3.7 µg NL

40-400 ng NL NL

OSHA (2825)

1997 Hoffmann & Hoffmann (1740)

1998 Hoffmann & Hoffmann (1741)

2001 Hoffmann & Hoffmann (1743)

2001 Hoffmann et al. (1744)

2001 Fowles & Bates (1217)

0.1-180 ng 3-13 ng ND-25 ng NL NL 1.5-110 ng NL ND-36 ng NL 0.12-3.7 µg 0.08-0.77 µg

10-40 ng NL ND-25 ng P, NYL P, NYL 6-30 ng P, NYL e 20-70 ng NL 0.2-3.0 µg 0.1-1.0 µg

0.1-180 ng 3-13 ng ND-2.8 ng NL NL 3-60 ng NL ND-68 ng ND 0.12-3.7 µg 0.08-0.77 µg

2-180 ng 3-13 ng ND-2.8 ng ND-1.0 ng ND-30 ng 3-110 ng ND-9 ng ND-68 ng ND 120-3.7 µg 0.08-0.77 µg

2-180 ng 3-13 ng ND-2.8 ng ND-1.0 ng ND-30 ng 3-110 ng ND-9 ng ND-68 ng NL 0.12-3.7 µg 0.08-0.77 µg

2-1000 ng 3-13 ng ND-2.8 ng ND-1.0 ng ND-30 ng 3-110 ng ND-9 ng ND-68 ng NL 0.12-3.7 µg 0.08-0.77 µg

24.4 ng 6.0 ng 8.3 n NL 12 ng 113 ng NL 30 ng NL 1.90 µg 300 µg

0.14-4.6 µg NL ND in MSS

NL NL NL

0.14-4.6 µg NL ND in MSS

ND-150 ng NL ND in MSS

NL NL NL

NL NL NL

19 ng 72.2 µg NYL

ND = not detected. A component listed in bold is no longer relevant (3300) c NL = not listed as a tumorigenic or carcinogenic component of cigarette MSS. d A range listed in bold type contains a numerical error and/or a unit error (ng vs. µg). e P = present; NYL = no yield level listed for cigarette MSS. a

b

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The Chemical Components of Tobacco and Tobacco Smoke

1986

693

N-Nitrosamines

Table XV-3 A Brief Chronology of the Research on Volatile N-Nitrosamines From 1937 to 1990 Year

Investigation

1937 1954 1956

Freund (15A13) reported the acute toxicity of NDMA in humans accidentally exposed to the reagent. Barnes and Magee (192) reported the hepatotoxicity of N-nitrosodialkylamines in several laboratory animal species. Magee and Barnes (2441a) reported that almost all rats fed a diet containing 50 ppm of NDMA developed malignant liver tumors within less than a year. Zak et al. (15A59) reported that feeding and daily oral dosing of rats with NDMA resulted in induction of lung tumors which adenomas, not the lung tumor type - squamous cell carcinoma - reported in various epidemiological studies to be associated with cigarette smoking. Rodgman (15A49) proposed that NNAs were likely cigarette MSS components. Tindall (15A55)] patented the preparation of NNAs from methyl nitrite and secondary amines.

1960

1960 1960

R1

R1 N-H + CH3-ONO

R2

N-NO + CH3OH R2

The demonstration of the presence of methyl nitrite in tobacco smoke [Laurene (2293), Philippe and Hackney (2841), Laurene et al. (2310)] led to the suggestion by Rodgman (15A49) that this was their mode of formation in tobacco smoke. This mechanism of formation of volatile NNAs was also proposed by Wynder and Hoffmann [see p. 437 in (4332)]: An opportunity for the formation of nitrosamines is the interaction of methyl nitrite and secondary amines. It could be demonstrated in these laboratories, that at least in the presence of water, methyl nitrite and diethylamine form DENA. This proposal was subsequently negated when Vilcins and Lephardt (4058) demonstrated that methyl nitrite does not exist in the smoke within the cigarette or in the smoke at the instant it issues from the mouth-end of the cigarette but begins to form artifactually immediately after the smoke exits the mouth-end of the cigarette. As the level of the methyl nitrite in the aging smoke increases, its methanol level decreases. This artifactual formation of methyl nitrite was recognized by Brunnemann and Hoffmann (480): Being aware of the artifactual formation of nitrogen dioxide and methyl nitrite by aging of smoke we prefer to report nitrogen oxides in cigarette smoke as NO [nitric oxide]. 1961

Druckrey et al. (1059) reported the results of their study on the formation, chemical structure, and tumorigenicity of NNAs. This publication did not deal with the possible presence in tobacco smoke of the NNAs but their findings probably led to the1962 publication by Druckrey and Preussmann (1057). 1962 Druckrey and Preussmann (1057) theorized that the conditions in a burning cigarette were appropriate for the generation of NNAs, i.e., present in the reaction mixture were secondary amines, water, and nitrogen oxides. 1962 Data reported by Dontenwill and Mohr (15A09) indicated that NDEA had an organ-specific effect in the tracheobronchial tree of hamsters. 1962 Pasternak (15A40) and Rapoport (15A45) reported the mutagenicity of NNAs in pre-Ames (Salmonella typhimurium) test systems. Numerous reports describing the mutagenicity of NNAs were issued over the next few years. The test systems used included Drosophila melanogaster, Escherichia coli, Neurospora crassa, Saccharomyces cerevisiae, among others [see review by Magee and Barnes (2442)]. 1963- Herrold (15A24) studied the tumorigenicity of NDEA. Herrold and Dunham (15A25) studied the tumorigenicity of 1964 subcutaneously injected NDMA and reported that intratracheal or intragastric administration of NDEA to laboratory animals resulted in a large number of respiratory tract tumors. 1963 Boyland et al. (15A01) discussed the possibility of the presence of NNAs in tobacco smoke, particularly “in the acidic environment of the cigarette smoke” (pH ≤ 6.7) as opposed to the alkaline environment (pH ≥ 7.0) of cigar and pipe smoke. 1964 Boyland et al. (422, 423) suggested that it was possible, because of the formation of NNAs by the reaction of NOx with secondary amines, that cigarette MSS could contain NAB and NNN because of the presence in tobacco MSS of nornicotine and anabasine. They reported that NAB, when administered orally to rats, produced numerous esophageal tumors in the treated animals. 1964 Neurath et al. (2751) reported the isolation and identification of N-nitroso-n-butylmethylamine and the isolation of two unidentified NNAs in cigarette MSS. 1964

Boyland et al. (422, 423) suggested that it was possible, because of the formation of NNAs by the reaction of NOx with secondary amines, that cigarette MSS could contain NAB and NNN because of the presence in tobacco MSS of nornicotine and anabasine. They reported that NAB, when administered orally to rats, produced numerous esophageal tumors in the treated animals. (Continued )

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Table XV-3 (Continued) A Brief Chronology of the Research on Volatile N-Nitrosamines From 1937 to 1990 Year

1964

Investigation

Serfontein and Hurter (3595) reported the identification of NNAs in the MSS from South African cigarettes. Serfontein (15A53) reported the identification of N-nitrosopiperidine (NPIP). Robertson (15A47), President of the National Cancer Association of South Africa, commented on Serfontein and Hurter’s report of the identification of NNAs in cigarette MSS: The significance of this discovery lies in the fact that although the nitrosamine compound is known as a carcinogen, this is the first time that it has been established beyond doubt that various nitrosamines occur in cigarette smoke.

1964- Serfontein and Hurter (3596-3598) developed a thin-layer chromatographic method for separation and analysis of extremely 1966 small amounts of NNAs and noted that “the method has been successfully applied to the analysis of nitrosamines in cigarette smoke.” In a detailed account of the identification of NNAs in CSC, they reported: In the course of initial scanning experiments, strong evidence was obtained by means of gas chromatographic analysis of the neutral fraction of cigarette smoke condensate…that various nitrosamines [N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), and N-nitrosopiperidine (NPIP)] were present in cigarette smoke in measurable quantities. They estimated the level of NPIP to range from 1 to 5 μg/cig. Neurath et al. (2750) discounted their reported 1964 findings (2751) on the identification of MSS NNAs because of their artifactual formation during their collection and analytical procedure. However, with a modified analytical and collection procedure, NDMA (4 ng/cig) and (NPYR) (4 ng/cig) were identified in MSS. The previously reported N-nitroso-n-butylmethylamine (NBMA) was found in the part of the collection system where artifactual formation was possible. Artifactual formation of NNAs during smoke generation, separation, and analysis was a recognized problem since the first NNA identification in MSS (573, 2750, 2751, 15A10, 15A33) and resulted in much debate. Krull et al. (15A33) discussed the artifactual generation of NNAs during their determination. Subsequent research eventually resolved the question concerning the presence or absence of NNAs in tobacco and/or tobacco smoke. However, some artifactual formation did occur, resulting in inflated values for NNAs in MSS and SSS [Caldwell and Conner (572-574)]. 1965 Eisenstark et al. (15A11), nearly a decade before Ames’ 1973 presentation on the use of Salmonella typhimurium to test for mutagenicity, described the high mutagenicity obtained with NNAs in tests with Salmonella typhimurium. Several potent NNAs became positive standards, e.g., N-methyl-N’-nitro-N-nitrosoguanidine in the Ames test with Salmonella typhimurium. 1965- Besides identifying several volatile NNAs in burley tobacco MSS with a procedure that precluded artifactual formation, 1967 Fredrickson (1236) demonstrated that MSS volatile NNA yields were significantly reduced (60-85%) by a plasticized cellulose acetate filter, a finding later confirmed (514, 1761, 2635). This reduction of volatile NNA yields by selective filtration paralleled that observed for phenols (2312, 4312). Concern over phenols and their promotion effect diminished after reports of removal of significant amounts of them from MSS by selective filtration. While concern about volatile NNAs did diminish, a new NNA concern arose: One involving TSNAs, a class of NNAs newly identified in tobacco and tobacco smoke, namely NNN and NAB. 1967 In their NNA review, Magee and Barnes (2442), cf. Barnes and Magee (192) noted: 1965

It is too early to be able to suggest with any confidence the part nitrosamines might play in the etiology of human cancer. In a whole range of experimental animals tumors can be produced in a number of different sites which bear in some cases a striking pathological resemblance to cancers seen in man. However, the species, the nature of the nitroso compound, and the dose and route by which it is administered can all play a part in determining the nature of the malignant lesion produced. 1967 1967

Brune and Henning (15A02) reported the induction of eyelid carcinoma in mice treated with methylbutyl-N-nitrosamine Wynder and Hoffmann noted [see p. 436 and p. 628 in (4332)]: To date, we lack a method of quantitative determination of nitrosamines in tobacco smoke although a few good quantitative techniques have emerged. Since the presence of nitrosamines in cigarette smoke bears considerable implications in tobacco carcinogenesis, it is hoped that further and more detailed studies will also be initiated by other groups to clarify fully this important factor… A most important question, however, is whether nitrosamines are indeed formed during smoking of tobacco and whether the induction of papillary tumors in the respiratory tree of hamsters bears any relation to the induction of human bronchiogenic cancer. They concluded [p. 639 in (4332)]:

1967

At this time one cannot deny the potential of tobacco smoke to form nitrosamines; however, we are not convinced that these agents actually exist in the cigarette smoke inhaled by man. Hoffmann and Wynder (1797) and Rathkamp and Hoffmann (3081, 3082) demonstrated that addition of nitrates to tobacco decreased the per cigarette yields of TPM, promoting/cocarcinogenic phenols, and tumorigenic PAHs (including B[a]P) in MSS and the tumorigenicity of the mainstream CSC to mouse skin. Later, Brunnemann et al. (471, 499) reported that increased levels of tobacco nitrate increased MSS yields of both volatile NNAs and TSNAs, resulting in recommendations to reduce the nitrate levels in tobacco stems and ribs.

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N-Nitrosamines

Table XV-3 (Continued) A Brief Chronology of the Research on Volatile N-Nitrosamines From 1937 to 1990 Year

Investigation

1968

Montesano and Saffiotti (15A37) studied the carcinogenic response of the respiratory tract of Syrian golden hamsters to different doses of NDEA. They also summarized over two dozen previous studies with NDEA. In their review of the identification and quantitation of NNAs in MSS, Johnson et al. (1952) wrote:

1968

It is possible…that little or no nitrosamines are present in cigarette smoke under normal conditions of smoking. Because of the importance of these compounds and the known high incidence of lung cancer, the establishment of their presence in smoke is of importance in the health of man… Even if the nitrosamines are identified and unequivocally established as being present in cigarette smoke at a certain level then it must be investigated whether they contribute to the total toxic activity of tobacco smoke. 1970

Volatile NNA tumorigenicity in laboratory animals was repeatedly cited with the implication that this property was extrapolable to man because of cigarette smoke NNAs. In laboratory animals, NNAs are organ-specific tumorigens and seldom have been shown to induce carcinoma at the painting site in mouse skin-painting experiments. Hoffmann and Wynder (15A29) noted: We…need to consider that nitrosamines have so far not been reported to be carcinogenic to man.

1971

1974

Hoffmann and Vais (1784) reported NDMA and NEMA in unaged MSS from an 85-mm nonfiltered U.S. blend cigarette: NDMA and NEMA yields were 80 and 30 ng/cig, respectively. NDEA and NDBA were not detected. The properties of an NNA thought to be NPIP did not match those of an authentic sample. The chapter in the 1972 Surgeon General’s report (4003) dealing with the harmful components of tobacco smoke noted that the reports describing the presence of various NNAs in cigarette smoke were published after the June 1970 conference on which the chapter was based. Morie and Sloan (2636) reported the substantial reduction of the volatile NNA N-nitrosodimethylamine (NDMA) by plasticized cellulose acetate filters vs. the negligible reduction obtained with paper filters. Substantial selective filtration of NDMA was demonstrated by the 85% reduction in its delivery vs. the 36% reduction observed in the delivery of total particulate matter with the plasticized cellulose acetate filter. Minimal selective filtration was obtained with the paper filter: 66% reduction in NDMA vs. 55% reduction in total particulate matter, cf. Fredrickson (1236). Hoffmann et al. (1761) confirmed the findings of Hoffmann and Vais (1784) on NNAs in cigarette MSS. They reported 84 ng/cig of NDMA, 30 ng/cig of NEMA, and less than 5 ng/cig of NDEA in the MSS of a nonfiltered U.S. blend cigarette. They also reported that selective filtration produced a 60 to 85% reduction of volatile NNAs by use of a plasticized cellulose acetate filter, cf. Fredrickson (1236), Morie and Sloan (2636). Barnes (191) [the co-discoverer with Magee of the tumorigenicity of NNAs (Magee and Barnes (2441a)] stated:

1976

Preoccupation with the occurrence and behavior of minute amounts of nitrosamines in the human environment will probably divert skills from more profitable studies of the behavior of nitrosamines in experimental systems… If [this essay] leaves the reader with the impression that nitrosamines have a much greater potential as research tools than they have as health hazards, it will have served its purpose. Magee et al. (2443) wrote:

1972

1973

1974

1977

That a wide range of species is susceptible to the carcinogenic action of nitrosamines suggests that man is probably not resistant…Many N-nitroso compounds are powerfully carcinogenic in experimental animals, and, although there is no proof, it is highly probable that they are also carcinogenic in man. Brunnemann et al. (514) reported that the volatile NNA levels in MSS and SSS were lower than previously reported, attributing the lower levels to the avoidance of artifactual formation of NNAs during smoke collection and analysis. They wrote: In fact, several of the cigarettes which were machine smoked earlier and analyzed without precautions, when smoked by us under the same conditions but with precautions, yielded 25 to 100% lower values for DMN [N-nitrosodimethylamine] and NPY [N-nitrosopyrrolidine] for the mainstream smoke…The nitrate content of the tobacco appears to be a determining factor for the concentration of volatile nitrosamines in the smoke. Selective removal of these nitrosamines does occur with cellulose acetate filter tips but not with charcoal filter tips. They determined the levels of volatile NNA for unaged MSS and SSS from 17 commercial and experimental cigarettes (Table XV-3). Level Found, ng/cig Volatile NNA NDMA NEMA NDEA NPYR

MSS 1.7 - 97 0.1 - 9.1 0 - 4.8 0 - 4.8

SSS 680 - 1770 9 - 75 8 - 73 8 - 73 (Continued )

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Table XV-3 (Continued) A Brief Chronology of the Research on Volatile N-Nitrosamines From 1937 to 1990 Year

1977

Investigation

The Royal College of Physicians (3364) reported that N-nitroso compounds were, along with the PAHs, the chief initiators of cancer in tobacco smoke. The College noted: The NNAs in food and drink are regarded as a potential health hazards at concentrations as low as one part per billion. N’-Nitrosonornicotine has been identified in both tobacco smoke and unburnt tobacco, the concentration in the latter being 2,000 to 9,000 parts per billion…concentrations much higher than those of other nitroso compounds found in meat, fish, or beverages. Its presence may be of great biological importance and could explain the correlation between tobacco chewing and the development of cancer of the mouth.

1978

1978 1979

The problem of the artifactual formation of volatile NNAs during smoke collection and analysis was discussed previously by Neurath (2750, 2751) and by Fredrickson (1236). It was once again revisited. Krull et al. (15A33) described the problem of artifactual formation of NNAs during the collection, fractionation, and analysis of cigarette smoke and proposed methodology to reduce the problem. This problem resurfaced several times in the next decade in the determination of both volatile NNAs [Eisenbrand et al. (15A10); Caldwell and Conner ( 572, 573)] and TSNAs in tobacco smoke (572, 573); preventative measures were described. Brunnemann and Hoffmann (477) described the results of their measurements of volatile NNAs in indoor air containing ETS. In the 1979 U.S. Surgeon General report [see p. 107 in (4005)], it was noted: The N-nitrosamine formation in tobacco smoke is determined by the nitrate content of the tobacco… More importantly… selective removal (70 to 80 percent) of volatile nitrosamines from the smoke can be achieved by cellulose filters [sic]a… At present, it has not been demonstrated that a significant reduction of volatile N-nitrosamines will lead to a significant reduction of the tumorigenic potential of cigarette smoke.

a

This should read “cellulose acetate.”

It was also stated that NNAs are animal carcinogens with the ability to induce pulmonary tumors (adenomas). 1979

1980

1980

Rinkus and Legator (3157) listed numerous tobacco and cigarette smoke components as mutagenic in the Salmonella typhimurium system. Among these were the following volatile NNAs [excluding (NMOR)] known to occur in tobacco smoke: NDMA, NDEA, NPYR, NDBA, NDPA, NMOR, NPIP. In discussing “The Less Harmful Cigarette,” Hoffmann et al. (1783) included a table which showed that nitrate fertilization of tobacco [which leads to increased NNAs formation] has led to significant reductions in MSS levels of “tar”, nicotine, and B[a]P as well as in the specific tumorigenicity of the “tar” administered via skin painting to laboratory animals. They wrote that “the reduction of the tar content of cigarettes [sic] was an important step in reducing the hazards of cigarette smoking.” Hoffmann et al. (1711) noted: In the mainstream smoke of a cigarette, these carcinogens [the volatile N-nitrosamines] can be reduced significantly by utilization of tobacco low in nitrate content and acetate filter tips that selectively retain volatile N-nitrosamines.

1980 1980

1980 1981

1982

1982

1982

They also stated that “most present-day commercial filter cigarettes are effectively reducing volatile NNAs.” This effective reduction in volatile NNAs in cigarette MSS has not lessened during the intervening years from 1980 to date! Brunnemann et al. (467) presented additional data on the levels of NNAs in MSS and SSS, cf. Brunnemann et al., (457). The SSS levels exceeded those in the MSS. Much of the MSS and sidestream data for NNAs were summarized by Hoffmann et al. (1685). Bartsch et al. (203) listed numerous NNAs as mutagenic in the Ames Salmonella typhimurium test system. The following volatile NNAs reported as tobacco and/or smoke components were included: NDMA, NDEA, NMPA, NDPA, NDBA, NPYR, NMOR, and NPIP. NNN was also tested. Rühl et al. (3366) reported the levels of volatile NNAs and TSNAs in the MSSs and SSSs from American, German, and French cigarettes. In the 1981 Surgeon General’s report (4009) on smoking vs. health, volatile NNAs were discussed as “organ-specific carcinogens.” The Surgeon General, citing Brunnemann et al. (514), noted: “The volatile nitrosamines…can be selectively reduced by filtration…” [cf. Fredrickson (1236), Morie and Sloan (2636)]. In the 3rd Annual Report on Carcinogens by the National Technical Information Service (2686), it was noted: “there is sufficient evidence for the carcinogenicity of N-nitrosodimethylamine (NDMA) in experimental animals.” Similar comments were made about NPYR (MSS yield estimated as being as much as 113 ng/cig) and NDEA (MSS, 8 ng/cig; SSS yield, about ten times that in MSS). Hoffmann and Wynder (1807a) included a table which indicated that nitrate fertilization (known to increase the levels of NNAs in the tobacco and the smoke from it) significantly reduced the biologically activity (carcinogenicity) of CSC to mouse skin. The PAH levels in the CSC were also reported to be reduced. In contrast to suggestions made in the late 1950s/early 1960s to control the pyrogenesis of PAHs by reduction of the tobacco wax components, e.g., long-chained saturated hydrocarbons such as n-hentriacontane, and/or the use of high-nitrate tobacco, Brunnemann and Hoffmann (480) recommended the following approaches - the direct opposite of the earlier suggestions from the Wynder and Hoffmann laboratory - to control both the PAHs and the NNAs in tobacco smoke:

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Table XV-3 (Continued) A Brief Chronology of the Research on Volatile N-Nitrosamines From 1937 to 1990 Year

Investigation

Selective filtration is highly effective in removing volatile N-nitrosamines from the smoke stream, but is ineffective for the selective reduction of tobacco-specific nitrosamines. Selective reduction of nitrate in tobacco stems offers one possible approach, but additional means of reducing nitrogen oxides and N-nitrosamines without diminishing PAH reduction need to be found. Selection of tobacco with high levels of long chain hydrocarbons (e.g. hentriacontane C31H64) may be helpful.

1982

These 1982 suggestions for the design of a “less hazardous” cigarette were in direct contradiction to those offered two decades previously when the main emphasis was not on NNAs (their presence in tobacco smoke was, at best, theoretical in the early 1960s) but on the tetracyclic and higher PAHs, particularly B[a]P, because of the known effect of it and other PAHs on the skin of laboratory animals. The 1982 report of the Surgeon General (4010), citing the studies of Magee et al. (2443) and the IARC (1866), concluded: More than 50 of the approximately 100 NNAs which have been tested have various degrees of carcinogenic potency in laboratory animals… There is a lack of direct evidence that these compounds are also human carcinogens. Nonetheless, many scientists concur with the [IARC] that, for practical purposes, these nitrosamines should be regarded as carcinogenic in humans.

1982 1983

It was noted that NDMA and NPYR were the most plentiful NNAs in cigarette smoke. NDMA is listed in this report as a “toxic and tumorigenic agent” in the vapor phase of cigarette smoke. Both NEMA (MSS delivery, 1 to 40 ng/cig) and NDEA (MSS delivery, 0.1 to 28 ng/cig) were reported as “among the most potent environmental carcinogens” of the NNAs. Stehlik et al. (3812) determined the levels of NDMA in the air of cigarette smoke-filled rooms. In his concluding remarks at the 1983 NNA conference (published in 1984), Magee (2441) stated: A major component of this evidence [that N-nitroso compounds probably can cause human cancer] is the large number of species known to be susceptible to cancer induction by nitrosamines… The question of whether any human cancer has been caused by nitrosamines remains open, but several relevant and interesting presentations were given during the meeting… Following up the well-established relationship between cigarette smoking and the incidence of human lung cancer, these workers [Hoffmann, Hecht, Castonguay, and their colleagues] presented persuasive evidence for a relationship between the use of chewing tobacco and snuff and human cancer…A role for nitrosamines in the causation of human cancer has not been established, but it should not be excluded and merits further study.

1984

Although their data showed that an increase in the nitrate content of cigarette tobacco reduced the levels of FTC “tar”, nicotine, carbon monoxide, catechol, and B[a]P, Adams et al. (28) emphasized that significantly higher yields of volatile NNAs and TSNAs were found in the MSS of an 85-mm nonfiltered cigarette. They concluded: The findings of this study support the recommendation that the nitrate content of tobacco products should be reduced.

1984

1984

[Cf. 1967/1970 studies and comments by Hoffmann and Wynder (1797, 1798) and Rathkamp and Hoffmann (3081, 3082) that use of high-nitrate tobacco was beneficial in that it reduced the levels of CSC PAHs and CSC tumorigenicity to mouse skin. Also, the findings of Brunnemann et al. (481, 482) that addition of stems, high in nitrate, did not reduce “tar”, nicotine, or carbon monoxide yields.] Despite three decades of a variety of claims against the PAHs and their role in carcinoma induction in laboratory animals skin-painted with CSC and their alleged role in carcinoma induction in cigarette smokers, it is interesting to note that in the American Chemical Society monograph (2nd edition) edited by Searle (3568), the only class of compounds in tobacco or cigarette smoke discussed with regard to their tumorigenicity in laboratory animals was the NNAs. Even though several chapters were written by experts in the fields of PAH, their nitrogen analogs, and aromatic amines, no mention was made throughout this two-volume 1400-page monograph of the numerous PAHs in tobacco or cigarette smoke, their levels, or their role in respiratory tract cancer attributed by some to the PAHs in cigarette smoke. The only class of tumorigens discussed was the NNAs and TSNAs. Most of the data cited were those of Hoffmann and his colleagues. The Preussmann and Eisenbrand summary (2990) of research on NNAs in tobacco and tobacco smoke was, according to their article, taken largely from a 1982 review by Hoffmann et al. Preussmann and Eisenbrand commented: Although Hoffmann et al. have clearly demonstrated the effectiveness of cellulose acetate filters in model experiments, the values for U.S. commercial cigarettes are about the same for filter as for nonfilter cigarettes; the reductive effect of filters in practice may be counteracted by variations in tobacco composition between the two types of cigarettes… In conclusion, tobacco and tobacco smoke represent the largest nonocccupational source of exposure for preformed nitrosamines.

1984 1984 1986 1987

Matsushita and Mori (2495) determined the levels of nitrogen dioxide and volatile NNAs in indoor air and cigarette SSS. Preussmann (15A43) tabulated the ranges of the reported levels of a variety of NNAs in tobacco and in cigarette MSS and SSS. The IARC (170) concluded that NDMA, NDEA, NPYR, and NEMA were tumorigenic to laboratory animals and that NDMA was one of the two most abundant volatile NNAs in cigarette MSS. Klus et al. (15A32) reported the levels of several volatile NNAs in ETS in several real life situations. (Continued )

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Table XV-3 (Continued) A Brief Chronology of the Research on Volatile N-Nitrosamines From 1937 to 1990 Year

Investigation

1987

The RTECS (Registry of Toxic Effects of Chemical Substances) (3095) reviewed the studies in which lung tumors were observed in laboratory animals treated with an NNA by a variety of administration routes. The RTECS categorized the positive inhalation findings involving NNAs as “equivocal.” E.g., the dose level used (200000 ng/m3) for NDMA in the inhalation experiments was significantly greater than the NDMA level observed (10 to 240 ng/m3) in ETS exposure.

1989- Caldwell and Conner (573) reported: 1990 The methodology previously reported [by others] leads to significant overestimation of N-nitrosamine concentrations in cigarette smoke. The overestimations were true for both volatile and tobacco-specific NNAs in MSS and SSS for the Kentucky Reference Cigarette 1R4F: MSS data indicated that the levels were 380% high for NPYR and 83%, 38%, 27%, and 19% for NAB, NAT, NNK, and NNN, respectively. Thus, it is probable that many of the previously reported levels of NNAs in MSS and SSS, tabulated in various articles [cf. Adams et al. (31), Hoffmann and Hecht (1727)] and cited by EPA (1148) and the U.S. Surgeon General (4005, 4009, 4010, 15A57) are incorrect. Hoffmann and Hecht (1727) did not acknowledge that the MSS levels listed for volatile NNAs and the TSNAs were likely to be incorrect (and high) because of the artifactual formation of both types during MSS (and SSS) collection for analysis as reported by Caldwell and Conner (572-574). EPA (1148) accepted without question the MSS volatile NNA and TSNA yields listed by Hoffmann and Hecht (1727) whose data were cited by the U.S. Surgeon General (4012). The levels of various NNAs reported in foodstuffs and beverages are also possibly in error because of artifactual formation of NNAs during the isolation procedure and subsequent quantitation. 1990

In their list of 43 “tumorigenic agents” in tobacco and/or smoke, Hoffmann and Hecht (1727) included the following volatile NNAs: NDMA, NDEA, NEMA, and NPYR. Little comment was made about these four volatile NNAs and their supposed tumorigenicity to smokers. However, they did note that IARC (1870) had evaluated the bioassay data from laboratory animals exposed to these NNAs and considered the data sufficient to classify all four as tumorigenic to animals. IARC did not express an opinion as to whether these four were tumorigenic to humans. Brunnemann et al. (1459, 460, 462) summarized data from several publications on the levels of various volatile NNAs (NDMA and NPYR) in indoor air at various sites (trains, offices, coffee shops, dance halls).

in tobacco and/or smoke. EPA had based its assessment of this compound on the Hoffmann-Hecht list of forty-three “tumorigenic agents in tobacco and tobacco smoke” (1727). Rodgman’s reasoning was as follows: Since the diethanolamine salt had not been used in the United States for nearly a decade, the level of this nitrosamine should now be substantially reduced in tobacco as well as in MSS and SSS from cigarettes containing such tobacco. The chronological pattern of decrease in levels of NDELA might parallel those reported for the decrease in levels of arsenic and DDT in tobacco (and its smoke) when arsenicals and DDT were no longer used on tobacco in the United States. For example, in 1952, arsenicals were removed from the list of recommended and permissible insecticides for tobacco. By 1968, the arsenic content of U.S.-grown tobacco had decreased to 0.5–1.0 μg/g from the 1951 level of about 50 μg/g of tobacco (1870, 4005); arsenic levels reported in 1975 by Griffin et al. (1391) were 0.5 to 0.9 μg/g of tobacco. Similarly, discontinuance of the use of chlorinated insecticides such as DDT in U.S. tobacco culture in the late 1960s resulted in a gradual and substantial reduction of DDT residues in leaf tobacco. Between 1968 and 1974, the residual DDT level in American flue-cured tobacco decreased rapidly and substantially (1870, 4005) from 52 μg/g in 1968 to 6 μg/g in 1970, and to 0.23 μg/g in 1974.

Hoffmann et al. (1696) had predicted that the NDELA level in tobacco would decrease: At present, NDELA [N-nitrosodiethanolamine] levels are relatively high in U.S. brands (290–300 mg/kg) but they are expected to decrease, since the herbicide was banned from use on tobacco as of October 1981 (1147).

In 1982, the U.S. Surgeon General concluded (4010) that NDELA was a carcinogen, noting not only did NDELA induce carcinomas in treated laboratory animals (carcinoma of the liver and kidneys in rats, carcinoma of the trachea in hamsters) but also it was present in tobaccos treated with the diethanolamine salt of maleic hydrazide. In the National Technical Information Service 3rd Annual Report on Carcinogens (2686), it was concluded that there was sufficient evidence to classify NDELA as a carcinogen in laboratory animals. In its review of tumorigenic components of tobacco and tobacco smoke, the IARC (1870) noted for NDELA: Its presence in tobacco products has been related to the use of the sucker growth inhibitor, maleic hydrazide when formulated with the diethanolamine salt (“MH-30” or “MH-40”) …; in the USA, that formulation has been replaced by the potassium salt … Tobaccos grown in a pesticide-free

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N-Nitrosamines

NO N HO

H N

H N

II

OH HO

I

OH

O

III

NO N O IV

Figure XV-1  N-Nitrosodiethanolamine (NDELA) and N-nitrosomorpholine (NMOR). environment and smoke generated from such tobaccos are devoid of N-nitroso-diethanolamine [NDELA].

Hoffmann and Hecht (1727) included five volatile NNAs [NDMA, NDEA, NEMA, NPYR, NMOR] and the nonvolatile NDELA in their list of forty-three “tumorigenic agents in tobacco and tobacco smoke.” They noted that NMOR had not been reported as a tobacco smoke component. Possible relationships between diethanolamine {I}, NDELA {II}, morpholine {III}, and NMOR {IV} are illustrated in Figure XV-1. It is possible that as the NDELA level in tobacco has declined, the levels of morpholine and NMOR also have declined. More recent major efforts in the NNA-tobacco area have been devoted to the study of TSNAs and N-nitrosamino acids rather than to the NDELA/NMOR question. Tobacco products and smoke, however, are not the only source of exposure to NDELA. As noted previously, it is highly likely that the current levels of NDELA in tobacco products is approaching zero because of the discontinued use of the diethanolamine salt of maleic hydrazide in U.S. tobacco agronomy. However, consumer exposure to NDELA from nontobacco sources is possible. Studies of NDELAcontaminated cosmetics indicated substantial levels of NDELA have been identified in cosmetics, for example, Fan et al. (15A12) detected NDELA in twenty-seven of twentynine products tested at levels ranging from 1 to 48,000 ppb; Klein et al. (15A31) detected it in five of ten cosmetic products (range = 20 to 4113 ppb). Hecht (15A15) found no NDELA in the products but did find N-nitrosomethyldodecylamine in six of seven cosmetics containing laurylamine (dodecylamine). NDELA is readily absorbed through the skin after application of NDELA-contaminated cosmetics and is detected in cosmetic users’ urine, [see Preussmann and Eisenbrand (2990)]. The other nonvolatile NNA is NPRO (see Table XV-1). It was not included by Hoffmann and Hecht (1727) in their list of forty-three “tumorigenic agents in tobacco and tobacco smoke” or any of the subsequent lists tabulated in Table XV-2. Scott et al. (3566) and Brunnemann et al. (511) reported that cigarette and chewing tobaccos differed in their NPRO levels: Cigarette tobacco contained ≈2 ppm (less than 1% of free proline was nitrosated), chewing tobacco contained about 35 ppm (up to 40% of free proline was nitrosated). They reported that the NPRO level is dependent on proline level, nitrate level, and curing method.

Brunnemann et al. (509) reported the measurement of the endogenous formation of NPRO in smokers and nonsmokers on a controlled diet, relatively low in proline and ascorbic acid. The NPRO in urine was determined in 24-h urine samples on days 3, 6, 9, and 12. Different groups in the study were administered proline and/or ascorbic acid at appropriate times during the experiment. Ascorbic acid intake reduced urinary levels of NPRO. Differences in NPRO excretion by smokers and nonsmokers on the controlled diet, ascorbic acid supplement, no proline supplement were not statistically significant. The results of numerous studies on the in vivo formation of NNAs were presented at the 1983 IARC conference [O’Neill et al. (15A39)]. Many dealt with the in vivo generation of NPRO in nitrite- and proline-treated mammalian species, including humans. Numerous investigations have been conducted on NPRO because of its presence not only in tobacco and tobacco smoke but also in a variety of consumer products (meat, bacon, ham, chicken, fish, toast, biscuits, cornflakes, beer) [Brunnemann et al. (509), Hansen et al. (15A14), Pensabene et al. (15A41), Pollock (15A42), Sen and Seaman (15A50), Sen et al. (15A51)]. In the IARC monograph (1870), it was noted that NPRO was detected in cigarette smoke at extremely low levels (<1 ng/cigarette) by Brunnemann et al. (511) despite the fact it is readily detected in tobaccos. Hoffmann et al. (1696) listed the levels of NPRO in various tobacco products (cigarette tobaccos, little cigars, cigars, chewing tobaccos, snuff). The reported values ranged from a low of 450 to a high of 22000 ng/g of tobacco (dry weight).

XV.C Tobacco-Specific N-Nitrosamines A year after the proposal by Druckrey and Preussmann (1057) that the conditions in a smoked cigarette were appropriate for the generation of NNAs, Boyland et al. (422, 423, 15A01) speculated that it was possible, because of the formation of NNAs by the reaction of nitrogen oxides with secondary amines, that cigarette MSS could contain NNN and NAB because of the presence of the secondary amines nornicotine and anabasine in tobacco and smoke. They also reported that oral administration of NAB to rats induced esophageal tumors. After nearly a decade of investigation on the volatile NNAs in tobacco smoke, attention was turned to the higher molecular weight NNAs. Figure XV-2 shows the relationships among the nicotinerelated alkaloids — nornicotine {V}, nicotine {VI}, anatabine {VII}, anabasine{VIII} — and the NNAs {IX, XI-XVII} and cotinine {X}. Table XV-4 summarizes some of the early research on the TSNAs. Between the early 1980s and 2004, a substantial number of studies were devoted to some aspect of the TSNAs in tobacco and/or its smoke. Included were conference presentations and journal publications in which were discussed analytical technology, artifactual TSNA generation during collection and analysis, quantitation, adverse biological effects and their inhibition, and effect on various biological systems and

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LEGEND

R

N H

R IX

R

R V

VI

R

N

N

N

NO

O XIII

N NO

R

X

R

O R

N OH R NO XIV

N H

VII

N H

R

VIII

V VI VII VIII IX X XI XII XIII

R= N

N

XI

NO

N

R

NO

NO

XV

XIV

CH=O

CH2OH N

XII

N

R

XVI

R NO

COOH N

NO

XV XVI XVII

XVII

Nornicotine Nicotine Anatabine {1,2,3,6-tetrahydro-2,3'-bipyridine} Anabasine {3-(2-piperidinyl)pyridine} N´-Nitrosonornicotine {NNN} Cotinine N´-Nitrosoanatabine {NAT} N´-Nitrosoanabasine {NAB} 4-(N-Methylnitrosamino)-1-(3-pyridinyl)-1butanone {NNK} 4-(N-Methylnitrosamino)-1-(3-pyridinyl)-1butanol {NNAL} 4-(N-Methylnitrosamino)-4-(3-pyridinyl)-4butanol {iso-NNAL} 4-(N-Methylnitrosamino)-4-(3-pyridinyl)butanal 4-(N-Methylnitrosamino)-4-(3pyridinyl)butanoic acid {iso-NNAC}

Figure XV-2  Tobacco-specific N-nitrosamines.

Table XV-4 A Brief Chronology of the Research on Tobacco-Specific N-Nitrosamines Year

Investigation

1964

Boyland et al. (422, 423) suggested that, because of the possibility of the formation of NNAs by the reaction of NOx with secondary amines, cigarette MSS could contain NAB and NNN generated from nornicotine and anabasine in tobacco MSS. NAB, when administered orally to rats, induced esophageal tumors in the treated animals.

1973

At the Austria Tabakwerke A.G., Klus and Kuhn (2136) detected 40 ng/cig of NNN in the MSS from cigarettes made with nornicotine-rich tobacco (1.95% nornicotine). However, they failed to detect NNN in the MSS from a blended commercial cigarette. They concluded: From the biological and toxicological points of view, the expected quantity of nornicotine nitrosamine developed from a commercial cigarette containing an average of 0.04% nornicotine is almost meaningless.

1973

Rathkamp et al. (3080) reported that MSS from an 85-mm U.S. blend nonfiltered cigarette contained NAT at less than 20 ng/cig.

1974

Hoffmann et al. (1761) confirmed the report by Klus and Kuhn (2136) of the presence of NNN in cigarette MSS. They suggested that nicotine and nornicotine were NNN precursors with nicotine actually being the more important precursor because of its preponderance in tobacco. Their results differed, however, from those of Klus and Kuhn on the level of NNN in MSS from a commercial blended cigarette; Hoffmann et al. (1761) reported that the MSS from a nonfiltered U.S. blended cigarette contained 137 ng of NNN.

1974

Hecht et al. (1576) reported the level of NNN in tobacco paralleled the nitrate level. They also suggested the TSNA levels in tobacco may be controllable by appropriate selection of the curing process. Flue-cured tobaccos usually show the lowest NNN level vs. the levels in tobaccos cured by other methods, e.g., air-curing.

1974

Hoffmann et al. (1733) reported that various types of commercial tobacco contained substantial levels of NNN at levels ranging from 2 to 90 mg/g (2 to 90 ppm). Two commercial cigarette samples showed NNN levels of 2.2 and 6.6 mg/g. They noted: This is to our knowledge the highest concentration of a positively identified NNA yet reported in an environmental source. NNAs in meat, fish, beverages, and related materials rarely exceed 0.1 ppm.

1976- Hecht et al. (1563, 1565) suggested that nicotine was the precursor of NNK and 4-(N-methylnitrosamino)-4-(3-pyridinyl)-11977 butanal in tobacco via opening of the pyrrolidine ring of nicotine. 1977

The Royal College of Physicians (3364) noted: N’-Nitrosonornicotine has been identified in both tobacco smoke and unburnt tobacco, the concentration in the latter being 2,000 to 9,000 parts per billion – concentrations much higher than those of other nitroso compounds found in meat, fish, or beverages. Its presence may be of great biological importance and could explain the correlation between tobacco chewing and the development of cancer of the mouth.

1979

For tobaccos, Hoffmann et al. (1679) reported levels of 0.2 to 45 ppm of NNN and 0.1 to 35 ppm of NNK. For cigarettes, they reported MSS levels of 0.2 to 3.7 μg/cig for NNN and 0.12 to 0.44 μg/cig for NNK.

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Table XV-4 (Continued) A Brief Chronology of the Research on Tobacco-Specific N-Nitrosamines Year

1979

1979 1980

1981 1981

1981

Investigation

After reviewing earlier data that indicated NNN was moderately carcinogenic in the Syrian golden hamster, Hoffmann et al. (15A28) concluded: Since NNN is present in ppm levels in tobacco and in microgram amounts in the smoke of a cigarette, it may contribute to the carcinogenicity of tobacco smoke. The U.S. Surgeon General (4005) reported the identification of NNN and NAT in MSS. MSS levels listed for NNN were those reported by Hoffmann et al. (1679) (0.2 to 3.7 μg/cig. No quantitative data were listed for NAT. Hecht et al. (15A18) reported high rates of benign and malignant tumors in two groups of F344 rats treated with TSNAs. One group of rats was treated with NNN; the other group was treated with NNK. For each group, the TSNA (3.4 mmol total dosage) was administered in 60 subdoses over a period of 20 weeks. Adams et al. (23) reported the results of their study on the transfer of 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK) from tobacco to MSS and its formation from tobacco components during the tobacco smoking process. McCoy et al. (15A36) studied the influence of ethanol in the diet on the tumorigenicity of NNN administered to Syrian golden hamsters at two dose levels. In the group of test animals whose caloric intake was equal to that of the control group, no accelerating effect of ethanol on NNN tumorigenicity was observed. Hoffmann et al. (1710) reported that, in a study involving subcutaneous injections into Syrian golden hamsters, the tumor production data indicated NNK was a more potent carcinogen than NNN. The authors stressed the importance of this finding because of the relatively high exposure (approximately 1 µg/cig for an 85-mm filtered cigarette) of smokers to NNK (see also Table 9) which they described: As a carcinogen more potent than the strongly carcinogenic N’-nitrosonornicotine… Exposure to NNK in tobacco and tobacco smoke should certainly be minimized.

1981

In the U.S. Surgeon General’s 1981 report (4009), the relative tumorigenicities of NNN, NNK, and (NAT were discussed: NNN is a moderately active carcinogen in mice, rats, and Syrian golden hamsters, whereas NNK is a strong carcinogen to the respiratory tract of all three species; NAT has so far not been bioassayed. After it was noted that conclusive epidemiologic data were not available to define the precise effect of NNN in humans, the following statement was cited from a 1978 IARC report: NNN should be regarded for practical purposes as if it were carcinogenic to humans.

1982

1982 1982

Brunnemann et al. (471) described the environmental occurrence of NNAs derived from foods and other consumer items, including tobacco products. They also discussed the possibility of the in vivo formation of NNAs in blood serum, gastric secretions, and urine. The IARC (1867) concluded that there was sufficient laboratory evidence to categorize NNN as carcinogenic in laboratory animals. In the 3rd Annual Report on Carcinogens by the National Technical Information Service (2686), the National Toxicology Program officials noted: Cigarette smokers, tobacco chewers, cancer researchers, and organic chemists are at greatest risk of exposure to N-nitrosonornicotine… Smokers and persons breathing tobacco smoke may inhale a significant amount of N-nitrosonornicotine. The amount of this substance in commercial U.S. tobacco products varies from 1.9 to 88.5 ppm; this is one of the highest values of an experimental nitroso compound reported in the literature.

1982

1982 1983

In the U.S. Surgeon General’s 1982 report (4011), it was stated: At this time, there is no experimental evidence on the formation of TSN (tobacco-specific nitrosamines) in the lung upon inhalation of tobacco smoke. However, a smoker of one or two packs of cigarettes daily retains…1 to 4 milligrams of nornicotine…thus, in vivo formation of tobacco-specific NNAs is a real possibility. The report also concluded that NNK is “…by far the most potent carcinogens of the TSNAs.” In this 1982 report, NNK was included in a list of “toxic and tumorigenic agents of cigarette smoke.” It was noted that the level of NAT in MSS of U.S. cigarettes ranged from 0.15 to 4.6 ng/cig. It was also pointed out that no carcinogenicity bioassay data were currently available for NAT in 1982. In their review on MSS and SSS composition and SSS:MSS ratios, Klus and Kuhn (2142) summarized the published data [Hoffmann et al. (1679)] on MSS and SSS yields of several tobacco-specific NNAs (NNN, NNK, NAT). Using radiolabeled compounds, Adams et al. (29) conducted a detailed study on the formation and transfer of NNK: It was reported that 6.9-11.0% of the tobacco component transferred to MSS; this amount represented 26-37% of the NNK in MSS, the remainder (63-74%) was considered to be formed from nicotine during the smoking process. However, conflicting data were later presented by Fischer et al. (1193, 1199) who reported that NNN and NNK in cigarette MSS arose only by transfer from the tobacco rod and were not formed pyrogenetically during the smoking process. (Continued )

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Table XV-4 (Continued) A Brief Chronology of the Research on Tobacco-Specific N-Nitrosamines Year

Investigation

1983

Hecht et al. (15A16) reported the induction of lung tumors in Syrian golden hamsters treated with a single dose of 1 milligram of 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK). Castonguay et al. (15A08) reported:

1983

As a result of tobacco smoking, NNN [N’-nitrosonornicotine] and NNK [4-(N-methylnitrosamino)-1-(3-pyridinyl)-1butanone] are among the most ubiquitous procarcinogens detected in the human environment. In their carcinogenicity study, Castonguay et al. found that a total dose of 0.1 mmol of NNK induced 3.76 lung tumor/mouse, or a total of 86.5 lung tumors. This value was 29 times higher than that found in the similarly treated NNN group. The number of lung carcinomas in the NNK group was 41 times higher than that in the NNN group. 1983 Brunnemann et al. (499) studied the influence of stem (and their nitrate content) on the volatile and tobacco-specific NNAs in MSS and SSS. They reported that the MSS yields of “tar”, nicotine, carbon monoxide, and carbon dioxide were not greatly influenced by filler nitrate content. This should be contrasted with previous reports from the same laboratory – at a time when nitrate addition or high-nitrate tobacco use was touted as beneficial – on the reduction in smoke yields of “tar”, nicotine, PAHs, phenols, and carbon monoxide as a result of nitrate addition [Wynder and Hoffmann (4332), Hoffmann and Wynder (1797, 1798)]. The SSS yield of NDMA was extremely high (>1000 ng/cig). SSS yields of NDMA and NNN were dependent on filler nitrate content. 1983- Hecht et al. (15A17, 15A22) and Hecht and Lin (15A21) demonstrated the genotoxicity (Ames test with Salmonella 1984 typhimurium) of NNK and NNN [Hecht et al. (15A17)]. 1984 As noted previously, since the early 1980s, Hoffmann and his colleagues at the American Health Foundation have presented or published numerous reviews, many repetitious in content, of their views on NNAs. In particular, they have emphasized the TSNAs, their levels in tobacco, in MSS and SSSs, and in ETS, their tumorigenicity in laboratory animals, and their supposed involvement in tumor induction in tobacco users, e.g., Hecht et al. (15A17), Hoffmann et al. (1688, 1730, 1731, 1746, 1770, 1772, 15A26, 15A27), Djordjevic et al. (1014), Hecht and Hoffmann (1571, 1571a, 15A20), Hoffmann and Hecht (1727); Brunnemann and Hoffmann (15A03). 1984 Although their data showed that an increase in the nitrate content of cigarette tobacco reduced the MSS levels of FTC “tar”, nicotine, carbon monoxide, catechol, and B[a]P, Adams et al. (28) emphasized that significantly higher yields of volatile NNAs and TSNAs were found in the MSS of an 85-mm nonfiltered cigarettes whose nitrate contents were increased by sodium nitrate addition. Despite reductions in MSS levels of “tar”, nicotine, B[a]P, and catechol, Adams et al. considered that the “carcinogenic potential” of the whole MSS from the enhanced-nitrate cigarettes was increased primarily due to elevated yields of nitrogen oxides (NOx), volatile NNAs, and TSNAs. They stressed the importance of the NOx as a precursor in the endogenous formation of NNAs during tobacco smoke inhalation. However, they ignored the fact that 1) only traces of nitrogen dioxide NO2 exist in cigarette MSS, 2) over 95% of its NOx content is nitric oxide, NO, and 3) other components in tobacco smoke reduce the nitric oxide-to-nitrogen dioxide conversion (NO→NO2) [Cooper (815), Cooper and Hege (816)]. On the basis of their findings. Adams et al. concluded: The findings of this study support the recommendation that the nitrate content of tobacco products should be reduced. 1984

Hoffmann et al. (1769) reported the following results from the MSS and SSS analyses of U.S. commercial cigarettes: Level Found, ng/cig

TSNA NNN NNK NAT

MSS 120-1000 80-770 140-1000

SSS 150-1700 170-410 150-270

In this study, subcutaneous injection of NNN (three levels: 9.0, 3.0, and 1.0 mmol/kg, thrice weekly for 20 weeks) into F344 rats showed a dose response with respect to nasal tumors (60% and 100% at the higher two levels) and carcinoma of the nasal cavity. Lung adenomas were observed at all three dose levels. In a parallel experiment with NNK, relatively high carcinogenicity in the rats was observed. They wrote: Perhaps the most important finding was that even the lowest dose of NNK induced a high percentage of lung tumors in males (85%) and a significant yield of lung tumors in females (30%). These lung tumors included squamous cell carcinomas. In an NAT experiment, similar to those for NNN and NNK, NAT was not carcinogenic at any of the three dose levels. 1986

IARC (1870) concluded that the TSNAs are the most abundant suspected carcinogens in tobacco smoke. It considered NNN and NNK to be proven carcinogens for laboratory animals. It considered the evidence limited for defining the carcinogenicity of NAB in laboratory animals and inadequate to label NAT as a carcinogen for laboratory animals.

1987

Adams et al. (31) presented data on the levels of TSNAs in MSSs and SSSs from different types of cigarette. TSNAs comprised NNN, NNK, NAB, and NAT. For the latter three, the per cigarette SSS levels substantially exceeded the MSS levels.

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N-Nitrosamines

Table XV-4 (Continued) A Brief Chronology of the Research on Tobacco-Specific N-Nitrosamines Year

Investigation

1987

Brunnemann et al. (469) identified a new TSNA 4-(N-methyl-nitrosamino)-4-(3-pyridinyl)-1-butanol (iso-NNAL) in snuff and cigarette tobaccos. It was not detected in either cigarette MSS or SSS. In a study involving iso-NNAL, NNN, and NNK, LAVOIE et al. (15A34) determined the tumorigenicity of the three in mice. Klus et al. (15A32) measured several ETS-related TSNAs in indoor air of an 83-m3 office under various smoking conditions. NNN varied from 0.7 to 6 pg/L, NNK varied from 0.2 to 10.7 pg/L. They found no correlation with the carbon monoxide levels. Tricker et al. (3945) reported that nicotine was not N-nitrosated to NNN under simulated gastric conditions. However, nornicotine, anabasine, and anatabine were N-nitrosated to NNN, NAB, and NAT, respectively, under such conditions. They also reported that NNK decomposed slightly under these conditions. Hecht and Hoffmann (15A19) considered both NNN and NNK as powerful carcinogens because they induced benign and malignant tumors of the lung, nasal cavity, esophagus, pancreas and/or liver in mice, rats, and hamsters. Caldwell and Conner (573) reported:

1987 1988

1989 19891990

1990

The methodology previously reported [by others] leads to significant overestimation of NNA concentrations in cigarette smoke. The overestimations were true for both volatile NNAs and TSNAs in MSS and SSS for the Kentucky Reference Cigarette K1R4F used in their study: MSS data indicate the levels found were 380% high for NPYR and 83%, 38%, 27%, and 19% for NAB, NAT, NNK, and NNN, respectively. Thus, it is highly probable that the levels of NNAs in smoke tabulated in articles such as those by Hoffmann and Hecht (1727) and frequently cited by the EPA and the Surgeon General are incorrect. Hoffmann and Hecht (1727) reviewed the evidence supporting the roles of various classes of tobacco smoke components in cancer induction by tobacco smoke. They concluded that PAHs and NNK are the major carcinogens involved in lung cancer induction by cigarette smoke. In their 1990 publication, they stated: These exposure estimates [for benzo[a]pyrene] and the determinations of the tumorigenic potential of [polycyclic aromatic hydrocarbons] in bioassays strongly suggest that [polycyclic aromatic hydrocarbons] play a significant role in the induction of respiratory tract cancer in smokers… Human exposure to [4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK)] is consistent with its potential role as a causative agent for lung cancer… These calculations [relating smoker exposure to 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK) to dose level needed to induce respiratory tract tumors in hamsters], which ignore the probable endogenous formation of [4-(Nmethylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK)…], point to a significant risk for the smoker and strongly support the role of [4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK)] as an important etiological factor in lung cancer. However, they also noted: The organospecificity of [4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK)] for the lung is consistent with its role in tobacco smoke-induced respiratory carcinogenesis. The lung is the main target organ for [4-(N-methylnitrosamino)1-(3-pyridinyl)-1-butanone (NNK)] administered [per os] or [subcutaneously] to rats and hamsters… Lung tumorsa have also been induced in mice after topical applications of high doses of [4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK)]… It has not been tested by inhalation.

1990

1991

a The tumor type was the adenoma, not the squamous cell carcinoma supposedly associated with cigarette smoking in smokers. In their list of 43 “tumorigenic agents in tobacco and tobacco smoke,” a list cited frequently in reports issued by various governmental agencies (EPA, USPHS), Hoffmann and Hecht (1727) listed three TSNAs: NNN, NNK, and NAB, the same three listed previously in 1986 by Hoffmann and Wynder (1808) and Iarc (1870) and subsequently by Hoffmann and his colleagues (1740, 1741, 1743, 1744, 1773) In the introduction to their publication on lung and pancreatic cancer, Hecht and Hoffmann (1571a) reiterated their previous conclusion on the role of PAHs and NNK in cancer causation in tobacco smokers:

Polynuclear aromatic hydrocarbons and NNK [4-(N-methyl-nitrosamino)-1-(3-pyridinyl)-1-butanone] are the major carcinogens involved in lung cancer induction by cigarette smoke and that NNK [4-(N-methylnitrosamino)-1-(3pyridinyl)-1-butanone] is a likely candidate for induction of pancreatic cancer in smokers. 1992

Mimicking intragastric conditions, Caldwell et al. (575, 576) studied nicotine N-nitrosation and found it to be extremely slow. They concluded: It is unlikely that nicotine itself contributes to exposure to nitroso compounds [N’-nitrosonornicotine (NNN), 4-(Nmethylnitrosamino)-4-(3-pyridinyl)-1-butanal, and 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK)] due to chemically mediated intragastric nitrosation. (Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table XV-4 (Continued) A Brief Chronology of the Research on Tobacco-Specific N-Nitrosamines Year

Investigation

Caldwell et al. confirmed, in part, the 1988 findings of Tricker et al. (3945) who had previously studied the potential endogenous formation of TSNAs under conditions simulating normal human gastric conditions. 1991- Brunnemann et al. (459, 460) sampled indoor air in bars, restaurants and trains; the levels found for NNN ranged from 0 to 23 1992 pg/L; for NNK, 1 to 29 pg/L; for NAT), 0 to 9 pg/L. 1992 In 1992 Chung et al. (793a) demonstrated that components, e.g., phenethyl isothiocyanate, indole-3-carbinol, in green tea and cruciferous vegetables inhibited lung tumorigenesis induced by NNK. 1993 Carmella et al. (15A05) identified 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanol (NNAL) and its glucuronide in the urine of cigarette smokers, thus providing the first evidence for metabolites of TSNAs in human urine. No NNK was detected. Results with smokers’ urine were consistent with those found previously with monkeys’ urine. 1993 Hoffmann et al. (1773) again cited the list of 43 tumorigens in tobacco and smoke from Hoffmann and Hecht (1727). Despite the fact that in 1991, Hecht and Hoffmann (1571a) concluded that “polynuclear aromatic hydrocarbons and NNK [4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone] are the major carcinogens involved in lung cancer induction by cigarette smoke and that NNK is a likely candidate for induction of pancreatic cancer in smokers”, they listed NNK, NNN, and NNAL in this publication only as “likely causative agents for tobacco-related cancers.” 1993 Castonguay (15A07) described the inhibition in A/J mice of NNK-induced lung tumorigenesis by ellagic acid, a polyphenolic dilactone.

XV.D N-Nitrosamino Acids

tobacco users. Figure XV-3 is a plot of the chronology from 1983 through 2004 of TSNA-related references listed in our Reference section. It is obvious from the graphical depiction that the decade from the late 1980s to the late 1990s was a highly productive period for such studies. It is also obvious from the references in bold print that the American Health Foundation was a major contributor to our knowledge on TSNAs.

15A22a

15A16 15A08 Ref. 3179 No. 2728 15A43 1724 15A27 1559 15A17 1558 3184 1003 2990 667 2441 650 2437 99 1696 98 1694 29 660 22 25 1983

1984

2852 1746 1725 728 595 468 26 24 1985

15A44 15A34 15A04 656 469 379 324 70 15A23 67 15A21 65 2559b 64 657 63 99 62 36 33 1986

1987

3947 3945 3184 3180 2436 1571 572 508 19 1988

The results of several epidemiological studies suggested an association between the use of chewing tobacco or snuff and oral cancer. These products differ from smoking products (cigarettes, cigars, pipe tobaccos) in that they are not subjected to the high temperatures encountered in the smoking process. Thus, smokeless products contain little, if any, of the combustion products alleged to be significant

15A56 15A20 15A19 15A06 15A03 3954 3181 4405 3948 2995 3944 3374 1770 3182 3373 1688 2994 2917b 1198 2235 2674 1197 1771 1676 1193 1750 1196 1191 1571a 1195 1036 1200 1194 1014 1199 1192 995 1013 1012 720 486 1002 573 484 573 484 464 547 483 459 543 326 325 466 205 202 204 201 76 1989

1990

1991

Reference numbers listed in bold print represent conference presentations and/or journal publications by Hoffmann and his American Health Foundation colleagues.

aReferences

3953 2168 1777 1005 739a 549 542 501 487 463 460 1992

Year

listed as 15A22, etc. may be found in the Bibliography at the end of the text and are listed as additional references to Chapter 15. 15A45 4128 4077 3943b 3342 3816 15A05 2916 3176a 4129 3177 2915 2917 3343 2996 2637 1305 2700 2992 4161 2561 1304 2638 1702 2997 2051 951 2618 1573a 2993 1988 557 2588 1562a 1775 2943a 1016 505 2362 554 502 2169 1011 279 2052 313 59 1001 670 50 507 1993– 1994

1995– 1996

1997– 1998

1999– 2000

2001– 2002

2003– 2004

Figure XV-3  References pertinent to tobacco-specific N-nitrosamines, 1983 to 2004.

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N-Nitrosamines

tumorigens, for example, the PAHs and their N-containing analogs, in tobacco smoke. As a result, snuff and chewing tobacco NNAs became suspect because they were the only components known to be laboratory animal tumorigens. Preformed NNAs in these tobacco products and NNAs endogenously formed in the product users were considered by many to be the causal factor for oral cancer in snuff dippers [Hoffmann and Adams (1677), Brunnemann et al. (507a, 510, 15A04), Hoffmann et al. (1684, 1697, 1707, 1713, 1722), Hecht et al. (15A23), Adams et al. (33), Prokopczyk et al. (15A44), Carmella et al. (15A06), Tsuda and Kurashima (15A56), Djordjevic et al. (1008)] and in tobacco chewers [Brunnemann et al. (468, 498), Wenke et al. (15A58), Hoffmann et al. (1730, 1731), IARC (1869), Prokopczyk et al. (2995), Tsuda and Kurashima (15A56)]. In studies to elucidate the possible tumorigens in chewing tobacco and snuff, the only known components tumorigenic in laboratory animals identified were various NNAs, particularly the TSNAs NNN and NNK plus a group of N-nitrosamino acids, including NPRO. Whereas discussions and investigations on volatile NNAs [Druckrey and Preussmann (1057), Serfontein and Hurter (3595–3599)] and several TSNAs NNN, NAB [Boyland et al. (422, 423)] have appeared in the literature for over four decades, reports on identifications of N-nitrosamino acids are much more recent. Ohshima et al. (2852) identified several N-nitrosamino acids, 3-(methylnitrosamino)propanoic acid [also known as Nmethyl-N-nitroso-β-alanine (NMPA)], 4-(methylnitrosamino) butanoic acid (NMBA), and 1-nitroso-2-piperidinecarboxylic acid (also known as N-nitrosopipecolic acid), in various types of tobacco (cigarette, chewing, pipe, cigar, and snuff tobaccos). Decarboxylation of these N-nitrosamino acids would yield NEMA, N-nitrosomethylpropylamine, and NPIP. IARC (1986) did note the 1985 Ohshima et al. findings on these N-nitrosamino acids in tobacco. Following their identification of several N-nitrosamino acids in snuff, Djordjevic et al. (992) investigated these acids in 1R1 and 1R4F reference tobaccos from the University of Kentucky. In addition to detecting 4-(Nmethylnitrosamino)-4-(3-pyridinyl)-1-butanol (iso-NNAL), 4-(N-methylnitrosamino)-4-(3-pyridinyl)-1-butanal, and the common TSNAs, the following N-nitrosamino acids were identified: 4-(N-methylnitrosamino)-4-(3-pyridinyl)butanoic acid (iso-NNAC), 4-(methylnitrosamino)butanoic acid (NMBA), 3-(methylnitrosamino)propanoic acid (N-methylN-nitroso-β-alanine; NMPA), 2-(methylnitrosamino)acetic acid (N-methyl-N-nitrosoglycine, N-nitrosarcosine (NSAR), 1-nitroso-2-piperidinecarboxylic acid, and NPRO. Djordjevic et al. considered these NNA compounds important in cancer causation, particularly in snuff and chewing tobacco users. Djordjevic et al. (992) confirmed the findings of Ohshima et al. (2852) on the presence of N-nitrosamino acids in tobacco. In addition to the N-nitrosamino acids identified by Ohshima et al., Djordjevic et al. identified 4-(N-methylnitrosamino)-4(3-pyridinyl)-1-butanoic acid (iso-NNAC). The highest concentrations of these N-nitrosamino acids were found in snuffs and black tobacco. They also identified 3-(methylnitrosamino)

705

propanoic acid (NMPA) in tobacco and MSS and estimated its transfer from tobacco to MSS to be 0.85%. In studies with N-nitrosamino acid-spiked cigarettes, Brunnemann et al. (466) reported that added NMPA did not completely decarboxylate. Some was esterified to the methyl ester. Some of the intact acid, its methyl ester, and its decarboxylation product, NEMA, appeared in the MSS. Similar to NMBA, some NMBA transferred intact from the tobacco to the MSS, some formed the methyl ester, which appeared in the MSS, and some decarboxylated to yield N-nitrosomethylpropylamine, which also appeared in the MSS. NPRO primarily decarboxylated to NPYR. NSAR primarily decarboxylated to NDMA. Djordjevic et al. (1012) identified 4-(N-methylnitrosamino)-4-(3-pyridinyl)-1-butanoic acid (iso-NNAC) in tobacco and in MSS. This acid was found only in the MSS from cigarettes containing tobacco spiked (2 mg/cigarette) with cotinine. From the results of in vitro nitrosation studies with radiolabeled cotinine and nicotine, Djordjevic et al. (995) proposed that the formation of 4-(N-methylnitrosamino)4-(3-pyridinyl)-1-butanoic acid (iso-NNAC) in tobacco proceeds via cotinine and its hydrolysis product 4-methyl-4(3-pyridinyl)-1-butanoic acid rather than via nicotine. Brunnemann et al. (464) presented a more detailed exposition of their 1989 findings on the fate in “spiked” cigarettes of several N-nitrosamino acids [2-(methylnitrosamino) acetic acid (NSAR), 3-(methylnitrosamino)propanoic acid (NMPA), 4-(methylnitrosamino)butanoic acid (NMBA), and N-nitrosoproline (NPRO)]. These acids are delivered intact to MSS, undergo esterification to the methyl ester and are delivered as such to MSS, and/or decarboxylate and are delivered to MSS as the NNAs NDMA, NEMA, NMPA, and NPYR, respectively. Djordjevic et al. (1013) described in greater detail their identification of 4-(N-methylnitrosamino)-4-(3-pyridinyl)1-butanoic acid (iso-NNAC) in tobacco and in MSS. They reported that iso-NNAC was found only in the smoke from cigarettes containing cotinine-spiked tobacco (2 mg/ cigarette) [see Djordjevic et al. (1012)]. Djordjevic et al. (1005, 1008) identified three new N-nitrosamino acids in snuff tobacco: 2-(methyl-nitrosamino)-3-phenylpropanoic acid, 2,5-di(methylnitrosamino)pentanoic acid, and 2,6di(methylnitrosamino)hexanoic acid. They discussed not only the identification of the three new N-nitrosamino acids but also the carcinogenic potential of these and other N-nitrosamino acids, particularly in the context of tobacco chewing or snuff dipping. Djordjevic et al. (993) reported that the levels of N-nitrosamino acids in snuff tobaccos were often 150 times those found in cigarette tobaccos (usually about 1 ppm). Examination of the results of the studies on N-nitrosamino acids in tobacco smoke reveals the importance of amino acids (and their precursors, the tobacco proteins) in N-nitrosamino acid formation before and during the smoking process. Figure XV-4 illustrates some of the relationships among the amino acids, N-nitrosamino acids, their methyl esters, and N-nitrosamines.

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The Chemical Components of Tobacco and Tobacco Smoke

H2N-(CH2)n-COOH

XVIII

COOH

H3C-N(NO)-(CH2)n-COOCH3 XXII

COOH N

NH2 H3C-NH-(CH2)n-COOH XIX

H3C-N(NO)-(CH2)n-COOH XX

HOOC-CH(NH2)-(CH2)n–1-COOH H3C-N(NO)-(CH2)n-H XXIII

XXI

H2N-(CH2)n-CH(NH2)-COOH

XXVIII

N H

COOH XXVIII

R-(CH2)n-CH(R)-COOH

n = 4 (-NH3) XXXII

XXV

XXVII

NO XXIX

NH XXXII

COOCH3

N NO

COOH

N

XXX

N NO

XXXI

COOH

COOH

where R = H3C-N(NO)-

XXIV n = 3 (-NH3)

XXVI

NO

N

NO

XXXIII

N

NO XXXIV

Figure XV-4  Relationships among amino acids, N-nitrosamino acids, their esters, and N-nitrosamines.

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N-Nitrosamines

XV.E Tobacco-Specific N-Nitrosamines: An Exception among the Major MSS Toxicants Since the mid-1950s various MSS toxicants, either as an individual component or a class of components, have had their moment of publicity but one by one their importance gradually faded. Chronologically, the first toxicants to become infamous were the tumorigenic PAHs, with B[a]P at the pinnacle because of its potent tumorigenicity to mouse skin and its per cigarette MSS yield. The chronology of the rise to notoriety of the various individual and/or class of toxicants has been previously depicted [see Figure  1 in Rodgman et al. (3307)] but not shown is when the prominence of most of them declined. In the mouse skin-painting bioassay, neither B[a]P nor the total tumorigenic PAHs accounted for the observed specific tumorigenicity (4354). The B[a]P content of CSC accounted for less than 2.5% and the total tumorigenic PAH content of CSC accounted for less than 3.5% of the CSC specific tumorigenicity [1056, 4312, see p. 626 in (4332)]. Inclusion of tumorigenic aza-arenes reported by Van Duuren et al. (4027) did not improve the situation. Hoffmann and Wynder (1798) reported that doubling or tripling the level of seventeen tumorigenic PAHs in CSC significantly increased the percent tumor-bearing animals (% TBA), whereas others reported that a 10-fold (3311) or 30-fold (2320) increase in the B[a]P level in CSC produced no change in the % TBA. In the early 1960s, the promoting effect of MSS phenols on tumorigenic PAHs was advanced to explain the tumorigenic response observed in CSC-painted mice. Inclusion of this effect in the assessment accounted for about 5% of the % TBA. In addition, reports of no change in the tumorigenicity of CSC when significant amounts (75% to 90%) of the phenols were removed from MSS (and the CSC) by selective filtration [see p. 626 in (55), 4344] and the inhibition of the specific tumorigenicity of B[a]P by phenol (149) diminished the alleged importance of the promoting effect of phenols. To offset the decrease in importance of the PAHs, azaarenes, and phenols, ciliastatic components in MSS then became the in-vogue toxicants. It was asserted, based on studies with clam cilia and mammalian ciliated tissue, that certain MSS toxicants impair lung ciliary activity, thus preventing removal of tumorigen-containing smoke particles from the lung. MSS components proposed as significant ciliastats included formaldehyde, acetaldehyde, acrolein, HCN, formic and acetic acids, and phenol. However, after the reported findings of Dalhamn et al. in 1968, the ciliary assertion faded because of the demonstration that less than a third of the ciliastats reach the lung cilia in human smokers (892, 893). In the mid-1960s, several other MSS toxicants had their brief moment of infamy, for example, 210Po, NO2, CO, Ni. In their comparison of lung cancer incidence in uranium miners exposed to 210Po vs. cigarette smokers exposed to MSS 210Po, Harley et al. (75) questioned the significance of 210Po in tobacco-induced lung cancer. Concern over NO2 diminished with the demonstration that over 95% of the NOx in MSS was

707

NO, not NO2, and the conversion of NO to NO2 was impeded by other MSS components (94). In the early 1960s, the formation of NNAs during tobacco smoking was suggested (423) as well as the possible presence of NNN and NAB in MSS (423, 3313). Between 1964 and the early 1970s, several volatile NNAs were identified in MSS. It was also reported that 60% to 85% of the volatile NNAs, like the phenols, are selectively filtered from MSS (514, 1236, 1761, 2635). The identification of several TSNAs, including NNN and NAB, then followed. Why have TSNAs maintained their status as important MSS toxicants while the importance of other individual and/ or classes of toxicants has faded? Alternate exposures are possible with toxicant classes other than the TSNAs, including NNAs, but the TSNAs, as defined, are “tobacco-specific.” In other words, no alternate exposure exists for TSNAs. In the detailed 1984 outline of chemical carcinogenesis edited by Searle (3568), the only class of MSS tumorigens discussed in 22 chapters comprising nearly 1400 pages was the NNAs [see pp. 839–844 in Preusmann and Eisenbrand (2990)]. Most of the data cited [see Tables VII to IX, pp. 841, 843, 844 in (2990)], are those from publications by Hoffmann and his colleagues (514, 1677, 1680, 1685). Since the early 1960s, a “less hazardous” cigarette has been defined on the basis of three criteria: (1) the per cigarette delivery of a specific toxicant has been lowered, (2) the ratio of the specific toxicant to MSS “tar” has been lowered, and (3) the specific tumorigenicity of the MSS “tar” as measured in the mouse skin-painting bioassay has been lowered. From bioassay results of more than 330 NNAs plus knowledge of fewer than sixty specific NNAs in MSS, it is obvious that the MSS NNAs cannot meet criterion (3). Over 330 N-nitroso compounds variously administered to forty different species have been reported as tumorigenic. No laboratory species is resistant to NNAs. In their summary of the results from 323 N-nitroso compounds bioassayed from 1956 to 1984, Preussmann and Stewart (2991) reported that 87% of the N-nitroso compounds are tumorigenic. Over 70% of the N-nitroso compounds studied were NNAs; the remainder were N-nitrosamides. Administration of most NNAs to laboratory animals via skin painting seldom results in carcinoma induction at the application site. Generally, tumors develop at site(s) remote from the painting site and various organs may be involved. This major difference between PAH and NNA tumorigenicity led to defining NNAs as organ-specific tumorigens. Failure to produce tumors with NNAs at the painting site subsequently led to studies of NNAs administered by alternate routes (injection [subcutaneous, intravenous, intraperitoneal], per os, intratracheal instillation, etc.). Administration of NNAs by inhalation was studied infrequently. Skin-painting studies with six NNAs (N-nitrosobutylmethylamine, NDEA, NDELA, iso-NNAL, NNK, NNN) present in tobacco and/or tobacco smoke were reported by Brune and Henning (15A02), F. Hoffmann and Graffi (15A30), Herrold (15A24), Herrold and Dunham (15A25), IARC (1870),

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Hoffmann et al. (1786a), and LaVoie et al. (15A34). Tumors developed elsewhere in the test animals but none at the painting site. In a painting study by Deutsch-Wenzel et al. (956a), NNN induced a few skin tumors, but no dose-response relationship was observed over a 12.5- to 200-µg range. In the same study, the tumorigenic potency to skin of N-nitrosoN-methylurea was estimated to be about 4% of that of B[a] P. In painting studies with N-nitroso-N-alkylureas, tumors did develop at the skin-painting site, but to date, no N-nitroso-Nalkylurea has been identified in tobacco or MSS.

XV.F Direct Transfer of TSNAs from Tobacco vs. Their Formation during the Smoking Process Nicotine, nornicotine, anabasine, and anatabine are precursors of TSNAs in tobacco and tobacco smoke (29, 1564). Both nicotine and nornicotine are considered to be NNN precursors. Since NNAs (both volatile and tobacco-specific) occur in tobacco, part of the NNAs in cigarette MSS was reported to be due to direct transfer of NNAs from tobacco to MSS, the remainder due to formation and transport during the smoking process (201). For NNK, the transfer from tobacco to MSS ranges from 6.9% to 11.0% of the amount in the tobacco; this represents about 30% of the NNK in MSS. Similarly, about 40% of the NNN in MSS is transferred from the tobacco. Hoffmann et al. maintain that the remainder of NNN and NNK in MSS is formed during the smoking process (1558, 1734). Both the levels of volatile NNAs and TSNAs in MSS are proportional to the nitrate content of the tobacco filler (3985). However, the premise of the pyrogenesis of NNN and NNK has been challenged by Fischer et al. (1193, 1199), who reported that these compounds occur in cigarette MSS only by transfer from the tobacco rod. Castonguay (15A07) stated that NNK is transferred from tobacco to smoke during the smoking process. In agreement with Fischer et al., Renaud et al. (15A46) concluded that direct tobacco-to-smoke transfer was the dominant factor explaining the presence of TSNAs in MSS. From their study of the contribution of 13C-nicotine

to 13C-NNN and 13C-NNK levels in MSS CSC, Moldoveanu et al. concluded that NNN and NNK are generated during the smoking process (2599), thus contradicting the views of Fischer et al. (1193, 1199), Castonguay (15A07), and Renaud et al. (15A46). Moreover, the pyrogenesis situation was further clouded by data on the effect of tobacco nitrate on the MSS TSNA yields (1552). Analysis of MSS TSNAs indicated that NNN and NAT yields increased when nitrate was added to the tobacco but the NNK yield did not.

XV.G Infrequently Studied Tobacco and/or Smoke Secondary Amines and Their N-Nitrosamines During extensive investigations of the composition of tobacco smoke in general and cigarette MSS in particular, much effort was expended in the early 1960s to define the nature of N-nitrosation during curing and the smoking process. As more and more N-nitrosamines (NNAs) were identified in tobacco and/or tobacco smoke, they were categorized as follows: volatile NNAs, nonvolatile NNAs, TSNAs, and N-nitrosamino acids. Within these four categories, only about sixty NNAs have been identified to date as tobacco and/or tobacco smoke components. Except for an excursion into the identification of N-nitrosamino acids, identification of NNAs in MSS almost ceased when NNK and to some extent NNN became the toxicants of choice. This situation raises the question, If a detailed study similar to those conducted on the PAHs and aza-arenes were conducted, how many additional NNAs could be identified in tobacco and/or tobacco smoke? Table XV-5 lists several NNAs reported as tobacco components that are seldom discussed. To date, none of them has been identified in tobacco smoke. While Table XV-6 is not necessarily complete, it suffices for the following discussion. In Table XV-6 are listed twenty-two dialkylamines, identified in tobacco and/or smoke as the amine or the NNA. For four NNAs (N-nitrosoisobutylmethylamine, N-nitrosoethylpropylamine,

Table XV-5 N-Nitrosamines in Tobacco and/or Tobacco Smoke Identified in Smoke (S) and/or Tobacco (T) N-Nitrosamines 1-Nitroso-2-azetidinecarboxylic acid 4-(N-Methylnitrosamino)-1-(3-pyridinyl)butanone oxide 1-Nitroso-4-hydroxyproline 1-Nitroso-3-piperidinecarboxylic acid 1-Nitroso-4-piperidinecarboxylic acid 3-Nitroso-4-thiazolidinecarboxylic acid a b

CAS No.

S

T

55556-98-4 76014-82-9 2443-30-3 65445-62-7 6238-69-3 88381-44-6

— — — — — —

+ + + + + +

Activity yesa

no [173]b

Bioassay results reported by Castonguay et al. (15A08) Bioassay results in laboratory animals are summarized in Preussmann and Stewart (2991); yes = tumor induction, no = negative response. Number in [] represents catalog number in Preussmann and Stewart (2991).

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N-Nitrosamines

Table XV-6 Aliphatic Secondary Amines and Volatile N-Nitrosamines in Tobacco and Tobacco Smoke R | R1-N-R2 R1 =

R2 =

CH3CH3CH3CH3CH3CH3CH3CH3CH3CH2CH3CH2CH3CH2CH3CH2CH3CH3(CH2)2CH3(CH2)2CH3(CH2)2(CH3)2CH(CH3)2CHCH3(CH2)3CH3(CH2)3(CH3)(C2H5)CH(CH3)3C-

CH3CH3CH2CH3(CH2)2(CH3)2CHCH3(CH2)3(CH3)2CHCH2(CH3)(C2H5)CH(CH3)2CH(CH2)2CH2=C(CH3)CH2CH3CH3(CH2)2(CH3)2CHCH2CH3(CH2)3CH3(CH2)2(CH3)2CH(CH3)(C2H5)CH(CH3)2CHCH3(CH2)3CH3(CH2)3(CH3)2CHCH2(CH3)(C2H5)CH(CH3)2CH-

a b

R=H Identified in Smoke (S) or Tobacco (T) CAS No. 124-40-3 624-78-2 627-35-0 4747-21-1 110-68-9

22023-64-9 109-89-7 20193-20-8 13360-63-9 142-84-7 21968-17-2 108-18-9 39099-23-5 111-92-2 20810-06-4 626-23-3

R = NO Identified in Smoke (S) or Tobacco (T)

S

T

CAS No.

S

T

+ + + + + — + + + + — — — + + + + + — + — +

+ + + + + — — — — + — — — + + — — — + — + —

62-75-9a 10595-95-6a 924-46-9

+ + + + + + — — — + + + + + — — + — + + — —

+ + + — — — — — — + + + — + — — — — + — — —

7068-83-9a 2504-18-9

55-18-5 a 25413-61-0 71607-99-3 621-64-7 a

601-77-4 924-16-3 a

Biological Activity yes [1]b yes [52]b yes [66]b yes [71]b

yes [7]b

yes [122]b yes [21] b

yes [34]b yes [36]b yes [45]b

Compound listed as a toxicant in one or more lists published since 1986 (1217, 1727, 1740, 1741, 1743, 1744, 1773, 1808, 1870, 2825). Bioassay results in laboratory animals are summarized in Preussmann and Stewart (2991); yes = tumor induction, no = negative response. Number in [] is catalog number in Preussmann and Stewart (2991).

N-nitrosoethylisobutylamine, N-nitroso-n-butylethylamine), the corresponding amines have not been identified in tobacco smoke. It is highly probable that the four amines are present as MSS components. Alternatively, NNAs corresponding to the other ten dialkylamines identified in tobacco and/or tobacco smoke have not yet been identified in smoke, for example, no NNA corresponding to sec-butylmethylamine, isopentylmethylamine, or isopropylidenemethylamine identified as MSS components has been identified in MSS. Synthetically, the corresponding NNAs are as easily prepared as N-nitrosodimethylamine or N-nitrosodiethylamine so their pyrogenesis during the smoking process should not be hindered. Thus, it is highly probable that the ten NNAs are present in tobacco smoke. Many other secondary amines have been identified in tobacco smoke but for most of them no corresponding NNA has been identified in smoke. These include a series of N-substituted anilines, all amenable to N-nitrosation {XXXV}. Others include the alkyl derivatives of pyrrolidine {XXXVI}, piperazine {XXXVII}, and piperidine {XXXVIII}. The amines pyrrolidine {XXXVI}, piperazine {XXXVII}, and 1,2,3,6-tetrahydropyridine {XXXIX} have been identified in cigarette MSS but not piperazine {XXXVII} (see structures in Table XV-7). For each piperazine, mono- and

di-N-nitroso derivatives are possible. Morpholine {XL} and an alkyl derivative have also been identified in tobacco. For completeness, azetidine {XLI} is included in Table XV-7. In many instances, the NNAs listed in Table XV-7 are readily synthesized and have been tested for tumorigenicity in laboratory animals [see Preussmann and Stewart (2991)]. Table XV-7 lists forty-six secondary amines, most of which have been identified as components of tobacco and/or its smoke. In only a few cases have the corresponding NNAs been identified as tobacco and/or smoke components. It is highly probable that the NNAs corresponding to the remaining secondary amines may also be tobacco smoke components. Among the numerous classes of smoke components are several other types of secondary amines, for example, the pyrroles, indoles, carbazoles, and imidazoles. However, their highly aromatic nature and the acidity of the imino hydrogen probably preclude any significant N-nitrosation either in the tobacco or during the smoking process. Despite the fact that a dozen or so theoretically N-nitrosatable substituted pyrroles; nearly fifty alkyl derivatives of indole {XLII}; carbazole {XLIII} and several of its alkyl derivatives, benzocarbazoles, and dibenzocarbazoles; and several alkyl derivatives of imidazole and benzimidazole {XLIV}

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710

have been identified in tobacco smoke, no NNA corresponding to any of them has been identified to date in tobacco smoke (Figure XV-5). It is obvious that the number of NNAs in tobacco and/or tobacco smoke might be substantially greater than the sixty

The Chemical Components of Tobacco and Tobacco Smoke

or so NNAs now known to be present. Since the per cigarette yields of the yet unidentified NNAs may be at the picogram or femtogram levels, their contribution to MSS toxicological properties may not be particularly meaningful or important. However, they may be just as important from a biological

Table XV-7 Aromatic and Cyclic Secondary Amines and N-Nitrosamines in Tobacco and Tobacco Smoke

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711

N-Nitrosamines

Table XV-7 (Continued) Aromatic and Cyclic Secondary Amines and N-Nitrosamines in Tobacco and Tobacco Smoke

point of view as those MSS components repeatedly listed as toxicants for which no or questionable quantitative data are available, for example, the much discussed dibenzo[def,p] chrysene (dibenzo[a,l]pyrene) (1557, 1727, 1740, 1741, 1743). To put the NNAs in perspective and to determine how many more are actually present in MSS, what may be needed is an extensive study corresponding to the excellent studies on PAHs (3756–3758) and aza-arenes (3750) conducted and

reported by U.S. Department of Agriculture (USDA) personnel in the late 1970s and early 1980s. It is also interesting to note that 4-(methylnitrosamino)-1(3-pyridyl)-1-butanol (NNAL), the major metabolite of NNK (1557), is usually not listed as a cigarette MSS toxicant even though NNAL has been reported to be both tumorigenic to several rodent species (15A08) and mutagenic in the Ames Salmonella typhimurium test.

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The Chemical Components of Tobacco and Tobacco Smoke

7

H N

6

2

5

3

4

1

8

7

2

N 2

3

6 5

XLII

9 N H XLIII

N H

4 XLIV

Figure XV-5  Indole {XLII}, carbazole {XLIII}, and 1H-benzimidazole {XLIV}.

XV.H Flue-Curing and TobaccoSpecific N-Nitrosamines As described by Williams (4247) there is general agreement among tobacco scientists that TSNAs are not present in either freshly harvested, that is, green flue-cured and burley tobaccos. As the tobaccos are cured either by air curing in the case of burley or in heated barns for flue-cured varieties, the amounts of TSNAs rise to their final levels. In the case of air curing, the process has changed little over the past fifty years. However, for flue curing, the process changed drastically in the United States during the 1960s and 1970s due to the introduction of energy-efficient bulk-curing barns heated by exhaust gases of liquid propane gas or similar burners. It is at this point that a breakdown must have occurred between tobacco agriculturists and chemists. The emission of NO2 during the combustion of liquid propane or natural gas is well known. In fact, the North Carolina Department of Environment and Natural Resources (NCDENR) has electronic spreadsheets available for download from its Web site that North Carolina industries may use in estimating their NO2 emissions during natural gas or liquid propane combustion. In retrospect, any competent chemist would predict the potential nitrosation of tobacco alkaloids during flue curing in the presence of combustion exhaust gases. However, without the knowledge of TSNA formation during direct heating of green tobaccos, the agricultural community adopted the new energy-efficient technique. It appears that prior to this “technological advance,” the formation of TSNAs during flue curing by traditional methods was not a problem. Earlier, at least two research groups discovered the problem with direct-heating flue curing of tobacco. Peele et al. (2917) demonstrated that modification of the curing process for flue-cured tobacco permitted significant control of its TSNA levels. The curing process was altered from one involving direct-fired burners to one involving a heat exchange system. During approximately the same period, Williams (258) applied for and was granted a U.S. patent on essentially the same modification of the flue-curing barns to achieve the same significant reduction in TSNAs. An example of the TSNA reductions in flue-cured tobacco and its smoke was shown by Rodgman and Green [see Figure 3, p. 522 in (3300)]. The tobacco data were from Williams (4247), the smoke data from Doolittle et al. (1051).

During the past few years, advances have been made to reduce NNAs, specifically TSNAs, in tobacco and tobacco smoke. The agronomic community with the help of the tobacco industry has made significant headway in discontinuing direct heating for flue curing as a means to reduce TSNAs in tobacco and tobacco smoke. This advancement is desirable from a product stewardship perspective and has little if any effect on tobacco quality. Biological response data on individual TSNAs indicate that TSNAs play a minor role in MSS carcinogenesis [see Tables 1 and 5 in Rodgman and Green (3300)]. Comparisons of the biological effects (Neutral Red cytotoxicity, mutagenicity in the Ames test with several Salmonella typhimurium strains) of mainstream CSCs from flue-cured tobacco cigarettes with normal and reduced levels of TSNAs, indicated no significant difference between the biological activity of the two CSCs [Doolittle et al. (1051)]. Although the Doolittle et al. data appear to support the hypothesis on a whole-smoke basis that mainstream TSNAs are of relatively minor toxicological importance, the sensitivity of the Ames assay is not sufficient to differentiate between the cigarettes tested. For example, consider the following points published by Doolittle et al. (1051): • The minimum amount of NNK needed for a mutagenic response in the Ames assay is 200 µg. • The maximum amount of CSC that can be tested is 250 µg. • In 250 µg of CSC there is 1.33 and 0.13 ng of NNK from direct-fired and heat-exchanged flue-cured tobacco, respectively. • The amount of NNK in the CSC from either fluecured tobacco smoke is too low for a response. Every practical effort should be made to reduce the amounts of alleged human carcinogens from tobacco products. However, whether the reduction or elimination of TSNAs from MSS will result in a “less hazardous” cigarette is unknown. Table XV-8 lists the sixty-seven N-nitrosamines identified to date in tobacco and/or tobacco smoke. Of these fifty-three N-nitrosamines have been identified in smoke, fifty-one in tobacco, and thirty-seven in both.

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713

N-Nitrosamines

Table XV-8 N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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714

The Chemical Components of Tobacco and Tobacco Smoke

Table XV-8 (Continued) N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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N-Nitrosamines

715

Table XV-8 (Continued) N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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716

The Chemical Components of Tobacco and Tobacco Smoke

Table XV-8 (Continued) N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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N-Nitrosamines

717

Table XV-8 (Continued) N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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718

The Chemical Components of Tobacco and Tobacco Smoke

Table XV-8 (Continued) N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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N-Nitrosamines

719

Table XV-8 (Continued) N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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720

The Chemical Components of Tobacco and Tobacco Smoke

Table XV-8 (Continued) N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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16

Nitroalkanes, Nitroarenes, and Nitrophenols

In his 1954 catalog of tobacco smoke components, Kosak (2170) listed no organic nitro-containing component. In 1959, Johnstone and Plimmer (1971), in their compilation of tobacco and tobacco smoke components, also listed no organic nitro-containing component. In their 1964 review (4319) and 1967 book (4332) on tobacco smoke carcinogenicity, Wynder and Hoffmann did not mention a nitroalkane or a nitroarene. In his 1968 review, Stedman (3797) listed no organic nitro-containing component identified in tobacco and tobacco smoke composition. His list of the agricultural chemicals used in tobacco agronomy [see Table XVI in (3797] also contained no nitro-containing compound. In their review of the N-containing components in tobacco and smoke, Schmeltz and Hoffmann listed thirty nitro components [see Table X in (3491)] separated into six nitroalkanes identified by Hoffmann and Rathkamp (1755) and Rathkamp et al. (3086) in the late 1960s, eight monocyclic nitroarenes identified by Hoffmann and Rathkamp in 1970 (1758), and sixteen nitrophenols, including one nitronaphthol, reported by Klus and Kuhn in 1975 (2137). In their 1980 catalog (1884), Ishiguro and Sugawara also listed thirty nitro components in tobacco smoke. All the nitro components they listed were those tabulated in the 1977 article by Schmeltz and Hoffmann (3491). With the limiting analytical technology available in 1982, Lee et al. (2329) at the American Health Foundation reported that they were unable to measure significant quantities of 4-nitro-1,2-benzenediol (4-nitrocatechol) in cigarette MSS. El-Bayoumy et al. in a conference presentation (1122) and a journal publication (1124) reported that 1-nitronaphthalene, 1-nitropyrene, and 6-nitrochrysene, if present in cigarette smoke, were at yields lower than their analytical capability. In its 1986 monograph on tobacco smoking, the International Agency for Research on Cancer (IARC) discussed many of the details of N-nitrosamines and tobacco-specific N-nitrosamines in tobacco smoke. Despite the reports prior to 1985 on the identification in tobacco smoke of many nitro components (1755, 1758, 2137, 3086), IARC listed only one nitro compound, 2-nitropropane, as a biologically active smoke component [see Table 19, pp. 86–87 in (1870)]. In its listing of the evaluation of tobacco smoke components for

carcinogenicity, IARC defined the evidence in 1986 of the carcinogenicity in animals and humans of 2-nitropropane as sufficient [see Appendix 2, p. 393 in (1870)]. Hoffmann and Wynder (1808) included 2-nitropropane in their list of major toxic and tumorigenic agents in nonfiltered cigarette MSS. Although not dealing with cigarette smoke in this particular 1987 study, Grimmer et al. (1406a) identified 1-nitropyrene in diesel exhaust. Of the many nitro components in tobacco smoke, only nitrobenzene, nitromethane, and 2-nitropropane were discussed repeatedly since 1986. In reports dealing primarily with commercial cigarettes, these three nitroalkanes were listed periodically in various publications as toxic smoke components, biologically active smoke components, tumorigenic smoke components, or carcinogenic smoke components: nitrobenzene (1741, 1743, 1744), nitromethane (1743, 1744), 2-nitropropane (1217, 1727, 1740, 1741, 1743, 1744, 1773, 1808, 2825). 2-Nitropropane was also described as a known carcinogen in the MSS from all-flue-cured or all-burley cigarettes (1716). In 2003, Cheng et al. (692, 693) reported the identification in CSC of five nitro-polycyclic aromatic hydrocarbons. They included 1-and 4-nitropyrene, 1,6- and 1,8-dinitropyrene, and 6-nitrochrysene. In 2004, Cheely et al. (683) described an analytical procedure that enabled the identification of 1-nitronaphthalene, 1-nitropyrene, and 6-nitrochrysene in cigarette MSS. Although 2-nitropropane was much discussed as a tumorigen or carcinogen in cigarette smoke and its categorization by IARC as having yielded sufficient evidence to rate it as both an animal and a human carcinogen, it seldom was designated as a “Hoffmann analyte.” While it did not use the term “Hoffmann analyte” in its report, the Department of Health (Canada) proposed that analytical data on the per cigarette yields of over forty components in tobacco smoke should be a requirement to indicate the hazardous nature of cigarette smoke (16A01). No nitroalkane was included in its list. Neither nitrobenzene nor nitromethane appeared in any “Hoffmann analyte” list. Table XVI-1 lists the nitroalkanes, nitroarenes, and nitrophenols identified in tobacco, tobacco smoke, and tobacco substitute smoke.

721

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722

The Chemical Components of Tobacco and Tobacco Smoke

Table XVI-1 Nitroalkanes, Nitroarenes, and Nitrophenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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Nitroalkanes, Nitroarenes, and Nitrophenols

723

Table XVI-1 (Continued) Nitroalkanes, Nitroarenes, and Nitrophenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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724

The Chemical Components of Tobacco and Tobacco Smoke

Table XVI-1 (Continued) Nitroalkanes, Nitroarenes, and Nitrophenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitroalkanes, Nitroarenes, and Nitrophenols

725

Table XVI-1 (Continued) Nitroalkanes, Nitroarenes, and Nitrophenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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17

Nitrogen Heterocyclic Components

XVII.A Monocyclic FourAND Five-Membered N-Containing Ring Compounds XVII.A.1 Background Tobacco (Nicotiana tabacum) is a unique agricultural crop used to prepare a variety of commercial products (cigarettes, pipe tobacco, cigars, chewing tobacco, snuff, etc.). Consumers enjoy tobacco by placing it into their mouth or nasal cavity (in the case of oral and snuff products) or by lighting the tobacco article (cigarette, cigarillo, cigar, etc.) and inhaling the tobacco smoke produced. As a result, the chemical composition of both the leaf and the tobacco smoke are important to consumers (for its flavor and appeal) and to scientists attempting to understand the chemical organoleptic, pharmacological, and toxicological properties of this extremely complex consumer product. Tobacco is a natural product that contains numerous classes of chemical compounds. As a living entity, tobacco contains all of the complex biological machinery necessary to sustain life. Chemical constituents in the tobacco leaf are influenced by numerous factors as the tobacco plant develops from seed to cured leaf. These factors include genetic potential, environmental conditions, cultural practices, and curing methods. Interactions among the factors also influence the chemical composition of the cured leaf. The genetic makeup of the plant provides the potential to produce or not to produce certain compounds, the realization of these potentials depend on environmental variations that the plant endures during growth and processing conditions employed to manufacture the finished tobacco product (677a). Although the chemical composition of the tobacco leaf is important, tobacco smoke also contains an extensive variety of chemical compounds. The presence and relative concentrations of these tobacco smoke components depend on (1) the composition of the tobacco leaf, (2) tobacco additives, (3) manufacturing processes, (4) the physical form and materials used to construct the different smoking articles, and (5) the smoking procedure. An elemental analysis for carbon, hydrogen, and nitrogen in foods and tobacco indicates that there is only about 5% nitrogen in dry tobacco (2439). The percent carbon, hydrogen, and oxygen (by difference) of dry tobacco leaf are about 43, 6, and 43%, respectively (2798), with the remainder being trace levels of metals and nonmetals. The majority of the nitrogen in tobacco leaf resides in the proteins, alkaloids, nitrates, and amino acids. The N-containing compounds in tobacco leaf have often been associated with the quality of the leaf. This is especially true with burley tobacco (3973). Nitrogenous

compounds in tobacco and smoke have an enormous range of taste and odor quality and intensity. Many are odorless and tasteless (proteins, nitrates), some have extremely pleasant tastes and odors, for example, some pyrazines (2439) and imidazoles, while others are very strong, pungent, and offensive, for example, some pyridines (1803). In this section, we present information on four- and five-membered N-containing ring compounds identified in tobacco, tobacco smoke, and tobacco substitute smoke. The classes of compounds include azetidines, pyrrolidines, 2- and 3-pyrrolines, pyrroles, pyrazoles, imidazolidines, imidazolines, imidazoles, and 1,2,4-triazoles (Figure XVII.A-1).

XVII.A.2 Four-Membered N-Containing Rings Few four-membered N-containing ring compounds have been identified in tobacco or tobacco smoke. These compounds are classified as azetidines. Nicotianamine, first isolated from tobacco by Noma et al. in 1971 (2796a), has also been identified in numerous other plant species (3528a). Nicotianamine is a derivative of 2-azetidinecarboxylic acid, an amino acid identified in numerous plant species, including Nicotiana tabacum (2330b). The precursor for the biosynthesis of azetidine in tobacco and azetidine-2-carboxylic acid, in particular, is considered to be methionine (2330b). The bacterial plant pathogen tabtoxin (L-threonine, N-[2-amino-4-(3-hydroxy-2-oxo-3azetidinyl)-1-oxobutyl]-) was isolated from wildfire tobacco (a wild species of Nicotiana tabacum) in 1971 (3819a). The scant information on azetidine compounds can be found in several review articles on the chemistry of compounds identified in tobacco and tobacco smoke. In their 1977 review, Schmeltz and Hoffmann (3491) reported the presence of 2-azetidinecarboxylic acid and nicotianamine in tobacco. Hecht et al. (1580) reported the identification of azetidine in both tobacco and smoke in 1977. Brunnemann and Hoffmann (486) reported the presence of the nitrosamine, 1-nitroso-2-azetidinecarboxylic acid in tobacco in 1991. Table XVII.A-1 lists the four-membered N-containing ring compounds identified in tobacco, tobacco smoke, and tobacco substitute smoke. Only five compounds are known to exist in tobacco and tobacco smoke that contain an azetidine ring. All five have been identified in tobacco. Azetidine has been identified in tobacco and tobacco smoke.

XVII.A.3 Five-Membered N-Containing Rings Tobacco and smoke chemists have shown an intense interest in the chemistry and biochemistry of this diverse class of compounds. Numerous studies on the presence of nitrogenous compounds in tobacco and tobacco smoke have appeared 727

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728

The Chemical Components of Tobacco and Tobacco Smoke

NH

5

Azetidine

5

2

4 3 2-Pyrroline

H N

H N

R

R

N

N R

3-Pyrrolines

R Pyrroles

R

N

Pyrazoles

2

H N

4 3 Pyrrolidine

R N

H N

R

5

2

3 NH

4 Imidazolidine

5 4

2 N

3 2-Imidazoline

N N Imidazoles

N R

H N N

1,2,4-Triazole

Figure XVII.A-1  Representative structures of the 4- and 5-membered N-containing ring compounds in tobacco, tobacco smoke, and tobacco substitute smoke.

over the past forty-five years and various aspects of the origin of these compounds in tobacco and their presence in tobacco smoke by direct transfer, pyrosynthesis, and combustion processes have been examined. Books, reviews, and articles by Wynder and Hoffmann (4332), Stedman (3797), Neurath (2724), Tso (3972, 3973), Chaplin (677a), Leffingwell (2337), Schmeltz and Hoffmann (3491), Hecht et al. (1580), Leete (2330c), Bush and Saunders (557a), Green (1351), Newell et al. (2769), Ishiguru and Sugawara (1884), Heckman and Best (1587), Gorrod and Wahren (1334d), Davis and Nielsen (910a), and Gorrod and Jacob (1334c) contain synopses of much of the information we know today on N-containing ring compounds in tobacco and tobacco smoke. During the 1970s and 1980s, an exceptional amount of research on tobacco and smoke component isolation and identification was conducted and published. This was

largely due to many scientific advancements that occurred in chromatographic methods during this period. The results of several excellent studies on tobacco leaf composition by Lloyd et al. (2389), Dickerson et al. (965), Roberts and Rohde (3219), Takahara et al. (3858), Demole et al. (937–939, 941, 943, 943a), Fujimori et al. (1247, 1249, 1250), Chuman et al. (731–739), Schumacher (3550), and Schumacher and Vestal (3561) are included here for reference. The Swedish Tobacco Company published nearly one hundred articles on the composition of tobacco, primarily Oriental tobacco. The many Swedish Tobacco Company investigators included Aasen, Almqvist, Behr, Enzell, Hlubucek, Kimland, Nishida, and Wahlberg, all of whom co-authored many tobacco composition articles (1–13, 52, 53, 84, 91–94, 227, 229–236, 1149–1157a, 1205a, 1660–1662, 2092–2095, 3315, 4083– 4102). Excellent detailed summaries of their identification

Table XVII.A-1 4-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

of hundreds of tobacco components and the generation of them from various terpenoid structures were presented and published in the late 1970s and early 1980s by Enzell (1149, 1150), Enzell and Wahlberg (1156), and Wahlberg and Enzell (4089, 4090). The basic five-membered N-containing ring compounds found in tobacco; whether they contain one or more nitrogens, arise from several metabolic and catabolic pathways. Additionally, many N-containing ring compounds are formed via nonenzymatic browning reactions. Amino acids and proteins are produced in living species and are essential compounds of tobacco plants. One of the most important metabolic pathways in plants is the Krebs tricarboxylic acid cycle (2337, 3973). The Krebs cycle controls the metabolic carbon-nitrogen balance in living plants by converting carbon dioxide via photosynthesis to such intermediates as oxaloacetic, a-ketoglutaric, and pyruvic acids. Concurrently, inorganic nitrogen as nitrates is assimilated through the plant roots and is subsequently reduced to ammonia by hydrogen originating from reactions occurring in the Krebs cycle. Ammonia then reacts with oxaloacetic, a-ketoglutaric, and pyruvic acids to form aspartic and glutamic acids and alanine, which provide the nitrogen for further synthesis of other amino acids (1351). These amino acids are then used as the nitrogen pool from which many of the other nitrogenous compounds of the tobacco plant are formed. For example, the pyrrolidine ring can be formed from arginine or ornithine via a series of metabolic reactions involving arginine decarboxylase or ornithine decarboxylase to form putrescine (1,4-diaminobutane) which is then converted to 4-methylaminobutanal via putrescine N-methyltransferase, S-adenosine-methionine, and methylputrescine oxidase. Via cyclization and demethylation, pyrrolidine is produced (3973). Numerous other metabolic reactions occur that produce five-membered N-containing ring compounds such as the pyrrolines, pyrroles, pyrazolines, pyrazoles, imidazolidines, imidazolines, and imidazoles. From the time of harvest through curing and aging, many changes take place in the concentrations of tobacco leaf amino acids and proteins (3972). According to Gaines and Miles (1270a), one of the extremely important aims of this process is to accomplish a degradation of tobacco proteins. This degradation produces numerous types of short-chained amino acid oligomers, free amino acids, and many functionalized N-containing compounds, such as alcohols, aldehydes, acids, aldehydes and esters. Among these catabolic breakdown products are the simple four-, five-, and six-membered N-containing ring compounds and a variety of alkaloids and alkaloid-type compounds that are oxidized, reduced, or otherwise functionalized. The origins of the five-membered N-containing ring compounds in leaf are also attributed at least partially to nonenzymatic browning or Maillard reactions between sugars and amino acids (965). Many compounds formed by nonenzymatic browning reactions have desirable flavor and aroma characteristics that taken together form the characteristic bouquet and taste associated with tobacco (2337).

729

A wide variety of five-membered N-containing ring compounds have been isolated and identified in tobacco smoke. Two general mechanisms are involved: direct transfer of tobacco components to tobacco smoke and the generation of smoke components by combustion and pyrolysis of tobacco. In 1977 it was estimated that the direct transfer of components from leaf to smoke accounted for about one-third of the smoke constituents identified in tobacco smoke at that time (1351). This process is relatively simple and many of its factors are understood. This process has been discussed in some length by Wakeham (4103). The second mechanism involves the pyrolysis, combustion, and subsequent pyrogenesis of smoke components. This process is complex and involves the tobacco, the means and materials used in constructing the smoking article, and the actual smoking process (puff volume, duration, puff interval, etc.). The relationships between various leaf constituents and their pyrolysis products are the ones most difficult to trace yet they are the most necessary to understand (1351). In contrast to the number of leaf components that generally transfer directly to smoke (~33%), only about 16% of the 313 tobacco and tobacco smoke compounds that contain a fivemembered N-containing ring were found in both tobacco and tobacco smoke. A considerable portion of the smoke yields from these compounds was no doubt due to transfer of the compounds directly from tobacco, although some of the yield of these compounds is produced by pyrolysis, combustion, and pyrogenesis of a variety of compounds in tobacco. As mentioned previously the largest contributors of organic leaf nitrogen are the leaf proteins, alkaloids, and amino acids. A majority of the protein in the tobacco consists of the enzymes associated with photosynthesis. The single most abundant protein in tobacco is called Fraction I and is designated functionally as ribulose-l,5-diphosphate carboxylase. Our knowledge of the genomic makeup of tobacco has advanced tremendously in the last twenty years. Once the Tobacco Genome Initiative is completed, over 90% of the genetic map of tobacco will be known (429b, 429c). Numerous databases of genes, enzymes, and reactions occurring in Nicotiana species are already available. The identities of the free amino acids of cured leaf are well known (1351). Of the forty-four amino acids reported in leaf, a majority have also been found in tobacco smoke. Proline and asparagine are the major amino acids in fluecured tobacco, whereas asparagine and aspartic acid are the major amino acids in burley tobacco. These plus glutamine and histidine are the principal amino acid precursors of the five-membered N-containing ring compounds in tobacco. High-temperature pyrolysis studies of protein and amino acids have been described in a series of papers by Smith et al. (3724, 3727a, 3728a, 3729), Patterson et al. (2902–2905), Higman et al. (1647), Schmeltz (3477–3479), Sugimura et al. (3829), and Yamamoto et al. (4365a). Under these pyrolytic conditions, pyrodegradation and pyrosynthesis were extensive. In general, pyrolysis gave complex mixtures that were qualitatively similar regardless of the specific amino acid being pyrolyzed. Compounds identified included aromatic hydrocarbons

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such as benzene and naphthalene, their N-containing analogs such as pyridine and quinoline, pyrrole, aromatic nitriles such as benzonitrile and 1-naphthonitrile, aniline, and phenols. As suggested by Patterson et al. (2904), this similarity of results indicates that the amino acids and proteins undergo degradation into common intermediates of two-, three-, and four-carbon types which subsequently recombine to form more thermally stable aromatic systems. To be discussed in a subsequent chapter is the pyrogenesis of the potent mutagens 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) from tryptophan (3829) and 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2) and 2-amino-6-methyldipyrido[1,2-a:3’,2’-d] imidazole (Glu-P-1) from glutamic acid (3828a, 4365a), all four of which were subsequently identified in tobacco smoke (3828c). Table XVII.A-2 catalogs many of the pyrolysis studies conducted on amino acids. Pyrolysis and smoke studies of amino acids indicate that they are potential precursors of several nitrogen heterocyclic ring systems found in tobacco smoke. Proline has been shown to be efficiently converted to pyrrole upon pyrolysis (3219, 3724) and in addition has been proposed as a possible precursor of pyrocoll (2593, 4336). g-Amino acids and dicarboxylic amino acids are capable, under pyrolytic conditions, of forming 2-pyrrolidones (1967, 3079) and by a similar mechanism, D-amino acids can form 2-piperidones (1967, 3079). A side effect of the pyrolysis of amino acids is the formation of hydrogen cyanide. Johnson and Kang (1967) studied the hydrogen cyanide yields from pyrolysis of compounds containing ring nitrogen and found that these heterocycles, particularly those with fivemembered rings, produced the highest yields of hydrogen cyanide. These results are in accord with those of Smith et al. (3724) in which proline was found to give high yields of hydrogen cyanide. The pathway seems to be through pyrrole which is formed in excellent yield (67%) on pyrolysis of proline. Patterson et al. (2908) had previously found that pyrrole on pyrolysis at 850°C is converted in 49% yield to hydrogen cyanide. This may not be the only pathway for the formation of hydrogen cyanide from proline because Johnson and Kang (1967) found that proline can generate hydrogen cyanide more readily than pyrrole. Protein and free amino acids found in tobacco leaf contribute significantly through pyrodegradation and pyrosynthesis to the formation of many nitrogenous compounds found in tobacco smoke. The nonvolatility of these compounds either as free acids, proteins, or members of tobacco pigment, for example, porphyrins, make them particularly liable to pyrolytic destruction because they, unlike nicotine and the other plant alkaloids, are not readily volatilized and swept away as the more intense heat of the cigarette coal approaches (3724). There are also interactions that occur among amino acids, proteins, and carbohydrates during plant growth and during smoke formation. These interactions form complex mixtures of leaf constituents and complex mixtures resulting from the pyrodegradation and pyrosynthesis of reaction products of amino acids, proteins, and carbohydrates.

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-2 Studies on the Pyrolysis of Amino Acids Amino Acid

CAS. No.

Amino acids

Alanine Arginine Asparagine Cysteine Cystine Glutamic acid

107-95-9 74-79-3 7006-34-0 52-90-4 24645-67-8 6899-05-4

Glutamine Histidine

56-85-9 71-00-1

Histidine, 3-methylLysine

56-87-1

Methionine Ornithine Ornithine, N5(aminocarbonyl){citrulline} Phenylalanine

63-68-3 70-26-8 372-75-8

Serine

6898-95-9

Threonine Tryptophan

72-19-5 73-22-3

Tyrosine Valine

60-18-4 7004-03-7

63-91-2

References Kato et al. (2048, 2049), Kosuge et al. (2178a), Masuda et al. (2486), Nebert et al. (2688a) Matsumoto et al. (2491b) Matsumoto et al. (2491b) Matsumoto et al. (2491b) Matsumoto et al. (2491b) Matsumoto et al. (2491b) Matsumoto et al. (2491b), Ohgaki et al. (2849b), Sugimura (3828a), Takeda et al. (3863a), Takayama et al. (3862b), Yamamoto et al. (4365a) Matsumoto et al. (2491b) Matsumoto et al. (2491b), Smith et al. (3722a) Smith et al. (3722a) Matsumoto et al. (2491b), Wakabayashi et al. (4102a) Matsumoto et al. (2491b) Matsumoto et al. (2491b) Matsumoto et al. (2491b)

Matsumoto et al. (2491b), Sugimura et al. (3829) Kato et al. (2048), Matsumoto et al. (2491b) Matsumoto et al. (2491b) Hosaka et al. (1835a), Matsukura et al. (2491a), Matsumoto et al. (2491b), Negishi and Hayatsu (2689a), Sugimura et al. (3829), Takayama et al. (3862d), Yamazoe et al. (4370a), Yoshida and Matsumoto (4390) Matsumoto et al. (2491b) Matsumoto et al. (2491b)

In freshly harvested leaf, both reducing sugars and amino acids are present, and these are known to react to form nonvolatile sugar-amino acid compounds, known as Amadori compounds (1671b). A number of these Amadori compounds have been isolated from flue-cured tobacco leaf by Cousins (841a), Tomita et al. (3923), Yamamoto et al. (4362), and Wahl (4081a). Noguchi et al. (2794a) have shown how the free amino acid concentration of leaf decreases during aging and the Amadori compound levels initially increase and then slowly decrease. These changes, especially the decrease in Amadori compounds, indicate the possible progress of Maillard-type reactions during natural aging of leaf tobaccos.

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Nitrogen Heterocyclic Components

Dickerson et al. (965) found evidence for progress of the Maillard reaction in their studies on aged flue-cured leaf where a number of formylpyrroles were isolated. Dickerson et al. (965) followed the formation of several formylpyrroles from a specific Amadori compound. The Amadori compound was converted via the Maillard reaction to a 3-deoxyosulose which further reacted with either an amino acid or an amine to form the isolated formylpyrroles. In addition to the formylpyrroles, a number of pyrazines and furans, characteristic of nonenzymatic browning reactions, were also isolated from flue-cured tobacco. Thus, there is evidence for the Maillard reaction occurring even before smoking. Sometimes in sugar-amine browning systems where pyrazines are isolated, there is also found another class of nitrogen heterocyclic compounds, the imidazoles (1835b, 1947a). These compounds have been reported in tobacco smoke by Schumacher and co-workers (3553). In contrast to the pyrazines, only a few imidazoles have been isolated from nonenzymatic browning reactions of foods. This might be due to the unusually high boiling points and polarity of these compounds. Grimmett (1410b) has reviewed the formation of imidazoles from the interaction of carbohydrates and amine sources, and many of the same compounds found to be pyrazines precursors can also form imidazoles. Simple sugars, starches, and cellulose — all known tobacco leaf constituents — are reported to react with amines, including ammonia, to form imidazoles (1351). Many of the reactions producing imidazoles in tobacco and tobacco smoke involve the interaction of carbohydrates with ammonia, which has several precursors in tobacco. Amino acids and proteins can contribute to the formation of smoke amines and the formation of ammonia. Johnson et al. (1964) conclusively demonstrated through experiments with 15N-glycine that it is an ammonia source. In addition to amino acids, nitrates have been shown to be efficiently converted during the smoking of a cigarette to ammonia (1964). This ammonia from nitrates was shown to participate in the formation of many nitrogenous compounds in smoke. Thus, leaf nitrates as well as amino acids and proteins are considered the major sources of ammonia in tobacco smoke. As to the mode by which certain leaf constituents may form imidazoles, it is commonly recognized that a-dicarbonyl compounds may react with aldehydes in the presence of ammonia to form nitrogen heterocyclic compounds such as imidazoles. The required a-dicarbonyl compounds and aldehydes are well-known pyrolysis products of carbohydrates either through thermal (1170a) or Maillard-type (1671a) degradations, and many of these compounds have been isolated from tobacco smoke (3797). It is possible that a-aminoketones, such as those proposed as intermediates in the formation of pyrazines, may also be involved with the formation of imidazoles because reactions producing imidazoles from these compounds have been reported (1410b). Although the formation of imidazoles through carbohydrate and amino acid or protein interaction is especially appealing due to the analogies which can be made with pyrazines, a second origin is also possible. Tobacco leaf contains an appreciable amount

731

of the amino acid histidine, either in its free form or as part of tobacco protein. Pyrodegradation of this compound in a manner similar to that of tryptophan (2047) could also be a source of some imidazoles in tobacco smoke. The contribution of the five-membered N-containing ring compounds in tobacco and tobacco smoke to smoke flavor is not as well known. The flavor evaluations of some tobacco-derived imidazoles have been described by Schumacher et al. (3553a). The flavors of these compounds are an example of how relatively nonvolatile, flavorless compounds in tobacco leaf can be transformed during the smoking process into a part of the characteristic aroma of tobacco smoke. Leffingwell et al. (2341) and Roberts (3215) in their review of natural tobacco flavor reported that several acetylpyrroles provided a nutty, woody, and sweet taste to tobacco smoke but that formylpyrroles often added harshness to the tobacco smoke aroma. Imidazoles have been reported to provide a sweet chocolate or nutty character to tobacco smoke at low levels but can be bitter at high levels (3215). The principal precursor for the biosynthesis of ring structures of pyrrolidine, pyrroline, and pyrrole is glutamine (2056b, 2659a, 2848a). Pyrrole structures can also be produced in plants from arginine or ornithine (2056b). The biosynthetic pathway for the production of the imidazole ring structure involves the biosynthesis of histidine through a series of ten enzymatic reactions (57a). The first intermediate of the pathway (phosphoribosyl pyrophosphate) is also the starting point for purine and pyrimidine biosynthesis. The amino acid glutamine provides much of the backbone for imidazole, which is an intermediate in histidine biosynthesis (429d). From imidazole glycerol phosphate five additional enzymatic steps are needed for the plant to produce histidine. The imidazoline and imidazolidines rings can be produced by enzymatic hydrogenation of the imidazole ring. The imidazolidine ring is also believed to be produced biosynthetically when glutamate condenses with carbamyl phosphate to form hydantoin or imidazolidine-2,4-dione. The hydantoin can be enzymatically reduced to imidazolidines (225a). Additionally, hydantoin can be produced in plants by hydrogenation of allantoin (2,5-dioxo-4-imidazolidinylurea), a cyclic amide naturally occurring in many plants (4068a). Pyrazolidine, pyrazoline, and pyrazoles are produced in plants from 1,3-diaminopropane via pyrazoles synthase (C3) (437a). The five-membered N-containing ring compounds with three nitrogens are the 1,2,3-triazoles and the 1,2,4-triazoles. Triazoles are not produced in plants naturally but are found as structural components of many pesticides and herbicides. Seven herbicides containing a five-membered N-containing ring have been identified in tobacco as residues. The pesticides containing a 1,2,4-triazole ring include three fungicides (Triadimefon®, Penconazole®, and Triadimenol®), one herbicide (Sulfentrazone®), and one insecticide (Triazophos®). Two 1,2,3-triazoles (as benzotriazoles) have been identified in tobacco and tobacco smoke to date, Azinphos-MethylOxon® and Azinphos-Methyl®. Both of these pesticides are insecticides. Azinphos-Methyl-Oxon® has also been

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The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-3 Distribution of 5-Membered N-Containing Ring Compounds between Tobacco and Tobacco Smoke Number of Identified 5-Membered N-Containing Ring Compounds in Tobacco and Tobacco Smoke Component

Total

Smoke

Tobacco

Smoke and Tobacco

Pyrroles Pyrrolidines Pyrrolines Pyrazoles Imidazoles Imidazolidines Imidazolines Triazoles

116 79 28 16 62 10 3 7

88 64 23 13 57 8 1 2

50 36 7 3 8 3 2 8

22 21 2 0 3 1 0 3

Totals

321

256

117

52

identified as a degradation product of Azinphos-Methyl®. All of these triazoles were reported as tobacco pesticide residues (928a, 2913a, 3663, 2650a). The remaining fungicide in this series of five-membered N-containing ring compounds with three nitrogens is Iprodione®. Iprodione® is an imidazolidinecarboxamide and has been reported as a fungicide residue on tobacco (3585, 3633, 3661a). Table XVII.A-3 lists the distribution of five-membered N-containing ring compounds identified in tobacco, tobacco smoke, and tobacco substitute smoke. Table XVII.A-4 lists 321 compounds, of which 116 are pyrroles, seventy-nine are pyrrolidines, and twenty-eight are pyrrolines. There are sixteen pyrazoles listed in Table XVII.A-4. Sixty-two imidazoles, ten imidazolidines, and three imidazolines have been identified in tobacco and tobacco smoke. Five compounds with a 1,2,4-triazole ring have been identified in tobacco. Two compounds with a 1,2,3-triazole ring (as benzotriazoles) have been identified in tobacco and tobacco smoke. The compounds in Table XVII.A-4 exhibit a great deal of functionality. Although each contains a five-membered N-containing ring, some are alcohols, ketones, sugaramines, acids, esters, and imides. Of the 321 compounds listed in Table XVII.A-4, 256 are found in tobacco smoke, 117 are found in tobacco, and 52 are present in both tobacco and tobacco smoke.

XVII.A.4 Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke With Multiple Five-Membered N-Containing Rings Porphyrins are a class of biologically important heterocyclic compounds with a characteristic chemical structure that includes four pyrrole groups (five-membered organic rings each containing a nitrogen atom) linked on opposite sides

(a position) through four methine bridges (=CH-) to form a large flat ring structure (see Figure XVII.A-2). A porphyrin in which no metal is inserted in its cavity is called a free base. Many organic analogs that contain a porphryin ring are biological pigments and are closely related molecules responsible for many of the vivid colors in living organisms. They often occur combined with metal ions and various substituents as coordination complexes. Chlorophylls are magnesium complexes of porphyrin derivatives (also called phorbines). In plants, these pigments are responsible for photosynthesis and play important roles as respiratory pigments, electron transport carriers, and oxidative enzymes. Several chlorophylls have been identified in tobacco, the most common being chlorophyll a and chlorophyll b. Chlorophyll a is a waxy blue-black microcrystalline green-plant pigment, C55H72MgN4O5, with a characteristic blue-green alcohol solution. Chlorophyll b is a similar green-plant pigment, C55H70MgN4O6, having a brilliant green alcohol solution. Several other chlorophyll derivatives have also been isolated from tobacco (3770a). The biosynthesis of porphyrin involves glycine and succinyl-CoA (from the citric acid cycle) to form d-aminolevulinic acid (dALA). Two dALA molecules are combined into porphobilinogen (PBG), which contains the pyrrole ring. Four PBGs are then combined through deamination into hydroxymethylbilane (HMB), which is hydrolyzed to form the circular tetrapyrrole, uroporphyrinogen III. This molecule undergoes a number of further modifications. The biosynthesis is complicated and requires anywhere from seven to thirty enzymatic reactions involving a variety of catalytic activities, including decarboxylation, methylation, metal ion chelation, and porphyrin ring oxidation. Intermediates are used in different species to form particular substances, but, in plants and tobacco in particular, the main end-product is protoporphyrin IX, which is combined with magnesium to form chlorophyll (3770a). Table XVII.A-5 lists the compounds in tobacco, tobacco smoke, and tobacco substitute smoke with multiple fivemembered N-containing rings. While fourteen porphyrincontaining compounds have been identified in tobacco, only porphyrin itself has been identified in tobacco smoke (1899, 3491).

NH

N

N

HN

Figure XVII.A-2  Porphyrin.

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Nitrogen Heterocyclic Components

Table XVII.A-4 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued)

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The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued) 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

735

Table XVII.A-4 (Continued) 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued) 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

737

Table XVII.A-4 (Continued) 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued) 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

739

Table XVII.A-4 (Continued) 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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740

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued) 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

741

Table XVII.A-4 (Continued) 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued) 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

743

Table XVII.A-4 (Continued) 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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744

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued) 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

745

Table XVII.A-4 (Continued) 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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746

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued) 5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

Table XVII.A-5 Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Multiple 5-Membered N-Containing Rings

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747

Nitrogen Heterocyclic Components

Table XVII.A-5 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Multiple 5-Membered N-Containing Rings

XVII.B Monocyclic Six-Membered N-Containing Ring Compounds XVII.B.1 Introduction Over the years several detailed composition studies on the volatile components in flue-cured [Lloyd et al. (2389) and Dickerson et al. (965)], burley [Roberts and Rohde (3219), Demole et al. (937, 938, 940–942), and Fujimori et al. (1249– 1252, 1256)], Maryland [Schumacher (3550)], and Oriental tobaccos [Kimland et al. (2092–2095), Almqvist et al. (52), Aasen et al. (5, 11b), Hlubucek et al. (1660, 1660a, 1661, 1662), Schumacher (3561), Fukuzumi et al. (1257, 1258), and Chuman et al. (731–739)] have been published (2337, 3797). Similarly,

the composition of tobacco smoke (3797) has advanced tremendously over the years (1373), notably by the works of Schumacher et al. (3553), Heckman and Best (1587), Grob (1412–1427), Bartle et al. (199, 200), Neurath (2719–2753), Elmenhorst (1129–1140), Newell et al. (2769), Hoffmann and colleagues (480, 486, 735, 1580), the tobacco research personnel at the U.S. Department of Agriculture, Atlanta, Georgia, and many others [see additional listing in (2337)]. Tobacco chemists have shown considerable interest in the chemistry and biochemistry of the diverse set of N-containing compounds in tobacco and tobacco smoke. Numerous studies on the presence of nitrogenous compounds in tobacco and tobacco smoke have been published. These studies have reported on various aspects of the origins of nitrogenous

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compounds in tobacco, their synthesis, pyrolysis, and transfer to smoke. Several books and reviews [Tso (3972–3974b), Neurath (2724), Stedman (3797), Wynder and Hoffmann (4332), Schmeltz and Hoffmann (3491), Leffingwell (2337), Hecht et al. (1580)] have been written on N-containing compounds in tobacco and tobacco smoke. The levels of chemical compounds in tobacco are affected by genetics, environmental conditions, and agronomic practices. Considering the six-membered N-containing ring compounds and especially the alkaloid-type components (five- and six-membered and multiple six-membered nitrogen heterocycles) of tobacco, this is especially true. There have been numerous reviews on factors affecting plant growth and nicotine/alkaloid accumulation in tobacco [Bush and Saunders (557a), Chaplin and Miner (677a), Bush and Crowe (17B04), Leete (2331a, 2331–2334), Bush (555a), Strunz and Findley (17B56), Bush et al. (17B05)]. Section XVII.B provides information on compounds in tobacco and tobacco smoke that contain a six-membered N-containing ring (piperidines, tetrahydropyridines, pyridines, piperazines, dihydropyrazines, pyrazines, pyrimidines, pyridazines, and triazines), compounds with a five-membered (pyrrolidine, pyrrole, imidazole) plus a six-membered N-containing ring (pyridine), and compounds containing two or more six-membered N-containing rings (piperidines, pyridines). The formation of these compounds in tobacco from biosynthetic pathways and from nonenzymatic processes will be presented, as well as means of their generation and delivery to tobacco smoke.

XVII.B.2 Biosynthesis of Six-Membered N-Containing Ring Compounds and the Five- and Six-Membered and Multiple Six-Membered Nitrogen Heterocycles of Tobacco The next few paragraphs will discuss the biosynthesis of the sixmembered N-containing ring compounds and especially the alkaloid-type components (five- and six-membered and multiple six-membered nitrogen heterocycles) of tobacco. Following the biosynthesis section, information will be provided on the formation of some of the six-membered N-containing ring compounds that occur during tobacco aging and processing. Finally, a discussion of how these six-membered N-containing ring compounds and especially the alkaloid-type components arise in tobacco smoke will be presented. Over sixty species of Nicotiana exist that produce nicotine alkaloids (nicotine, nornicotine, anatabine, anabasine). Nicotine is the predominant alkaloid in over 50% of the Nicotiana species. Nornicotine is the major alkaloid in about 30% to 40% of Nicotiana species. Anabasine and anatabine are not usually the principal alkaloids in Nicotiana (17B05). Tobaccos that accumulate and have high levels of alkaloids tend to also have accumulations of minor alkaloids, for example, cotinine, myosmine, nicotyrine, 2,3′-bipyridine, and numerous derivatives of the major alkaloids, for example, alkyl, acyl, and nitroso derivatives of nicotine and the other

The Chemical Components of Tobacco and Tobacco Smoke

major alkaloids. The starting materials for the biosynthesis of the alkaloids are all present in tobacco. The precursors for pyridine, pyrrolidine, piperidine, and the most abundant nicotine alkaloids (nicotine, anabasine, anatabine, cotinine, myosmine) are well known and have been reviewed by Bush et al. (17B05). Although great advances in our understanding of alkaloid biosynthetic processes have occurred over the last fifty years, the metabolic and degradative processes occurring in Nicotiana species are still being researched. The biosynthesis of some of the six-membered N-containing ring compounds (pyrazines, pyridazines, and triazoles) is still not completely understood. As mentioned above, the biosynthesis of pyridine, pyrrolidine, and piperidine will be presented. The subsequent biosynthesis of the major alkaloids will then follow. It should be noted that although biosynthesis is the most important means of producing the six-membered N-containing ring compounds and the alkaloids found in tobacco, other processes for their production in leaf are also operative. Several tobacco processing operations such as aging, fermentation, thermal treatments of tobacco prior to use in products, tobacco expansion, blending operations, and additive applications can vary (both increase or decrease) the concentration of various six-membered N-containing ring compounds and alkaloids. Pyridine and the pyridine ring of nicotine, nornicotine, anabasine, and anatabine are formed from nicotinic acid. Yang et al. (17B62) reported that quinolinic acid was the precursor to nicotinic acid via quinolinic acid phosphoribosyl-transferase. Glyceraldehyde-3-phosphate (from glycerol) and aspartic acid via a series of enzymes are converted to quinolinic acid. Jackanioz and Byerrum (17B17) showed that 14C-labeled aspartate and malate incorporated into the C-2 and C-3 positions of the pyridine ring when these amino acids were fed to tobacco plants. The total biosynthetic pathway and intermediates involved have not yet been completely elucidated. The most accepted biosynthetic pathways for piperidine is lysine via D‘-piperidine (3973, 17B05). Piperidine can also be formed through decarboxylation and dehydrogenation of nicotinic acid (17B37). The pyrrolidine ring and particularly the N-methylpyrrolidine ring of nicotine is biosynthesized through putrescine (1,4butanediamine), N-methylputrescine, and 4-methylaminobutanal to the N-methyl-D‘-pyrrolinium salt (17B41). Dewey et al. (17B11) and Leete (17B29) fed 14C-ornithine to tobacco and found incorporation of activity in the C-2′ and C-5′ carbons of the N-methylpyrrolidine ring. Arginine via arginine decarboxylase forms agmatine that is converted to putrescine as a second source of this intermediate for the production of the pyrrolidine ring. Again, some of the intermediates and enzymes involved in the biosynthetic production of pyrrolidine are still not completely known (2334, 17B02, 17B63, 17B64). Dawson et al. (17B07, 17B08) showed that nicotinic acid formed the pyridine ring in nicotine. Yang et al. (17B62) showed that the pyrrolidine ring of nicotine was attached at the C-3 position of the pyridine ring of nicotine. Dawson et al. (17B07) in another publication showed that the hydrogen at

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the C-6 position of nicotinic acid was lost during nicotine formation. Dawson and Osdene (17B09) and Leete (2330c) showed that nicotine formation proceeds through the reduction of nicotinic acid to 3,6-dihydronicotinic acid. Friesen and Leete (1241a) proposed that dihydronicotinic acid forms a zwitterion by proton transfer that readily decarboxylates to yield 1,2-dihydropyridine. 1,2-Dihydropyridine in turn reacts with N-methyl-D‘-pyrrolinium salt to yield 3,6-dihydronicotine. The 3,6-dihydronicotine is oxidized with the loss of the hydrogen originally present at the C-6 position of nicotinic acid and retention of the hydrogen added in the reduction step to 3,6-dihydronicotinic acid. This pathway adequately explains the majority of the intermediates formed during nicotine biosynthesis and the fact that all nicotine in tobacco plants is (-)-2‘S-nicotine (Figure XVII.B-1). Although nicotine is formed and is present in large quantities in tobacco, it is important to understand that the vast majority of all nicotine in tobacco is present in the form of organic salts. Very little nicotine exists in the free base form due to the acidic nature of tobacco. The exact identities of the nicotine salts that exist in tobacco are not known but there have been several reports by Perfetti (2918a, 2924, 2926, 3156), Seeman et al. (17B48), and Dixon et al. (989) who have speculated on the various salt forms of nicotine.

H

COOH

H

H

2H

N

Both of the six-membered N-containing rings of anatabine (pyridine and piperidine) can be formed from the two methylene carbons and nitrogen of aspartate and two carbons from a glycerol derivative via nicotinic acid (2330c, 17B32, 17B33, 17B37). Nicotinic acid is reduced to 3,6-dihydronicotinic acid and decarboxylated to 1,2-dihydropyridine and 2,5-dihydropyridine. 1,2-Dihydropyridine reacts with 2,5-dihydropyridine via an electrophilic attack to form 3,6-dihydroanatabine which aromatizes to (-)-2‘S-anatabine (17B36). Although one might expect that anatabine and anabasine could be interconverted enzymatically in the plant, as these compounds differ by only two hydrogens, this does not appear to be true. The pyridine ring of anabasine has been shown to originate from nicotinic acid via decarboxylation (17B54). The precursor for the piperidine ring is lysine via D‘-piperidine with the nitrogen derived from the e-nitrogen of lysine (17B35). This was shown to occur via 14C-lysine feeding studies by Leete (17B30, 17B34). 14C was incorporated into the C-2‘ position of the piperidine ring of anabasine. Nornicotine is formed from nicotine during the growth period of the tobacco plant and during senescence (17B06). Enzymatic demethylation of nicotine yields nearly equal quantities of the (+) and (-) isomers of nornicotine (17B05).

COOH

-CO2

N

N H

H 3,6-Dihydronicotinic acid

Nicotinic acid

H

1,2-Dihydropyridine N-methylpyrrolium ion H

N H

N

CH3

-2H

N

H

H

(-)-2'S-Nicotine -CH3

-CH3

H 3,6-Dihydronicotine

N H

N (-)-Nornicotine

N

H -2H

-2H

H H N (+)-Nornicotine COOH

N N Myosmine

CH3

N

N Nicotinic acid

Figure XVII.B-1  Proposed biosynthetic pathways for production of several pyridine alkaloids (17B05).

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Myosmine can be formed from nornicotine by enzymatic dehydrogenation (2332, 17B24). Cotinine and 2,3‘-bipyridyl and their derivatives represent the major oxidized alkaloids in tobacco. Cotinine is synthesized from nicotine via enzymatic oxidation or autooxidation (1157, 17B03). 2,3‘-Bipyridyl is formed by oxidation of anatabine. Frankenburg et al. (1221a, 1222-1224) were the first to identify 2,3‘-bipyridyl as a fermentation product along with 3-acylpyridine. Other oxidized alkaloids identified in green and cured tobacco are nicotyrine, nicotinic acid, nicotinamide, and nicotine-N-oxides. Enzell et al. (1149a) found that these oxidation products of tobacco alkaloids tend to increase in yield during curing and storage of tobacco. Pyrimidines play a central role in cellular regulation and metabolism. They are substrates for DNA and RNA biosynthesis, regulators of biosynthesis of some amino acids, and cofactors in the biosynthesis of phospholipids, glycolipids, sugars, and polysaccharides (17B45). Pyrimidine biosynthesis is very complicated and involves formic acid, glutamate, and aspartate as starting materials in a series of enzymatic reactions to eventually form orotic acid. Orotic acid, or uracil6-carboxylic acid, is an intermediate in the metabolism of pyrimidine nucleotides. The naturally occurring derivatives of pyrimidine are components of the nucleic acids cytosine, thymidine, and uracil. Free pyrimidine and functionalized pyrimidine compounds in tobacco are believed to be formed from the catabolism of various nucleosides (17B21). Although pyrazines, for example, pyrazine-2-carboxylate and pyrazine 2,3-dicarboxylate, are formed biosynthetically, the vast majority of the varied pyrazine derivatives in tobacco are formed during curing via nonenzymatic reactions. Pyrazines can arise in tobaccos by a number of chemical pathways ranging from the heating or aging of proteins and amino acids to the interaction of amino acids and/or ammonia with sugars or carbonyl constituents. No single pathway is involved in the formation of pyrazine. The formation of pyrazine compounds is complex and depends on a variety of factors and chemical mechanisms (2339b). Adachi et al. (17B01) postulated that tetramethylpyrazine is derived enzymatically from two moles of acetoin (acetylmethylcarbinol) and two moles of ammonia. This finding was supported by the findings of Demain et al. (17B10) that a block in the isoleucinevaline pathway leads to the accumulation and excretion of a large amount of tetramethylpyrazine. Shu (17B51) treated acetoin with amino acids to determine whether ammonia is released, leading to the formation of tetramethylpyrazine. His results showed that all reactions between amino acids and acetoin generate not only alkylated pyrazines, for example, tetramethylpyrazine, but also the corresponding Strecker aldehydes. Pyridazines and triazines are not usually biosynthesized in plants. The exception is azathymine (6-methyl-1,2,4-triazine-3,5(2H,4H)-dione) which has been identified in modified bases from DNA of tobacco mosaic virus (3973). The majority of the identified pyridazines and triazines in tobacco are believed to originate from residues of agronomic chemicals. The pyridazine structure is found in herbicides containing

The Chemical Components of Tobacco and Tobacco Smoke

maleic hydrazide. The triazine structure is found in the tobacco herbicide Metribuzin® and the fungicide Anilizine®. A variety of alkyl-, acyl-, and hydroxyacyl-substituted alkaloids exists in tobacco. These have been identified and studied by a number of research groups [Bolt (389), Warfield et al. (4133), Matsushima et al. (17B39), Severson et al. (17B49), Zador and Jones (17B65)]. The mechanisms proposed for the biosynthesis of these alkaloids are oxidation or formylation. For example, N‘-formylnornicotine [2-(3pyridinyl)-1-pyrrolidinecarboxaldehyde] can be formed by formylation of nornicotine or by oxidation of the N-methyl group of nicotine (2330c, 17B03). Additionally, Burton et al. (17B03) have proposed that many acylated alkaloids are formed via acylation of secondary amine alkaloids (994). The concentrations of these alkylated and acylated alkaloids are small in comparison to the total alkaloid concentration in tobacco. Their occurrence is mainly influenced by plant genetics and agricultural practices (17B05). It is believed that their accumulation in leaf may be significant to flavor perception (17B05). A number of tobacco N-nitrosamines are listed in this chapter. Chapter 15 is devoted to N-nitrosamines, but a few comments must be included here. Interest in tobacco-specific N-nitrosamines (TSNAs) has been a result of reports that some of them have induced malignant tumors in mice, rats, and hamsters [Boyland et al. (421a, 422, 423), Hecht et al. (1557–1559, 1563–1571a, 1574–1585)]. The TSNAs of greatest interest are N‘-nitrosonornicotine (NNN), N‘-nitrosoanatabine (NAT), N‘-nitrosoanabasine (NAB), and 4-(methylnitrosamino)-1(3-pyridyl)-1-butanone (NNK). The formation of TSNAs can be biosynthetic (via mechanisms within the plant itself), produced by bacteria on the surface of the plant, and by organic reactions of flue gas during curing practices [Peele et al. (2917), see also Figure 5 in Rodgman and Green (3300)].

XVII.B.3 Other Means for the Formation of the Six-Membered N-Containing Ring Compounds Found in Tobacco Nitrogenous compounds in tobacco account for approximately 12% to 25% of the dry weight of freshly harvested tobacco leaves (841a, 2337), (2% to 6% expressed as nitrogen). As previously mentioned, the large variation in types and yields of nitrogenous compounds in tobacco is due to the great number of Nicotiana species, the variety of different agricultural practices, and soil types worldwide for the cultivation of different tobaccos. The major organic nitrogen constituents of tobacco leaf are nicotine and related alkaloids, proteins, and amino acids (2337). The alkaloids as discussed above are biosynthesized along with a portion of most of the six-membered N-containing ring compounds found in tobacco. But there are also other ways that these compounds can be produced. The varied methods of curing and aging tobacco cause only a small decrease in the total nitrogen content, but significant changes occur as a result of organic transformations from one type of nitrogenous compound to another, for

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example, the enzymatic hydrolysis of leaf protein produces free amino acids (1493). After curing, dynamic changes continue to occur during aging of tobacco leaf. Weybrew et al. (4226) and Tomita et al. (3923) recognized in 1965 that chemical reactions of amino acids in tobacco play an important role in the formation of tobacco flavor. Employing model systems, reactions of amino compounds with sugars or carbonyl compounds were shown to produce flavor compounds present in tobacco (2047, 2048, 2337, 3649). During aging, tobacco undergoes a natural “sweating” process several times. This “sweating” is a mild natural fermentation that produces some heating of the tobacco. This fermentation releases reducing sugars, amino acids, phenolics, and flavonoids through nonenzymatic browning reactions to produce the flavor characteristic of aged tobacco. Much of the flavor that is produced is due to Maillard and Strecker reactions of amino acids with reducing sugars (or other carbonyls). The role of nonenzymatic browning reactions of amino acids and sugars is generally accepted as being one of the most important processes in which natural flavors are produced (2337). There are at least three other ways (other than through biosynthesis) that the six-membered N-containing ring compounds can be formed in tobacco leaf (2337). • Oxidative transformations • Ambient temperature nonenzymatic transformations • Heat-induced nonenzymatic transformations It must be remembered that compounds formed by enzymatic processes can react subsequently in a nonenzymatic transformation. Additionally, by examining the chemical transformations involved in the production of compounds via nonenzymatic browning reactions, several routes can be involved in the production of the same compounds from different precursors (2337). A type of Maillard reaction that occurs naturally in tobacco which requires the presence of active a-dicarbonyl components is the Strecker degradation of a-amino acids to aldehydes and ketones of one less carbon atom. Schonberg and Moubacher (17B46, 17B47) studied the mechanism of the Strecker degradation involving pyruvaldehyde and aalanine leading to the formation of 2,5-dimethylpyrazine and 2,5-dimethyl-3-ethylpyrazine. The fact that different amino acids can produce the same flavor compounds has been shown by a number of workers in studies on the relative formation of pyrazines under controlled reaction conditions between amino acids and glucose (2048, 2337). Similar studies have shown that thermal decompositions of various amino acids and other aminohydroxy compounds such as glucosylamine can directly form pyrazine mixtures (17B60). Because of the complexity of the chemical interactions and transformations involved, the types and ratios of active flavor products, for example, pyrazines, formed by nonenzymatic browning are dependent on the reaction conditions that may occur during aging or during the smoking process itself.

Examples of how processing tobacco affects the production of flavorful pyrazine was provided by Mays et al. (17B40) and Green et al. (1369) of R.J. Reynolds Tobacco (RJRT) Company. Ammonia/carbon dioxide expansion was conducted on flue-cured, burley, and processed tobacco sheet. Test and control cigarettes were fabricated. The tobacco aroma of the ammonia/carbon dioxide-processed tobaccos increased in all cases after processing vs. the control materials. Comparison of the per cigarette MSS yields of eight pyrazines indicated their yields in the MSS from ammonia/carbon dioxide-expanded tobacco were significantly greater than those in the control tobacco MSS [see Tables 3, 4, and 5 in (3261)]. Additionally, browning reactions can occur during the smoking process (2337). Some of the reaction products occurring during the smoking process involve six-membered N-containing ring compounds that can significantly contribute to tobacco smoke flavor and aroma, for example, some pyrazine and pyridine derivatives (2339b).

XVII.B.4 Six-Membered N-Containing Ring Compounds in Tobacco and Tobacco Smoke Knowledge of tobacco smoke composition grew rapidly each year by the application of new analytical methods. Prior to 1959, only sixteen nitrogen compounds had been reported in tobacco and tobacco smoke. In 1959, Johnstone and Plimmer (1971) summarized the identification of about fifty nitrogen compounds. Ten years later, Neurath (2724) reported on the presence in tobacco and tobacco smoke of 181 nitrogen compounds, among which were two piperidines, twenty-four pyridines, ten pyridines, and eleven alkaloids. In this report, we have cataloged thirty-seven piperidines, 312 pyridines, seventy-eight pyrazines, and over 160 alkaloids. Table XVII.B-1 details the distribution of six-membered N-containing ring compounds in tobacco and tobacco smoke. Table XVII.B-1 Distribution of 6-Membered N-Containing Ring Compounds between Tobacco and Tobacco Smoke Number of Identified 6-Membered N-Containing Ring Compounds in Tobacco and Tobacco Smoke Component

Total

Piperidines Tetrahydropyridines Dihydropyridines Pyridines Piperazines Dihydropyridazines Pyrazines Pyrimidines 1,2,4-Triazines 1,3,5-Triazines

37 5 6 341 10 3 100 33 2 1

Totals

538

Tobacco

Smoke and Tobacco

31 2 4 295 10 1 83 14 0 0

11 4 2 116 0 3 62 20 2 1

5 1 0 70 0 1 45 1 0 0

440

221

123

Smoke

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H N

5

R

6

N

N

Piperidine

Tetrahydro pyridine

Dihydropyridines

N

N

N

Pyrazidine

N Pyrazine

N Pyrimidine

N

H N

3 2

Pyridine

R N

N

4

N NH*

1,2,4-Triazines

N H Piperazine

N

N

R

N 1,3,5-Triazines

Figure XVII.B-2  Structures of the 6-membered N-containing compounds found in tobacco and tobacco smoke.

Of the 538 identified compounds, about 82% (or 440 compounds) are found in tobacco smoke and about 41% (or 221 compounds) are found in tobacco. Eighteen percent (98 compounds) are found only in tobacco and 59% (317 compounds) are found only in tobacco smoke. Of the 538 compounds, 23% (123 compounds) are found in both tobacco and smoke. Figure XVII.B-2 illustrates the general structures for the ten types of six-membered N-containing ring compounds found in tobacco and tobacco smoke. The four major compound classes are the piperidines, pyridines, pyrazines, and the pyrimidines. A brief discussion of general information on each of these four classes of six-membered N-containing ring compounds follows. XVII.B.4.1 Piperidine and the Tetraand Dihydropyridines Piperidine and D3-piperidine were first identified by Neurath et al. in 1965 (2749) and 1966 (2734), respectively [see Table 3 in Neurath (2724)]. The piperidines in tobacco and tobacco smoke are found as substituted ketones, acids, and alkyl derivatives. None of the forty-eight nonaromatic sixmembered N-heterocycles found in tobacco and tobacco smoke has been shown to provide positive contributions to the flavor of tobacco smoke, although piperidine is on the GRAS list as a food flavor (3215). Pyrolysis and smoke studies of amino acids indicate that they are potential precursors of several nitrogen heterocyclic ring systems found in tobacco smoke (1351). For example, indole can be formed from tryptophan, proline has been shown to be efficiently converted to pyrrole upon pyrolysis (3219, 3726), and g-amino acids can be pyrolyzed to form 2-pyrrolidones (1967, 3079). By a similar mechanism, g-amino acids form 2-piperidones (1967, 3079). XVII.B.4.2 Pyridines A great variety of pyridines (currently 341) has been identified in tobacco and tobacco smoke. As a class, there are more pyridines in smoke than any other heterocycle. Vohl and Eulenberg (4064) were the first to isolate and identify pyridine in tobacco smoke in 1871. Since that time a wide variety of substituted (methyl- [picolines], dimethyl- [lutidines],

ethyl-, allyl-, butyl-, vinyl-, cyano-, formyl-, alkylamino-) pyridines have been identified. Most of the substituted groups in these pyridines occur at the three-position, although there are some substituted pyridines with functionalities at the two- and four-positions (2724). The presence of pyridine compounds in smoke is naturally associated with the tobacco alkaloids. The formation of substituted pyridines that occur during the pyrolysis of nicotine has long been known [Woodward et al. (4275a), Kaburaki et al. (2006), Jarboe and Rosene (1923a), Schmeltz et al. (3499)]. Pyridine, 3-methyl- and/or 4-methylpyridine, 3-vinylpyridine, and 3-cyanopyridine have all been identified as major pyrolysis products of nicotine. Minor pyridine pyrolysis products included 2-methylpyridine, dimethylpyridines, 3-ethylpyridine, and 2- and/or 4-cyanopyridine. All have been identified in tobacco smoke. While the formation of pyridines from nicotine might be expected to involve simple rupture of the pyridine-pyrrolidine bond, a more complex pathway is taking place. When either nicotine-N-methyl14C or nicotine-2‘-14C was pyrolyzed, several alkylated 14Clabeled pyridines were among the products. This indicated that fragments of the pyrrolidine ring can recombine and aromatize to give pyridines (1580). The pyrolytic formation of pyridines has been observed in studies on a number of nitrogenous substances. Pyrolysis of tobacco pigment and of tobacco leaf gave a spectrum of pyridines similar to those observed in smoke [Schmeltz et al. (3499), Schlotzhauer and Schmeltz (3463)]. Pyridines were observed in the pyrolysis of proline [Higman et al. (1647)] and pyridine was a product of pyrolysis of poly-L-proline [Johnson et al. (1968)]. Pyrolysis of nicotinamide at 1050°C gave pyridines and 3-cyanopyridine, among other products [Bruzel and Schmeltz (515)]. Pyridines were also observed in pyrolysates of pyrrole, maleic hydrazide, and N,Ndimethyldodecylamine [Patterson et al. (2907, 2908)]. In view of the above mentioned results on pyrolysis of nicotine14C and previous mechanistic studies [Hurd et al. (1851)], it is not surprising that pyridines should arise on pyrolysis of such diverse N-containing compounds. Studies on cigarettes enriched in nicotine or nornicotine indicated that nornicotine was an important precursor for pyridines [Glock and Wright (1316), Hecht et al. (1580)].

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Pyridines can be formed by mechanisms other than pyrolysis. The reaction of aldehydes with amino acids has been shown to generate pyridines (50). When a glycine-propanal mixture was heated to 180°C, 3,5-dimethyl-2-ethylpyridine, 3,5-dimethyl-4-ethylpyridine, and 3,5-dimethylpyridine formed. Glycine-propanal mixtures, also heated to 180°C, gave 2,5dimethylpyridine and 3,4-dimethylpyridine. This is an example of a nonpyrolytic method of forming pyridines. As smallchain aldehydes required for this reaction are abundant in smoke, this is a feasible route to pyridines. Pyridines contribute to the characteristic tobacco flavor of smoke. Fujimori (1248) identified twenty-six pyridines as components of tobacco aroma. Leffingwell et al. have tabulated the flavor and aroma characteristics of many pyridines (2341). Pyridines as a class of compounds enhance tobacco flavor, add burley flavor, or can add flue-cured flavor. Pyridines are responsible for that characteristic note in smoke that identifies the smoke as that from tobacco (1587a). Hoffmann and Wynder (1803) have made the comment that pyridines are responsible for the off-taste and irritancy of the smoke from large cigars and that pyridines reduce the inhalability of cigar smoke. Roberts commented that two particular pyridine compounds were noteworthy, 2-acetylpyridine [1-(2-pyridinyl)ethanone] and 2-methyl-5-isopropylpyridine [2-methyl-5-(1methylethyl)-pyridine] (3215). The former adds some sweet, roasted, and musty notes and the latter adds body and burley character to the tobacco blend. Additionally some pyridines may react with other smoke compounds synergistically. For example, it is believed that some pyridines reduce the sweet burnt-sugar taste of cyclopentenones and furanones (3215). XVII.B.4.3 Pyrazines Pyrazines constitute a very small percentage by weight of smoke condensate (5 to 50 mg/cigarette), but pyrazines as a class of tobacco and tobacco smoke compounds are very important because of their positive flavoring properties. Pyrazine, methylpyrazine, and 2,6-dimethylpyrazine were first recognized in tobacco smoke in 1965 by Testa and Testa (3888). To date, one hundred pyrazines have been identified in tobacco and tobacco smoke. Over 50% of the identified pyrazines are found in both tobacco and tobacco smoke. In the 1968 review by Stedman (3797), he listed only three pyrazines as components of tobacco smoke: pyrazine, 2-methylpyrazine, and 2,6-dimethylpyrazine. In that same year, Neurath and Dünger (2732) identified eight additional pyrazines, including 2-methyl-5-(2’-furyl)pyrazine. Leffingwell in 1976 (3237) mentioned six new pyrazines, including three acetyl-substituted pyrazines. Green (1351), in 1977, disclosed another eight novel pyrazines, including 2-methyl-5-phenylpyrazine, 3-methylpyrazinol, and pyrrolo [1,2-a]pyrazine. Heckman and Best (1587) have also identified a number of pyrazines, including five cyclopentapyrazines. There is a great diversity of pyrazines that have been identified in tobacco smoke.

753

Pyrazines have also been isolated from tobacco (938). Their presence in leaf arises from biosynthesis and from browning reaction chemistry that can occur during curing and tobacco processing. At present, sixty-two pyrazines have been identified in tobacco. Bright et al. (431) have demonstrated that the necessary precursors for the formation of pyrazines are present in tobacco leaf. In their experiments, the levels of dimethylpyrazine in untreated tobaccos were measured and then the same tobaccos were heated at 120°C for four hours and the levels measured again. In each case, the level of dimethylpyrazine was found to be very low in the untreated tobacco and appreciably increased following the roasting. Their results also showed a decrease in amino acid levels during the heat treatment of the tobaccos, indicating the possible involvement of amino acids in the formation of the pyrazines. Some pyrazines have been isolated from flue-cured (965) and burley tobaccos (937). The presence of pyrazines in tobaccos may be due to reactions of leaf precursors at the temperature used in curing of these tobacco types (1351). Amadori compounds are b-ketoamino acids that are structurally similar to b-hydroxyamino acids. Amadori compounds can yield pyrazines. Leffingwell (2337) and Green (1351) have both mentioned the presence of Amadori compounds in leaf, as has Tomita (3923), who stated that Amadori compounds account for as much as 2% of the dry weight of fluecured leaf. Thermal treatment of Amadori compounds does, in fact, give pyrazines as decomposition products [Shigematsu et al. (17B50)]. The formation of 2,5-bis-(tetrahydroxybutyl) pyrazine (fructosazine) from the reaction of fructose or glucose with alcoholic ammonia and from self-condensation of glucosamine or isoglucosamine has been known for a long time (17B57); in fact, the earliest reports date back to the beginning of the twentieth century. Deoxyfructosazine and its 2,6-isomer have been isolated from mixtures obtained by reaction of glucose and fructose with ammonia under weakly acidic conditions (1153, 1156, 17B13). The fructosazine and deoxyfructosazine isomers can be obtained synthetically by use of such sugar-ammonia reactions. The yields and isomer ratios are somewhat contingent on the choice of sugar (glucose or fructose) and the mole ratio of sugar to ammonium formate (1153). For example, xylose and aqueous ammonium formate yielded 2,5-bis (D-threo-trihydroxypropyl) pyrazine (xylulosazine) and the related 2,5- and 2,6-deoxyxylulosazines (1248). Several deoxyfructosazine isomers have been isolated from tobacco (1352). The tobacco-derived deoxyfructosazines were shown to improve the aroma and taste of tobacco (1351). Lynm (2420, 2421, 2423, 2424) at RJRT conducted several studies on the presence, formation, and analysis of deoxyfructosazines in tobacco and tobacco products. Two mechanisms have been suggested for pyrazine formation during smoking; pyrolytic decomposition of leaf constituents and nonenzymatic sugar-amine reactions. Kato et al. (2048) showed that direct pyrolysis of serine yielded pyrazine, methylpyrazine, ethylpyrazine, 2-ethyl-6-methylpyrazine, 2,6diethylpyrazine, and 2,6-diethyl-6-methylpyrazine. Pyrolysis of threonine gave 2,5-dimethylpyrazine, trimethylpyrazine,

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754

and 2,5-dimethyl-3-ethylpyrazine. Sugars condense with amino acids to form sugar-amino acid adducts which then undergo Amadori rearrangement to give Amadori compounds. Although pyrolysis of selected leaf constituents generates pyrazines, the diversity and abundance of pyrazines in smoke cannot be adequately accounted for by this mechanism alone. Maga and Sizer (2439) and Enomoto et al. (17B12) have reviewed the occurrence of pyrazines in roasted foods and proposed pathways for pyrazine formation. Their summaries present a large array of pyrazines found in the flavor fractions of a number of roasted foods. It is striking that nearly all pyrazines commonly found in tobacco smoke have been identified in at least one roasted food. For example, 2,3-dimethylpyrazine has been found in peanuts, barley, coffee, baked potatoes, mushrooms, lamb fat, and tobacco smoke (1587a). Of particular interest in relating leaf to smoke composition are the studies of Koehler and co-workers (17B26, 17B27) on the formation of pyrazine compounds in sugar-amino acid systems. Using model systems, Koehler and Odell (17B27) showed that pyrazines are formed when sugars and amino acids are heated between 100 and 150°C. Glucose reacts with either an amino acid or ammonia to form a glycosylamine. The amino acid complex then undergoes a Strecker-type degradation to yield an eneaminol which can also be formed by the loss of water from glucosylamine. The eneaminol then isomerizes and undergoes reverse aldol condensation to form 1-aminoacetone which is known to self-condense to yield pyrazines (116). As shown by Schonberg and Moubacher (17B46), during the condensation of the aminoacetone further reaction with aldehydes can take place. Similar pathways can be postulated for the generation of 1-aminoacetaldehyde, 1-aminopropionaldehyde, and 1-amino-2-butanone from sugar-amine reactions. Hypothetical reaction of these aminocarbonyl compounds either individually or in pairs can account for most of the alkylpyrazines reported in smoke (1351). Additionally, Koehler and Odell (17B27) showed that a number of smaller compounds, acetaldehyde, glycerol, glyoxal, 2,3-butanedione, and acetol also yielded pyrazines when heated with nitrogen sources. Koehler et al. (17B26) had previously shown, using radiotracer techniques, that the sugar moiety served as the principal source of carbon atoms and that the amine furnished only nitrogen to the pyrazine molecule. These data imply that sugar decomposes to small intermediary carbonyl compounds which in turn react with the nitrogen source, for example, amine or amino acid, to form pyrazines. Other possible mechanisms for the formation of pyrazines during smoking are possible. For instance, leaf carbohydrates could be degraded either through pyrolysis or Maillard reactions to form a-dicarbonyl compounds, which could, in turn, react with amino acids to undergo a Strecker degradation forming

The Chemical Components of Tobacco and Tobacco Smoke

the a-aminocarbonyl compounds [1671a, 2439, Velisek et al. (17B59)] which can condense to form pyrazines (1351). Pyrazines are the most important N-heterocycles in characterizing the aroma and flavor of tobacco and tobacco smoke (2341, 3215, 3491, 3553). The alkylpyrazines, for example, provide the cocoa and nutty-type notes associated with tobacco smoke. 2-Acetylpyrazine [1-pyrazinylethanone], isolated and identified in burley tobacco by Roberts (3202, 3204) in 1963, contributes a nutty, popcorn-type flavor unique to tobacco smoke. Pyrazines, in general, contribute the “brown notes” associated with tobacco smoke taste (3215). It is obvious that cigarette MSS flavor and aroma may be enhanced by addition of appropriate pyrazine compounds to the tobacco blend, for example, among the 460 pure compounds listed by Doull et al. (1053) as possible cigarette tobacco ingredients used by U.S. cigarette manufacturers are twenty-three (5%) pyrazine derivatives. In 1977, RJRT conducted an immense study on Philip Morris’s Merit cigarette that advertised the use of a “flavor package.” One of the interesting results of that study was that the MSS from Merit contained numerous alkylpyrazines, particularly higher levels of tetramethylpyrazine, and several trimethylpyrazines compared to other commercial cigarettes brands of similar FTC “tar.” Much of the Merit research conducted at RJRT was summarized by Lloyd (2385a). XVII.B.4.4 Pyrimidines There are thirty-three pyrimidine derivatives identified in tobacco and tobacco smoke. The vast majority of these compounds (67%) have been identified in tobacco. Only fourteen are known to exist in tobacco smoke. As previously mentioned, the naturally occurring derivatives of pyrimidine are components of nucleic acids: cytosine, thymidine, and uracil. Free pyrimidine and functionalized pyrimidine compounds in tobacco are believed to be formed from the catabolism of various nucleosides (17B21). Several of the pyrimidinecontaining compounds in tobacco are agronomic chemical residues while other compounds identified in tobacco smoke are formed from those agronomic residues. Pyrimidine derivatives do not generally have positive flavor notes and are considered neutral to poor. Some pyrimidinederived flavors (although not found in tobacco or tobacco smoke) have meaty notes. There are also some pyrimidine flavorants that do possess good flavor potential for tobacco products, for example, 2-methyl-5,7-dihydrothieno[3,4-d]pyrimidine. This compound contains a bicyclic ring structure and has been identified in tobacco. 2-Methyl-5,7-dihydrothieno[3,4-d]pyrimidine is said to have a fresh roasted, sweet nut flavor with a popcorn character (17B22). It is a compound listed by Doull et al. as an ingredient in flavor formulations used by one or more members of the U.S. tobacco industry (1053).

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755

Nitrogen Heterocyclic Components

Table XVII.B-2 Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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756

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

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Nitrogen Heterocyclic Components

757

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

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758

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

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Nitrogen Heterocyclic Components

759

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

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760

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

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761

Nitrogen Heterocyclic Components

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

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762

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

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Nitrogen Heterocyclic Components

763

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

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764

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

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Nitrogen Heterocyclic Components

765

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

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766

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

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767

Nitrogen Heterocyclic Components

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

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768

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

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Nitrogen Heterocyclic Components

769

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

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770

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

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Nitrogen Heterocyclic Components

771

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

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772

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

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Nitrogen Heterocyclic Components

773

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

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774

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

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Nitrogen Heterocyclic Components

775

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

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776

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

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777

Nitrogen Heterocyclic Components

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

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778

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

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Nitrogen Heterocyclic Components

779

Table XVII.B-2 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

XVII.B.5 Compounds in Tobacco and Tobacco Smoke Containing a Five-Membered and a Six-Membered N-Containing Ring The origin of all the work that has been done on the isolation and identification of the tobacco and tobacco smoke began with this relatively small group of compounds. The initial tobacco and tobacco smoke compound that was of so

much interest was nicotine. Literally thousands of scientific articles, reviews, and books have been published on various aspects of nicotine, for example, pharmacological and metabolic properties, chemical and structural properties, occurrence, biogenesis, and pyrolysis. The scope of all the work on nicotine alkaloids is so broad that a comprehensive review is beyond the scope of this chapter. The several hundred references listed in Table XVII.B-4 testify to the enormous

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780

amount of research that has been conducted on the nicotine alkaloids. Instead, a brief history of the initial work on the isolation and identification of nicotine follows. XVII.B.5.1 Nicotine and Tobacco Alkaloids with a Six-Membered N-Containing Ring and a Second Five-Membered N-Containing Ring Nicotine is the unique component of tobacco. The history associated with the discovery of nicotine and use of the “oil” derived from tobacco dates to about 1571 (17B16). This “oil” prepared by the French chemist Gohory undoubtedly contained some level of nicotine and was used as a remedy for diseases of the skin. In 1660, another French chemist, Lefevre, described means to steam distill tobacco to obtain oil that had medicinal uses (3477). In 1807, Cerioli discovered what he called the “olio essenziale” of tobacco (17B15). In 1809, Vauquelin apparently made the same discovery. Both researchers described the oil as a volatile and colorless substance. Vauquelin recognized the basic nature of the material but failed to recognize its alkaloidal properties. He attributed the basicity of the material to the presence of ammonia (410). In 1822, Hermbstädt confirmed Vauquelin’s results of the presence of the oil described in sixteen different species of what is now known as Nicotiana (17B15). It was not until 1828 that Posselt and Reimann (2981) succeeded in isolating a pure sample of the oil and recognized it as an alkaloid. They characterized it as a water-clear liquid, boiling at 246°C under atmospheric pressure, and miscible with water, alcohol, and ether. They named the pure compound nicotine after Jean Nicot who introduced tobacco into the French court in about 1560 (17B42). In 1826, Unverdorben isolated a water-soluble base from a dry distillate of tobacco (282). The base contained nicotine. Melsens (2528), in 1843, succeeded in isolating nicotine from the smoke of pipe tobacco and assigned the empirical formula, C12H14N2 (2724). In 1893, Pinner (17B44) reported on the final clarification of the constitution of nicotine, determined via degradation studies. Pinner’s structural formula for nicotine was confirmed by the classical synthesis of nicotine by Pictet and Rotschy (17B43) in 1895. For many years, nicotine was believed to be the only alkaloid in tobacco (17B18). It was not until 1928 that Ehrenstein reported the identification of nornicotine in tobacco [see Markwood (17B38)]. Anabasine was isolated in tobacco by Smith (17B53) in 1935. Späth and Kesztler (17B55) isolated anatabine in tobacco in 1934 [Markwood (17B38)]. Gautier and LeBon in 1892 were the first chemists to clearly recognize that additional alkaloids accompanied nicotine in tobacco smoke. These additional alkaloids were the secondary alkaloids and decomposition products of alkaloids. Unfortunately, Gautier and LeBon did not report further on their observations (2223, 2224). Wenusch and Schöller (4210, 4211) in the early 1930s worked diligently to separate the secondary alkaloids in tobacco smoke. Though they were not wholly successful they did discover and determine the formula for myosmine in cigar smoke in 1936 with the collaboration of Späth (2224). By 1936, Wenusch and Schöller (4213)

The Chemical Components of Tobacco and Tobacco Smoke

had distinguished a large number of tobacco smoke bases in cigar and cigarette smoke by their behavior during steam distillation and extraction. Several of the alkaloid-related components (a-, b-, and g-socratine, obelin, lohitam, anodmin, lathraein, poikiline, and gudham) first reported by Wenusch and Schöller (4210, 4211) were subsequently demonstrated to be mixtures or mislabeled components of previously known alkaloids. Until the study by Kuffner, Schick, and Bühn in 1959, there was much confusion concerning the correct identity of the secondary alkaloids of tobacco smoke. Kuffner et al. (2224) demonstrated that obelin was a salt of ammonia, a- and b-socratine were mixtures of nicotyrine and 2,3’bipyridine, and g-socratine was l-nornicotine. Poikiline was characterized as 4-amino-1-(3-pyridyl)-butanone. Many of these characterization corrections are described in Johnstone and Plimmer (1971) and Borgerding et al. (410). To date, ninety-five alkaloids with both a five-membered and a six-membered N-containing ring have been identified in tobacco and tobacco smoke [see Table XVII.B-4]. In all cases, the six-membered ring is pyridine; the attached fivemembered ring may be a pyrrolidine, pyrroline, pyrrole, or an imidazole ring. The vast majority of these tobacco alkaloids contain a pyrrolidine ring that is substituted at the three-position of the pyridine ring. Table XVII.B-3 shows the distribution of the ninety-five tobacco alkaloids that occur in tobacco, tobacco smoke, and in both. Table XVII.B-4 lists the compounds containing a five-membered N-containing ring plus a six-membered N-containing ring that have been identified in tobacco and/or tobacco smoke. Sixty-two nicotine alkaloids have been identified in tobacco. Fifty-four have been identified in tobacco smoke and twentyone of the ninety-five nicotine alkaloids are found in both tobacco and tobacco smoke. The vast majority of the nicotine alkaloids (fifty-four of sixty-two) contain a pyrrolidine ring connected to a pyridine ring. The most common functionalities associated with the pyrrolidine-containing nicotine alkaloids are alkyl, nitroso, carboxyl, amino, and acyl groups.

Table XVII.B-3 Distribution of Components with a 6-Membered N-Containing Ring and a Second 5-Membered N-Containing Ring between Tobacco and Tobacco Smoke Number of Identified Compounds in Tobacco and Tobacco Smoke with a 6- and a 5-Membered Ring Component

Total

Smoke

Tobacco

Pyridine Ring with a 2nd N-Containing Ring (Type) Pyrrolidine 72 34 54 (nicotinoids) Pyrroline 2 1 2 Pyrrole 19 18 5 Imidazole 2 1 1 Totals

95

54

62

Smoke and Tobacco 16 1 4 0 21

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781

Nitrogen Heterocyclic Components

Table XVII.B-4 Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered N-Containing Ring Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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782

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-4 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered N-Containing Ring

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Nitrogen Heterocyclic Components

783

Table XVII.B-4 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered N-Containing Ring

(Continued )

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784

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-4 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered N-Containing Ring

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Nitrogen Heterocyclic Components

785

Table XVII.B-4 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered N-Containing Ring

(Continued )

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786

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-4 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered N-Containing Ring

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Nitrogen Heterocyclic Components

787

Table XVII.B-4 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered N-Containing Ring

(Continued )

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788

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-4 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered N-Containing Ring

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789

Nitrogen Heterocyclic Components

Table XVII.B-4 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered N-Containing Ring

The structures of some of the most common tobacco alkaloids found in smoke are shown in Figure XVII.B-3. The transfer rate for nicotine is generally about 10% to 12% but a number of factors, including the cut width of the tobacco, the shape of the cigarette, the moisture content of the tobacco, and various tobacco additives can significantly affect nicotine delivery to mainstream smoke [Kuhn and Klus (2231), Hecht et al. (1580)]. Many of the alkaloids of tobacco smoke consist of components originally in the tobacco, which transfer unchanged, and various pyrolysis products of the nicotine alkaloids. Nicotine is a major precursor of a large number of volatile bases in tobacco smoke. On heating nicotine at temperatures greater than 400°C, various patterns of fragmentation occur

N H

N N Nicotine

N N

N

CH3

Nornicotine

O

CH3

Cotinine

N N

CH3

2',3'-Dehydronicotine

N

N H

N

N

Myosmine

Nicotyrine

Figure XVII.B-3  Common tobacco alkaloids found in tobacco and tobacco smoke.

depending on the gaseous atmosphere and other experimental conditions. Myosmine (4275a) and 3-cyanopyridine [Woodward et al. (17B61)] are two of many pyrolysis products of nicotine at 500 to 730°C. The yields and type of pyrolysis products depend on the substrate used to hold the alkaloid, the particular alkaloid tested, for example, nicotine or nornicotine, the temperature ramping regime, the final temperature attained, the holding time at maximum temperature, and reactor type employed for the pyrolysis experiment. The major identified pyrolytic products of nicotine at temperatures 400 and 900°C (in a nitrogen or helium atmosphere) include all of the compounds shown in Figure XVII.B-3. In addition to these compounds, ammonia, methylamine, and a number of smaller fragments are formed from heterolytic cleavage of nicotine. Nicotine is not fragmented significantly at temperatures below 600°C in reactors without packing. At reactor temperatures of 600°C (with samples in an inert atmosphere) about two-thirds of the nicotine is split mainly into myosmine (1’,2’-dehydronornicotine) and 3-vinylpyridine. At 700°C, nicotine is completely decomposed, with the major products being 3-vinylpyridine, 3-methylpyridine, and pyridine. At 800 and 900°C, extensive cleavage and recombination of fragments occur to yield such products as quinoline, naphthalene, and benzonitrile. From examination of the pyrolysis products produced, dehydrogenation, demethylation, and scission of the pyrrolidine ring are initial steps in the pyrolysis of nicotine. In a Cl-C2 fragmentation of this ring, dehydrogenation of the resulting N-methylaminoalkyl chain would give metanicotine which,

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790

on further elimination, produces the observed 3-(1,3-butadienyl) pyridine and subsequently 3-vinylpyridine by appropriate cleavage. Fragmentation of the pyrrolidine ring in the 2,3- or 1,5 positions might ultimately give 3-cyanopyridine after dealkylation of the side chain (3797). The mechanism of thermal degradation of nornicotine is generally similar to nicotine although differences in thermostability exist (175, 17B25). Nornicotine is less stable than nicotine and the pyrrolidine ring fragments at temperatures below 400°C. At 400°C (in an inert atmosphere) myosmine and 3-methylpyridine are major pyrolytic products, but at 500°C only a small amount of myosmine is formed. Since myosmine is relatively stable (44% unchanged) on pyrolysis at 500°C, this compound may not be an intermediate of nornicotine pyrolysis at higher temperatures (175). An alternative explanation is that myosmine formed from nornicotine may react with other pyrolytic products which are not produced when myosmine is pyrolyzed alone. Although the available evidence is sparse, it appears that the pyrolytic mechanism of myosmine is different from that of nicotine and nornicotine (175). At 500°C (in an inert atmosphere) myosmine gives lower yields of 3-methylpyridine and 3-ethylpyridine and higher yields of 3-cyanopyridine than nornicotine. This pattern may indicate that a C3-C4 split is favored in the five-membered ring; scission of this bond might be preferred over a C2-C3 fragmentation adjacent to the relatively stable C=N bond (3797). Studies with cigarettes treated with 14C-nicotine have been valuable in determining the delivery of nicotine and its pyrolysis products to MSS and sidestream smoke (SSS). These experiments were reviewed in 1975 by Jenkins et al. (1933a). In a typical study with nicotine-2’-14C, the total 14C-activity in mainstream total particulate matter (TPM) was 15.4% of the original activity in the tobacco burned, while the contribution of the alkaloids to mainstream TPM was 14.9% (1836). Thus, 96.8% of the 14C- activity of the mainstream TPM was due to transfer of alkaloids and 3.2% was due to products formed from nicotine during smoking; mainstream gas phase (4.1%) contained only pyrolysis products. In the sidestream TPM, 41.1% of the original 14C was detected, that is, 10% of this material was decomposition products. Sidestream gas phase (16.3%) exclusively comprised pyrolysis products. Most of the remaining 14Cactivity (20.2%) was found in the butt. Thus, approximately 30% of nicotine in a cigarette is converted to products that appear in the SSS and MSS. Pyrolysis studies on nicotine, discussed in the previous section, indicate that pyridines would comprise a significant portion of the particulate-phase products. However, nicotine can undergo other transformations during smoking, including reactions with nitrogen oxides (1580). These are discussed in the chapter on nitrosamines (see Chapter 15). Several studies have been conducted on the fate of nicotine during smoking. Jenkins and Comes (17B20) and Perfetti (2920–2922, 2924) have examined the fate of exogenous vs. endogenous transfer of nicotine during smoking. These authors concluded that the transfer into smoke of exogenous nicotine (regardless of its form [free base or salt, d- or l- conformation]) was similar to that of endogenous material, in contrast to observations with tobacco sterols. Thus, use of 14C-nicotine in

The Chemical Components of Tobacco and Tobacco Smoke

tracer studies on cigarette smoke is justified. A comparison of the fate of 14C-nicotine in a pyrolysis study vs. its fate during the smoking of a cigarette resolved a long-standing disagreement between those investigators who maintained that the fate of a compound on pyrolysis at a temperature similar to that in a burning cigarette was the same as the fate of that compound in a smoked cigarette and those who maintained that the fates would definitely be different. Schmeltz et al. (3512), with 14C-nicotine in a study on pyrolysis vs. cigarette smoking, reported that the fates were quite different. On the basis of their findings, they stated: “These results suggest to us that pyrolysis experiments may be of limited value for establishing the fate of nicotine and possibly other tobacco components in a burning cigarette.” The transfer rate of nornicotine during smoking is significantly lower than that of nicotine, with typical values ranging from 5% to 8% [Glock and Wright (1316), Haag and Larson (17B14)]. When high nornicotine tobaccos were smoked, significant increases in the levels of myosmine were observed compared to conventional burley cigarettes. Similar results were obtained when cigarettes were enriched with nornicotine (1316). Thus, nornicotine is not only an efficient precursor for pyridines, but also for myosmine as previously mentioned. This is thought to contribute to the unfavorable taste of smoke from nornicotinerich (so-called “Cherry-red”) tobacco. The ease of formation of myosmine from nornicotine is likely to be an important factor in its relatively low transfer rate. The nicotine alkaloids contribute substantially to the unique flavor of tobacco smoke, mainly due to their rather large concentration in tobacco and their rather substantial transfer to tobacco smoke. The nicotine alkaloids as a class are not considered positive flavorants as they contribute a harsh, irritating flavor to the smoke. Nicotine and its contribution to smoking satisfaction is a subject unto itself that is fraught with numerous social and scientific controversies and will not be discussed here. It is well known that tobacco products that contain no or very low levels of nicotine (for numerous reasons) have never found consumer acceptance or commercial success. XVII.B.5.2 Compounds in Tobacco and Tobacco Smoke with Two or More SixMembered N-Containing Rings In tobacco and tobacco smoke, the seventy-six identified compounds with two or more six-membered N-containing rings (Table XVII.B-5) include 2,2‘-bipiperidine, several bipyridines, anatabine-type compounds, anabasine-type compounds, anatalline, and nicotelline-type compounds. They are distributed as follows:

1. A total of thirty-nine bipyridines, the majority of which are derivatives of 2,3’-bipyridine, plus several 2,2’-, 2,4’-, 3,3’-, and 4,4’-bipyridine derivatives. 2. Anatabine and anabasine derivatives, which number sixteen and fifteen, respectively. 3. Three compounds with two pyridine rings and a piperidine ring [anatalline (2,4-di(3-pyridinyl)piperidine] and anabasamine [5-(2-piperidinyl)-2,3’bipyridine] plus its methyl derivative].

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Nitrogen Heterocyclic Components

Table XVII.B-5 Distribution of Components with Two or More 6-Membered N-Containing Rings between Tobacco and Tobacco Smoke Number of Identified Compounds in Tobacco and Tobacco Smoke with Two 6-Membered N-Containing Rings Component

Total

Smoke

Tobacco

Smoke and Tobacco

Compounds with two or more 6-membered N-containing rings (Type) 1 0 1 0 Piperidine + piperidine 15 11 8 4 Pyridine + piperidine (anabasine-type) 39 38 8 7 Pyridine + pyridine (bipyridines) 16 12 9 5 Pyridine + di- or tetrahydro-pyridine (anatabine-type) 3 1 3 1 2 Pyridines + piperidine 3 Pyridines 2 2 2 2 Totals 76 64 31 19



4. Two compounds with three pyridines, the so-called terpyridines, one of which is nicotelline (3,2’:4’,3’’terpyridine). 5. One bipiperidine compound has been identified in both tobacco and tobacco smoke (2,2‘bipiperidine).

Of the seventy-six compounds in this class, sixty-four have been identified in tobacco smoke, thirty-one have been identified in tobacco, and nineteen in tobacco and tobacco smoke. Figure XVII.B-4 illustrates the structures of some of the common tobacco alkaloids found in tobacco and tobacco smoke with two or more six-membered N-containing rings. Although nicotine is the principal alkaloid in commercial tobaccos (Nicotiana tabacum and Nicotiana rustica), nornicotine is the main alkaloid in most other species of Nicotiana. Anabasine is the third most abundant tobacco alkaloid. Anabasine is found in the stem of the Nicotiana glauca plant. Anatabine has been reported as a minor alkaloid in the roots of these plants, although it is present also in the leaf and stem H N

H N

2,2'-Bipiperidine

N

N H

Anatabine

5 6

4 N

3

4'

2'

N 2,3'-Bipyridine

N

N H

Anabasine

(3491). All of the alkaloids in Figure XVII.B-4, including bipiperidine, the bipyridines, anatabine, anabasine, anatalline, and nicotelline, can be biosynthesized from lysine and nicotinic acid in Nicotiana species to some extent depending on the species (429b, see KEGG, Alkaloid biosynthesis II — Reference pathway, EC-Number 1.1.1.206, Pathway 00960, see http:// www.genome.jp/kegg/pathway/map/map00960.html). Nicotelline (3,2’:4’,3’’-terpyridine) is another minor alkaloid of tobacco initially isolated from tobacco by Kuffner and Kaiser (17B28). It was originally believed be formed by the condensation of two molecules of nicotinoylacetic acid (17B31), although this compound could also result from the degradation of nicotine. However, feeding experiments of [2’-14C]-nicotine or ethyl [carbonyl-14C]-nicotinoyl acetate to tobacco (17B58) failed to yield labeled nicotelline. Currently, nicotelline and anatalline [2,4-di(3-pyridinyl)-piperidine] are considered to be formed by the trimerization of dihydropyridines from nicotinic acid (17B23). A similar reaction is proposed for the formation of the terpyridines. These alkaloids are possibly artifacts produced by nonenzymatic reactions which could occur during the harvesting and curing of tobacco. The lack of optical activity in the isolated anatalline supports this hypothesis (17B31). Various bipyridines are also formed during tobacco fermentation [Frankenburg and Gottscho (1223)]. As much as 3% of the nicotine originally present in cigar tobacco was converted to 2,3’-bipyidine and other oxidative compounds (3973). One study by Dubinin and Chelintsev (1075a) reported on the pyrolytic products of anabasine heated at 580 to 650°C in a charcoal-filled reactor. Exclusive of gases, the major products were reported to be pyridine, 2-methylpyridine, 2-ethylpyridine, 5-methylisoquinoline, and 2,3’-bipyridine. The preponderance of the 2-alkylpyridines might indicate preferential cleavage of the pyridine ring, which would be unexpected; evaluation of these findings is difficult since the use of charcoal in the reactor may have produced a catalytic effect and altered the pyrolytic reactions markedly (3797). In terms of the flavor potential of this class of compounds, very little is known. A minor tobacco alkaloid, 2,3’-bipyridine, has been reported (17B19) to exhibit a sensitizing effect on tobacco flavor and to suppress astringency (3215, 17B52). Table XVII.B-6 lists the compounds containing two or more six-membered N-containing rings identified in tobacco and tobacco smoke.

H

5' 6'

N N N

2,2'-Bipyridine N

N-Methylanabasine HN

N N Nicotelline

CH3

N

N Anatalline

Figure XVII.B-4  Common tobacco alkaloids found in tobacco and tobacco smoke with two or more 6-membered N-containing rings.

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792

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-6 Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Two or More 6-Membered N-Containing Rings

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Nitrogen Heterocyclic Components

793

Table XVII.B-6 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Two or More 6-Membered N-Containing Rings

(Continued )

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794

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-6 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Two or More 6-Membered N-Containing Rings

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Nitrogen Heterocyclic Components

795

Table XVII.B-6 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Two or More 6-Membered N-Containing Rings

(Continued )

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796

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-6 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Two or More 6-Membered N-Containing Rings

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797

Nitrogen Heterocyclic Components

Table XVII.B-6 (Continued) Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Two or More 6-Membered N-Containing Rings

Detailed examination of the lists presented in this chapter on monocyclic nitrogen heterocycles indicates 709 compounds have been identified to date in tobacco and tobacco smoke. The data are summarized in Table XVII.B-7.

It is obvious from the tabulation that the six-membered N-containing ring compounds with one or more nitrogens represent nearly 75% of the compounds identified to date.

Table XVII.B-7 Tobacco and Tobacco Smoke Compounds with 6-Membered Rings, with a 5- and a 6-Membered Ring, or with Two or More 6-Membered N-Containing Rings Ring Type 6-Membered Ring with One or More Nitrogens

No. of Compds. (No. of Agronomic Chemicals)

Pyridine Ring with a 2nd N-Containing Ring (Type)

Piperidines

37

Tetrahydropyridines

5

Pyrrolidine (nicotinoids) Pyrroline

Dihydropyridines

6

Pyrrole

Pyridines

341 (4)a

Imidazole

Piperazines Dihydropyridazine Pyrazines Pyrimidines 1,2,4-Triazines 1,3,5-Triazines

10 3 (3)b 100 (1)c 33 (4)d 2 (1)e 1 (1)f

Totals

538

a b c d e f g h

No. of Compds. (No. of Agronomic Chemicals) 72 (2)g 2 19 2 (1)h

Compounds with Two or More 6-Membered N-Containing Rings (Type) Piperidine + piperidine Pyridine + piperidine (anabasine-type) Pyridine + pyridine (bipyridines) Pyridine + di- or tetrahydropyridine (anatabine-type) 2 Pyridines + piperidine 3 Pyridines

95

No. of Compds. (No. of Agronomic Chemicals) 1 15 39 16 3 2

76

Chlorpyrofos® (insecticide), Chlorpyriphos® (insecticide), Nitrapyrin® (bacteriocide), Picloram® (herbicide) Maleic hydrazide and salts (herbicide) Thionazine® (insecticide) Primicarb® (insecticide), Pirimiphos-methyl® (insecticide), Dimetherimol® (fungicide), Diazinon®, (insecticide) Metribuzin® (herbicide) Anilazine® (fungicide) Black Leaf 40® (insecticide) Admire® (insecticide)

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The Chemical Components of Tobacco and Tobacco Smoke

XVII.C Lactams Kosak (2170) listed no lactam identified in tobacco smoke prior to 1954. In 1959, Johnstone and Plimmer (1971) listed cotinine as an alkaloid in tobacco and smoke. They did not categorize it or any other tobacco or smoke component as a lactam. In its 1963 monograph on tobacco and smoke components, Philip Morris (2939) listed cotinine as a tobacco and smoke component. Ishiguro and Sugawara (1884), in their 1980 monograph on tobacco smoke components, listed a total of seventy-two amides, imides, and lactams; a total of sixteen lactams was listed [see Table I-15 in (1884)]. The reference for all of the sixteen lactams listed was Schumacher et al. (3553). The International Agency for Research on Cancer (IARC) Working Group met in 1985 to assess the carcinogenic risk from tobacco smoking. Its monograph summarizing the IARC findings was published in 1986. In it, the IARC stated that there was a large spectrum of amides, imides, and lactams in tobacco smoke (including some fifty aliphatic amides) [see p.109 in (1870)]. The IARC view on these three compound classes was based on the 1977 review by Schmeltz and Hoffmann (3491) and publications in 1977 and 1981 by Schumacher et al. (3553) and Heckman and Best (1587), respectively. Of the thirty-five lactams reported in tobacco smoke by Schumacher et al. (3553) at the 1975 Tobacco Chemists’ Research Conference (TCRC) and published in 1977, twentyone were new to the tobacco smoke literature. As noted in Chapter 13 and Chapter 14, used in this study was a recently developed analytical technology that permitted fractionation and identification of the water-soluble components of cigarette smoke condensate (CSC). Similarly in their 1978 TCRC presentation and 1981 publication, Heckman and Best (1587) reported the identification of two additional new lactams in tobacco smoke, 3-ethyl-5-methylene-3-pyrrolid-2-one and N-methyl-5-(1-methylethylidene)-3-pyrrolid-2-one. They also confirmed the presence in tobacco smoke of many of the lactams previously reported (3553). In his earlier study of the mainstream smoke from an all-burley tobacco cigarette, Heckman (1986) identified eight lactams. Lactams frequently reported in both tobacco and its smoke but seldom classified as lactams are 1-methyl-5-(3-pyridinyl)2-pyrrolidinone (cotinine) and several of its derivatives such as norcotinine. Ishiguro and Sugawara (1884) listed them as alkaloids [see Table I-12 in (1884)] not lactams. Examination of the structures of several of the CSC components indicates that the decision regarding their categorization is somewhat difficult. In Figure XVII.C-IA, representative structures for an imide and a lactam are presented. To which of these categories—imide or lactam—should the smoke component 1,7-dihydro-6H-purine-2,6-dione (xanthene) {I} be assigned? Its structure {I} is depicted in Figure XVII.C-IB. In Structure {II} in Figure XVII.C-1B, its imide configuration is accentuated. Structure {III} illustrates that two lactam configurations exist in the xanthene molecule. This same situation is present with the other purine-derived smoke components. Although there may be some disagreement on the preciseness of our selection, for the sake of completeness

O

O

N H Imide configuration

O N H Lactam configuration

Figure XVII.C-1A  The imide and lactam configurations.

O

N N H

N H

NH O

O

N N H

NH N H

O

N N H

O

I II 6H-Purine-2,6-dione, 1,7-dihydro-(xanthine) (CAS No. 69-89-6)

NH N H

O

III

Figure XVII.C-1B  The imide {II} and lactam {III} configurations in 1,7-dihydro-6H-purine-2,6-dione (xanthine) {I}.

such components are listed in each chapter in its major catalog table. As a result, the total number of components in each of the major catalog tables may be slightly inflated. Table XVII.C-1 lists a total of 118 lactams identified in tobacco and/or tobacco smoke. Of the 118, thirty-five were identified in tobacco, ninety-seven were identified in tobacco smoke, and fourteen were identified in both tobacco and tobacco smoke.

XVII.D Oxazoles and Oxazines Several oxazoles and oxazines have been identified in tobacco and tobacco smoke. Oxazoles are generally known as 1,3-azoles or five-membered-ring aromatic heterocyclic compounds with an oxygen and a nitrogen separated by one carbon. Oxazole is the parent compound. Isoxazoles are in this same family of compounds and are generally known as 1,2-azoles. These five-membered-ring aromatic heterocyclic compounds contain adjacent oxygen and nitrogen atoms. Oxazole is an analog of imidazole where the nitrogen atom in position 1 is replaced by oxygen. Isoxazole is an analog of pyrazole, that is, the nitrogen atom at position 1 is replaced by oxygen [Gilchrist (17D01)]. Oxazolidine and isoxazolidine are the reduced forms of oxazole and isoxazole, respectively. Several oxazolidine and isoxazolidine derivatives, for example, oxazolidinediones and isoxazolidinones, have also been identified in tobacco and tobacco smoke. One other component identified in tobacco is related to the oxazoles and isoxazole. It is an oxadiazole derivative, N-(4-bromophenyl)5-(1-naphthalenylmethyl)-1,3,4-oxadiazol-2-amine. Benzoxazole is a heterocyclic aromatic organic compound with a fused benzene-oxazole ring structure. Benzoxazole (1-oxa-3-azaindene) and several alkylated benzoxazoles have been identified in tobacco smoke. Benzoxazoles found in

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Nitrogen Heterocyclic Components

799

Table XVII.C-1 Lactams in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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800

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.C-1 (Continued) Lactams in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

801

Table XVII.C-1 (Continued) Lactams in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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802

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.C-1 (Continued) Lactams in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

803

Table XVII.C-1 (Continued) Lactams in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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804

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.C-1 (Continued) Lactams in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

tobacco smoke are believed to arise by the mutual condensation of the oxazole and benzene rings during the combustion/ pyrolysis of tobacco (1884). The only substituted benzoxazole known in tobacco is residue from the organophosphate insecticide Phosalone®. Oxazines are six-membered-ring analogs of piperazine where the nitrogen atom in position 4 is replaced by an oxygen atom. The oxazines in tobacco and tobacco smoke are morpholine and several morpholine derivatives. The most discussed morpholine recently is N-nitrosomorpholine (NMOR). This volatile N-nitrosamine (NMOR) has been identified in both tobacco and tobacco smoke. Morpholine is an organic heterocycle that features both amine and ether functional groups. Morpholine is also called tetrahydro-1,4oxazine. Figure XVII.D-1 illustrates the parent structures of the oxazoles and oxazines identified in tobacco and tobacco smoke. Numerous reviews have been written on the compounds identified in tobacco and tobacco smoke over the last five

decades (1884, 1900, 1971, 2170, 2270, 2939, 3224, 3797). Few have listed the oxazole- and oxazine-related compounds identified in tobacco and tobacco smoke. Latimer (2270) in 1955 listed 231 compounds identified from tobacco and tobacco smoke. In his review, he listed tetrahydro-2-methyl-6-(3pyridyl)-1,2-oxazine, a tobacco alkaloid, as the first oxazine identified in tobacco smoke. Roberts et al. in 1975 (3224) listed 2783 compounds identified in tobacco and tobacco smoke. In their report, five oxazole-related compounds identified in tobacco smoke were listed (2,4-dimethylbenzoxazole, 2-methylbenzoxazole, oxazolidinedione, 5-ethyl-N-methyl2,4-oxazolidinedione, and 5-methyl-2,4-oxazolidinedione). Roberts et al. did not report any oxazole- or oxazine-related compounds found in tobacco. In 1980, Ishiguro and Sugawara (1884) listed 1889 identified tobacco smoke components in their monograph, only six oxazole-related compounds were listed (dimethyloxazole, 5-methyl-2,4-oxazolidinedione, 2,4-oxazolidinedione, 3,4,5-trimethylisoxazole, 2-methylbenzoxazole, and 2,5-dimethylbenzoxazole). The citations

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805

Nitrogen Heterocyclic Components

O

O N

Oxazole

O

N

H N

N

O

NH Oxazolidine

4 N

O Isoxazole

3 N

2 O 1 1,3,4-Oxadiazole

Isoxazolidine

Benzoxazole

H N

5

O Morpholine

Figure XVII.D-1  Parent structures of the oxazoles and oxazines identified in tobacco and tobacco smoke.

by Ishiguro and Sugawara for all but the dimethyloxazole were to the Schumacher et al. (3553) and Newell et al. (2769) reports on tobacco smoke composition. Roberts in 1988 (3215) tabulated 5868 identified compounds in tobacco and tobacco smoke. By functional groups, 3044 compounds had been identified in tobacco, 3996 had been identified in smoke, and 1172 were identified in both tobacco and tobacco smoke. A large portion of the oxazole- and oxazine-related compounds in tobacco and tobacco smoke was originally identified by employees at the Research and Development Department of R.J. Reynolds Tobacco Company (RJRT) who were highly proficient in the isolation and identification of compounds in tobacco and tobacco smoke. From 1955 until 1988, they reported on nineteen (of the forty-four) oxazoleand oxazine-related compounds in smoke and six (of the fourteen) oxazole- and oxazine-related compounds in burley, Maryland, flue-cured, Oriental, and Perique tobaccos (965, 1075, 1360, 1364, 1375a, 1586, 1587, 1590, 2270, 2337, 2339a 2761, 2762, 2765, 2766, 2767, 2769, 2775, 2777, 3547, 3549, 3550, 3553, 3557). Demole (4570a) at Firmenich (Geneva, Switzerland), under contract to RJRT, identified twenty-five additional oxazoles in cigarette smoke condensate. Oxazole- and oxazine-related compounds do not appear to be endogenous in green tobacco but are found in tobaccos that undergo heat treatments during curing and tobacco processing (965, 1590, 2337, 2339c, 2359). Additionally, it is known that in certain biomolecules, oxazoles can result from the cyclization and oxidation of serine or threonine nonribosomal peptides (17D02). Whether similar reactions occur in tobacco is not known. The Maillard or nonenzymatic browning reaction has generated much interest over the past seventy years [Nagodawithana (17D07)]. The Maillard reaction mainly involves the reaction of free amino groups of amino acids and reducing sugars (17D07). The principal chemistry of this reaction was reviewed by Hodge in 1953 (17D03). The aromas in most thermally processed foods, such as bread, cereal products, roasted peanuts, and roasted coffee, are generated during Maillard reactions [Maga (17D05, 17D06)]. Numerous heterocyclic compounds arising from the Maillard reaction have been identified in food

and model systems. These heterocycles include furans, thiazoles, thiophenes, oxazoles, pyrroles, pyridines, and pyrazines (17D07). Several mechanisms have been proposed for the formation of oxazole- and oxazine-related compounds in food flavors, including the Strecker degradation (17D04). For example, hydroxyacid amides can react with acetone to produce oxazoles. Similar reaction products from the Maillard reaction and Strecker degradation are known in tobacco (965, 1590, 2337, 2339c, 2359). Maga (17D06) has reviewed the occurrence of oxazoles and oxazolines in a variety of processed food systems. Most of them possess green, sweet, and nutty aroma qualities and have been identified in coffee, soy sauce, wheat, and cooked beef and some of them have very low odor thresholds. In 1976, Leffingwell discussed how certain flavorants (reaction products) can be produced in tobacco and tobacco smoke (2337). Because of the complexity of the chemical interactions and transformations involved, the types and ratios of active flavor products formed by nonenzymatic browning are dependent on the reaction conditions that may occur during aging or during the smoking process itself. One of the flavorants discussed by Leffingwell (2337) that was identified in tobacco by Lloyd et al. (2389) was 3,4-dihydro-3-oxo-4-(phenylmethyl)-1H-pyrrolo[2,1-c][1,4] oxazine-6-carboxaldehyde. This particular tobacco flavor has a hot peppery characteristic (2337). Leffingwell and Alford (2339a) and Li et al. (2359) identified 2,4,5-trimethyloxazole in Perique and burley tobacco, respectively, and reported it has a boiled beef, nutty, sweet, and green flavor. The application of oxazole-and oxazine-related flavor compounds to tobacco is not normally undertaken because the flavor and aroma characteristics of these compounds are rather weak. No oxazole- or oxazine-related compound was included in the list by Doull et al. (1053) of individual flavor compounds used by one or more of the U.S. cigarette manufacturers or individual flavor compounds used outside the United States [see Tables 1 and 7A in (3266)]. Agrochemical residues containing an oxazole-related functionality that have been found on tobacco include Clomazone®, a broad spectrum herbicide, Phosalone®, an organophosphate

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Table XVII.D-1 The Distribution of Oxazole- and Oxazine-Related Compounds Identified in Tobacco and Tobacco Smoke Oxazole-Related Compounds

Total No. Compounds

Tobacco

Smoke

Both

Agrochemical Product

Benzoxazole Isoxazole Oxazole Oxazolidine Morpholine

9 4 30 4 9

1 3 1 1 8

8 1 29 3 3

0 0 0 0 2

1 1 0 1 1

Total

56

14

44

2

4

commonly used as an insecticide, and Vinclozolin®, a common fungicide. Dimethomorph® or Acrobat® is a common fungicide used on tobacco that contains morpholine functionality. Analytical measurements for the determination and quantification of oxazole- and oxazine-related compounds in tobacco and tobacco smoke include gas chromatography (GC) with packed or capillary columns, high performance liquid chromatography (HPLC) usually with reverse phase (RP) columns, and mass spectrometry (MS) methods (GC-MS and LC-MS). Table XVII.D-1 lists the distribution of oxazole- and oxazine-related compounds identified in tobacco and tobacco smoke. A total of fifty-six compounds have been identified: nine are benzoxazole derivatives, four are isoxazole derivatives, thirty are oxazole derivatives, four are oxazolidine derivatives, and nine are morpholine derivatives. Fourteen of the compounds are found in tobacco, forty-four are found in tobacco smoke, and two are found in both tobacco and tobacco smoke. Table XVII.D-2 lists the fifty-six oxazoleand oxazine-related compounds identified in tobacco and tobacco smoke.

XVII.E Aza-Arenes An aza-arene is defined as a fused ring compound with two or more fused rings and consisting only of carbon, hydrogen, and nitrogen. Alkyl-substituted derivatives are also included in the aza-arene category. Overall, many of the aza-arenes are structurally comparable to the polycyclic aromatic hydrocarbons (PAHs) but include at least one nitrogen in the ring. In his early 1954 compilation of reported tobacco smoke components, Kosak (2170) listed no fused-ring polycyclic nitrogen compounds in tobacco smoke, the class of compounds subsequently termed the aza-arenes. Five years later, the only fused-ring N-heterocyclic compound listed by Johnstone and Plimmer (1971) as a tobacco smoke component was the bicyclic compound quinoline. Except for the replacement of a –CH= linkage with a nitrogen (–N=) at the 1-position, quinoline is structurally similar to the PAH naphthalene (Figure XVII.E-1). However, the reference cited by Johnstone and Plimmer was the 1929 study by Gabelya and Kipriyanov (1263), who described the identification of quinoline in a “destructive

distillate” of tobacco, not in a sample of tobacco smoke prepared by a tobacco smoking procedure. A similar identification of benzo[a]pyrene (B[a]P) in the destructive distillate of tobacco by Roffo (3323, 3325) was criticized by Wynder and Hoffmann (4319, 4332), who asserted that a tobacco destructive distillate was not tobacco smoke. In 1960, Van Duuren et al. (4027), in an extension of their studies on the tumorigenic PAHs in mainstream cigarette smoke condensate (CSC), described their findings on tumorigenic N-heterocyclic compounds in the CSC. They reported the identification of dibenz[a,h]acridine {I}, dibenz[a,j]acridine {II}, and 7H-dibenzo[c,g]carbazole {III} (Figure XVII.E-2) in CSC at per cigarette levels of 0.1 ng, 2.7 ng, and 0.7 ng, respectively. These levels were substantially less than that of the reported per cigarette yield of B[a]P in the late 1950s or early 1960s. Similar to the situation noted above that quinoline is a nitrogen analog of naphthalene, dibenz[a,h]acridine {I} is a nitrogen analog of dibenz[a,h]anthracene (DB[a,h] A) {IV}. These two compounds are dimensionally similar. Over five decades ago, these three N-heterocyclics had been reported as tumorigenic to mouse skin [see the summary by Hartwell (1544)]. Two of these compounds, dibenz[a,h] acridine and dibenz[a,j]acridine, were also reported by Van Duuren et al. to be present in the pyrolysates (750°C, nitrogen atmosphere) from both nicotine and pyridine. Contradictory findings have been reported on the presence or absence of these three N-heterocyclic compounds, for example, Wynder and Hoffmann (4319, 4332) reported that members of their research group, Candeli et al. (587), were able to confirm the presence of dibenz[a,j]acridine but not dibenz[a,h]acridine in mainstream CSC. The per cigarette yield of dibenz[a,j]acridine reported by Candeli et al. was significantly greater than that reported by Van Duuren et al. (4027), 10.0 ng/cigarette vs. 2.7 ng/cigarette. Other than brief mentions by Wynder and Hoffmann (4319, 4332) of the results obtained by Candeli et al. (587) on dibenz[a,j]acridine in CSC, the experimental procedures involved in its identification do not appear to have been published in the usual way in a peer-reviewed journal. At a mainstream smoke (MSS) yield for dibenz[a,j]acridine of 2.7 ng/cigarette or 10.0 ng/ cigarette, as reported by Van Duuren et al. and Candeli et al., respectively, it is difficult to understand why no confirmation

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807

Table XVII.D-2 Oxazoles- and Oxazine-Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table XVII.D-2 (Continued) Oxazoles- and Oxazine-Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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809

Table XVII.D-2 (Continued) Oxazoles- and Oxazine-Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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N Quinoline

of investigators to confirm the presence of the two dibenzacridines and the 7H-dibenzo[c,g]carbazole in nicotine pyrolysates. They wrote: Naphthalene

Figure XVII.E-1  Quinoline and naphthalene.

of the presence of this aza-arene had been reported by highly competent investigators from the early 1960s through the mid-1990s! Similarly, no confirmations of the presence of dibenz[a,h]acridine or 7H-dibenzo[c,g]carbazole have been presented to date. Studies on these and other aza-arenes in cigarette MSS or nicotine pyrolysates are described briefly in the following paragraphs. The question remains: Was the preliminary isolation procedure (vacuum distillation of the smoke condensate at 100°C, 0.5 mm pressure) used by Van Duuren et al. (4027) responsible for the formation of the dibenzacridines and the dibenzocarbazole? In 1970, Kaburaki et al. (2006) reported the results of their detailed study of the pyrolysis of nicotine at various temperatures in air and in an inert atmosphere (nitrogen). They did not report the identification of the two tumorigenic benzacridines reported previously by Van Duuren et al. (4027) as identified components in their nicotine pyrolysates. From their study of the pyrolysis of several nitrogenous components of tobacco, including nicotine, Schmeltz et al. (3499) reported: We could not detect benzo(a)pyrene in nicotine pyrolyzates, nor could we confirm the presence of the physiologically active dibenzacridines and dibenzcarbazole [sic] reported in tobacco smoke and in nicotine and pyridine pyrolyzates by Van Duuren [4027].

In their review of the pyrogenesis of tobacco smoke components, Chortyk and Schlotzhauer (722) emphasized these reported findings, that is, the failures of several groups

N I

N II

N H III

IV

Figure XVII.E-2  Some polycyclic components of tobacco smoke.

Since nicotine is the most abundant and best known tobacco alkaloid, its pyrolysis has been thoroughly studied [Woodward et al. (4275a), Jarboe and Rosene (1923a)]. More recent work [Kaburaki et al. (2006)] on the pyrolysis of nicotine and various alkyl-pyridines has resulted in a proposed mechanism for the thermal degradation of nicotine … Schmeltz [Schmeltz et al. (3499)] also studied nicotine and identified a number of previously unreported compounds in the nicotine pyrolysates … These included pyrrole, acenaphthene, indole, skatole, and anthracene and/or phenanthrene. However, the presence of dibenzacridines and dibenzcarbazole, previously reported in nicotine and pyridine pyrolysates, could not be confirmed [Van Duuren et al. (4027)].

Schmeltz and Hoffmann (3491), in their review of the N-containing components of tobacco and tobacco smoke, discussed the generation of various pyridines from nicotine during both the actual smoking process and pyrolysis. They did report the identification by Van Duuren et al. (4027) of the two dibenzacridines in cigarette smoke and nicotine pyrolysate. They did not, however, comment on the reports issued between 1960 and 1977 on the inability of several other groups of investigators [Candeli et al. (587), Kaburaki et al. (2006), Schmeltz et al. (3499)] to confirm the 1960 findings of Van Duuren et al. (4027). In 1979, Schmeltz et al. (3512) reported their results from an elaborate study on the fate of radiolabeled nicotine during pyrolysis and during the actual smoking of a radiolabeled nicotine-treated cigarette. Their major findings included: (1) Under combustion-tube pyrolysis conditions, nicotine in either silica gel matrix (pyrolysis temperatures at 600°C, 750°C, or 900°C) or tobacco matrix (pyrolysis temperature at 600°C) underwent extensive degradation to a mixture of pyridines, quinolines, arylnitriles, and aromatic hydrocarbons. (2) In a burning cigarette during actual smoking, a substantial portion of the nicotine (about 41%) remains intact, 12.5% is oxidized to carbon dioxide, as much as 11% is degraded to volatile alkylpyridines, and negligible amounts are converted to neutral or acidic components of the particulate phase. (3) Dibenz[a,h]acridine and dibenz[a,j]acridine reported nearly two decades earlier by Van Duuren et al. (4027) were not identified in this study by Schmeltz et al. (3512). They noted: In ongoing studiesa we are now identifying those compounds that are formed from nicotine only as minor compounds (<0.1%) which nevertheless can contribute to the toxicity of the smoke. To this group of minor smoke constituents having nicotine as a precursor belong the dibenzacridines [Van Duuren et al. (4027)] … No report of the confirmation of the presence of the dibenzacridines (or the dibenzocarbazole) as a result of these ongoing studies has been found to date.

a

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(4) From the experimental results, the authors concluded: “Pyrolysis experiments may be of limited value for establishing the fate of nicotine and possibly other tobacco components in a burning cigarette.” (5) The pyrolysis system used in this study [see Higman et al. (1648)] was designed, according to Higman et al., to be the optimum simulation of the smoking process. Obviously, nicotine did not behave in this pyrolysis system as it did in the burning cigarette during actual smoking. Close examination of the text and the conclusions expressed in the 1979 Schmeltz et al. publication on the fate of nicotine during pyrolysis and during actual smoking reveals that at least two of the authors (Hoffmann and Schmeltz) have definitely changed their opinion with regard to their long-held view on the supposed equivalence of compound behavior during pyrolysis and actual smoking; for example, Wynder and Hoffmann (4332) earlier wrote in support of this equivalence: Most pyrolysis studies with tobacco, tobacco extracts, extract fractions, individual components, and tobacco additives are performed in a nitrogen atmosphere. This procedure has often been criticized on the grounds that many of the toxic constituents formed during smoking of tobacco products occur as a result of combustion in air rather than in a nitrogen atmosphere. This criticism, however, cannot

be maintained in view of studies by Newsome and Keith [2780] which demonstrated that a reducing rather than an oxidizing atmosphere exists at the cone region of a burning cigarette.

With regard to the production of dibenzacridines and the dibenzocarbazole from nicotine during pyrolysis and the smoking process, Table XVII.E-1 summarizes the current state of knowledge. For example, authors of numerous articles in the 1980s [Hoffmann and Wynder (1808)], in the 1990s [Hoffmann and Hecht (1727), Hoffmann et al. (1773), OSHA (2825), Hoffmann and Hoffmann (1740, 1741)], and in the 2000s [Hoffmann and Hoffmann (1743), Hoffmann et al. (1744), and Fowles and Bates (1217)] on the toxicants in tobacco and tobacco smoke repeatedly listed dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole as tumorigenic or adversely biologically active MSS components despite the following: (1) The presence of these three azaarenes in MSS had not been confirmed in several investigations conducted between 1963 and 1990 (3260). (2) Between 1990 and 2000, additional studies failed to confirm their presence in MSS (2021, 3414). (3) Several summaries of the attempts to confirm the findings of Van Duuren et al. have been published (172, 3260, 3265). In 2002, Rustemeier et al. (3370) did report the presence of dibenz[a,j]acridine in the

Table XVII.E-1 Dibenz[a,h]acridine {I}, Dibenz[a,j]acridine {II}, and 7H-Dibenzo[c,g]carbazole {III} in Nicotine Pyrolysates (Pyr) and Mainstream Cigarette Smoke Condensate (CSC) Dibenz[a,h]acridine

Dibenz[a,j]acridine

7H-Dibenzo[c,g]carbazole

Investigators

Pyr

CSC

Pyr

CSC

Pyr

CSC

Van Duuren et al. (4027) Candeli et al. (587); Wynder and Hoffmann (4319, 4332) Kaburaki et al. (2006) Schmeltz et al. (3499) Schmeltz et al. (3512) Snook (3733) Snook et al. (3750) Grimmer et al. (1409) Kamata et al. (2021) Sasaki and Moldoveanu (3414) Rustemeier et al. (3370)

yes NE

yes no

Yes NE

yes yes

no NE

yes NE

no no no NE NE NE NE NE NE

NE NE no no no no no no no

No No No NE NE NE NE NE NE

NE NE no no no no no no yes

NE no no NE NE NE NE NE NE

NE NE no no no no NE NE NE

yes = Compound identified. no = Compound not found or identified. NE = Substrate not examined for compound in question. Examination of these results indicates that Van Duuren et al. (4027) reported the identification of the three N-heterocyclic compounds {I, II, and III} in MSS CSC and two of them {I and II} in a nicotine pyrolysate; whereas, Candeli et al. (587) failed to identify I but did identify {II} in MSS CSC. The 1963 Candeli et al. findings on {II} in MSS CSC were not confirmed in 1979 by investigators (3512) from the same laboratory: Hoffmann participated in both the 1963 and 1979 studies. Two studies (3499, 3512) confirmed the 1960 report by Van Duuren et al. that 7H-dibenzo[c,g]carbazole {III} was not present in a nicotine pyrolysate.

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MSSs from several ingredient-treated cigarettes. All yields were reported as less than 2.72 ng/cigarette. It might have been appropriate, in view of the numerous failures to confirm the presence of dibenz[a,j]acridine in cigarette smoke, for Rustemeier et al. to have provided more meaningful information on its presence. Other tumorigens in cigarette MSS, including several whose presence was and is suspect, have been listed since the early 1960s. In 1960, Mold et al. (2592) reported the isolation and identification of the tricyclic N-heterocyclic 5H,10Hdipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) {V} (Figure XVII.E-3) from CSC and demonstrated its relationship to its precursor in tobacco, the amino acid proline. Obviously, pyrocoll is not an aza-arene but an amide. Rodgman and Cook (3279) reported the identification of indole, carbazole, and several alkylated indoles and carbazoles in CSC and confirmed the presence of 5H,10Hdipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) {V} described previously by Mold et al. (2592). Rodgman and Cook also assessed previously reported biological studies on indole, 3-methylindole (skatole), and carbazole: None was reported to be tumorigenic in laboratory animals [Hartwell (1544), Shubik and Hartwell (3664)]. Poindexter and Carpenter (2972) identified 9H-pyrido[3, 4-b]indole (norharman) {VI} and 1-methyl-9H-pyrido[3, 4-b]indole (harman) {VII} (Figure XVII.E-3) isolated from CSC. They reported the yield of the total harmans in burley and flue-cured smokes to be between 15 and 20 mg/g of tobacco smoked, values 40 to 50 times that of the total harmans in the unsmoked tobaccos. Since the weight of tobacco in cigarettes sold at that time approximated 1 g, the delivery of these two compounds was about 15 to 20 mg/cigarette. They concluded from experiments with radiolabeled tryptophan that the harmans (found to be radiolabeled in the smoke) were generated pyrogenetically from a reaction between aldehydes (formaldehyde for norharman, acetaldehyde for harman) and the tryptophan in tobacco. Schmeltz et al. (3505) reported 5H,10Hdipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) {V}, 9H-pyrido[3,4-b]indole (norharman) {VI}, and 1-methyl-9H-pyrido[3,4-b]indole (harman) {VII} in tobacco smoke. Testa and Testa (3886, 3887) also confirmed the presence of 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) in CSC.

O N N O V

N

N

N H

N H

VI

VII

CH3

Figure XVII.E-3  Some amino acid-derived N-heterocyclics identified in tobacco smoke.

In 1964, the Advisory Committee to the U.S. Surgeon General (3999) briefly discussed only four fused-ring N-heterocyclic compounds in tobacco smoke: quinoline plus the two dibenzacridines (dibenz[a,h]acridine, dibenz[a,j] acridine) and the dibenzocarbazole (7H-dibenzo[c,g]carbazole) reported by Van Duuren et al. (4027). In his 1968 review of tobacco and tobacco smoke composition, Stedman (3797) discussed the identification of tumorigenic N-heterocyclic compounds [dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole] reported by Van Duuren et al. (4027), as well as the identification of the following N-heterocyclic compounds: 5H,10H-dipyrrolo[1,2a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), 9H-pyrido[3,4-b] indole (norharman), 1-methyl-9H-pyrido[3,4-b]indole (harman), and 9H-pyrido[2,3-b]indole. In his early 1970s outline of recent research on tobacco and tobacco smoke composition, Wakeham (4103) noted the reported presence of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) in cigarette smoke and discussed their possible formation by reaction of tryptophan and an aldehyde. As noted by Rodgman (3253a), the structure of the aldehyde reacting with tryptophan ultimately dictates the structure of alkylated norharmans found in CSC (see Table XVII.E-2). In addition to 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5, 10-dione (pyrocoll), Izard et al. (1899) reported the identification of its homolog methyl-5H,10H-dipyrrolo[1,2-a:1’,2’-d] pyrazine-5,10-dione (methylpyrocoll) in CSC. During a presentation at the 1975 TCRC and in a 1977 publication on their study of the water-soluble portion of CSC, Schumacher et al. (3553) reported the identifications of 1-methyl-9H-pyrido[3,4-b]indole (harman), 5H,10Hdipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), octahydro-5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (octahydropyrocoll), and 2-ethyl-9H-pyrido[2,3-b]indole. The results of research in Japan in the late 1970s brought attention not to any aza-arenes themselves but to a group of their amine derivatives, many of which showed inordinately high mutagenicity in the Ames test with several strains of Salmonella typhimurium. The source originally studied was cooked foodstuffs and pyrolysis products from several amino acids, which resulted in their being described as “cooked food” mutagens. Later, they became known as the N-heterocyclic amines. When the N-heterocyclic amines were shown to be tumorigenic in addition to being highly mutagenic and subsequently identified in tobacco smoke, they were included by Hoffmann and his colleagues in their numerous lists of tobacco smoke tumorigens published in 1997 and later (1740, 1741, 1743, 1744). The N-heterocyclic amines had not been included in their numerous lists published between 1986 and 1997 (1727, 1773, 1806) nor in similar lists by IARC (1870) and OSHA (2825). Even though their number in tobacco smoke is low, we decided to discuss them in a separate section that follows this one on aza-arenes. In the 1979 Surgeon General’s report (4005), the aza-arenes dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g] carbazole, quinoline, and alkylated quinolines in CSC were

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Table XVII.E-2 Chronology of Selected Aza-Arenes: Dibenz[a,h]acridine, Dibenz[a,j]acridine, 7H-Dibenzo[c,g]carbazole, Quinoline Year

Event

1929

Gabelya and Kipriyanov (1263) reported the identification of quinoline in a destructive distillate from tobacco. Destructive distillation of tobacco is not considered to be equivalent to the tobacco smoking process [see comments by Wynder and Hoffmann (4319, 4332)].

1935

Barry et al. (194) (members of the Kennaway group in the United Kingdom) compared the tumorigenicity of dibenz[a,h] anthracene (DB[a,h]A) with that of heterocyclic compounds in which one or both of the meso-carbons were replaced by nitrogen. The aza-arene dibenz[a,h]acridine was found to be less tumorigenic (mouse skin) than its PAH counterpart DB[a,h]A. They also reported that the tumorigenicity of dibenz[a,j]acridine was less than that of dibenz[c,h]acridine.

1937

In the first reported investigation of the tumorigenicity of 7H-dibenzo[c,g]carbazole, Boyland and Brues (421a) reported that mice skin painted with it developed carcinomas at the painting site.

1937

Bachmann et al. (137a) reported that dibenz[a,j]acridine injected subcutaneously induced sarcomas in mice, i.e., dibenz[a,j] acridine was sarcogenic. Its sarcogenicity was relatively weak compared to that noted for similarly injected PAHs.

1940

Badger et al. (140) reported that oral administration to 10 mice of 5 mg/week/mouse of dibenz[a,h]acridine resulted in one mouse with an epithelioma and papilloma of the forestomach; another mouse showed stomach papillomas. Duration of the experiment was 627 days. Similar administration of dibenz[a,j]acridine (10 mice, 5 mg/week/mouse) gave no tumors in 572 days. In their introduction, the authors stated: There is now little doubt that cigarette smoking is the major factor concerned with the ever-increasing incidence of bronchogenic carcinoma in men. Both cigarette-tobacco tars and particulates from air pollution contain various carcinogenic polynuclear compounds.

1940

In their study of the response of the lungs of strain Aa mice to various compounds, Andervont and Shimkin (79) demonstrated that 20 of 20 strain A mice given a single injection of 0.5 mg of dibenz[a,h]acridine in 0.1 ml of tricaprylin developed multiple adenomas in 14 weeks but no sarcomas at the injection site. All 14 mice administered a single injection of 1 mg of dibenz[a,h]acridine in 0.3 ml of sesame oil developed multiple adenomas in 40 weeks but no sarcomas at injection site. Andervont and Shimkin also compared the response of the lungs of strain A mice to a single intravenous injection of 0.25 mg of each of nine compounds dispersed in 0.25 ml of water. Among the nine compounds were DB[a,h]A, B[a]P, benz[a]anthracene (B[a]A], dibenz[a,h]acridine, and 7H-dibenzo[c,g] carbazole. A calculated “carcinogenic index” [% tumor bearing animals x mean number of adenomas in animals showing a positive response for each of these compounds at 8, 14, and 20 weeks] gave the following sequence: DB[a,h]A > 7H-dibenzo[c,g]carbazole > B[a]P > dibenz[a,h]acridine > B[a]A a

The strain A mouse was developed for lung tumor research in laboratory animals. Without treatment of any kind, 70 to 90% of strain A mice develop adenomas, a type of lung tumor, between 12 and 18 months of age [Shimkin (3652)].

1946

Dubinin and Chelintsev (1075a) reported quinoline, isoquinoline, and several substituted pyridines in a pyrolysate of anabasine, a tobacco alkaloid structurally related to nicotine.

1951

Hartwell (1544) listed several studies in which dibenz[a,j]acridine and 7H-dibenzo[c,g]carbazole were reported to be tumorigenic in skin-painting (epitheliomas) and subcutaneous-injection (sarcomas) experiments.

1954

At the International Cancer Congress, São Paolo, a new short-term test was reported by Smith (3722a). By this test, the “tumorigenicity” of a test compound could be estimated in less than a week vs. the 18 to 20 months required in skin-painting studies. The extent and rapidity of the disappearance of the sebaceous glands after 4 daily applications of the test compound (PAHs, aza-arenes, etc.) were considered to be related to the tumorigenicity of the test compound. Because of the absence of the ultimate end point – a tumor, this test did not receive the endorsement originally anticipated.

1954

Kosak (2170) did not list quinoline as a tobacco smoke component, perhaps because it was reported as a component of a destructive distillate of tobacco rather than a component of tobacco smoke. However, he did list B[a]P as a questionable tobacco smoke component even though it too was identified in a destructive distillate of tobacco by Roffo (3323, 3325).

1956

Lacassagne et al. (2247a) reported the tumorigenicity of dibenz[a,h]acridine and dibenz[a,j]acridine to the skin and subcutaneous tissue of mice. The tumorigenicity of 76 other unsubstituted and substituted benzacridines was also cataloged. The authors noted: All [angular benzacridines] have a characteristic odor which is reminiscent of cigar smoke. Since 1967, two unsubstituted angular benzacridines (benz[a]acridine, benz[c]acridine) and over a dozen of their alkyl substituted derivatives have been identified in tobacco smoke (1409, 2021, 2120, 2132, 2596a, 3300, 3337, 3339, 3499, 3750, 3752).

1957

In the first supplement to Hartwell’s 1951 compilation of compounds tested for tumorigenicity, Shubik and Hartwell (3664) summarized the results of additional published studies on the tumorigenicity of 7H-dibenzo[c,g]carbazole in mice and rats. (Continued)

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Table XVII.E-2 (Continued) Chronology of Selected Aza-Arenes: Dibenz[a,h]acridine, Dibenz[a,j]acridine, 7H-Dibenzo[c,g]carbazole, Quinoline Year

Event

1959

Johnstone and Plimmer (1971) listed quinoline as a tobacco smoke component, but the reference cited was the report of Gabelya and Kipriyanov (1263) who identified quinoline in a destructive distillate of tobacco.

1960

Van Duuren et al. (4027) vacuum distilled a solution of the basic portion of 250 grams of cigarette “tar” at 100°C/0.5 mm pressure. The residue (10 g) was successively chromatographed on alumina and several Whatman’s papers. Bands corresponding to the aza-arenes dibenz[a,h]acridine and dibenz[a,j]acridine were rechromatographed until their ultraviolet absorption and fluorescence spectra were identical with those of authentic samples. Chromatography of the neutral fraction of the CSC gave an isolate whose properties were identical with an authentic sample of 7H-dibenzo[c,g]carbazole. No 7H-dibenzo[c,g]carbazole was detected. The estimated amounts of dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole isolated from the “tar” were 0. 1, 2.7, and 0.7 ng/cig, respectively. They estimated the levels of B[a]P and DB[a,h]A in the same CSC to be 5.0 and 0.5 ng/ciga, respectively. Van Duuren et al. noted: It is clear that the heterocyclics here described make a significant contribution to the reported carcinogenicity of tobacco tars. a It is interesting to note the deliveries recorded by Van Duuren et al. for B[a]P (5 ng/cig) and DB[a,h]A (0.5 ng/cig) and compare them to values subsequently listed by Hoffmann and Hecht (1727) and Hoffmann and Hoffmann (1740) who listed a range for B[a]P of 20–40 ng/cig and a single value for DB[a,h]A of 4 ng/cig! Why did these authors not acknowledge the values reported by Van Duuren et al.?

1960

Van Duuren et al. (4027) also investigated the possibility that pyridine and nicotine were precursors of these nitrogen heterocyclics. Pyrolysis of pyridine or nicotine (750 °C, nitrogen atmosphere) yielded pyrolysates in which dibenz[a,h]acridine and dibenz[a,j] acridine were identified by the same procedures used with CSC. As in the CSC case, dibenz[a,j]acridine was more plentiful than dibenz[a,h]acridine in the pyridine and nicotine pyrolysates. No 7H-dibenzo[c,g]carbazole was found in either pyrolysate.

1960

Van Duuren et al., citing unpublished data by Nelson et al. (2689d) on mouse skin-painting with the basic fraction of CSC, noted that the skin-painting experiments gave negative results and attributed this finding to the fact that: The basic fraction used in those experiments would not have been sufficient to yield skin tumors even if the benzacridines had been as potent for the skin as benzo[a]pyrene, which is not the case. They also noted that Wynder and Wright (4354) reported weak tumorigenicity with more concentrated fractions from the basic fraction.

1961/ 1962

Balasubrahmanyam and Quin (175) identified quinoline, isoquinoline, and various substituted pyridines in the pyrolysates from the tobacco alkaloids nornicotine and myosmine.

1962

Van Duuren (4022a) described methods for the separation and identification of 7H-dibenzo[c,g]carbazole in cigarette MSS.

1962

Rodgman and Cook (3279) reported the isolation in crystalline form and the identification of a series of homologous indoles (indole, skatole, etc.) as well as several carbazoles from cigarette MSS. Candeli et al. (587) investigated the aza-arenes in CSC with the method described by Van Duuren et al. in 1960. It was noted:

1963

With some modifications, this method …by Candeli et al…enabled us to isolate from 100 cigarettes 1.0 mg [dibenz[a,j] acridine]. The presence of [dibenz[a,h]acridine] could not be confirmed. 1963

Wynder and Hoffmann (4317) described the results of mouse skin-painting tests with dibenz[a,j]acridine applied in 0.5 and 0.1% acetone solutions three times weekly to the backs of 20 Swiss female mice. After 12 to 14 months, tumors were induced in 16 (80%) and 15 (75%) mice, respectively, with 60% of the animals in each test developing carcinomas. Wynder and Hoffmann (4332) offered the following explanation for the difference between these extremely high results and the much lower one reported by LacassagnE et al. (2247a): This relatively high tumor response in mouse skin (compared to the findings of Lacassagne et al. (2247a)) might be partially explained by the high purity of the compounds, due mainly to the absence of the ‘Morgan’s base’ a dihydrodibenz[a,j]acridine. Only by repeated column chromatography on alumina can a [dibenz[a,j]acridine] be isolated that is free of the dihydro product (absence of N-H band in infrared absorption spectrum). In another study reported by Wynder and Hoffmann (4317), mouse skin was initiated with a single application of 300 mg of 7,12-dimethylbenz[a]anthracene and then painted with a 0.5% solution of dibenz[a,j]acridine, three times weekly. The same tumor response was observed as with dibenz[a,j]acridine alone except that the tumors appeared 2 to 3 months earlier. The investigators interpreted this finding as indicating: There is no significant tumor-promoting activity of [dibenz[a,j]acridine], despite its strong hyperplastic effect.”

1964

The report of the 1964 Advisory Committee to the U.S. Surgeon General (3999) identified dibenz[a,h]acridine, dibenz[a,j] acridine, and 7H-dibenzo[c,g]carbazole as carcinogenic polycyclic compounds isolated from cigarette smoke, classified them as weakly carcinogenic, and listed their amounts in cigarette MSS as 0.1, 2.7, and 0.7 ng/cig. The report also listed quinoline as a tobacco smoke component.

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Table XVII.E-2 (Continued) Chronology of Selected Aza-Arenes: Dibenz[a,h]acridine, Dibenz[a,j]acridine, 7H-Dibenzo[c,g]carbazole, Quinoline Year 1964

1964

Event

In addition to discussing the dibenzacridines and dibenzocarbazole in tobacco smoke and the two dibenzacridines in a nicotine pyrolysate reported by Van Duuren et al. (4027), Wynder and Hoffmann (4319) discussed the identification by Jarboe and Rosene (1923a) of quinoline in a nicotine pyrolysate produced at 600–900°C in an inert atmosphere. Kuhn (2228) reviewed the pyrogenesis of aza-arenes from tobacco and nicotine. The dibenzacridines were tabulated with reference to the 1960 paper of Van Duuren et al. (4027). He listed quinoline as a pyrolysis product of nicotine and nornicotine but not as a tobacco smoke component.

1964

Testa and Testa (3886) report quinoline as a tobacco smoke component. Its presence was subsequently confirmed by Grob and Völlmin (1427) and Kaburaki et al. (1992a).

1965

Sawicki et al. (3419a) identified dibenz[a,h]acridine and dibenz[a,j]acridine in polluted air in the amounts of 80 and 40 ng/1000 m3 of air, respectively.

1968

Stedman (3767) wrote: The presence of the dibenzacridines and 7H-dibenzo[c,g]carbazole in cigarette smoke…is of special interest since these compounds are carcinogenic and may contribute to the weak tumorigenic activity of the basic fraction in laboratory animals [Wynder and Wright (4354); Wynder and Hoffmann (4319)]. NOTE: Stedman apparently missed the point that 7H-dibenzo[c,g]carbazole, because of its structure, was not present in the basic fraction but was found in the neutral fraction of CSC [see Van Duuren et al. (4027)].

1969 1970

Rothwell and Whitehead (3339) improved the method of isolation of 7H-dibenzo[c,g]carbazole from complex mixtures such as CSC by formation of complexes of the aza-arenes and PAHs with purines. In a study of the composition of nicotine pyrolysates (400°, 500°, 550°, 600°, 650°, 700°, 800°C; nitrogen and air atmospheres), Kaburaki et al. (2006) were unable to confirm the presence of the aza-arenes (dibenz[a,h]acridine, dibenz[a,j]acridine) reported by Van Duuren et al. in 1960 for nicotine pyrolysis (750°C, nitrogen atmosphere). Because there is sufficient overlap between the pyrolysis conditions used by Kaburaki et al. and by Van Duuren et al., the profound difference in composition results (presence vs. absence of the aza-arenes in question) cannot be explained by minor differences in pyrolysis conditions. In addition, the tumorigenicity of 7H-dibenzo[c,g]carbazole was compared with that of B[a]P: Weekly administration of 3 mg of 7H-dibenzo[c,g]carbazole for 15 weeks resulted in 13% more animals dying with respiratory tract cancer than died with same dose level of B[a]P. With lower total dose levels (15 mg) of B[a]P only, 30% of the animals developed respiratory tract tumors vs. 89% of the animals treated with the same dose of 7H-dibenzo[c,g] carbazole. The tumors in the 7H-dibenzo[c,g]carbazole group appeared earlier than those in the B[a]P-treated group.

1972

Schmeltz et al. (3499) studied the pyrolysis (800-860 °C, nitrogen atmosphere) of nitrogen-containing materials (tobacco, tobacco pigment, nicotine) and reported: We could not detect benzo(a)pyrene in nicotine pyrolyzates, nor could we confirm the presence of the physiologically active dibenzacridines and dibenzcarbazole reported in tobacco smoke and in nicotine and pyridine pyrolyzates by Van Duuren… Here again, the slight difference in the temperature (750°C vs. 800–860°C) of the inert atmosphere (nitrogen) pyrolysis cannot explain the profound difference in the compositional findings (presence vs. absence of the aza-arenes in question).

1973

The IARC Working Group reported that skin painting with dibenz[a,h]acridine induced skin tumors in mice (1864a). Subcutaneous injection into mice produced sarcoma at the injection site plus an increased incidence of pulmonary adenomas. In 1973, dibenz[a,h]acridine had not been tested by other administration routes or in other species. The IARC noted that no human data were available, but it did note: Coal tar and other materials which are known to be carcinogenic to man may contain [dibenz[a,h]acridine]. The IARC concluded that dibenz[a,j]acridine induced skin tumors in mice following topical application. At the highest dose tested by subcutaneous injection, it induced sarcomas at the injection site and an increased incidence of pulmonary adenomas. Negative results were obtained by the oral route in the mouse, but the test was considered inadequate because of the small number of animals tested. Dibenz[a,j]acridine had not been tested in other species at that time. No human data were available, but the IARC considered that some materials known to be carcinogenic to man may contain dibenz[a,j]acridine.

1973

The IARC Working Group considered 7H-dibenzo[c,g]carbazole to be: Carcinogenic in the mouse, rat, hamster, and possibly in the dog. It has both a local and a systemic carcinogenic effect. Following oral administration in the mouse, forestomach tumors and hepatomas occurred; intratracheal administration to hamsters produced tumors of the respiratory tract. In comparison with benzo[a]pyrene, [7H-dibenzo[c,g]carbazole] appears to be a stronger respiratory tract carcinogen for the hamster. (Continued)

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Table XVII.E-2 (Continued) Chronology of Selected Aza-Arenes: Dibenz[a,h]acridine, Dibenz[a,j]acridine, 7H-Dibenzo[c,g]carbazole, Quinoline Year

1976

1976

Event

Though 7H-dibenzo[c,g]carbazole had been reported as a component of CSC, no case reports or epidemiological data concerning human exposure were available. In his review on polycyclic tumorigens, Dipple (983) labeled dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g] carbazole as “carcinogenic heterocyclic compounds” with “slight” activity. However, in a later review in 1984, Dipple et al. (984) revised the assessment of 7H-dibenzo[c,g]carbazole, listing it as a highly potent tumorigen. Wynder and Hoffmann (4347) listed dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole as: Tumorigenic agents identified in the particulate phase of tobacco smoke, each possessing low biological activity and only traces detected in the smoke of 100 cigarettes. Dibenz[a,j]acridine was detected in amounts of 1.0 microgram per 100 cigarettes [10 ng/cig]. They categorized dibenz[a,j]acridine and dibenz[a,h]acridine as “known animal carcinogens,” but noted that these aza-heterocyclic compounds are “minor carcinogens” in tobacco smoke.

1976

Hoffmann et al. (1780) reported that the basic fraction of CSC which contains dibenz[a,h]acridine and dibenz[a,j]acridine was not tumorigenic to mouse skin, cf. Wynder and Wright (1957), Wynder and Hoffmann (4319, 4332).

1977

Schmeltz and Hoffmann (3491), in their review of N-containing compounds in tobacco and tobacco smoke discussed the benzacridines: Nicotine has…been shown to produce on pyrolysis the animal carcinogens, dibenz[a,h]acridine…and dibenz[a,j]acridine…both of which are present in tobacco smoke…Acridans have been reported in smoke… Subsequent dehydrogenation of the acridans could lead to acridines. The only examples of the latter reported in smoke are two benzacridines [dibenz[a,h]acridine, dibenz[a,j] acridine]; these have been shown to form during pyrolysis from nicotine… A dibenzocarbazole [7H-dibenzo[c,g]carbazole]…has also been reported in tobacco smoke… The last three fused ring compounds cited are tumorigenic in the experimental animal. Schmeltz and Hoffmann listed quinoline as both a tobacco and a tobacco smoke component as well as an “animal carcinogen (rat liver).”

1979

In a brief section of the chapter on cigarette smoke composition, the aza-arenes (including dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole), their tumorigenicity, and their mutagenicity were discussed in the 1979 Surgeon General’s report (4005). The report noted: Mutagens thus far identified in cigarette smoke are: Quinoline (MS 1.7 mg/cigarette; SS 18 mg/cigarette), all seven isomeric methylquinolines MS (0.7 mg/cigarette; SS 8 mg/cigarette)… Quinoline induces hepatomas when fed in high doses to rats…

1979

Rinkus and Legator (3157) reported dibenz[a,h]acridine and dibenz[a,j]acridine to be mutagenic substances in the Ames Salmonella typhimurium test.

1979

Schmeltz et al. (3512) studied the fate of radiolabeled nicotine during pyrolysis and during actual smoking in a burning cigarette spiked with radiolabeled nicotine. The radiolabeled nicotine was pyrolyzed (nitrogen atmosphere) from a silica gel matrix at several temperatures (600°C, 750°C, and 900°C) and from a tobacco matrix at 600 °C. None of three aza-arenes – dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g]carbazole – identified by Van Duuren et al. (4027) in CSC was found in the smoke study by Schmeltz et al. Neither of the two dibenzacridines reported by Van Duuren et al. in a nicotine pyrolysate was found in the several nicotine pyrolysates generated by Schmeltz et al. (3512). The differences concerning the presence or absence of these aza-arenes in several such studies involving CSCs and/or nicotine pyrolysates were summarized by Rodgman (3255, 3257).

1982

In the 1982 Surgeon General’s report (4010), the aza-arenes dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g] carbazole were described as “tumor-initiating agents in the particulate phase of tobacco smoke” and their MSS levels as 0.1, 3 to 10, and 0.7 ng/cig, respectively. It was noted, from data provided by Hoffmann et al. (1781, 1782), that dibenz[a,j]acridine possessed much higher tumorigenic activity than dibenz[a,h]acridine and 7H-dibenzo[c,g]carbazole, cf. Dipple et al. (983).

1982

Adams et al. (35) reported the identification and quantitation of quinoline (0.2 to 1.3 mg/cig), isoquinoline (0.1 to 0.9 mg/cig), and the seven isomeric methylquinolines (0.5 to 2.5 mg/cig) in the MSS of several commercial cigarettes. They noted: Quinoline is the most abundant aza-arene in [mainstream] cigarette smoke.

1984

In their review of polycyclic aromatic tumorigens, Dipple et al. (983) classified dibenz[a,h]acridine and dibenz[a,j]acridine as possessing only Slight tumorigenicity. They classified 7H-dibenzo[c,g]carbazole as possessing High tumorigenicity (same category as 1,2-dihydrobenz[j]aceanthrylene (cholanthrene), 3-methyl-1,2-dihydrobenz[j]aceanthrylene (3-methylcholanthrene), 7,12-dimethylbenz[a]anthracene, and B[a]P).

1984

In their review of tumorigenic aromatic amines in which fused ring polycyclic amines are discussed, Garner et al. (1275a) neither mention nor list quinoline as a tumorigenic compound

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Table XVII.E-2 (Continued) Chronology of Selected Aza-Arenes: Dibenz[a,h]acridine, Dibenz[a,j]acridine, 7H-Dibenzo[c,g]carbazole, Quinoline Year

Event

1985/86 The IARC (1870) in its 1986 report on its 1985 deliberations found sufficient evidence to classify dibenz[a,h]acridine, dibenz[a,j] acridine, and 7H-dibenzo[c,g]carbazole as carcinogenic in laboratory animals. The IARC noted that “nicotine is a specific precursor for the two acridines”, totaling ignoring contradictory evidence from several groups of investigators who were unable to confirm the presence of these dibenzacridines in nicotine pyrolysates. The IARC listed quinoline as a smoke component but did not include it in its tabulation of compounds vs. “the degree of evidence [for carcinogenicity] in animals (and humans). ” 1986 Hoffmann and Wynder (1808) published a list of components classified as toxicants and/or tumorigens in tobacco and smoke. Much of the information in their report on quinoline, dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole had been provided to the IARC for inclusion in its 1986 article (1870). 1990 Hoffmann and Hecht (1727), in their compilation of 43 “tumorigenic components of tobacco and tobacco smoke”, listed dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g]carbazole, and quinoline as tumorigenic aza-arenes in CSC. This list was subsequently used by the EPA (1990) in its attempt to have environmental tobacco smoke classified as a Group A (human) carcinogen. Hoffmann and Hecht paid little attention to the discrepancies between the 1960 report of Van Duuren et al. on the presence of these aza-arenes in CSC and nicotine pyrolysates and later reports from other investigators who failed to confirm the Van Duuren findings on these compounds either in CSC or nicotine pyrolysates [see Table XVII.E-1)]. In their tabulation, Hoffmann and Hecht listed quinoline with no comment as to its carcinogenicity as reported in the “IARC evaluation of evidence of carcinogenicity in laboratory animals [and] in humans.” In their text, they noted: Quinoline, a liver carcinogen in rats…and in newborn mice…, is present in cigarette smoke at a concentration of 1-2 mg/ cigarette [Dong et al. (1042)]. 1991

1994

1994

1997

1998

2000 2001

In a memorandum to the EPA, Rodgman (3255) summarized the inconsistencies between the 1960 findings reported by Van Duuren et al. on dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole in nicotine pyrolysates and/or mainstream CSC vs. the findings in the comparable 1963 study of Candeli et al. [reported by Wynder and Hoffmann (4319, 4332)], the 1970 study of Kaburaki et al. (2006), the 1972 and 1979 studies of Schmeltz et al .(3499, 3512), and the 1986 and 1987 reports by Grimmer et al. (1409). The expanded summary is shown in Table XVII.E-1. Summaries of the studies of benzacridines in cigarette smoke by Kamata et al. (2021) and Sasaki and Moldoveanu (3414) were added. A possible explanation of the differences in the results concerning the presence or absence of these three aza-arenes in mainstream CSC may be the differences between cigarettes fabricated in 1960 and those fabricated more recently after the 1970s. The pre-1960 cigarettes were substantially higher in nicotine. However, there does not appear to be a logical explanation for the difference in the results (presence vs. absence) of these three compounds in nicotine pyrolysates prepared in 1960, 1963, 1970, 1972, and 1979. Post-1960 advances in analytical technology should have improved the ability to isolate/identify low levels of these three aza-arenes. Osha (2825), in its goals for clean air legislation, presented its own list of 43 tobacco smoke components tumorigenic in animals or man. Its list differed slightly from that of Hoffmann and Hecht (1727). OSHA included the three aza-arenes reported by Van Duuren et al. (4027) but omitted quinoline. In a response to the OSHA (2825) publication, Rodgman (3257) presented the information in Table XVII.E-1 as reasons why the benzacridines and the benzocarbazole should be removed from the list. Valid scientific reasons for deleting other listed components were also presented. Hoffmann and Hoffmann (1740) revised the 1990 Hoffmann-Hecht list of “43 tumorigenic components” of tobacco smoke (1727), expanding the list to 60 components by deleting chrysene and crotonaldehyde in agreement with the OSHA (2825) list and by adding 19 other components, including the 8 N-heterocyclic amines known as the “cooked food” mutagens. Still retained in the HoffmannHoffmann 1997 list were the aza-arenes quinoline, dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole. In a letter to the Editors of Beiträge Tabakforschung zur International, Hoffmann and Hoffmann (1741) submitted a list of biologically active components of cigarette MSS, including the four aza-arenes quinoline, dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole. Fowles and Bates (1217) included dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole in their list of tobacco and tobacco smoke toxicants. Hoffmann and Hoffmann (1743) in their list of tobacco and tobacco smoke toxicants again included dibenz[a,h]acridine, dibenz[a,j] acridine, and 7H-dibenzo[c,g]carbazole despite the numerous reports of research that failed to confirm the 1960 Van Duuren et al. reported finding. Hoffmann et al. (1744) again included dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole in their list of tobacco and tobacco smoke toxicants.

2003

Rodgman (3265) assessed the various published reports in which numerous tobacco and tobacco smoke components were classified as toxicants (1217, 1727, 1740, 1741, 1743, 1744, 1773, 1808, 2825). The numerous deficiencies and errors in the reports were cataloged.

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made the following interesting observation, pertinent to the alleged “carcinogenicity” of benzene, frequently used as a solvent in tumorigenicity studies in the 1930s, 1940s, and 1950s: “These molecules [the angular benzacridines] are very soluble in benzene and acetone (two solvents currently used for the investigations of carcinogenic activity).” In addition to the exposure to acridines and benzacridines in tobacco smoke, other exposures to various acridines and benzacridines have been cataloged in the scientific literature. Many of the sources (Table XVII.E-5) comprise environmental pollutants. Unlike the PAHs and the N-nitrosamines, nontobacco smoke exposure to the acridines/benzacridines does not include foods. However, exposures other than tobacco smoke to polycyclic nitrogen compounds include exposures to the N-heterocyclic amines, the so-called “cooked food” mutagens, in a variety of foods. Table XVII.E-6 lists, with appropriate citations, the azaarenes reported in tobacco and tobacco smoke. Table XVII.E-7 summarizes the variation in the structures of the aza-arene compounds identified in tobacco and/ or tobacco smoke. Of particular interest with regard to the 294 aza-arenes cataloged in Table XVII.E-6 is that only twenty-three of the 294 have been identified as tobacco components. Of the twenty-three, just fifteen have been identified in both tobacco and smoke. The number of azaarenes identified in smoke is 286. Those isolated from or identified in tobacco in greater than trace amounts include 1H-indole, 2,3-dihydro-1H-indole, 9H-pyrido[3,4-b]indole (norharman), 1-methyl-9H-pyrido[3,4-b]indole (harman), 1H-purine, and quinoline. Because of their classification as significant tumorigens in tobacco smoke (1740, 1741, 1743, 1744) and their inordinately high mutagenicity in the Ames test with Salmonella typhimurium (2327c, 3828c), the amino derivatives of several

discussed but not the presence or biological properties of any of the “cooked food” mutagens identified in tobacco smoke. In the 1982 report of the Surgeon General [see Table 10, p. 214 in (4010)], 9H-pyrido[3,4-b]indole (norharman) and 1-methyl9H-pyrido[3,4-b]indole (harman) were classified as “toxic and tumorigenic agents of cigarette smoke” in amounts of 3.2 to 8.1 mg/cigarette and 1.1 to 3.1 mg/cigarette, respectively, in mainstream CSC. None of the other highly mutagenic N-heterocyclic amine mutagens present in tobacco smoke was discussed. Table XVII.E-2 lists, with appropriate citations, the chronology of the studies pertinent to the aza-arenes and other polycyclic nitrogen compounds in tobacco smoke. A similar chronology of studies pertinent to the N-heterocyclic amines, the “cooked food” mutagens, is presented in a subsequent section.

XVII.E.1

Alternate Exposures to Aza-Arenes

In the several lists of tumorigenic components in tobacco and/or tobacco smoke, three N-heterocyclic compounds (dibenz[a,h]acridine, dibenz[a,j]acridine 7H-dibenzo[c,g]carbazole) appear on the list of forty-three by Hoffmann and Hecht (1727) and OSHA (2825) and the list of sixty by Hoffmann and Hoffmann (1740). Quinoline was on several lists but was omitted from the OSHA list (Table XVII.E-3). Table XVII.E-4 lists the many tobacco smoke components similar in structure to those listed in Table XVII.E-3. Even though, as indicated in Table XVII.E-1 and the text accompanying it, the presence of the three pentacyclic N-heterocyclic compounds in tobacco smoke is equivocal, the alternate exposure to them and similar components is discussed below. In their 1956 review of angular benzacridines and dibenzacridines and their tumorigenicity, Lacassagne et al. (2247a)

Table XVII.E-3 Summary of Lists of Tumorigenic Aza-Arenes in Tobacco Smoke IARC Evaluationd of Evidence re Tumorigenicity in Component Quinoline Dibenz[a,h]acridine Dibenz[a,j]acridine 7H-Dibenzo[c,g] carbazole

Ho & Hea

OSHAb

Ho & Hoc

MS Level Wt/cigc

Laboratory Animals

Humans

× × × ×

…

× × × ×

1–2 mg 0.1 ng 3–10 ng 0.7 ng

… sufficient sufficient sufficient

… … … …

× × ×

Ho & He = Hoffmann and Hecht (1727) OSHA = OSHA (2825) c Ho & Ho = Hoffmann and Hoffmann (1740) d See IARC (1870) a

b

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819

Nitrogen Heterocyclic Components

Table XVII.E-4 Tobacco Smoke Components Related to Aza-Arenes in Tumorigen Listsa Quinolines [35]b

Acridines [28]b

Quinoline Quinoline, 5-aminoQuinoline, butylQuinoline, dihydroQuinoline, dihydroethyl(3 isomers) Quinoline, dihydromethyl(3 isomers) Quinoline, dimethyl-(5 isomers) Quinoline, ethyl-(2 isomers) Quinoline, methyl-(6 isomers) Quinoline, (1-methylethyl)Quinoline, methyltetrahydro(2 isomers) Quinoline, propylQuinoline, tetrahydro-(2 isomers) Quinoline, tetramethyl-

Acridine Acridine, 9,10-dihydroAcridine, 9,10-dihydro(4 homologs) Acridine, ethylAcridine, methylAcridine, propyl-

Carbazoles [20]b 9H-Carbazole 9H-Carbazole, 2-amino9H-Carbazole, dimethyl(4 isomers) 9H-Carbazole, 9-ethyl9H-Carbazole, methyl(5 isomers) 9H-Carbazole, tetramethyl9H-Carbazole, trimethyl-

Benz[a]acridine Benz[a]acridine, dimethyl-

11H-Benzo[a]carbazole

Benz[c]acridine

5H-Benzo[b]carbazole

Benz[c]acridine, dimethyl(5 isomers) Benz[c]acridine, methyl(5 isomers) Benz[c]acridine, trimethyl(2 isomers)

Quinoline, trimethyl-

7H-Benzo[c]carbazole

1H-Dibenzo[a,c]carbazole Dibenz[a,h]acridine

Quinolinecarbonitrile (2 isomers)

13H-Dibenzo[a,i]carbazole Dibenz[a,i]acridine

8-Quinolinol 8-Quinolinol, 7-methyla b

7H-Dibenzo[c,g]carbazole Dibenz[a,j]acridine Dibenz[c,h]acridine

Omitted from the list are the N-heterocyclic amines discussed in a subsequent chapter. Number in square bracket = number of reported components

Table XVII.E-5 Aza-Arene Sources Other than Tobacco Smoke Acridine/Benzacridine Source Automobile exhaust Coal-fired residential furnace emission Coal distillate Coal tar Crude oil High boiling petroleum distillate Industrial stack effluent Urban suspended particulate matter Cigarette smoke condensate

Reference 3419b, 4247a 1407b 1334c, 2210a 2261a, 2534a 1407a, 3519c 2519a 3419a 35, 636a, 1040a, 3419c 1884, 3491

aza-arenes are discussed in detail in Section XVII.F devoted to the N-heterocylic amines identified in tobacco smoke. However, in addition to the N-heterocylic amines, several azaarene-related fused N-containing ring compounds with two or more ring nitrogens plus various functional groups have been identified in tobacco and/or tobacco smoke. Classic examples of such compounds in tobacco include adenosine, 5’-adenylic acid, and many purines. Table XVII.E-8 lists many such components identified in tobacco and/or tobacco smoke. Examination of the structures of the various derivatives indicates the inclusion of a variety of functional groups, for example, amino, carboxylic acid, carboxamide, hydroxyl, and various carbohydrates. It should be noted that Table XVII.E-8 does not include the nine N-heterocyclic amines because they are described and discussed in detail in Section XVII.F. In contrast to the azaarenes which occur predominately in tobacco smoke, fifty-five of the seventy-six components with functional groups listed in Table XVII.E-8 were identified in tobacco and only twentyfour were identified in tobacco smoke.

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820

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6 Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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Nitrogen Heterocyclic Components

821

Table XVII.E-6 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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822

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

823

Table XVII.E-6 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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824

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

825

Table XVII.E-6 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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826

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

827

Table XVII.E-6 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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828

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

829

Table XVII.E-6 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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830

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

831

Table XVII.E-6 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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832

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

833

Table XVII.E-6 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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834

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-7 Structures of Aza-Arenes in Tobacco and Tobacco Smoke Identified in Smoke

Present in Tobacco

No. of Nitrogens

No. of Nitrogens

Ring Type

1

2

3

Total

1

2

4

Total

Bicyclic Tricyclic Tetracyclic Pentacyclic Hexacyclic

107 43 30 10 0

63 28 0 0 1

3 0 0 0 0

173 71 30 10 1

14 2 0 0 0

4 2 0 0 0

1 0 0 0 0

19 4 0 0 0

Total

190

92

3

285

16

6

1

23

XVII.F N-Heterocyclic Amines Although not originally classified at the time as “cooked food” mutagens, several amino acid-derived N-heterocyclic compounds were identified in cigarette smoke condensate (CSC) in the early 1960s: 5H,10H-Dipyrrolo[1,2-a:1’,2’-d] pyrazine-5,10-dione (pyrocoll) {I} by Mold et al. (2592) and 9H-pyrido[3,4-b]indole (norharman) {II} and 1-methyl-9H-pyrido[3,4-b ]indole (harman) {III} by Poindexter and Carpenter (2972) (Figure XVII.F-1). Proline is the precursor in tobacco of 5H,10H-dipyrrolo[1,2a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) {I} in tobacco smoke. Tryptophan is the major precursor in tobacco of 1-methyl-

9H-pyrido[3,4-b]indole (harman) {II} and 9H-pyrido[3,4-b] indole (norharman) {III} as well as indole and its alkylated homologs in tobacco smoke. In the late 1970s, Japanese investigators, in their detailed studies of components of various “cooked foods,” isolated and identified the first of a series of N-heterocyclic amines as pyrolysis products of several amino acids. Sugimura et al. (3829) reported the isolation and identification of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (designated as Trp-P-1) {IV} and 3-amino-1-methyl-5H-pyrido[4,3-b] indole (Trp-P-2) {V} (Figure XVII.F-2) from tryptophan pyrolysates.

O N

N

N O I 5H,10H-Dipyrrolo[1,2-a:1',2'd]pyrazine-5,10-dione (pyrocoll)

N

N H

N H

II 9H-Pyrido[3,4-b] indole (norharman)

III 1-Methyl-9H-pyrido[3,4-b]indole (harman)

CH3

Figure XVII.F-1  Pyrocoll, norharman, and harman.

R1 N

N N H

R2 IV R1 = R2 = CH3 V R1 = CH3 R2 = H

N

NH2 R1

NH2

N

VI R1 = CH3 VII R1 = H

NH2

R1

N H

N

VIII R1 = H IX R1 = CH3

N NH2 N

N

R1

R2

X R1 = CH3 R2 = H XI R1 = R2 = CH3

Figure XVII.F-2  N-Heterocyclic amines, the “cooked food” mutagens.

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Nitrogen Heterocyclic Components

835

Table XVII.E-8 Derivatives of Fused N-Containing-Ring Compounds with Two or More Nitrogens in the Rings

(Continued )

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836

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-8 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

837

Table XVII.E-8 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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838

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-8 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Nitrogen Heterocyclic Components

839

Table XVII.E-8 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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840

The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-8 (Continued) Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

Yamamoto et al. (4365a) reported the isolation and identification of the mutagenic N-heterocyclic amines 2-amino6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1) {VI} and 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2) {VII} from glutamic acid pyrolysates. Yoshida and Matsumoto (4388) and Matsumoto et al. (2492) reported the identification of 2-amino-9H-pyrido[2,3-b]indole (AaC) {VIII} and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC) {XIII-IX} in CSC (Figure XVII.F-2).

A unique feature of several of compounds {IV–VII} was their inordinately high mutagenicity in the Ames system (Salmonella typhimurium). Mutagenic activities on a revertant per microgram basis as determined in the Ames test with Salmonella typhimurium strains TA 98 and TA 100 for several of these compounds are shown in Table XVII.F-1 [Sugimura (3828c), Lee et al. (2327c)]. To put in perspective the extremely high values for the mutagenic activities listed in Table XVII.F-1, it should be noted that the mutagenic activity

Table XVII.F-1 Mutagenic Activities of N-Heterocyclic Amines Towards Salmonella typhimuriuma

Compound Dipyrido[1,2-a:3’,2’-d] imidazole, 2-amino-6-methylDipyrido[1,2-a:3’,2’-d] imidazole, 2-amino5H-Pyrido[4,3-b]indole, 3-amino-1,4-dimethyl5H-Pyrido[4,3-b]indole, 3-amino-1-methyl9H-Pyrido[2,3-b]indole, 2-amino9H-Pyrido[2,3-b]indole, 2-amino-3-methylImidazo[4,5-f]quinoline, 2-amino-3-methylImidazo[4,5-f]quinoline,2amino-3,4-dimethyl9H-Pyrido[3,4-b]indole 9H-Pyrido[3,4-b]indole, 1-methylCigarette smoke condensate Benzo[a]pyrene

Mutagenic Activity, Revertant/μg

Identified in Tobacco Smoke

TA 98b

TA 100b

TA 98c

TA 100c

Glu-P-1

yes

49000

3200

73000

4000

Glu-P-2

yes

1900

1200

600

400

Trp-P-1

yes

39000

1700

20000

500

Trp-P-2

yes

104200

1800

103000

2000

AaC

yes

300

20

—

—

MeAaC

yes

200

120

—

—

IQ

yes

433000

7000

222000

11000

MeIQ

yes

661000

30000

1327000

70000

norharman harman

yes yes

— —

— —

— —

— —

CSC B[a]P

— yes

— —

— —

2 200

—

Abbreviation

1

Tests with Salmonella typhimurium involved use of S-9 mix. Ames test data with Salmonella typhimurium reported by Sugimura (3828c). c Ames test data with Salmonella typhimurium reported by Lee et al. (2327c). a

b

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Nitrogen Heterocyclic Components

of benzo[a]pyrene (B[a]P) (strain TA 98) when tested under the same conditions is about 200 revertant/mg of B[a]P. In separate studies, Levitt et al. (2355a) and Nagao et al. (2667b) demonstrated the mutagenicity of the previously identified tobacco smoke components 9H-pyrido[3,4-b]indole (norharman) {II} and 1-methyl-9H-pyrido[3,4-b]indole (harman) {III}. Heckman and Best (1587) reported the identification of nearly 270 previously unidentified and confirmation of over 150 previously identified N-containing components in CSC. These included several components structurally similar to some of the N-heterocyclic amines 9H-pyrido[2,3-b]indole, 2-methyl9H-pyrido[2,3-b]indole, 2-(2-methylpropyl)-9H-pyrido[2,3-b] indole, 2-pentyl-9H-pyrido[2,3-b]indole, 1-butyl-9H-pyrido [3,4-b]indole, 1-propenyl-9H-pyrido[3,4-b]indole, and a partially characterized norharman. In addition to their mutagenicity in the Ames test (Salmonella typhimurium), several of the mutagenic N-heterocyclic amines were subsequently reported to be tumorigenic, particularly in feeding experiments, to several laboratory animal species. The tumorigenicity in mice of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl5H-pyrido[4,3-b]indole (Trp-P-2) was reported by Matsukura et al. (2491a) and in rats by Hosaka et al. (1835a). Takayama et al. (3862d) demonstrated the tumorigenicity in rats of 3-amino1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1 -methyl-5H-pyrido[4,3-b]indole (Trp-P-2). Ohgaki et al. (2849b) described the tumorigenicity in mice and Takayama et al. (3862b) described the tumorigenicity in rats of 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1) and 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2). 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) {X} was reported to be tumorigenic in rats by Takayama et al. (3862c) and Tanaka et al. (3865c) and in mice by Ohgaki et al. (2849, 2849a). Ohgaki et al. (2849, 2849a) also reported the tumorigenicity in mice of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and

2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), both compounds being components in broiled fish, fried beef, and beef extract. As indicated in Table XVII.F-1, both 2-amino-3 -methylimidazo[4,5-f]quinoline (IQ) (4367, 4368) and 2-amino-3,4-dimethyl-imidazo[4,5-f]quinoline (MeIQ) (2039) have been reported in tobacco smoke. Rodgman (3253a) discussed the theoretical relationships (Figures XVII.F-3 and XVII.F-4) among glutamic acid {XII}, its possible degradation products 4-aminobutanoic {XIII} and 2-aminobutanoic acid {XIV}, 2-amino-3-methylpyridine {XV} and 2-amino-6-methylpyridine {XVI}, 2-aminopyridine {XVII} and the possible reactions between these substituted aminopyridines to form 2-amino-6-methyldipyrido[1,2a:3’,2’-d]imidazole (Glu-P-1) {VI}, 2-aminodipyrido[1,2a:3’,2’-d]imidazole (Glu-P-2) {VII}, and two similar products, 2-amino-9-methyldipyrido[1,2-a:3’,2’-d]imidazole {XVII} and 2-amino-3,6-dimethyldipyrido[1,2-a:3’,2’-d]imidazole {XIX}, not yet identified in tobacco smoke or cooked foods. The aminobutanoic acids {XIII and XIV} and the aminopyridines {XV-XVII} noted in Figures XVII.F-3 and XVII.F-4 have been reported as tobacco smoke components. Rodgman also discussed the already identified and other possible theoretical relationships (Figure XVII.F-5) between tryptophan {XX} and 9H-pyrido[3,4-b]indole (norharman) {II its methyl homolog 1-methyl-9H-pyrido[3,4-b]indole (harman) {III} and other substituted norharmans {VI, R = C2H5, CH3CH=CH, and n-C4H9}, the tryptophan pyrolysis products 3-amino-1,4-dimethyl-5H-pyrido-[4,3-b]indole (Trp-P-1) {IV} and 3-amino-1-methyl-5H-pyrido[4,3-b] indole (Trp-P-2) {V}; the alkyl- and dialkyl-indoles; indole3-acetonitrile ; the 2-amino-9H-pyrido[2,3-b]indoles [AaC {VIII} and MeAaC {IX}] plus other pyrido[2,3-a]indoles {R = H, CH3, C2H5, (CH3)2CHCH2, or n-C5H11} (see Table XVII.F-6). All of the compounds noted in (Figure XVII.F-4) have been reported as tobacco smoke components.

COOH

COOH NH2 COOH HOOC

H2N

NH2

XII

HOOC

XIII

XIV

NH2 CH3

XV

N

CH3 NH2

NH2

N

COOH

HOOC HOOC

COOH +

COOH NH2

N

XVII

NH2

NH2 XVI

Figure XVII.F-3  Theoretical conversion of glutamic acid {XII} to aminobutanoic acids {XIII, XIV} and aminopyridines {XV–XVII}.

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842

The Chemical Components of Tobacco and Tobacco Smoke

N

N

NH2

CH3

XV

N

XVII

CH3 XVII

N

VI N

NH2

N XVII

VII CH3

CH3 N

XVI

N

N

XV

NH2

NH2

N N

XVII

N

XVIII N

NH2

N

+ NH2

CH3

N

+ NH2

NH2

N

+ NH2

NH2

N

+ NH2

N

N

CH3 XV

NH2

CH3 N

CH3 XIX

Figure XVII.F-4  Theoretical routes for conversion of glutamic acid-derived aminopyridines to possible tobacco smoke components.

In the 1979 report of the U.S. Surgeon General (4005), the aza-arenes dibenz[a,h]acridine, dibenz[a,j]acridine, 7Hdibenzo[c,g]carbazole, quinoline, and alkylated quinolines in CSC were discussed but not the presence or biological properties of the N-heterocyclic amines identified in tobacco smoke. However, in the 1982 report of the Surgeon General (4010), 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) were classified as “toxic and tumorigenic agents of cigarette smoke” in amounts of 3.2 to 8.1 mg/cigarette and 1.1 to 3.1 mg/cigarette, respectively, in mainstream CSC. None of the N-heterocyclic amines present in tobacco smoke was discussed. Snook and Chortyk (3739, 3740) reported the cigarette mainstream smoke (MSS) yield of 9H-pyrido[3,4-b]indole (norharman) to be 1.2 to 13.4 mg/cigarette; that for 1-methyl9H-pyrido[3,4-b]indole (harman) to be 0.3 to 3.8 mg/cigarette. They found a linear relationship between the yield of MSS “tar” and the yields of 9H-pyrido[3,4-b ]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman). In contrast to the 1962 findings of Poindexter and Carpenter (2972),

Snook and Chortyk reported yields of these two compounds were not influenced by the tobacco type. In his review of the studies of the mutagenicity of CSC, DeMarini (933) discussed the significance of the findings of Yoshida and Matsumoto (4388) and Matsumoto et al. (2492) on the mutagenicity of 2-amino-9H-pyrido[2,3-b] indole (AaC) (80 ng/cigarette) and 2-amino-3-methyl-9Hpyrido[2,3-b]indole (MeAaC) (7 ng/cigarette). None of the authors contributing to the American Chemical Society’s 1984 monograph [Searle (3568)] on chemical carcinogens mentioned the N-heterocyclic amines as mutagens and/or tumorigens. Yamashita et al. (4367, 4368) identified and quantitated the following N-heterocyclic amines in mainstream CSC: 2amino-3-methylimidazo[4,5-f]quinoline (IQ) (0.3 ng/cigarette), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) (0.3 ng/cigarette), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) (0.2 ng/cigarette), 2-amino-9H-pyrido[2,3-b]indole (AaC) (16.9 ng/cigarette), and 2-amino-3-methyl-9H-pyrido [2,3-b]indole (MeAaC) (1.6 ng/cigarette).

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Nitrogen Heterocyclic Components

R

N N H VIII R = H IX R = CH3

R

COOH NH2

NH2

N H

XX

NH2

N H

R2

R-CHO COOH

N H

N

R

NH N H

R

CN

N H

R1 NH N H

R

N H

R2

NH N H

R

Figure XVII.F-5  Possible tryptophan-derived compounds in tobacco smoke.

In his 1986 review of the isolation and identification of the N-heterocyclic amines, the high mutagenicity in the Ames test (Salmonella typhimurium) of several of them, their tumorigenicity in laboratory animals, and their various sources, including CSC, Sugimura (3828c) wrote the following about their importance as human carcinogens: Taking various factors into consideration, it is probably impractical and not realistic to make risk estimations from the carcinogenicity data on rodents given a single carcinogen. However, for a simple extrapolation of animal data for risk estimation, TD50 values, which are the doses needed to develop cancers in 50% of animals fed on carcinogens [IQ, Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, AaC, and MeAaC] for their life time, have been calculated based on mouse experiments … If we assume the average TD50 value of heterocyclic amines should be about 8 mg/kg/day, we can roughly estimate the risk of these carcinogenic heterocyclic amines for human beings. The intake of heterocyclic amines was calculated from available data on their quantities in foods. Apparently the human intake is about 0.0002% times the TD50 obtained from animal data. This means that heterocyclic amines may not be so serious for human cancer development.

Sugimura added: On the other hand, it is also true that human beings are being exposed to many heterocyclic amines and many other carcinogens with tumor promoters and/or suppressing factors

for carcinogenesis. At this moment, it is honest to state that no solid information on the estimation of risk of heterocyclic amines has been obtained in any direction, either positive or negative. As in the case of the carcinogens whose activity can be substantially reduced by anticarcinogens [see review by Rodgman (3255)], Lee et al. (2327c) reported that mainstream CSC significantly inhibited the mutagenicity of several of these N-heterocyclic amines when tested in the Ames assay with Salmonella typhimurium, strain TA 98 in the presence of the S-9 mix. The N-heterocyclic amines tested included 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-6-methyl-dipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1), 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2), 3-amino1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), and 3-amino1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). The mutagenic activities of these mutagens were suppressed as much as 80% by addition of 50 to 100 mg of CSC per plate. Enzymatic studies indicate that CSC is a potent inhibitor of cytochrome P-450 dependent monooxygenase. Therefore, it appears that CSC exerts its antimutagenicity by inhibiting the P-450 system. Lee et al. (2327c) also reported that fractionation of CSC yields fractions that show low mutagenicity themselves but are significantly antimutagenic. Although many of the N-heterocyclic amines are indeed present in cigarette MSS, it should be remembered that the

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Table XVII.F-2 Summary of Lists of Tumorigenic N-Heterocyclic Amines in Tobacco Smoke Mainstream Smoke Yield (ng/cig) Reported by

Component

1986–1994 IARC (1870), Hoffmann & Wynder (1806), Hoffmann & Hecht (1727), Hoffmann et al. (1773), OSHA (2825)

1997 Hoffmann & Hoffmann (1740)

1998 Hoffmann & Hoffmann (1741)a

2001 Hoffmann & Hoffmann (1743) Hoffmann et al. (1744)

2001 Fowles & Bates (1217)

1997–2001 Smith et al. (3711–3713)

NL b NL NL NL NL NL NL NL NL

25–260 2–37 0.37–0.89 0.25–0.88 11–23 0.26 NL 0.29–0.48 0.82–1.1

25–260 2–37 0.37–0.89 0.25–0.88 11–23 0.3 NL 0.3–0.5 0.8–1.1

25–260 NL 0.37–0.89 0.25–0.88 11–23 0.3 NL 0.3–0.5 0.8–1.1

NL b NL NL NL NL NL NL NL NL

ND c–258 1.6–37 ND–0.89 0.25–0.88 ND–22.9 0.26–0.49 0.28–0.75 0.19–0.3 ND–0.2

AaC a MeAaC Glu-P-1 Glu-P-2 PhIP IQ MeIQ Trp-P-1 Trp-P-2

AaC = 2-amino-9H-pyrido[2,3-b]indole; MeAaC = 2-amino-3-methyl-9H-pyrido[2,3-b]indole; Glu-P-1 = 2-amino-6-methyldipyrido[1,2-a:3’,2’-d] imidazole; Glu-P-2 = 2-aminodipyrido[1,2-a:3’,2’-d]imidazole; PhIP = 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine; IQ = 2-amino-3-methyl3H-imidazo[4,5-f]quinoline; MeIQ = 2-amino-3,4-dimethyl-3H-imidazo[4,5-f]quinoline; Trp-P-1 = 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole; Trp-P-2 = 3-amino-1-methyl-5H-pyrido[4,3-b]indole. b NL = not listed. c ND = not detected a

major part of the research on this class of compounds was initiated and extended because of their presence in a great number of cooked foodstuffs consumed by a great number of people. When the N-heterocyclic amines were shown to be tumorigenic in addition to being highly mutagenic and subsequently identified in tobacco smoke, they were included by Hoffmann and his colleagues in their numerous lists of tobacco smoke tumorigens published in 1997 and later (1740, 1741, 1743, 1744). The N-heterocyclic amines had not been included in their numerous lists published between 1986 and 1997 (1727, 1773, 1806) nor in similar lists published by IARC (1870) and OSHA (2825). Table XVII.F-2 summarizes some details of these N-heterocyclic amines in tobacco smoke. Because of their concerns about the mutagenicity of numerous commonly consumed heated foods, many of the studies of the isolation, identification, and estimation of N-heterocyclic amines in heated foodstuffs or heated food components, particularly amine-containing components such as amino acids, proteins, and peptides, were conducted by Japanese investigators. This becomes obvious from examination of the authors and coauthors of the references listed in Table XVII.F-3. With the reporting of the Ames mutagenicity test with Salmonella typhimurium in the mid-1970s and the demonstration of its utility, the number of studies on potential mutagenic systems and the mutagenicity-tumorigenicity relationship virtually exploded. By highly competent application of up-to-date isolation and characterization techniques plus utilization of the Ames test, Sugimura and his staff at the Japanese National Cancer Research Institute contributed

significantly to our knowledge of the structures, properties, and precursors in foods of the N-heterocyclic amines. While the methodologies differed, the 1977 isolation and identification of the N-heterocyclic amines (Trp-P-1, Trp-P-2) from a tryptophan pyrolysate paralleled the historic 1932 isolation and identification of polycyclic aromatic hydrocarbons (PAHs) [B[a]P, benzo[e]pyrene (B[e]P), benz[a]anthracene (B[a]A), perylene] from coal tar. In the 1930s, the Kennaway group in the United Kingdom used ultraviolet spectrophotometry [Hieger (1631)] to monitor coal tar PAHs during their concentration and purification by repeated precipitations and recrystallizations of PAH-picric acid complexes [Cook et al. (796a, 797)]. In the mid-1970s, Sugimura et al. (3829a) in Japan used the Ames test (Salmonella typhimurium, TA 98 strain/S-9) to monitor tryptophan pyrolysate mutagens (TrpP-1, Trp-P-2) during their concentration and purification by sequential chromatography on silicic acid, alumina, and CM-Sephadex® columns. References to several early studies on the identification of biologically active compounds in heated foodstuffs are included in Table XVII.F-3, for example, the 1956 study by Kuratsune (2237) of PAHs such as B[a]P in roasted coffee and the similar mid-1960s studies of PAHs in broiled meat [Lijinsky and Shubik (2364a, 2364b)]. PAHs such as B[a] P were identified in both studies. The major concern of the early investigators was the possible presence of tumorigenic PAHs, particularly B[a]P, in the heated foodstuff. Of course, it was subsequently demonstrated that B[a]P, in addition to its tumorigenicity to mouse skin, is also mutagenic in the Ames test. However, its specific mutagenicity is insignificant

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Table XVII.F-3 N-Heterocyclic Amines: Mutagenicity of Beverages, Heated Foods, and Heated Food Components Food or Food Component

References

  Herring, broiled   Mackerel, broiled   Pike, broiled   Sardine, broiled   Sardine, broiled

Felton and Knize (1177d), Matsumoto et al. (2492), Nagao et al. (2667a), Sugimura (3828c, 3828e, 3828f), Sugimura et al. (3829), Sugimura and Nagao (3929b), Tanaka et al. (3865b) Commoner et al. (790a), Hargraves and Pariza (1501a), Hayatsu et al. (1555b), Ohgaki et al. (2849a), Takayama et al. (3862c), Turesky et al. (3988b) Commoner et al. (790a), Felton et al. (1177d), Hayatsu et al. (1555a, 1555b), Jägerstad et al. (1916b), Kasai et al. (2037d), Lijinsky and Shubik (2364a, 2364b) a, Nagao et al. (2667c), Ohgaki et al. (2849a), Takayama et al. (3862c), Yasuda et al. (4382a) Ohgaki et al. (2849a), Yamaguchi et al. (4361a)   Sugimura and Nagao (3828b)  Kasai et al. (2037c, 2037d), Nagao et al. (2667c), Yamaizumi et al. (4361b), Yasuda et al. (4382a)   Nagao et al. (2667f)   Ohgaki et al. (2849a), Takayama et al. (3862c)

Protein pyrolysates   Albumin   Soybean globulin   Calf thymus   Egg white   Serum albumin   Casein, collagen,   Gluten, histone,   Insulin, lysozyme,   Ovalbumin, zein,   Tobacco protein   Polypeptides   Carnosine   Glycyl glycine a   Glycyl glutamic acid   Glycyl proline   Glycyl tryptophan   Leucyl glycyl    phenylalanine   Tryptophanyl alanine   Tryptophanyl glycine   Tryptophanyl    tryptophan   Tryptophanyl tyrosine

Matsumoto (2491c), Nagao et al. (2667f), Nebert et al. (2688a), Yoshida and Matsumoto (4387b), Yoshida et al. (4390) Yasuda et al. (4382a) Ohgaki et al. (2849b),Yoshida et al. (4389a)   Nagao et al. (2667b)     Matsumoto et al. (2491c)   Johnson et al. (1968)       Matsumoto et al. (2491c)      

Amino acid pyrolysates   Phenylalanine   Lysine   Tryptophan

Kato et al. (2048, 2049), Kosuge et al. (2178a), Masuda et al. (2486), Nebert et al. (2688a) Sugimura et al. (3829) Wakabayashi et al. (4102a) Hosaka et al. (1835a), Matsukura et al. (2491a), Negishi and Hayatsu (2689a), Sugimura et al. (3829), Takayama et al. (3862d), Yamazoe et al. (4370a), Yoshida and Matsumoto (4390) Ohgaki et al. (2849b), Sugimura (3828a), Takeda et al. (3863a), Takayama et al. (3862b), Yamamoto et al. (4365a) Smith et al. (3722a)

Foods, heated (grilled, broiled, etc.)   Beef, extract   Beef, broiled, fried, and/or charred   Cuttlefish, broiled   Eggs, fish, meat   Flour, rice   Soybeans   Fish, broiled, charred

  Glutamic acid   Histidine   Histidine, 3-methyl-

(Continued)

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Table XVII.F-3 (C0ntinued) N-Heterocyclic Amines: Mutagenicity of Beverages, Heated Foods, and Heated Food Components Food or Food Component

References

  Alanineb, arginine,   Asparagine, citrulline,   Cysteine, cystine,   Glutamic acid,   Glutamine, histidine,   Lysine, methionine,   Ornithine,   Phenylalanine, serine,   Threonine, tryptophan,   Tyrosine, valine

     Matsumoto et al. (2491b)     

Beverages   Coffee, roasted   Coffee, instant   Tea   Brandy   Sake

Aeschbacher and Würzner (38a), Kuratsune (2237) c, Nagao et al. (2667d, 2667e), Sugimura (3828d) Aeschbacher and Würzner (38a), Fujita et al. (1256a), Kosugi et al. (2178b) Nagao et al. (2667e), Sugimura (3838d) Sugimura (3828d) Takase and Murakami (3862a)

Cigarette smoke condensate

DeMarini (930-933), Matsumoto et al. (2492), Sugimura (3828d), Yoshida and Matsumoto (4388)

No mutagens detected in glycyl glycine pyrolysate. The pyrolysates from the various amino acids studied showed mutagenicities (Ames test) in the following sequence (revertant/mg of pyrolysate), the amino acid (tryptophan) yielding the highest mutagenic pyrolysate listed first: Tryptophan, serine, glutamic acid, ornithine, lysine, arginine, citrulline, threonine, alanine, cystine, glutamine, methionine, cysteine, tyrosine, phenylalanine, histidine, asparagine, valine. c This was a polycyclic aromatic hydrocarbon (PAH) study, with emphasis on the generation of B[a]P. a

b

compared to that of several of the N-heterocyclic amines (see Table XVII.F-1). The presence of PAHs in numerous foods was discussed previously. From their studies of heated foods or food pyrolysates (thirty different foods, including rice, flour, soy beans, fish, meat, eggs), Sugimura (3828b) reported: • Mutagenicity was proportional to the protein content. • Mutagenicity was proportional to the levels of specific amino acids (tryptophan, glutamic acid, etc.) in the constituent protein. • Mutagenicity was dependent on water content and heating temperature, for example, for foods with low water content, the mutagens appear at 300°C; for those with high water content, the mutagens appear at 400°C. Estimates of daily exposures to PAHs and N-nitrosamines in foods, beverages, and other factors have been made by numerous investigators. Estimates of exposures to N-heterocyclic amines are limited. Part of the reason is the difference in time span since the particular class of compounds was found to be tumorigenic and/or mutagenic: Exposures to PAHs tumorigenic in laboratory animal bioassays have been studied for more than seven decades (since the

early 1930s and the identification of B[a]P in coal tar by Cook et al. (796a, 797), exposures to N-nitrosamines tumorigenic in laboratory animal bioassays have been studied [Magee and Barnes (2441a)] since the mid-1950s. In contrast, exposures to N-heterocyclic amines tumorigenic in laboratory animal bioassays have only been studied for about thirty years (since the mid-1970s and the availability of the Ames test). Sugimura (3828b) reported comparisons of the mutagenicities (Ames test) of various beverages (coffee, brandy, tea) and CSC. The data are summarized in Table XVII.F-4.

Table XVII.F-4 Mutagenicity of Common Beverages vs. Cigarette Smoke Condensate Agent Cigarette Coffee Teab Brandy a b

Exposure Level

ST Straina

S-9 Mix

Revertants

one, inhaled 200 ml 200 ml 50 ml

TA 98 TA 100 TA 100 TA 100

yes no no no

4000 180000 mutagenic 10500

ST = Salmonella typhimurium Japanese green tea

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Table XVII.F-5 Benzo[a]pyrene Equivalency of Extracts of Charred Fish and Meat Analyte Sardine Mackerel Beefsteak a b

Sample wt., g

B[a]P Equivalency, ng

Cigarette Equivalency Based on B[a]Pa

100 (3.5)b 60 (2.1) 190 (6.7)

35800 68200 85500

2983 5683 7125

Calculation based on assumption of MSS yield of 12 ng/cig of B[a]P. Number in parentheses is weight in ounces.

As noted previously, Sugimura (3828c) reported in his 1986 review his estimate of the exposure of humans to N-heterocyclic amines with the limited data at his disposal. From his estimate, Sugimura concluded that at that time N-heterocyclic amines might not be serious in human cancer development and no solid information on the estimation of risk of N-heterocyclic amines had been obtained in any direction, either positive or negative.

In another comparison of mutagenicities toward Salmonella typhimurium TA 98, Nagao et al. (2667c) calculated the B[a]P equivalency of extracts of charred fish and meat. Their data, with additions [charred food weight in ounces, cigarette equivalents based on B[a]P], are shown in Table XVII.F-5. Table XVII.F-6 lists identified tobacco smoke components actually or possibly derived from the amino acids glutamic acid, tryptophan, or proline. In the mid-1980s, Rodgman (3253a) discussed both the known relationships as well as several theoretically possible relationships between the three amino acids and many of the compounds listed in Table XVII.F-6. It also lists, with appropriate citations, the amino acid-derived compounds reported in tobacco smoke and citations to the studies demonstrating their mutagenicity and tumorigenicity. Additional references to the tobacco smoke components may be found in the section on the azaarenes (Section XVII.E) and Chapter 4 on the three amino acids (Section IV.B). Table XVII.F-7 summarizes the chronology of the studies pertinent to the N-heterocyclic amines in tobacco smoke and in commonly consumed cooked foodstuffs. Included in Table XVII.F-7

Table XVII.F-6 Components Related to N-Heterocyclic Amines in Tobacco Smoke: Identification and Biological Properties References to Compound Glutamic acid-derived: Glutamic acid Butanoic acid, 2-aminoButanoic acid, 4-amino2-Pyridinamine 2-Pyridinamine, 3-methyl2-Pyridinamine, 6-methylDipyrido[1,2-a:3’,2’-d] imidazole, 2-amino{Glu-P-2} Dipyrido[1,2-a:3’,2’-d] imidazole, 2-amino-6-methyl{Glu-P-1} Tryptophan-derived: Tryptophan 9H-Pyrido[3,4-b]indole {norharman} 9H-Pyrido[3,4-b]indole, 1-butyl9H-Pyrido[3,4-b]indole, 1-ethyl-

Identification in Smoke

Mutagenicitya

Tumorigenicityb

Buyske et al. (526), Izawa et al. (1910), Izawa and Taki (1914) Hecht et al. (1580) Izawa et al. (910), Izawa and Taki (1914) Heckman and Best (1587), Saint-Jalm and Morée-Testa (3386) Lippiello et al. (2378a) Lippiello et al. (2378a), Sanders et al. (3410) Clapp (751), Clapp et al. (755, 756), Massey (2484a)

Yamamoto et al. (4365a), Sugimura (3828c), Lee et al. (2327c)

Ohgaki et al. (2849a, 2849b), Takayama et al. (3862c), Sugimura (3828c)

Clapp (751), Clapp et al. (755, 756), Massey (2484a)

Yamamoto et al. (4365a), Sugimura (3828c), Lee et al. (2327c)

Ohgaki et al. (2849a, 2849b), Takayama et al. (3862c), Sugimura (3828c)

Poindexter and Carpenter (2972)

Levitt et al. (2355a), Nagao et al. (2667g)

USPHS (4010)

Heckman and Best (1587) Schumacher et al. (3553)

(Continued)

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Table XVII.F-6 (Continued) Components Related to N-Heterocyclic Amines in Tobacco Smoke: Identification and Biological Properties References to Compound 9H-Pyrido[3,4-b]indole, 1-methyl- {harman} 9H-Pyrido[3,4-b]indole, 1-methyl1,2,3,4-tetrahydro- 9H-Pyrido[3,4-b]indole, 1-propenyl5H-Pyrido[4,3-b]indole, 3-amino1,4-dimethyl{Trp-P-1} 5H-Pyrido[4,3-b]indole, 3-amino-1methyl- {Trp-P-2} 1H-Pyrido[2,3-b]indole 9H-Pyrido[2,3-b]indole, 2-ethyl9H-Pyrido[2,3-b]indole, 2-methyl9H-Pyrido[2,3-b]indole, 2-(2methylpropyl)9H-Pyrido[2,3-b]indole, 2-pentyl9H-Pyrido[2,3-b]indole, 2-amino{AaC} 9H-Pyrido[2,3-b]indole, 2-amino-3methyl- {MeAaC}

Imidazo[4,5-f]quinoline, 2-amino-3,4dimethyl- {MeIQ}

Imidazo[4,5-f]quinoline, 2-amino-3methyl- {IQ} Indole, 2,3-dimethylIndole-3-acetonitrile Proline-derived: Proline 5H,10H-Dipyrrolo[1,2-a:1’,2’-d] pyrazine-5,10-dione {pyrocoll}

Identification in Smoke Poindexter and Carpenter (2972)

Heckman and Best (1587) Yamashita et al. (4367, 4368)

Yamashita et al. (4367,4368)

Mutagenicitya

Tumorigenicityb

Levitt et al. (2355a), Nagao et al. (2667g) Schumacher et al. (3553)

USPHS (4010)

Sugimura et al. (3828c, 3829, 3829a), Lee et al. (2327c)

Matsukura et al. (2491a), Hosaka et al. (1835a), Takayama et al. (3862d), Sugimura (3828c) Matsukura et al. (2491a), Hosaka et al. (1835a), Takayama et al. (3862d), Sugimura (3828c)

Sugimura et al. (3829, 3829a), Sugimura (3828c), Lee et al. (2327c)

Heckman and Best (1587) Schumacher et al. (3553) Heckman and Best (1587) Heckman and Best (1587) Heckman and Best (1587) Yoshida and Matsumoto (4388), Matsumoto et al. (2492), Yamashita et al. (4367, 4368) Yoshida and Matsumoto (4388), Matsumoto et al. (2492), Yamashita et al. (4367, 4368) Bao et al. (179a), Levasseur et al. (2354a), Massey (2484a), Rodgman (3255, 3257, 3265), Rodgman and Green (3300), Smith et al. (3714) Yamashita et al. (4367, 4368)

Yoshida and Matsumoto (4388), Matsumoto et al. (2492), DeMarini (933), Sugimura (3828c) Yoshida and Matsumoto (4388), Matsumoto et al. (2492), DeMarini (933), Sugimura (3828c)

Ohgaki et al. (2849b), Sugimura (3828c)

Ohgaki et al. (2849), Lee et al. (2327c)

Ohgaki et al. (2849)

Yoshita et al. (4389a), Ohgaki et al. (2849a), Lee et al. (2327c)

Ohgaki et al. (2849a), Takayama et al. (3862b, 3862c), Tanaka et al. (3865c).

Ohgaki et al. (2849b), Sugimura (3828c)

Rodgman and Cook (3279), Izard et al. (1898), Schmeltz et al. (3506) Izard et al. (1898) Izawa et al.(1910), Izawa and Taki (1914) Mold et al. (2592), Rodgman and Cook (3279), Schmeltz et al. (3505), Testa and Testa (3886) Izard et al. (1898)

5H,10H-Dipyrrolo[1,2-a:1’,2’-d] pyrazine-5,10-dione, methyl{methylpyrocoll} 5H,10H-Dipyrrolo[1,2-a:1’,2’-d] Schumacher et al. (3553) pyrazine-5,10-dione, 1,2a,3,5a,8,10ahexahydro5H,10H-Dipyrrolo[1,2-a:1’,2’-d] Schumacher et al. (3553) pyrazine-5,10-dione, 1,2a,3,5a,8,10a-hexahydro-3-methyl5H,10H-Dipyrrolo[1,2-a: 1’,2’-d] Schumacher et al. (3553) pyrazine-5,10-dione, octahydroa b

Mutagenic (Salmonella typhimurium). Tumorigenic to mammalian skin.

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Table XVII.F-7 Chronology of N-Heterocyclic Amine Studies Year

Event

1959

The only fused ring N-heterocyclic compound listed by Johnstone and Plimmer (1971) as a component of tobacco smoke was the bicyclic compound quinoline. Mold et al. (2592) reported the isolation and identification of the tricyclic N-heterocyclic 5H,10H-dipyrrolo[1,2-a:1’,2’-d] pyrazine-5,10-dione (pyrocoll) from CSC and its relationship to its precursor in tobacco, the amino acid proline. Poindexter and Carpenter (2972) reported the isolation and identification of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) from CSC. They reported that the yield of the total harmans in burley and flue-cured MSSs was between 15 and 20 mg/gram of tobacco smoked, values which were 40 to 50 times that of the harmans in the unsmoked tobacco. Since the weight of tobacco in cigarettes sold at that time approximated 1 gram, the yield of these two compounds was about 15-20 mg/cig. Poindexter and Carpenter concluded from experiments with radiolabeled tryptophan that the harmans (found to be radiolabeled in the smoke) were generated pyrogenetically from a reaction between aldehydes (formaldehyde for norharman, acetaldehyde for harman) and the tryptophan in tobacco. Rodgman and Cook (3279) confirmed the presence in CSC of 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) and also reported the identification of indole, carbazole, and several alkylated indoles and carbazoles. Rodgman and Cook (3279) also reviewed the previously reported biological studies on indole, 3-methylindole (skatole), and carbazole: None of the three was reported to be tumorigenic. Schmeltz et al. (3505) reported 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) as tobacco smoke components. Testa and Testa (3886) also identified 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) as components of CSC. The Advisory Committee to the U.S. Surgeon General (3999) briefly discussed only four fused-ring N-heterocyclic compounds in tobacco smoke, quinoline and the two dibenzacridines (dibenz[a,h]acridine, dibenz[a,j]acridine) and the dibenzocarbazole (7H-dibenzo[c,g]carbazole) reported by Van Duuren et al. (4027). In his review of tobacco smoke composition, Stedman (3797) discussed the identification of tumorigenic N-heterocyclic compounds (dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g]carbazole) reported by Van Duuren et al. (4027) as well as the following N-heterocyclic compounds: 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) reported by Mold et al. (2592) and 9H-pyrido[3,4-b]indole (norharman), 1-methyl-9H-pyrido[3,4-b]indole (harman), and 9H-pyrido[2,3-b]indole reported by Poindexter and Carpenter (2972). Wakeham (4103) noted the reported presence of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) in cigarette smoke and discussed their formation from a reaction product of tryptophan and an aldehyde. As noted by Rodgman (3253a), the structure of the aldehyde reacting with tryptophan ultimately dictates the structure of alkylated norharmans found (see Table XVII.F-6) in CSC. In addition to 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), Izard et al. (1899) reported the identification of methyl-5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (methylpyrocoll) in CSC. In a 1974 in-house report, a 1975 TCRC presentation, and a 1977 publication on their study of the water-soluble portion of CSC, Schumacher et al. (3553) reported the identifications of 1-methyl-9H-pyrido[3,4-b]indole (harman), 5H,10Hdipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), octahydro-5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (octahydropyrocoll), and 2-ethyl-9H-pyrido[2,3-b]indole. Sugimura et al. (3829a) reported the isolation and identification of the N-heterocyclic amines 3-amino-1,4-dimethyl-5Hpyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) from tryptophan pyrolysates. In separate studies, Levitt et al. (2355a) and Nagao et al. (2667b) demonstrated the mutagenicity of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) in the Ames test. Yamamoto et al. (4365a) reported the isolation and identification of 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1) and 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2) from glutamic acid pyrolysates. Heckman and Best (1587) reported the identification of nearly 270 previously unidentified and over 150 previously identified N-containing components in CSC. These included several components structurally similar to the N-heterocyclic amines: 9H-pyrido[2,3-b]indole, 2-methyl-9H-pyrido[2,3-b]indole, 2-(2-methylpropyl)-9H-pyrido[2,3-b]indole, 2-pentyl-9H-pyrido[2,3-b] indole, 1-butyl-9H-pyrido[3,4-b]indole, 9H-1-propenyl-pyrido[3,4-b]indole, and a partially characterized norharman isomer. In the 1979 Surgeon General’s report (4005), the aza-arenes dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g] carbazole, quinoline, and alkylated quinolines in CSC were discussed but not the presence or properties of the N-heterocyclic amines identified in tobacco smoke. Yoshida and Matsumoto (4388) and Matsumoto et al. (2492) reported the identification of 2-amino-9H-pyrido[2,3-b]indole (AaC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC) in CSC.

1960 1961/1962

1962

1964

1964

1968

1971/1972

1974 1974/1975/ 1977

1977 1977 1978 1978/1981

1979

1980/1981 1981

Matsukura et al. (2491a) demonstrated the tumorigenicity in mice of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). Hosaka et al. (1835a) demonstrated the tumorigenicity in rats of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). (Continued)

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Table XVII.F-7 (Continued) Chronology of N-Heterocyclic Amine Studies Year

Event

1982

In the 1982 report of the Surgeon General (4010), 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) were classified as “toxic and tumorigenic agents of cigarette smoke” in amounts of 3.2 to 8.1 mg/cig and 1.1 to 3.1 mg/cig, respectively, in cigarette MSS. None of the other N-heterocyclic amines present in tobacco smoke was discussed. Snook and Chortyk (3739) reported the MSS yield of 9H-pyrido[3,4-b]indole (norharman) to be 1.2 to 13.4 mg/cig; that for 1-methyl-9H-pyrido[3,4-b]indole (harman) to be 0.3 to 3.8 mg/cig. They found a linear relationship between the yield of cigarette MSS “tar” and the yields of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman). In contrast to the 1962 findings of Poindexter and Carpenter, Snook and Chortyk reported that the MSS yields of these two compounds were not influenced by the tobacco type. Demarini (933) reviewed the studies on the mutagenicity of CSC. He discussed the studies of Yoshida and Matsumoto (4388) and Matsumoto et al. (2492) on the mutagens 2-amino-9H-pyrido[2,3-b]indole (AaC) (80 ng/cig) and 2-amino-3methyl-9H-pyrido[2,3-b]indole (MeAaC) (7 ng/cig). None of the authors contributing to the 2nd edition of the American Chemical Society’s monograph, edited by Searle (3568), on chemical carcinogens mentioned the tumorigenic and mutagenic N-heterocyclic amines reported in cigarette smoke and/or numerous cooked foods. In fact, the only class of tumorigens in cigarette MSS discussed in the 1400-page treatise was the N-nitrosamines. No tumorigenic PAH was mentioned as a component of cigarette MSS. Ohgaki et al. (2849) demonstrated the tumorigenicity in mice and Takayama et al. (3862b) demonstrated the tumorigenicity in rats of 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1) and 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2). Takayama et al. (3862c) demonstrated the tumorigenicity in rats of the tobacco smoke component 2-amino-3methylimidazo[4,5-f]quinoline (IQ). Ohgaki et al. (2849a, 2849b) demonstrated the tumorigenicity in mice of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), found in broiled fish, fried beef, beef extract, and CSC. Takayama et al. (3862d) demonstrated the tumorigenicity in rats of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). Tanaka et al. (3865b) demonstrated the tumorigenicity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). In an in-house presentation, Rodgman (3253a) discussed the already identified and other possible theoretical relationships between tryptophan and the substituted norharmans, the tryptophan pyrolysis products 3-amino-1,4-dimethyl-5Hpyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), the 2-amino-9H-pyrido[2,3-b] indoles (AaC and MeAaC), indole-3-acetonitrile, and the alkyl- and dialkylindoles. He also discussed the theoretical relationships among glutamic acid, its possible degradation products 2- and 4-aminobutanoic acid, 2-aminopyridine, 2-amino-3- and 6-methylpyridine, and the possible reactions between these substituted aminopyridines to form 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1), 2-aminodipyrido[1,2a:3’,2’-d]imidazole (Glu-P-2), and two similar products not yet identified. In its 1985 review, published in 1986, of the various problems from exposure to numerous components in tobacco smoke, the IARC (1870) did not designate the N-heterocyclic amines as a problem. IARC did list several tryptophan-derived tobacco smoke isolates including 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman). The per cigarette MSS yields of these two components were listed as 9.5 to 14.1 and 2.5 to 5.8 mg/cig, respectively. No mention was made of the N-heterocyclic amines in CSC or the degree of evidence for their carcinogenicity in animals and humans.

1982/1984

1983

1984

1984

1984/1985 1985

1985

1985/1986

1985/1986

The identification of several N-heterocyclic amines was reported in 1985 and 1986 by Yamashita et al. (4367, 4368). Yamashita et al. (4367,4368) identified and quantitated the per cigarette yields of the following N-heterocyclic amines in CSC: 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) 2-amino-9H-pyrido[2,3-b]indole (AaC) 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC)

1986 1986

0.3 ng/cig 0.3 ng/cig 0.2 ng/cig 16.9 ng/cig 1.6 ng/cig

Hoffmann and Wynder (1808) in their list of tobacco and tobacco smoke tumorigens did not list any N-heterocyclic amine. Sugimura (3828c) reviewed the isolation and identification of the N-heterocyclic amines, their high mutagenicity in the Ames test (Salmonella typhimurium) of several of them, their tumorigenicity, and their various sources – including CSC for many. However, Sugimura did write the following about the importance of the “cooked food” mutagens as human carcinogens: Taking various factors into consideration, it is probably impractical and not realistic to make risk estimations from the carcinogenicity data on rodents given a single carcinogen. However, for a simple extrapolation of animal data for risk estimation, TD50 values, which are the doses needed to develop cancers in 50% of animals fed on carcinogens [IQ, TrpP-1, Trp-P-2, Glu-P-1, Glu-P-2, AaC, and MeAaC] for their life time, have been calculated based on mouse experiments… If we assume the average TD50 value of heterocyclic amines should be about 8mg/kg/day, we can roughly estimate the risk of these carcinogenic heterocyclic amines for human beings. The intake of heterocyclic amines was calculated from available data on their quantities in foods. Apparently the human intake is about 0.0002% times the TD50 obtained from animal data. This means that heterocyclic amines may not be so serious for human cancer development.

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Table XVII.F-7 (Continued) Chronology of N-Heterocyclic Amine Studies Year

Event

Sugimura added: On the other hand, it is also true that human beings are being exposed to many heterocyclic amines and many other carcinogens with tumor promoters and/or suppressing factors for carcinogenesis. At this moment, it is honest to state that no solid information on the estimation of risk of heterocyclic amines has been obtained in any direction, either positive or negative. 1990 1990 1991

1993

Felton and Knize (1177d) reviewed the results of numerous studies on the mutagenicity and tumorigenicity of the N-heterocyclic amines. Manabe et al. (2448) identified the N-heterocyclic amine 1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridin-2-amine (PhIP) in CSC. By their addition to tobacco, Clapp (751) reported the contribution of various individual amino acids (asparagine, aspartic acid, arginine, glutamine, glutamic acid, histidine, proline, lysine, tryptophan, phenylalanine, creatine, creatinine) to the Ames test mutagenicity of cigarette MSS. Lee et al. (2327c) reported that the CSC from cigarette MSS significantly inhibited the mutagenicity of several N-heterocyclic amines as measured in the Ames assay with Salmonella typhimurium, strain TA 98 in presence of the S-9 mix. The N-heterocyclic amines tested included: 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1), 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). The mutagenic activities of these mutagens were suppressed as much as 80% by addition of 50 to 100 mg of CSC per plate.

1993 1994 1997

In their list of toxicants and tumorigens in tobacco and MSS, Hoffmann et al. (1773) did not include any N-heterocyclic amines. In its list of toxicants and tumorigens in MSS, OSHA (2825) did not include any N-heterocyclic amines. Hoffmann and Hoffmann (1740) issued a revised list of tumorigenic components in tobacco and tobacco smoke. Their revision of the Hoffmann-Hecht (1727) list included, in addition to several vapor-phase components, the following eight N-heterocyclic amines: 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1), 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). 2-amino-9H-pyrido[2,3-b]indole (AaC) 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC)

1998

In a letter to the editors of Beiträge zur Tabakforschung International, Hoffmann and Hoffmann (1741) listed eight N-heterocyclic amines as biologically active agents in the MSS of non-filtered cigarettes. They also included the three aza-arenes reported as MSS components by Van Duuren et al. in 1960. Clapp et al. (755,756) reported that reduction of the level of protein in flue-cured tobaccos by 70% resulted in a reduction of 80% in the mutagenicity of the MSS “tar” (strain TA 98 Salmonella typhimurium) and 50% (strain TA 100). Reduction of the protein level in burley tobacco by 50% resulted in reductions in mutagenicity of its MSS “tar” of 81% and 54%, with strain TA 98 and TA 100, respectively. Hoffmann and Hoffmann (1743) and Hoffmann et al. (1744) listed eight N-heterocyclic amines as biologically active agents in the MSS of non-filtered cigarettes. In both publications, the three aza-arenes reported as MSS components by Van Duuren et al. in 1960 were listed. In a presentation and publication, Rodgman and Green (3300) discussed the deficiencies of many of the lists of toxicants in cigarette MSS. Rodgman (3265) outlined the major problems with the lists published by Hoffmann and colleagues (1740, 1741, 1743, 1744) and others. Kinae et al. (2095a) reported that N-heterocyclic amines [2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4dimethylimidazo[4,5-f]quinoline (MeIQ), 1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridin-2-amine (PhIP)] were produced in an incubated solution of D-glucose and several amino acids at much lower temperatures and longer time periods than those encountered in the cooking of various foodstuffs (beef, poultry, fish). Several N-heterocyclic amines not found in CSC were also generated. The generation of the N-heterocyclic amines, as measured by the Ames test (Salmonella typhimurium TA 98), increased in proportion to the conditions imposed: 37°C (90 d), 50°C (30 d), 128°C (2 h)

1999/2000

2001

2002/2003 2003 2005

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Table XVII.F-8 N-Heterocyclic Amines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Table XVII.F-8 (Continued) N-Heterocyclic Amines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

are events pertinent to the studies of 5H,10H-dipyrrolo[1,2a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), 9H-pyrido[3,4-b]indole (norharman), and 1-methyl-9H-pyrido[3,4-b]indole (harman). Although none is an N-heterocyclic amine, their pyrogenesis from specific amino acids was the background for the subsequent studies on N-heterocyclic amines, each of which is derived from an amino acid.

Table XVII.F-8 lists, with appropriate citations, the N-heterocyclic amines reported in tobacco and tobacco smoke. While Table XVII.F-8 lists the citations pertinent to the nine highly mutagenic N-heterocyclic amines, as noted previously, citations pertinent to tobacco smoke components related to them are available in Sections IV.B (amino acids) and XVII.E (aza-arenes).

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18

Miscellaneous Components

XVIII.A Sulfur-Containing Components Sulfur is a well-known constituent of tobacco and is essential for growth of the plant. In 1990, Tso (3973) reviewed the chemistry, biology, and physiological aspects of sulfur in tobacco. It is absorbed by the plant as sulfate, some of which undergoes reduction during assimilation and becomes incorporated into amino acid components of proteins (18A11). The sulfur content of tobacco varies by tobacco type and has been reported (3973) to range from 0.4% for flue-cured varieties to 1.1% for the Maryland tobacco (4246). Sulfurcontaining (S-containing) compounds in or on tobacco can also come from added flavors and casings such as cocoa, as a contaminant of the leaf or of flavors and casings, or from agrochemicals (fertilizers, pesticides, herbicides, insecticides, etc.) applied to the tobacco. Endogenous S-containing compounds of tobacco include numerous proteins, peptides, nucleotides, several amino acids (methionine, cysteine, cystine, taurine, homocysteine), and B vitamins (thiamine and biotin). Sulfur is also available as various inorganic sulfates or sulfides found in tobacco. Sulfur is found in many casings and flavors used on tobacco. Solid flavorants or casing materials used on tobacco, such as cocoa and licorice, are natural products and just like tobacco they contain S-containing amino acids and proteinaceous substances. Some flavor additives used on tobacco products are S-containing compounds. In 1994, the tobacco rod of a cigarette produced by any of the then six major manufacturers could have had any combination of 599 different ingredients (1053), 460 of which were individual compounds as described by Rodgman (3266). Of the 460, Rodgman listed 212 identified as untreated tobacco components, 245 identified in its smoke, and 168 in both tobacco and smoke. Those numbers have changed slightly since several of the 460 components have recently been identified in tobaccos by Leffingwell and Alford (2339a) and Peng et al. (2917a). Within the compounds listed by Doull et al. (1053) are nine S-containing compounds, for example, methyl sulfide, d,l-methionine, 5-methyl-2-thiophenecarboxaldehyde, 3-methylthiopropionaldehyde, and methional. Tobacco contains residual levels of the S-containing compounds in agrochemicals that are used to treat tobacco, for example, Benfuracarb®, Oryzalin®, Thiofide®, Malathion®, Pebulate®, Cyolane®; Thiodicarb®, Trapex®, and Zineb®. Cigarette mainstream smoke (MSS) contains a wide variety of S-containing compounds, for example, S-containing amino acids, residues of herbicides, pesticides, insecticides, and growth promoters (Malathion®, Captan®, Thiodan®, α- and β-Endosulfan®, Disulfoton®, Guthion®, and Chlorpyriphos®), certain organic sulfates and sulfides, and decomposition

products of S-containing agrochemicals. MSS components possess a wide variety of S-containing functionalities (thiol, alkylthio, mercapto, isothiocyanatoalkyl, thiazolyl, phosphinothioyl, alkyldithio, phosphoramidothio, phosphonodithio, thiacycloalkyl, thiadiazinyl, thienyl, thiocarbamato, sulfide, sulfonate, sulfonyl, sulfuroxides, and trisulfide). MSS also contains several polycyclic compounds that contain sulfur (18A14), for example, benzothiophenes, dibenzothiophenes, and nonbenzeniod aromatic heterocycles, for example, benzodioxathiepins. The sulfur compounds in cigarette MSS reside in both the volatile and semivolatile fractions of MSS. Some S-containing compounds are also present in the particulate phase of MSS. The largest amount of research on S-containing compounds in MSS has been on those in the vapor phase of MSS. The low molecular weight S-containing compounds are volatile and highly odorous at parts per million and parts per billion concentrations. Their odor characteristics have been reported by a GC-port sniffing technique [Alford and Houpt (18A01), Ayya (18A03)]. Because of the odiferous nature of many of the vaporphase S-containing compounds in MSS their presence has often been considered undesirable. However, it must be kept in mind that smoke is a complex mixture and the contribution of any single component, depending on its concentration, can actually add to the overall characteristic of tobacco smoke. Certain S-containing compounds are excellent tobacco flavors, such as butyl sulfide (floral), furfuryl mercaptan (coffee), and allyl disulfide (garlic, nutty) and provide positive smoke taste characteristics, although their aromas are considered harsh or garlic (2341). S-containing compounds in tobacco are also possible precursors to Maillard reaction flavors. S-containing compounds can participate in Amadori rearrangement and Strecker degradation (18A03). The unpleasantness of single odorants should never be a valid reason to ignore or to reduce their effects in a complex mixture like tobacco smoke. Ayya (18A03) in 1994 posed the question of whether any of the S-containing compounds of tobacco smoke might be important pharmacologically if present in sufficiently high concentration. There are a number of S-containing compounds that are pharmacologically active [Rezanka et al. (18A12)], but none is found in tobacco smoke at concentrations that are of any concern. In terms of any of the S-containing compounds in tobacco or tobacco smoke being biologically active, the International Agency for Research on Cancer (IARC) has only tested sulfur dioxide, and various sulfites, bisulfites, and metabisulfites. In their 1992 monograph (18A05), IARC stated: There is inadequate evidence for the carcinogenicity in humans of sulfur dioxide, sulfites, bisulfites and metabisulfites. There

855

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is limited evidence for the carcinogenicity in experimental animals of sulfur dioxide. There is inadequate evidence for the carcinogenicity in experimental animals of sulfites, bisulfites and metabisulfites. Overall evaluation: sulfur dioxide, sulfites, bisulfites and metabisulfites are not classifiable as to their carcinogenicity to humans (Group 3).

IARC provides a classification for it overall evaluations of carcinogenicity to humans (18A04). It classifies individual compounds and mixtures into five categories based on scientific data on humans and animals. The classification is: • • • •

Group 1: Carcinogenic to humans Group 2A: Probably carcinogenic to humans Group 2B: Possibly carcinogenic to humans Group 3: Not classifiable as to carcinogenicity to humans • Group 4: Probably not carcinogenic to humans There are no known S-containing compounds in tobacco or tobacco smoke in Group 1, 2A, or 2B. There are only six compounds that are found in Group 3 (Malathion®, ethylenethiourea, Parathion®, Parathion-methyl®, sulfur dioxide, and ethylene sulfide). The evidence for the carcinogenicity in humans of all these compounds was classified as inadequate (18A04). Periodically during the past five decades, various reviews and catalogs on the composition of tobacco and tobacco smoke have been published. Some have listed S-containing compounds in tobacco and tobacco smoke, while others have not. In 1936 Bruckner (451) listed 120 known components in tobacco and tobacco smoke. Of the identified compounds that Bruckner listed only one contained sulfur (sulfate). In 1954 Kosak (2170) categorized about fifty components in tobacco smoke whose identities were certain. Under his heading of Inorganic Components Kosak listed hydrogen sulfide and thiocyanic acid (?). The question mark indicated that Kosak did not consider the evidence in the literature to be definitive proof of the identity of the component. Latimer (2270) in 1955 listed 231 compounds identified from tobacco and tobacco smoke. Cystine, methionine, thiamine, and sulfur were present in tobacco and thiocyanic acid, carbonyl sulfide, and methyl mercaptan were identified in tobacco smoke. Johnstone and Plimmer in 1959 (1971) listed 950 compounds in tobacco and tobacco smoke. In their review, they listed only two sulfur compounds as identified in tobacco, cystine and methionine. Obi and Nakano conducted studies on sulfur in tobacco and tobacco smoke, in 1962 (2822). They determined that the sulfur content in Japanese tobacco was 0.3% to 3%, of which 30% to 60% is organic sulfur. In a review of compounds identified in tobacco and tobacco smoke, Philip Morris, Inc. in 1963 (2939) listed seventeen S-containing compounds. Stedman (3797) in 1968 listed 950 identified compounds in tobacco and tobacco smoke, of these only ten compounds were S-containing and all were from tobacco smoke. Izawa (1900) in 1961 reported on 440 identified tobacco and tobacco smoke components, of these only two S-containing compounds in tobacco were mentioned (cystine and methionine). Roberts et al. in 1975 (3224) listed 2783

compounds identified in tobacco and tobacco smoke. In their report, they listed forty-one S-containing compounds identified in tobacco smoke. There were no S-containing compounds reported in tobacco. In 1980, Ishiguro and Sugawara (1884) listed 1889 identified tobacco smoke components in their monograph, forty-six S-containing compounds were listed. IARC in 1986 (1871) listed only three S-containing agrochemicals in tobacco. Elmenhorst and Schultz in 1986 (1140) listed thirteen S-containing compounds in their publication. Roberts in 1988 (3215) tabulated that there were 5868 identified compounds in tobacco and tobacco smoke. By functional groups, 3044 compounds had been identified in tobacco, 3996 had been identified in smoke, and 1172 were identified in both tobacco and tobacco smoke. Under the function group heading Sulfur Compounds, three compounds had been identified in tobacco, thirty-seven were identified in tobacco smoke, and two compounds were found in both tobacco and tobacco smoke. In 1994, Ayya (18A03) summarized the previous work on S-containing compounds in tobacco smoke. He listed thirty-two sulfur compounds that had previously been identified in tobacco smoke. In his report he cited work at Brown and Williams Tobacco Company on the odor characterization of low molecular weight S-containing compounds employing a gas chromatograph with a sniffing port. As mentioned previously several reviews on tobacco and tobacco smoke have not included or have omitted the S-containing compounds in tobacco and tobacco smoke These include the reports by Bentley and Berry in 1959 and 1960 (282, 283), Berry (296) in 1963, and the reports by Sakuma et al. (3394, 3397, 3398) in 1983 and 1984. Bentley and Berry reported in 1959 that “Sulphur compounds have been found in smoke [Izawa et al. (1905)] but these have not been identified.” Whether there was a lack of analytical instrumentation and/or methodology for the determination of S-containing compounds in tobacco and smoke or a lack of concern for these types of compounds cannot be said. But it is interesting that even by 1994 (18A03) only about forty S-containing compounds were identified as components of tobacco and tobacco smoke. From 1966 through 1974 several notable studies were conducted on S-containing compounds in tobacco smoke. In 1966, Philippe (2940) reported on the identification of thiocyanogen, thiocyanic acid, hydrogen sulfide, carbonyl sulfide, methylthionitrite, dimethy1 sulfide, carbon disulfide, and thiophene in MSS. In that same year, ethyl mercaptan was qualitatively detected by Grob (1419). Williams and McRae (4246) in 1967 examined the fate of S-containing compounds in tobacco during cigarette smoking. The nonfiltered cigarettes in their experiments contained approximately 0.5% sulfur. They determined that 61.4% of the total sulfur content of the cigarette was found in the cigarette ash and 33.2% was found in the cigarette butt. They reported that the sulfur content of the whole MSS was 39 µg per cigarette, which was equivalent to 0.5% of the total sulfur in the cigarette. In total, they could account for over 95% of

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Miscellaneous Components

the total sulfur content measured in the cigarettes used in their experiments. Groenen and Van Gemert (1429) in 1971 and Horton and Guerin (1831) in 1974 reported on the identification of S-containing compounds in the vapor phase of MSS. Both investigator groups employed flame photometric detection (FPD) gas chromatography (GC) for the determination of sulfur compounds in smoke (1831). Groenen and Van Gemert identified thirty-seven compounds while Horton and Guerin identified twenty-eight S-containing compounds. Typical cigarette yields reported by Horton and Guerin were approximately 85 µg of H2S, 35 µg of COS, 2 µg of CS2, and 3 µg of SO2 per cigarette when smoked under standard conditions. Horton and Guerin reported that the vapor phase of MSS contained at least twenty-eight sulfur components but that the quantitative distribution of these components was highly sensitive to sampling methodologies. Quantitation is an obvious issue as Williams and McRae (4246) only could account for 39 µg of sulfur per cigarette in whole MSS. Generally, sulfur compounds in tobacco samples can be converted by wet oxidation to sulfate. The sulfate is then reduced to H2S which is separated by distillation and determined as methylene blue, by the method of Johnson and Nishita (18A06). Protein sulfur can also be determined by the oxidation of sulfur to sulfur dioxide and titration with 0.1 N I2 with starch as an indicator (18A02). These classic methods serve as determinations of total sulfur in a sample. Similar wet methods for the analysis of sulfur compounds in tobacco now employ autoanalyzers and robotics [Mottershead (18A10)]. Total sulfur in the sample can also be analyzed by X-ray emission spectroscopy [Keen et al. (18A07)], atomic absorption spectrometry [Sah and Miller (18A13)], atomic emission spectroscopy (AES) and inductively coupled plasma (ICP-AES) [Littlefield et al. (18A08)] or a variety of other instrumental methods. For example, ESR (electron spin resonance) which is equivalent of EPR (electron paramagnetic resonance) has also been used for the analysis of the presence of sulfur in tobacco (18A09). Specific S-containing amino acids in tobacco, for example, methionine, cysteine, and cystine, are generally analyzed by GC, GC-MS or liquid chromatographic techniques such as HPLC and LC-MS. Sulfur in proteins, nucleotides, and peptides are normally analyzed by digestion of samples into free amino acids and then determination of the amino acids by GC or LC. Flame photometric detection (FPD) gas chromatography (GC) (1429, 1831) and flame ionization detection (FID) GC (1419) have been used for the determination of S compounds in tobacco smoke. Although these methods are still used today, GC-mass spectrometry is normally the preferred method for the determination and quantification of S-containing components in MSS. Table XVIII.A-1 lists the S-containing components in tobacco, tobacco smoke, and tobacco substitute smoke. A total of 260 S-containing components have been identified in tobacco and tobacco smoke. Of these compounds, 119 were identified in tobacco smoke, 178 were identified in tobacco, and thirtyseven were identified in both tobacco and smoke. It is interesting to note that seventy-nine of the 260 S-containing components

in tobacco and/or its smoke are compounds used in tobacco agronomy.

XVIII.B Halogenated Components All of the halogens (chlorine [Cl], bromine [Br], fluorine [F], and iodine [I]) are minor constituents of tobacco and are essential for growth of the plant. In 1990, Tso (3973) reviewed the chemistry, biology, and physiological aspects of each halogen in tobacco. Soil contains low levels of all of the halogens in the form of salts (halides). Low levels of these halogenated salts generally promote growth in the plants and improve quality and yield. At high levels of absorption all halides can cause toxicity (3979). The various halides are absorbed by the plant roots and are important in certain oxidative, enzymatic, and plant regulatory processes (3973). The content of Cl, Br, F, and I in tobacco varies by tobacco type, soil, and climatic conditions. Typical ranges of Cl, Br, F, and I reported in tobacco are 0.07% to 3%, 100 to 200 ppm, 4 to 40 ppm, and 0.55 to 1.75 ppm, respectively (3979). Other sources of halogens in tobacco come from trace amounts of halides in fertilizers and from agrochemical treatments of tobacco. Over the last seventy years, several review articles on the constituents of tobacco and tobacco smoke have been published. In 1936 Bruckner (451) discussed the biochemistry of tobacco. In his book, he briefly mentioned that tobacco contained chloride. Kosak (2170) in 1954 categorized about fifty components in tobacco smoke whose identities were certain. Under his heading of Inorganic Components KOSAK listed “Chlorides” (?). The question mark indicated that Kosak did not consider the evidence in the literature to be definitive proof of the identity of the component. Latimer (2270) in 1955 listed 231 compounds identified from tobacco and tobacco smoke. At that time, methyl chloride was the only halogenated compound identified in tobacco smoke. Johnstone and Plimmer in 1959 (1971) listed 950 compounds in tobacco and tobacco smoke. In their review, they listed only one halogenated compound as identified in tobacco, l,l,dichloro-2-2(4,4’-dichlorodipheny1)ethane (TDE or DDD) and two in tobacco smoke, methyl chloride (specifically) and certain other unnamed volatile chlorides. Bentley and Berry in 1959 and 1960 (282, 283), and Berry (296) in 1963 failed to report any halogenated compounds in tobacco or tobacco smoke. Izawa (1900) in 1961 reported 440 identified compounds in tobacco and tobacco smoke. In his report he listed only methyl chloride as being identified in tobacco smoke. In a review of compounds identified in tobacco and tobacco smoke, Philip Morris, Inc. in 1963 (2939) listed seven halogenated compounds: Cl, bromomethane, chloromethane, chloroethane, bromoethane, Endrin®, and TDE. Stedman (3797) in 1968 listed 950 identified compounds in tobacco and tobacco smoke, of these only seventeen compounds were halogen-containing. Cl, F, and I were identified in tobacco, along with tobacco residues of methylene bromide, l,l,l-trichloro-2-(4,4’-dichlorodipheny1)ethane (DDT), Dieldrin®, Dyrene®, Endrin®, TDE, Telodrin®, Thiodan®, Toxaphene®, Trichlorfon®, and Diclone®. o-Chloroaniline,

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The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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859

Table XVIII.A-1 (Continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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861

Table XVIII.A-1 (Continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (Continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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863

Table XVIII.A-1 (Continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (Continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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865

Table XVIII.A-1 (Continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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866

The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (Continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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867

Table XVIII.A-1 (Continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (Continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Miscellaneous Components

869

Table XVIII.A-1 (Continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (Continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Miscellaneous Components

871

Table XVIII.A-1 (Continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (Continued) Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Miscellaneous Components

ethyl chloride, and agrochemical residues from TDE, Endrin®, chloro-2,2-bis-(4’-chlorophenyl)ethylene (TDEE), Telodrin®, Thoidan®, and Dyrene® were reported in tobacco smoke. Roberts et al. in 1975 (3224) listed 2783 components identified in tobacco and tobacco smoke. In their report, they listed thirty chloro compounds, two bromo-containing compounds, two fluoro-containing compounds, and one iodocontaining compound. Thirty-one halogenated compounds were identified in tobacco smoke and twelve were identified in tobacco, several were found in both tobacco and tobacco smoke. In 1980, while noting that the number of confirmed components exceeded 2500, Ishiguro and Sugawara (1884) listed 1889 identified tobacco smoke components in their monograph; seventeen were halogenated. In their review, Ishiguro and Sugawara stated: All of the halogenated compounds found in smoke are chlorinated compounds. These probably originate from the chloride ions [3797] in the tobacco or from residual chlorinated organic additives. The chlorine atom in methyl chloride originates [712] mainly from inorganic chlorides.

They listed Cl, Br, I, and F as identified components in tobacco smoke. In their review, Ishiguro and Sugawara also examined several agrochemicals and their decomposition products transferred to smoke. The distribution of the chlorinated organic chemicals was examined in detail. It was clear to them that chlorinated organic agricultural chemicals produced the chlorinated compounds mentioned in their review during smoking. They stated: At present, the use of chlorinated organic insecticides has been banned in many countries, and their residues in tobacco have been decreasing every year. Organophosphorus types and synthetic organic compounds which are less likely to persist have become the mainstay of agricultural chemicals for tobacco cultivation, displacing the chlorinated organic types.

Unfortunately, their prediction was not totally correct as a great variety of chlorinated organic agrochemicals are still being discovered and used today in parts of the world. However, since 1969 the use of chlorinated pesticides has been banned in the cultivation of tobacco in the United States. As a result, l,l,l-trichloro-2-(4,4’-dichlorodipheny1)ethane (DDT) and TDE in tobacco and in cigarette smoke have decreased drastically. In the tobacco of a cigarette made in 1965, 13.4 ppm DDT and 20.2 ppm TDE were measured, and in the tobacco of the leading cigarette brand made in 1993, only 0.02 ppm DDT and 0.013 ppm TDE were detected, a decrease of more than 98% (999). The small amounts of residual DDT and TDE in more recently produced cigarettes appear to originate from imported tobaccos used for blended cigarettes (1714). It is interesting to note the following: despite the fact that DDT was banned from agronomic use on tobacco in the United States in 1969, Chopra and his colleagues between 1969 and 1973 conducted exceptionally detailed studies on the degradation products generated during the smoking process from the p,p’-DDT in p,p’-DDT-treated cigarettes (703,

873

707–709, 711–714). Examination of the citations in the catalog (Table XVIII.B-3) of chloro compounds identified in the smoke from DDT-containing tobacco indicates that Chopra and his colleagues identified ten chloro compounds, including transferred DDT. New types of chlorinated organic agrochemicals are still being developed. Their popularity and efficiency have not been displaced by organophosphorus types of agrochemicals or other synthetic organic compounds. Sakuma et al. (3394, 3397, 3398) in 1983 and 1984 reported on the identification of numerous compounds in tobacco smoke; no halogenated compounds were reported. IARC, in 1986 (1871), listed only four halogen-containing compounds in tobacco and tobacco smoke in their report on the evaluation of the carcinogenic risk of chemicals to humans: vinyl chloride and the agricultural chemicals, DDT, Captan®, and Endrin®. Of these compounds, only vinyl chloride and DDT showed sufficient evidence of carcinogenicity in experimental animals according to the IARC criteria. Most recently in 2005, Eberhardt (21A19) prepared an extensive review of pesticides used on tobacco, the transfer rates of pesticides to MSS and sidestream smoke (SSS), and decomposition products of pesticide residues identified in MSS. In his review, much data previously presented by Ishiguro and Sugawara (1884) were presented and updated. The vast majority of the halogenated compounds presented in this chapter are covered in other chapters of this book, for example, Chapters 4, 9, 10, 19, 20, and 21. One particular group of halogenated compounds only reviewed in this chapter is the dioxins. Dioxins are polychlorinated heterocycles. The three forms found in tobacco and tobacco smoke are polychlorodibenzo-p-dioxins, polychlorodibenzofurans, and polychlorinated biphenyls. Another group of compounds that is not reviewed elsewhere in the book is the Freon® compounds. Green et al. (1375b) recently reviewed the various chemicals used in the expansion of tobacco and their effect on cigarette MSS properties. In their review, Green et al. (1375b) discussed the use of various Freon® compounds for tobacco expansion. Rix, in 1989, analyzed expanded tobacco for the expansion agent Freon® 123 (4859). Additionally, sulfur hexafluoride and perfluoropropane have been investigated as alternate tobacco expanding agents (4860, 18B17). As a result, these classes of compounds will not be discussed further in this chapter and the reader is directed to the review by Green et al. (1375b) and references from R.J. Reynolds Tobacco Company (4859, 4860, 18B05, 18B06 18B08, 18B16, 18B17). In 2002, Rodgman and Green (3300) reviewed the literature on tobacco smoke toxicants. In their review, they discussed the polychlorodibenzo-p-dioxins and polychlorodibenzofurans (PCDDs and PCDFs) identified in tobacco and tobacco smoke. Rodgman and Green noted that among the smoke toxicants conspicuous in their absence from all toxicant lists except that of Fowles and Bates (1217) are the polychlorodibenzo-p-dioxins (PCDDs) and polychlorodibenzofurans (PCDFs). The presence of dioxins in cigarette smoke was first reported in 1980 by Crummett (854). There are at least five other publications in which the presence of dioxins

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(PCDDs and PCDFs) in cigarette tobacco or its MSS (3300) is reported. These include publications by Muto and Takizawa (2664), Ball et al. (177), Matsueda et al. (2490, 2491), and Löfroth and Zebühr (2391). The smoke yield data of Muto and Takizawa (2664) were obtained from a single smoking puff that entirely consumed the cigarette and is clearly not appropriate for comparisons of MSS yields obtained by FTC or CORESTA methods. The MSS and SSS data of Löfroth and Zebühr (2391) were obtained from only one Swedish cigarette brand. The PCDD and PCDF data reported by Matsueda et al. (2491) were for the amount of these compounds contained in the cigarette tobacco, rather than the smoke. The smoke yield data for the Ball et al. (177) and Matsueda et al. (2490) experiments were similar. The Ball et al. data were collected and analyzed by a well-validated method, and the laboratory where the analyses were performed, that is, ERGO Forschungsgesellschaft mbH, Hamburg, has been accredited by the World Health Organization (WHO) for dioxin analysis (177). The analytical data of Ball et al. (177) represent results from the ten top-selling brands in Germany during the fourth quarter of 1989. The ERGO scientists chose to present individual data on each of the tested cigarettes. It should be noted that the most toxic isomer, 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD), was not detected in any of the samples and additionally, not every isomer present was quantifiable in each product tested. The total amount of total PCDDs and PCDFs was 7.50 and 2.98 pg/cigarette, respectively (see Table  2 of 3300). In 1998, Radovanovic  ´ and Mišic  ´ (18B15) examined the MSS of Yugoslavian cigarettes for polychlorinated biphenyls (PCBs). They identified ten PCBs. The level of PCBs identified ranged from less than 1 ng/g to 78.1 ng/g of smoke condensate (18B15). Generally, the levels of PCBs in MSS are considerably less than the PCDDs and PCDFs (3715). Dioxins are not typical herbicides used on tobacco. So where do they come from and why are they so important? 2,4-Dichlorophenoxyacetic acid (2,4-D) was introduced in 1944 as the first of the phenoxy herbicides, phenoxyacetic acid derivatives, or hormone weed killers. The phenoxy herbicides have complex mechanisms of action resembling those of auxins (growth hormones). They affect cellular division, activate phosphate metabolism, and modify nucleic acid metabolism. These herbicides are highly selective for broadleaf weeds and are translocated throughout the plant. 2,4-D provided most of the impetus in the commercial search for other organic herbicides in the 1940s. Several compounds belonged to this group, of which 2,4-D and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) are the most familiar. Other important compounds in this group are 4-(2,4-dichlorophenoxy)butyric acid (2,4-DB), 2-methyl-4-chlorophenoxyacetic acid (MCPA), and 2-(2,4,5-trichlorophenoxy)propionic acid (Silvex® or Fenoprop®) [Ware and Whitacre (18B18)]. 2,4-D, MCPA, and 2,4,5-T have been used worldwide for years in very large volume. The latter product, 2,4,5-T, used mainly to control woody perennials, became the subject of extended investigation, particularly because of its use in Vietnam in combination with 2,4-D as Agent Orange.

The Chemical Components of Tobacco and Tobacco Smoke

Certain samples were found to contain small amounts of a highly toxic impurity, TCDD (2,3,7,8-tetrachlorodibenzo-pdioxin), commonly referred to as tetrachlorodioxin, or dioxin. Although alterations in manufacturing procedures reduced the dioxin content to minimal levels, 2,4,5-T registrations were cancelled and the product voluntarily removed by the manufacturers in 1985 (18B18). 2,4-D has been and continues to be one of the most useful herbicides ever developed. More than 33 million pounds manufactured in the United States are used each year in thirty-five ester and salt forms. In agriculture, it is used on cereal, grain crops, and sugar cane for the control of broadleaf weeds, and on rights-of-way, turf and lawns, and in forest conservation programs. The manufacturing process for 2,4-D used in the United States does not result in any level of tetrachlorodioxin contamination. Other members of the phenoxys in wide use are 2-(2,4-dichlorophenoxy)propionic acid (Dichlorprop® or 2,4-DP), 4-(4-chloro-2-methylphenoxy) butanoic acid (MCPB), and 2-(4-chloro-2-methylphenoxy) propanoic acid (Mecoprop® or MCPP) (18B18). None of these compounds [2,4-DB, 2,4-DP, MCPB, MCPA, MCPP, 2-(2,4,5-trichlorophenoxy)propionic acid] has been found in tobacco or tobacco smoke. Of the three forms of dioxins found in tobacco and tobacco smoke, the polychlorodibenzo-p-dioxins (PCDDs, PCDFs, and PCBs) are a group of chemical compounds that are among the most toxic and hazardous pollutants in the environment. The PCDDs, PCDFs, and PCBs compounds, collectively referred to as dioxins, are impurities associated with certain end products resulting from the treatment of chlorinated benzenes at elevated temperature and pressure under alkaline conditions. The most notable contaminant of the group is TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) which can be formed along with other dioxin compounds during the manufacture of several commercially important products such as the herbicide 2,4,5-T, the fungicide pentachlorophenol, and the germicide Hexachlorophene® (18B19). Numerous investigators have found PCDDs, PCDFs, and PCBs in tobacco as well as tobacco smoke [1457, Gichner et al. (18B14), Djordjevic et al. (1000, 1006), Radovanovic ´ and Mišic ´ (18B15)]. Suspicions of the possible long-term health hazards of dioxins arose after it was found that 2,4,5-T was teratogenic in the rat and mouse [Courtney et al. (18B10)]. Shortly thereafter it was discovered that the 2,4,5-T sample used in this study contained about 30 ppm TCDD (18B10). It was primarily the report by Courtney et al. (18B10) implicating TCDD as a contaminant of 2,4,5-T that led to its further evaluation for teratogenicity [Courtney and Moore (18B11)] and its eventual testing for mutagenicity. These and other similar reports published during the late 1960s and early 1970s also stimulated toxicological studies on other dioxin derivatives as well as studies dealing with issues such as environmental contamination and movement and analytical detection of these compounds. Numerous detailed reviews summarizing work in these areas have been published. The latest and perhaps the most comprehensive review was prepared by the World Health Organization in 2002 (18B07). Additionally, IARC has prepared a monograph

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Miscellaneous Components

on dioxins (7A03) and Wassom et al. (18B19) reviewed the genetic toxicology of polychlorodibenzo-p-dioxins. Dioxins are produced inadvertently as a by-product of chemical production or during combustion and are widespread pollutants in the environment. They are ubiquitous. The biggest source of PCDDs, PCDFs, and PCBs is the large-scale burning of municipal and medical waste. Other sources include: • The production of iron and steel; • Backyard burning of household waste, especially plastics; • Fuel burning, including diesel fuel and fuel for agricultural purposes and home heating; • Wood burning, especially if the wood has been chemically treated; • Electrical power generation; and • Tobacco smoke. Dioxins can also be produced from natural processes, such as forest fires, explosions, and volcanic eruptions. Most dioxins are introduced to the environment through the air. The airborne chemical can attach to small particles that can travel long distances in the atmosphere. PCDDs, PCDFs, and PCBs are found in very small amounts in the environment, including in the air, water, and soil. As a result they are also present in some foods. They can also present a health risk at elevated dosages. As for tobacco smoke, the dosage of dioxins from cigarettes is extremely low. Exposure estimates suggest that the smoking of twenty cigarettes per day contributes approximately 2% to 4% of the total daily exposure to dioxins for a 70 kg adult (177). The major source of exposure to PCDDs, PCDFs, and PCBS is the diet [Canady et al. (18B07)]. Rodgman and Green (3300) noted in their review of MSS toxicants that certain dioxins are antitumorigens. Slaga and DiGiovanni (3685) summarized the studies in which dioxins were shown to interfere with the enzyme pathways responsible for tumorigenesis of several of the most potent polycyclic aromatic hydrocarbons (PAHs). The dioxins were not listed as MSS toxicants in previous tabulations of MSS toxicants reviewed by Rodgman (3255, 3255a, 3257, 3265) and Rodgman and Green (3300). In fact, only one MSS toxicant list issued since 1990, that of Fowles and Bates (1217), has included the dioxins even though their presence in MSS was known in 1980 (854). Dioxins are antitumorigenic to DMB[a]A (7,12-dimethylbenz[a] anthracene), MC (3-methylcholanthrene, more recently named 1,2-dihydro-3-methylbenz[j]aceanthrylene), B[a]P (benzo[a]pyrene), 7-MB[a]A (7-methylbenz[a]anthracene), 12-MB[a]A (12methylbenz[a]anthracene), 5-MeC (5-methylchrysene), and DB [a,h]A (dibenz[a,h]anthracene) [Berry et al. (18B04), Cohen et al. (18B09), DiGiovanni et al. (976, 18B12)].

875

The IARC classification of carcinogenicity places twenty-five halogen-containing compounds in tobacco or tobacco smoke in Groups 1, 2A, 2B, and 3. Table XVIII.B-1 lists the individual halogen-containing chemicals (agents) and families of chemicals (groups of agents) identified in tobacco and tobacco smoke. IARC lists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and vinyl chloride as Group 1 human carcinogens. Trichloroethylene, epichlorohydrin [(chloromethyl)oxirane], ethylene dibromide, and polychlorinated biphenyls (PCBs) are listed by IARC as Group 2A (probably carcinogenic to humans). Ten halogen-containing compounds are listed in Group 2B (possibly carcinogenic to humans): Chlordane®, p-chloroaniline, chloroform, chlorophenoxy herbicides, chlorothalonil (2,4,5,6-tetrachloro-1,3-benzenedicarbonitrile), DDT (p,p’-DDT), dichloromethane (methylene chloride), 1,3-dichloropropene, Heptachlor®, and hexachlorobenzene. Nine halogen-containing compounds are listed in Group 3 (not classifiable as to carcinogenicity to humans): chloroethane, m-dichlorobenzene, o-dichlorobenzene, 1,2-dichloropropane, Hexachlorophene®, Methoxychlor®, methyl iodide, polychlorinated dibenzofurans, and 1,1,1-trichloroethane. There are numerous analytical methodologies to identify and quantify halogenated compounds in tobacco and smoke. The method of analysis will vary among the halogenated compounds and particularly the pesticide types. Sources of methods include the FDA Pesticide Analytical Manuals (PAMs) I and II (18B13), the FDA Index of Residue Analytical Methods (RAM) (18B13), the methods in the Journal of the Association of Official Analytical Chemists (18B02, 18B03), and methods found in journal articles. Generally, the preferred methods of analysis involve gas chromatography (GC), liquid chromatography (LC), or GC-mass spectrometry (MS) techniques. Flame ionization detectors (FID) are normally used for quantitative analysis of halogen-containing organics, while electron capture detectors (ECD) are preferred for quantitative determination of PCDDs, PCDFs, PCBs and other pesticides [Radovanoviic  ´ and Mišiic  ´ (18B15)]. There are 242 identified halogenated compounds in tobacco and/or tobacco smoke. As seen in Table XVIII.B-2, the vast majority (192 compounds) contain chlorine only. Over 85% of all the halogenated compounds found in tobacco and tobacco smoke are either halogenated agrochemicals, impurities found in the agrochemicals (PCDDs, PCDFs, PCBs), or decomposition products from the agrochemicals. Table XVIII.B-3 lists the 242 halogenated compounds identified in tobacco and/or tobacco smoke. In a few cases, a halogenated component has been identified in tobacco substitute smoke. Table XVIII.B-3 is divided by halogen type (chloro-, bromo-, iodo-, and fluoro-compounds) and includes several halogenated compounds with two or more halogens (mixed halogenated compounds).

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876

The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-1 Halogenated Components Identified in Tobacco and Tobacco Smoke (18A04) IARC Group Classification Group 1:

Group 2A:

Group 2B:

Group 3:

IARC Chemical Name (Number of Compounds)

CAS No.

IARC Volume, Date

2,3,7,8-Tetrachlorodibenzo-para-dioxin

1746-01-6

Vol. 69, 1997

Vinyl chloride

75-01-4

Vol. 19, Suppl. 7, Vol. 97, in preparation

Trichloroethylene Epichlorohydrin

79-01-6 106-89-8

Vol. 63, 1995 Vol. 11, Suppl. 7, Vol. 71, 1999

Ethylene dibromide

106-93-4

Vol. 15, Suppl. 7, Vol. 71, 1999

Polychlorinated biphenyls (11)

1336-36-3

Vol. 18, Suppl. 7, 1987

Chlordane p-Chloroaniline Chloroform Chlorophenoxy herbicides (5) Chlorothalonil DDT [p,p’-DDT] Dichloromethane [methylene chloride] 1,3-Dichloropropene Heptachlor Hexachlorobenzene

57-74-9 106-47-8 67-66-3

Vol. 79, 2001 Vol. 57, 1993 Vol. 73, 1999 Vol. 41, Suppl. 7, 1987 Vol. 73, 1999 Vol. 53, 1991 Vol. 71, 1999 Vol. 41, Suppl.7, Vol. 71, 1999 Vol. 79, 2001 Vol. 79, 2001

Chloroethane m-Dichlorobenzene o-Dichlorobenzene 1,2-Dichloropropane Hexachlorophene Methoxychlor Methyl iodide Polychlorinated dibenzofurans (18) 1,1,1-Trichloroethane

1897-45-6 50-29-3 75-09-2] 542-75-6 76-44-8 118-74-1 75-00-3 541-73-1 95-50-1 78-87-5 70-30-4 72-43-5 74-88-4

Comment by IARC Overall evaluation upgraded from 2A to 1 with supporting evidence from other relevant data.

Overall evaluation upgraded from 2B to 2A with supporting evidence from other relevant data. Overall evaluation upgraded from 2B to 2A with supporting evidence from other relevant data.

Vol. 52, Vol. 71, 1999 Vol. 73, 1999 Vol. 73, 1999 Vol. 41, Suppl. 7, Vol. 71, 1999 Vol. 20, Suppl. 7, 1987 Vol. 20, Suppl. 7, 1987 Vol. 41, Suppl. 7, Vol. 71, 1999 Vol. 69, 1997 Vol. 20, Suppl. 7, Vol. 71, 1999

71-55-6

Agents, groups of agents, mixtures and exposure circumstances (associated with tobacco) evaluated in IARC Monographs Volumes 1-95. This list contains all agents evaluated as of November-December 2006 that are considered: Carcinogenic to humans (Group 1), probably carcinogenic to humans (Group 2A), and possibly carcinogenic to humans (Group 2B). For details of the evaluation, the relevant Monograph should be consulted, see http://monographs.iarc.fr/ENG/Classification/crthgr01.php. Those agents listed have been identified in tobacco or tobacco smoke.

Table XVIII.B-2 The Distribution of Halogenated Components Identified in Tobacco and Tobacco Smoke Total No. Compounds

Tobacco

Smoke

Tobacco and Smoke

Agrochemical/ Decomposition Product

Other

Chloro Bromo Iodo Fluoro Mixed halogens

192 12 4 14 20

123 11 3 13 19

111 6 2 3 9

42 5 1 2 8

171 7 2 9 11

21 5 2 5 9

Total

242

169

131

58

200

42

Halogen

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Miscellaneous Components

877

Table XVIII.B-3 Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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878

The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Miscellaneous Components

879

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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880

The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Miscellaneous Components

881

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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882

The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Miscellaneous Components

883

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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884

The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Miscellaneous Components

885

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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886

The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Miscellaneous Components

887

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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888

The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Miscellaneous Components

889

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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890

The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Miscellaneous Components

891

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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892

The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued) Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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19

Fixed and Variable Gases

This chapter deals with gases found in tobacco and tobacco smoke. The gases discussed will be mainly inorganic and not organic gases. Two types of gases will be discussed, fixed gases and variable gases. In the atmosphere, gases, the volume percentages of which do not change, are called fixed gases. Table XIX-1 gives the volume percentages of these fixed gases. At altitudes below 100 km, nitrogen (N2) makes up about 78% of all atmospheric gas by volume and oxygen (O2) makes up about 21%. The volume percentages of these fixed gases are constant with increasing altitudes, and the partial pressures of N2 and O2 are constant fractions of air pressure. Together, N2 and O2 make up 99% of all gases in the atmosphere by volume. Argon (Ar) at 0.93% makes up the bulk of the remaining 0.97%, with neon (Ne), helium (He), krypton (Kr), and xenon (Xe) present in trace quantities (19A04). As a result, the concentrations of fixed gases are the same not only in the atmosphere but in every material present on the Earth’s surface where atmospheric gases reside. Variable gases are gases with volume percentages that change with time and location. For example, water vapor in different areas of the world varies with climatic conditions and geography. Radon is a variable gas as it occurs in only specific areas of the world. The major variable gases are water vapor (H2O), carbon dioxide (CO2), carbon monoxide (CO), ozone (O3), sulfur dioxide (SO2), nitric oxide (NO), nitrogen dioxide (NO2), low molecular weight hydrocarbons, and simple aromatic chemicals. Much of the variability in the concentration of these gases in the atmosphere arises from the combustion of fossil fuels. Table XIX-2 summarizes the volume percentages of some variable gases in a clean atmosphere and a polluted atmosphere, such as urban or industrial areas. Water vapor can vary tremendously and is dependent primarily on the environment. For example, water vapor in the atmosphere is always higher in areas near water and always lower in desert areas. As can be seen, some of the inorganic and organic gases change appreciably (CO, SO2, NO, NO2, organic gases) while others change minimally (CO2, O3), even in polluted atmospheres (19A04). For example, the concentration of CO2 at point sources such as smoke stacks can be very elevated. Ozone concentrations during electrical storms can be elevated to the point that its characteristic odor is noticeable. As a result they are termed variable gases. Again, just as the fixed gases are present in nearly every material present on the Earth’s surface, variable gases are also present in all materials that are porous and can be found on the surfaces of many other materials. Tobacco contains all of the fixed gases that are present in the atmosphere. It also contains a variety of variable gases

because it is grown in areas lacking a pristine atmosphere. Tobacco is often treated with agrochemicals (fertilizers, pesticides, herbicides, etc.). As such, these chemicals can decompose and create residues in or on the tobacco. Additionally, as tobacco is often cured in atmospheres that contain pollutants and/or combustion gases, for example, NO, NO2, SO2, SO3, the concentration of variable gases in the leaf can be elevated. Nitrogen and oxygen are the most plentiful fixed gases found in tobacco. Although the other fixed gases Ar, Ne, He, Kr, and Xe have not been identified in tobacco there is no reason to believe that they are not present. The variable gases found in tobacco include ammonia (NH3), bromine (Br2), CO2, CO, chlorine (Cl2), fluorine (F2), iodine (I2), phosgene (COCl2), hydrazine (H2N-NH2), hydrogen cyanide (HCN), isocyanic acid (H-N=C=O), nitrous oxide (N2O), NO, NO2, mixed nitrogen oxides [N2O + NO + NO2] or NOx, phosphine (PH3), radon (Rn and 222Rn), and H2O. Biochemically, some of these variable gases are produced by the plant to regulate growth processes, for example, NO, NO2, while others are formed, for example, NH3 via fertilization, or absorbed by the plant (H2O) and used as energy sources. Some of the variable gases are found as plant residues from the atmosphere (Rn), while some are residues from water sources (halogens), agrochemicals (phosgene, hydrazine, HCN, isocyanic acid, phosphine, etc.) or from other environmental sources, for example, SO2. The concentration of the fixed and variable gases in tobacco smoke is not directly related to the concentration of these gases in tobacco. As tobacco smoke is the result of combustion and pyrolysis of tobacco, the concentration and types of fixed and variable gases formed vary considerably. Over the years, several scientific articles and reviews have been published that catalog the fixed and variable gases found in tobacco and tobacco smoke (172, 1140, 1067, 1140, 1971, 2068, 2170, 2799a, 3224, 3797, 4012, 4332, 19A05). One of the earliest articles that identified certain fixed and variable gases in tobacco smoke was published by Kosak (2170) in 1954. Kosak listed O2, NH3, CO, CO2, HCN, other “cyanides” (?), hydrogen sulfide (H2S), thiocyanic acid (?), “chlorides” (?), “nitrates” (?), and “unsaturated hydrocarbons.” The question marks associated with some of the compounds listed by Kosak indicate that he did not consider the evidence in the literature to be definitive proof of the identity of the component. It is conceivable that the designation “chlorides” (?) and “nitrates” (?) could have indicated the presence of chlorine, NO, NO2 and other nitrogen oxides (NOx) in tobacco smoke. Johnstone and Plimmer (1971) reviewed the constituents of tobacco and tobacco smoke in 1959 and listed CO, CO2, carbonyl sulfide (COS), NH3, carbon disulfide (CS2), cyanogen [(CN)2], hydrogen cyanide (HCN), thiocyanogen [(SCN)2], NO, and numerous small saturated and unsaturated 893

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894

The Chemical Components of Tobacco and Tobacco Smoke

Table XIX-1 Volume Percentages of Fixed Gases in the Earth’s Atmosphere Gas Name

Chemical Formula

Molecular nitrogen Molecular oxygen Argon Helium Neon Krypton Xenon

N2 O2 Ar He Ne Kr Xe

Percent 78.08 20.95 0.93 0.0015 0.0005 0.0001 0.000005

hydrocarbons as components of the vapor phase of cigarette mainstream smoke (MSS). Keith and Tesh reported in 1965 on the measurement of the total MSS issuing from a burning cigarette (2068). By using a simple puffing mechanism that employed a cold trap packed with 5 Å molecular sieve pellets, they were able to quantitatively measure the total vapor mixture from a burning cigarette. This quantity, when combined with the separately trapped particulate material, provided a measure of the total effluent. It was found, contrary to previous thinking, that the vapor components of smoke comprised over 95% of the weight of material collected from a burning cigarette. By far the greatest proportion of the collected weight of the total MSS vapor phase was contributed by the air entering the cigarette. Wynder and Hoffmann in 1967 (4332) reviewed the known constituents of the particulate and vapor phase of MSS. Chapter VIII of their book provided historical information on our understanding of cigarette combustion processes and the composition of the vapor phase of tobacco smoke at that time. Wynder and Hoffmann cited the pioneering work of

Jarrell and de la Burde (1924) and Keith and Tesh (2068), who reported in 1965 that the O2 content in whole MSS is a function of air entering through the burning cone of the cigarette, part of which is consumed during combustion, and diluting air entering through the cigarette paper. The cigarette burning rate, dictated by the cigarette rod packing density, the tobacco type employed, and the cigarette paper air permeability, affected O2 consumption. Nitrogen and argon do not react with tobacco constituents during the burning as they are inert gases. Their concentrations were affected by the air entering through the burning cone, mainly the diluting air. Jarrell and de la Burde (1924) found that the burning zone of a cigarette represented a reducing atmosphere. The H2 in the whole smoke was derived nearly exclusively from the burning of tobacco. During burning, certain tobacco components split off elementary hydrogen, which for the most part formed water with available oxygen. The presence of 8% H2 (by volume) in the gas leaving the burning cone was indicative of the existence of a reducing atmosphere in the fire cone. The large concentrations of both CO and CO2 relative to air indicated that several combustion and pyrolysis processes were occurring in the burning cigarette. The low ratio of CO2 to CO indicated that incomplete combustion of tobacco was occurring. The ratio of CO2 to CO is considered to be an index (3482) of the combustibility of tobacco. Generally, the ratio of CO2 to CO is less than three in nonfiltered cigarettes. In 1968, Stedman reviewed the chemical composition of tobacco and tobacco smoke (3797). The review noted that gaseous NH3, I2, and H2O were identified constituents of tobacco. It also listed CO, CO2, NH3, CS2, COS, Cl2, F2, H2S, HSCN, and (SCN)2 as compounds present in the vapor phase of MSS. In 1968, Elmenhorst and Schultz (1140) reported on the concentrations of various inorganic gaseous components in the vapor phase of MSS (Table XIX-3).

Table XIX-2 Volume Percentages of Some Variable Gases (Inorganic and Organic) in the Atmosphere (19A04) Gas Name Inorganic Water vapor Carbon dioxide Carbon monoxide Ozone Sulfur dioxide Nitric oxide Nitrogen dioxide Organic Methane Ethane Ethene Formaldehyde Aromatics

Chemical Formula

Clean Atmosphere (ppbv)

Polluted Atmosphere (ppbv)

H2O CO2 CO O3 SO2 NO NO2

3000-4.0 × 107 365000 40-200 10-100 0.02-1 0.005-0.1 0.01-0.3

5.0 × 106-4.0 × 107a 365000 2000-10000 10-350 1-30 0.05-300 0.2-200

CH4 C2H6 C2H4 HCHO C6H5R

1800 0-2.5 0-1 0.1-1 —

1800-2500 1-50 1-30 1-200 1-30

ª 4.0 × 107- indicates that the volume percentage is negligible, on average. R = hydrogen or alkyl functionality

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895

Fixed and Variable Gases

Table XIX-3 Fixed Gases in the Vapor Phase of MSS (1140) Compound H2 O2 N2 Ar H2O

Concentration/Cigarette 0.7-1.8 vol % 11-17 vol % 67-78 vol % 0.8 vol % 6-9 mg

In 1975, Roberts et al. (3224) reported on R.J. Reynolds Tobacco Company’s (RJRT) literature study of tobacco and smoke components. RJRT had been collecting information from the literature and conducting extensive research on the identification of chemicals in tobacco and smoke since the earlier 1950s. As of 1975, RJRT had compiled a listing of 2783 components from tobacco, tobacco smoke, and other smoking products. Of these compounds 1235 were tobacco isolates, 2266 were tobacco smoke components, and 356 had been identified from other smoking products. Approximately one-half of all the tobacco and smoke components were first isolated by RJRT research personnel. The lists were divided into functional group classes, including fixed and variable gases found in tobacco and smoke. Twenty-five gases had already been identified in tobacco and smoke by 1975. The number of fixed and variable gases identified in tobacco and tobacco smoke has not changed substantially since then. Ishiguru and Sugawara in 1980 (1884) cataloged the components of tobacco smoke. In their review, they listed 1889 components of tobacco smoke [see Table 1 in (1884)]. They commented that the number could be about 2500 but they had omitted those components that were only partially identified. Among the components that they discussed were the fixed and variable gases in tobacco smoke. In 1982, Dube and Green (1067) calculated the contribution of the fixed gases from 500 mg of unfiltered cigarette MSS. From 500 mg of whole smoke, 22.5 mg was the wet

particulate matter and 67.5 mg was vapor-phase compounds, of which ~10% (or 6.75 mg) was water vapor, ~80% (or 54 mg) was CO2, and ~10% was organic compounds. The remaining 410 mg of whole smoke contained 310 mg of N2, 65 mg of O2, 20 mg of CO, an additional 5 mg of CO2, 4 mg of Ar, and 1 mg of H2. Similar analyses were conducted by Keith and Tesh in 1965 (2068), Norman in 1977 (2799a), and Hoffmann and Hecht in 1990 [see Table 1 in (1727)]. Table XIX-4 illustrates the data on fixed and variable gases in whole tobacco smoke that was provided by these investigators. In 1999, Norman (19A05) and Baker (172) reviewed the literature on cigarette design and materials and smoke chemistry, respectively. Their works represent the most recent and comprehensive reviews on these subjects. Baker discussed the present fundamental knowledge of cigarette combustion and smoke formation including how the concentrations of fixed gases, for example, O2 and H2, fluctuate during cigarette combustion and how variable gases, for example, CO and CO2, are formed. Norman discussed the complicated field of cigarette design and how each design variable (tobacco type, cigarette shape, weight, and size, cigarette paper properties, filter designs, etc.) affects cigarette performance and ultimately cigarette smoke yields (including fixed and variable gases).

XIX.A Analytical Methods In 1996, Green and Rodgman (1373) summarized all the historical and currently used analytical methods for the identification of chemicals isolated from tobacco and tobacco smoke. Their review is so complete and so well documented that the reader is directed to read their review article to determine the analytical method best suited for the analysis of a particular chemical constituent in tobacco and smoke. All of the past and current methods for the determination of fixed and variable gases in tobacco and tobacco smoke can be found in their article and will not be included in this chapter. Only a few specific examples of analytical methods for the most important variable gases will be provided (1884).

Table XIX-4 Major Fixed and Variable Gases in Non-Filtered Whole Tobacco Smoke Keith and Tesh (2068)

Dube and Green (1067)

Norman (2799a)

Hoffmann and Hecht (1727)

Component

mg/cig (%)

mg/cig (%)

% only

mg/cig (%)

Nitrogen Oxygen Carbon dioxide Carbon monoxide Water Argon Hydrogen

295 (67.2) 66.8 (13.3) 68.1 (9.8) 16.2 (3.7) 5.8 5.0 (0.8) 0.7 (2.2)

310 (62a) 65 (13) 59 (11.8) 20 (4.0) 6.75 (1.4) 4 (0.08) 1 (0.2)

58 12 13.0 3.5 1 0.5 (Ar + H2) —

280-320 (56-64b) 50-70 (11-14) 45-65 (9-13) 14-23 (2.8-4.6) 7-12 (1.4-2.4) 5 (1.0) 0.5-1.0

Total weight (or %)

457.6 (97)

465.75 (93.2)

88

401.5-496 (81.7-99)

Percent of total tobacco smoke generated based on 500 mg of whole smoke (1067). b Number in parentheses represents % of individual compound identified in fixed gases from whole smoke (1727). a

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896

Although there is no standard International Organization for Standardization (ISO) or U.S. Federal Trade Commission (FTC) method for the analysis of fixed gases in cigarette smoke, fixed gases are normally analyzed by mass spectrometry (MS), gas chromatography (GC), or GC-MS. Generally, the fixed gases, such as N2, O2, Ar, He, and H2, have been determined chromatographically with separation based on molecular size. A molecular sieve packing is normally used in a stainless steel packed column. Samples are introduced with either a gas-tight syringe or a sampling valve with a fixed volume loop. Upon injection, the sample is swept through a gas chromatograph with carrier gas. After separation in the column, components are quantified based on the difference in thermal conductivity between the carrier gas and the component. For the analysis of H2 and He, argon is used as the carrier. Helium is used for all the other gases, such as N2 and O2. Detection limits using a thermal conductivity detector are typically 0.01% by volume (19A08). Gas samples can be analyzed by MS via a gas inlet port on the mass spectrometer. Methods for the determination of fixed gases in cigarette smoke have been reported by Routh (19A06) and Reynolds and Wheeler (3120). There are several methods for the analysis of the major variable gases from tobacco smoke, for example, CO, CO2, NO, NO2, HCN, and NH3. The current standard methods approved by the ISO, FTC, and Cooperation Centre for Scientific Research Relative to Tobacco (CORESTA) for the determination of the variable gases are described by Counts et al. along with analytical results from a recent worldwide market sample of cigarette brands (19A02, 19A03).

XIX.A.1 Carbon Dioxide (CO2) and Carbon Monoxide (CO) CO2 is a major vapor-phase MSS component exceeded only by N2. Its concentration is about 10% of the weight of the whole tobacco smoke (4145), similar to that of O2. The concentration of CO is next highest, being about 4% (4145). The ratio of CO2 to CO is considered to be an index (3482) of the combustibility of tobacco. The currently approved methods for the determination of CO are ISO Standard Methods 3308, 3402, 4387, 8454, 10315, and 10362-1. In these methods, CO is determined by non-dispersion infrared (NDIR) spectroscopy (19A02). Historically, GC (474, 2123, 2662, 4145) and NDIR spectroscopic analysis (781, 782, 4251, 4252) have generally been the preferred methods for analysis of CO2 and CO in MSS, but an electrochemical transducer (ECT) method (447) has also been used for the analysis of CO, in which the electrochemical reaction during oxidation by catalysis is converted to electrical signals. Sample treatments before GC or NDIR

The Chemical Components of Tobacco and Tobacco Smoke

analyses, such as oxidation (474, 4145) of CO to CO2 with iodine pentoxide, reduction (2123, 2124) of CO to CH4 with a Ni catalyst, and separation (2634) by lowering the column temperature to -70°C have also been studied. Gas chromatography (2662) with 5 Å molecular sieves as the packing materials has also been employed. The levels of both CO2 and CO in smoke increase (4251) as the number of puffs increases. The amounts of these combustion gases produced in the early puffs of a cigarette are lower than those analyzed at the end of a cigarette during smoking (4251, 4252). The relationship to the length of the cigarette is such that the concentrations of these components in the vapor phase decrease (3881, 3883) with increasing length, and this can be explained by the reduction in the amount of tobacco burnt and diffusion of CO from the wrapper during smoking (19A05). Tobacco quality is an important factor in terms of the amount of CO and CO2 produced during cigarette combustion. The amount of CO produced (474, 3088) is greater for low- to mediumgrade tobaccos, and the amount of CO2 increases (474) as tobacco quality becomes higher. Experiments with 18O as the source of atmospheric oxygen indicated that more than 50% of the oxygen atoms in the CO2 and CO molecules come from the atmosphere (1884).

XIX.A.2 Nitrogen Oxides (NO, NO2, N2O, NOx) NOx in tobacco smoke has been quantified by calorimetric analyses (189, 3441, 3720), such as the Saltzman method (19A07), and by the chemical emission method (2122), which has been shown to be a rapid method for quantification (1884). Most of the NOx present in fresh MSS is NO, only a small amount of NO2 is present (189, 816, 2803). The concentration of NO2 in MSS increases (189, 2803, 3691) with the age of the smoke, and can reach levels of 200 ppm after 60 seconds (189). NO2 formation is believed to result from the auto-oxidation of NO. It has also been suggested that some of the NO2 produced by oxidation is converted (2941, 4058) to methyl nitrite through a reaction with methanol in the smoke (1884). Predominate precursors of NO are nitrates (189) and other N-containing compounds in the tobacco. N2O (2941) and HNO3 (4058) have also been reported as components of MSS in addition to the above compounds (1884). The currently preferred method for the determination of NOx is chemiluminescence (1930, 19A02).

XIX.A.3 Hydrogen Cyanide (HCN) HCN in smoke has been analyzed by colorimetry (110, 779, 780, 3088), by the ion selective electrode method (3482), and by gas chromatography (513). An analysis of HCN in tobacco smoke by Vickroy and Gaunt (4053) illustrated that HCN can vary from 144 to 351 µg/cigarette depending on the brand of

© 2009 by Taylor & Francis Group, LLC 78836_C019.indd 896

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Fixed and Variable Gases

cigarettes. The concentration of HCN in MSS increases (110) with puff number similar to other MSS components. HCN is present in both the vapor phase and the particulate phase of MSS (110). Considerable amounts of HCN have also been found in cigarette butts (110, 779, 780). Today, the preferred method for the determination of HCN in the vapor and particulate phase of MSS is colorimetry. HCN is converted to cyanogen chloride, treated with pyridine, and complexed with diethyl acetone dicarboxylate (779, 780, 3145). Schmeltz and Hoffmann (3491) found that tobacco smoke contains cyanogen and that up to about 5% of the HCN analyzed was produced by conversion of HCN to cyanogen during analysis (1884).

XIX.A.4 Ammonia (NH3) The preferred method for the determination of NH3 in MSS is currently ion exchange chromatography (IEC) (2681a, 19A02). In this method, NH3 is collected from Cambridge pads and sulfuric acid traps and then analyzed by IEC (19A02). Previous methods for the analysis of NH3 in MSS, such as titration and colorimetry, suffered from interferences (2724, 2787, 19A01.), principally low-boiling amines. Quantification of NH3 by means of selective electrodes (3693) has been attempted, but the results were affected (475) by methylamine. Gas chromatography (129, 475, 2541) has also been employed with good results, since the effects of the presence of other substances

897

can be substantially reduced. Early methods for the determination of NH3 involved trapping MSS in an aqueous acidic solution. The trapped MSS solution was then steam distilled under alkaline condition to obtain the sample for analysis. It was discovered that this early method produced extra NH3 (30% to 80%) during the steam distillation procedure (475, 1884). NH3 collected from MSS should be analyzed directly to achieve accurate quantification (1884). Cigarette blends with higher levels of nitrogen, such as blends high in burley tobacco, tend to have higher yields of MSS NH3. The yield of NH3 in MSS is known to vary with the permeability of the cigarette wrappers, when cigarettes were tested with comparable blends (475). The amount of NH3 produced was greater for wrappers with higher air permeability. The rate of formation of NH3 depended strongly on temperature. The yield of NH3 increased with decreasing temperature (1884). Therefore, it was thought that variations in the burning temperature resulting from differences in wrapper quality or its air permeability determined the amount of NH3 produced (1884). Table XIX-5 is a catalog of the fixed and variable gases in tobacco, tobacco smoke, and tobacco substitute smoke. The catalog contains only thirty-five entries. This number of entries represents a very small fraction of the total number of identified components in tobacco and tobacco smoke but amazingly the weight contributed by fixed and variable gases represents about 90% of the whole smoke from a cigarette.

© 2009 by Taylor & Francis Group, LLC 78836_C019.indd 897

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898

The Chemical Components of Tobacco and Tobacco Smoke

Table XIX-5  
 


  
 

 
 


 



Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke (,
"
+1&(%

#'#,+
,"
(&)('',
#',# #
#'
,((
+-+,#,-,
+&($
/+
'(,
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa. ,,
#'
,((
+&($
(*
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.*+




(





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(%%,#.
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*!('





*


 



 
  
 
 
 
 
 
 





 


 


 




 








  
 
 


  


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© 2009 by Taylor & Francis Group, LLC 78836_C019.indd 898

11/13/08 5:43:24 PM

899

Fixed and Variable Gases

Table XIX-5 (continued) Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


%





'$(



#
&'

%"") +
$,



  


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(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C019.indd 899

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900

The Chemical Components of Tobacco and Tobacco Smoke

Table XIX-5 (continued) Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


$





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"
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© 2009 by Taylor & Francis Group, LLC 78836_C019.indd 900

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901

Fixed and Variable Gases

Table XIX-5 (continued) Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


)





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'
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(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C019.indd 901

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902

The Chemical Components of Tobacco and Tobacco Smoke

Table XIX-5 (continued) Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


&





(%)



$
'(

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© 2009 by Taylor & Francis Group, LLC 78836_C019.indd 902

11/13/08 5:43:30 PM

903

Fixed and Variable Gases

Table XIX-5 (continued) Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


'





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%
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(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C019.indd 903

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904

The Chemical Components of Tobacco and Tobacco Smoke

Table XIX-5 (continued) Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


)





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© 2009 by Taylor & Francis Group, LLC 78836_C019.indd 904

11/13/08 5:43:31 PM

905

Fixed and Variable Gases

Table XIX-5 (continued) Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


&




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&##*!,
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© 2009 by Taylor & Francis Group, LLC 78836_C019.indd 905

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20

Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts

XX.A Elements, Isotopes, and Ions in Plants Plants require numerous nutrients and compounds to sustain life. There are at least twenty elements that are used by plants that are considered essential for growth and reproduction (20A06, 20A10). For higher plants (such as tobacco) a significantly higher number of other elements are needed. Justus von Liebig (1803–1873) in the mid-nineteenth century stated that nutrients are essential for plant life: We have determined that a number of elements are absolutely essential to plant life. They are essential because a plant deprived of any one of these elements would cease to exist (20A58).

Von Liebig (20A58) taught of the absolute need to provide plants with essential minerals necessary for successful agricultural production. If the soil is not replenished with these essential elements and associated ions, plant yields decrease and numerous plant diseases occur. Healthy plants require and thus contain a great variety of elements, isotopes, and ions. In general, significant efforts are normally exerted to maintain a plant’s requirement for nitrogen (N), phosphorus (P), and potassium (K) through fertilization, while taking for granted its basic need for carbon (C), hydrogen (H), and oxygen (O). Knowing the nutrients required to grow plants is only one aspect of successful crop production. Optimum plant yield also requires knowing the rate to apply, the method and time of application, the source of nutrients to use, and how the elements are influenced by soil and climatic conditions. The primary nutrients — N, P, and K — are commonly found in blended fertilizers, for example, 10-10-10, or equivalent grades. Primary nutrients are utilized in the largest amounts by crops and, therefore, are applied at higher rates than secondary nutrients and micronutrients. The secondary nutrients; calcium (Ca), magnesium (Mg), and sulfur (S) are required in smaller amounts than the primary nutrients. The major source for supplementing the soil with Ca and Mg is dolomitic lime, although these nutrients are also available from a variety of fertilizer sources. Sulfur is available in fertilizers in the form of potassium and magnesium sulfate, gypsum (calcium sulfate), and elemental sulfur. Micronutrients; iron (Fe), manganese (Mn), zinc (Zn), copper (Cu), boron (B), and molybdenum (Mo) are required in even smaller amounts than secondary nutrients. They are available in manganese, zinc and copper sulfates, oxides, oxy-sulfates and chelates, as well as in boric acid and ammonium molybdate. Table XX-1 gives the elemental composition of a typical plant. It is interesting to note that about 96% of the makeup of a plant is C, H, and O. These elements come from carbon

dioxide and water. The carbon dioxide in the atmosphere contributes the C and O found in plants. It is taken up by plants through small pores located in the leaves. Water, on the other hand, is taken up by the roots of plants and is responsible for contributing only H to the makeup of a plant. However, the H used to produce water also comes from the atmosphere. Table XX-1 also shows the classification of the elements in plants. The elements are classified as structural elements, primary and secondary nutrients, and micronutrients. Therefore, the atmosphere and sun provide about 96% of the necessary ingredients for plant growth; and minerals provide about 4% of the necessary ingredients for plant growth (20A10). The elemental composition in Table XX-1 of a typical plant is nearly identical with the elemental composition of tobacco, with the exception that tobacco generally has a slightly higher N level. Elemental analyses for C, H, and N in tobacco indicate that there is about 5% N in dry tobacco (2798, 20A06, 20A10). The percent C, H, and O (by difference) of dry tobacco leaf are about 43%, 6%, and 43%, respectively (2798, 20A06, 20A10), with the remainder being trace levels of metals and nonmetals (3973).

XX.A.1 Elements, Isotopes, and Ions in Tobacco As of 2007, the periodic table contains 117 elements whose discoveries have been confirmed. Ninety are found naturally on Earth, and the rest are synthetic elements that have been produced artificially in particle accelerators. Of these ninety naturally occurring elements, nearly eighty have been identified in tobacco. Additionally, forty-four isotopes and twenty-four ions have been identified in tobacco. Tobacco is undoubtedly one of the plant materials most thoroughly evaluated for metal content. It should be noted that the omission of information about other microelements does not necessarily imply the absence of these elements in tobacco, but rather a lack of information (3973). The discovery of elements, isotopes, and ions in tobacco (and for that matter tobacco smoke) has only been limited by the discovery and advancement of new analytical techniques. Over the years, numerous scientific articles, reviews, and books have been published that catalog the elements, ions, and isotopes found in tobacco. One of the earliest articles on the identification of metals in tobacco was published by Grandeau in 1862 (20A25) on the identification of rubidium (Rb) and cesium (Cs) in tobacco. Although it was well known in the 1860s that numerous metals and nonmetals existed in tobacco and higher plants (20A58), analytical techniques to isolate the small levels of metals were not established. A 1934 bibliography by Heffer and Sons (20A26) reviewed literature 907

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908

The Chemical Components of Tobacco and Tobacco Smoke

Table XX-1 Elemental Composition of a Typical Plant (1127b, 20A10) Element

Symbol

Percent of Wet Weight

Percent of Dry Weight

Oxygen Carbon Hydrogen

O C H

81.0 6.8 11.5

45.0 44.5 6.0

Nitrogen Phosphorus Potassium

N P K

0.2 0.03 0.15

1.5 0.2 1.0

Primary nutrients

Calcium Magnesium Sulfur

Ca Mg S

0.05 0.03 0.02

0.35 0.20 0.15

Secondary nutrients

Chlorine Iron Molybdenum Zinc Boron Copper Others

Cl Fe Mo Zn B Cu

0.015 0.015 0.008 0.003 0.003 0.001 0.175

0.10 0.10 0.05 0.02 0.02 0.01 0.80

citations for 1921 to 1933 on antimony (Sb), bismuth (Bi), cadmium (Cd), chromium (Cr), cobalt (Co), Cu, lead (Pb), Mn, mercury (Hg), nickel (Ni), thallium (Tl), tin (Sn), and Zn. Johnstone and Plimmer (1971) published their review of chemical constituents of tobacco and tobacco smoke in 1959. In 1966, Tso (20A105) published an excellent historical review of elements identified in tobacco to that date. Stedman (3797), in his 1968 review, listed aluminum (Al), arsenic (As), Cu, Cr, Co, iron (Fe), Pb, Mn, Mo, Ni, titanium (Ti), vanadium (V), and Zn as identified elements in tobacco and smoke. In 1974, Elliot (1127b) reviewed the nutritional requirements of tobacco, including metals and metal ions, and Franzke et al. (1227) published their investigation of the heavy metals in tobacco. In 1977, Norman (2799a) reviewed the subject of metals in tobacco at the Tobacco Chemists’ Research Conference (TCRC). The most recent review, in 1996, by Jones and Wilkinson (20A54), concerning historical agronomic achievements in tobacco science, provided current information on elements identified in tobacco. The most prolific writer on elements, isotopes, and ions in tobacco is Tso. From his 1966 review of the subject to his 1972 book on the physiology and biochemistry of tobacco plants (3972) and his 1990 book (3973) on the production, physiology, and biochemistry of the tobacco plant, Tso has continuously provided tobacco scientists with valuable information. His 1990 book (3973) devoted three chapters to metals, isotopes, and ions in tobacco. In Chapters 17 and 19 (3973), Tso discussed the presence, physiology, and biochemistry of the following elements in tobacco plants: Al, As, barium (Ba), beryllium (Be), bismuth (Bi), B, bromine (Br), Cd, cerium (Ce), cesium (Cs), chlorine (Cl), Cr, Co, Cu, dysprosium (Dy), erbium (Er), fluorine (F), gadolinium (Gd), germanium (Ge), gold (Au), hafnium (Hf), holmium (Ho), indium (In), iodine (I), iridium (Ir), Fe, lanthanum (La), Pb, lithium (Li), magnesium (Mg),

Descriptor Essential structural elements available from air and water

Micronutrients

Mn, Hg, Mo, neodymium (Nd), Ni, N, osmium (Os), palladium (Pd), P, platinum (Pt), polonium (Po), K, praseodymium (Pr), radium (Ra), rhenium (Re), rhodium (Rh), rubidium (Rb), ruthenium (Ru), samarium (Sm), scandium (Sc), selenium (Se), silicon (Si), silver (Ag), sodium (Na), strontium (Sr), sulfur (S), tantalum (Ta), tellurium (Te), terbium (Tb), TI, thorium (Th), thulium (Tm), Sn, Ti, tungsten (W), uranium (U), V, ytterbium (Yb), Zn, and zirconium (Zr). As Tso stated (3973), “No attempt is made to include all publications about each element; in fact, some papers were eliminated intentionally to avoid duplication.” Tso (3973) estimated that tens of thousands of article have been written on the production, physiology, and biochemistry of the tobacco plant. In Chapter 18 (3973), Tso discussed radiochemical elements in tobacco and smoke and in Chapter 19 he discussed the physiological disorders in tobacco plants associated with deficiencies in minerals and micronutrients. Tobacco plants, like other higher plants, are autotrophs possessing the capacity to synthesize all of its complex organic materials provided that carbon dioxide, water, minerals, and the proper physical environment are available. Their chemical composition is influenced by environmental factors such as light, temperature, moisture, soil type, and cultural practices, as well as inorganic nutrition. The inorganic requirements of tobacco were considered in the 1962 book by Sutcliffe (20A101) and in reviews by Steinberg and Tso (20A98) and others, for example, McMurtrey (20A66). The essential elements of tobacco may be grouped into categories depending on their source and the relative amounts required. C, H, and O are considered structural elements and are grouped separately because they are derived from air or water. Obviously, C, H, and O are found in the vast number of the organic components identified in tobacco. Evans and Russell (20A20) described the

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Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts

requirements for these elements that were established when early investigators determined the basic chemical composition of tobacco matter and elucidated the essential nature of the respiratory and photosynthetic processes that occur in plants. Another group of elements referred to as primary nutrients include P, K, N, S, Ca, and Mg. These elements also make up a relatively large portion of the inorganic components of tobacco tissues and were established to be essential by plant physiologists such as Knop, Nobbe, and Sachs (20A101) prior to 1910. In this period, reagent chemicals were exceedingly crude and contained many of the essential trace elements that were being investigated. As a consequence, the proof of many trace elements in tobacco could not be established until chemists learned how to purify the analytical reagents for testing. Another group of elements, including B, Cl, Co, Cu, Fe, Mn, Mo, and Zn, occur in exceedingly small concentrations in plant materials and are referred to as micronutrient elements. Fe was shown to be essential by Sachs (20A101) prior to 1910, but the other trace elements were demonstrated to be essential only after 1920 (20A20). During the period 1923 to 1931, Sommer and Lipman (20A96) established that a variety of plants including tobacco required Zn and Cu. During the same period, Warrington (20A111) in England demonstrated that boron was a required in micronutrient in broad beans. Since then, it has become clear that these elements are needed for a variety of species, including tobacco. In 1939, Arnon and Stout (20A05) demonstrated that tomato plants required Mo and since then it has become apparent that all species need this element for metabolism (20A20). The biochemical role of minerals in metabolic processes of various organisms has been covered in several reviews by Malstrom and Neilands (20A60), McElroy and Nason (20A65), Nason and McElroy (20A81), and Nicholas (20A84). The function of C, H, and O are obvious since they are constituents of fats, carbohydrates, and proteins. N and S are constituents of amino acids, proteins, coenzymes, and other compounds. Ca forms a complex with pectic acid and functions as a constituent of the middle lamella of cell walls. Dixon and Webb (20A13) showed that Ca also plays a role as a cofactor for certain adenosine triphosphate hydrolyzing enzymes, for phospholipases, and as a cofactor for the amylases from a variety of plants. Many elements, especially the cations, play essential roles as cofactors for the enzymes of various metabolic sequences. Tso (3973) provided numerous examples in which mineral deficiency such as Fe or Mo resulted in metabolic lesions that have been satisfactorily interpreted on the basis of detailed knowledge of the biochemical role of metals in enzymes of important metabolic pathways. This biochemical approach to plant nutrition problems has proved exceedingly valuable to plant scientists and agricultural producers in terms of identifying diseases and finding solutions to improve crop yields. Today, an enormous amount of work is being undertaken to understand the total genome of tobacco (429b, 429c). Detailed analyses of the metabolic pathways, enzymes involved, and

909

feed-back control and gene repressor mechanisms, including the metal and nonmetal elements and ions, as essential catalysts in tobacco, are being thoroughly documented (429b, 429c). Mineral ions participate in a wide variety of metabolic processes, electron transport mechanisms, and in nitrate reduction. By manipulation of the level of inorganic elements and ions in the nutrient medium, it is possible to influence the constituents in plants. For over 100 years, tobacco scientists have employed a fundamental research approach in attempts to understand the complex physiology and biochemistry of tobacco involved in the biosynthesis of compounds in tobacco (3973). Their efforts have greatly improved the economics of tobacco production and have led to advancements in understanding of health issues associated with tobacco and its various commercial uses (20A20). Inorganic ions play a very important role in tobacco metabolism (20A20). There are various sites where inorganic ions, for example, Ca2+, Mn2+, Mg2+, PO43-, Zn2+, and K1+, participate in glycolytic reactions. Phosphate participates in a majority of the reactions as a component of sugar-phosphate compounds. Phosphate also functions as an important component of coenzymes such as uridine diphosphate-glucose, di- and triphosphopyridine nucleotides, adenosine di- and triphosphate, etc. Practically every reaction in which phosphate is transferred requires Mg as a cofactor, but most of these enzymes are not highly specific for a divalent cation activator and will respond to other cations such as Mn (2489). Another interesting aspect of the glycolytic enzymes is that Zn is required for alcohol dehydrogenase, lactic acid dehydrogenase, aldolase, and triosephosphate dehydrogenase. The role of Zn as an important inorganic ion, as a bound component of dehydrogenases and other enzymes, has been discussed in detail by Vallee (20A110). K ion is a cofactor for the aldolase reaction. Pyruvic kinase from all known sources also requires univalent cations, in addition to a divalent cation. This enzyme needs K, ammonium, or Rb ions as a cofactor. Mg ions serve an important function in photosynthetic processes in tobacco as it is an essential constituent of chlorophyll a and chlorophyll b. Some heavy metal and nonmetal ions are toxic to tobacco and can serve as metabolic inhibitors. The toxicity of fluoride, for example, is explained in part on the basis of the formation of a magnesium-fluorphosphate complex that inhibits the enolase reaction in glycolysis. Other enzymes are inhibited by substrate analogs, sulfhydryl complexing agents, and metal chelating agents. Several cations function as essential cofactors for enzymes of the citric acid cycle. Magnesium is necessary for the pyruvic acid oxidase complex and ferrous iron is necessary for the activity of aconitase from certain sources (20A20). The isocitric dehydrogenase system which catalyzes a dehydrogenation of isocitric acid and also the decarboxylation of oxalosuccinate to yield α-ketoglutarate requires Mn for the decarboxylation step (20A03). Mg is a necessary cofactor for the α-ketoglutarate dehydrogenase complex and Fe is a cofactor for succinate dehydrogenase (20A19, 20A64, 20A65, 20A80, 20A84). There are numerous cofactors

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(Fe2+, -SH compounds, Mn2+, Mg2+, PO43-) and inhibitors (SCN1-, Br1-, I1-, Cl1-, Na1+, Cu2+, Hg2+, and CN1-) of citric acid cycle enzymes in tobacco. It is apparent that the various enzymes not only require cations but are inhibited by substrate analogs, substrate competitors, heavy metals, and sulfhydryl complexing agents (20A20). Mineral ions play important roles in the electron transport portion of the terminal respiratory process in tobacco. In this process, nonheme iron serves an important function in the electron transfer process. There is also convincing evidence that Cu ion is important in the process (20A20). Mineral ions also play an important role in the electron transport processes of the initial reactions of photosynthesis. In the photosynthetic processes of tobacco Fe, Cu, Mn, and chloride ions are essential to the electron transfer processes (20A20). Metal ions play an important role in nitrate reduction. The discovery and characterization of the pyridine nucleotide enzymes involved in nitrate reduction (20A18, 20A65, 20A81, 20A83) made it possible to understand the role of mineral ions in the nitrate reduction processes. Reduced pyridine nucleotides and flavin adenine dinucleotide function as cofactors in reduction of nitrate, nitrite, hyponitrate, and hydroxylamine. The first step of the reaction involves the reduction of nitrate to nitrite, and Mo is essential for this reaction. The reduction of nitrite to hyponitrite and hyponitrite to hydroxylamine requires Cu and Fe ions (20A20). Many types of tobacco contain radioactive elements such as 226Ra and 210Po at concentrations ranging from 0.1 to 0.47 pCi/g (1742, 2815, 3982, 3983). Phosphate fertilizers are the major source of these radioelements (3982, 3983); minor contributions come from airborne particles carrying 210Pb and 210Po. These particles are trapped by the trichomes on the undersides of the tobacco leaves (2467) and were first reported by Nystrom and Bellin (2815) in 1964. The 1999 CORESTA monograph on tobacco (910a) pointed out that trace elements and metal ions can have a profound effect on tobacco quality. Iron, for example, has been implicated in the speckling effects which develop in “grey tobacco” deficiency of Virginia tobacco (2338). Al is associated with development of the black color of cured tobacco, or so-called “black tobacco” (20A57). Tso (3973) devoted an entire chapter in his 1990 book to a discussion on the absolute need for trace elements in tobacco disease prevention (3973, 20A106). Although concentrations of most of these metals are not very high in tobacco (usually well below percent levels, typically in the low to middle ppm range) many of these elements are extremely important to the health of the plant. Trace levels of metals (Mn, Fe, etc.) in tobacco are important as quality factors as they can affect the combustibility and smolder rate of tobacco. Some of the metals in tobacco are desirable as quality factors while others are not (Cd, Pb, Cr) as they have been associated with human health concerns (20A100). The type and amount of certain inorganic ions are also important factors in determining the burn and smolder properties of tobacco. Peterson and Tibbitts (20A86) found that the concentrations of K1+, Cl1-, SO42+, S2-, Mg2+, and NO31- in tobacco (in descending order of importance) account

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for 80% of the variation in leaf combustibility and smolder (4332). Tobacco is probably the most frequently examined plant in the study of microelements. Many microelements are important for normal tobacco growth and development (3973). However, the specific roles of some of these elements are still not well understood. Frequently the presence of certain microelements is merely a result of the circumstances of site, season, or species, and therefore may not bear any physiological or agronomic significance. Tobacco plants are widely distributed in various locations of the world under different climatic, soil, and culture conditions. Any report of a certain microelement regarding its level, distribution, and fertilizer and soil requirements may or may not be applicable to that particular element under different circumstances. In 1986, Isakander et al. (20A47) determined twenty-eight elements were in American cigarette tobacco. Today, nearly 150 elements, ions, and isotopes have been identified in tobacco.

XX.A.2 Elements, Isotopes, and Ions in Tobacco Smoke In 1954, Kosak (2170) published a list of components reported to be present in tobacco smoke. His list included “Inorganic Components.” The inorganic compounds included ammonia, carbon monoxide, carbon dioxide, hydrogen cyanide, hydrogen sulfide, thiocyanic acid (?), oxygen, arsenic (probably present as As2O3.), “acetates” (?), “chlorides” (?), “cyanides” (?), and “nitrates” (?). The question marks in Kosak’s publication indicated that he did not consider the evidence in the literature to be definitive proof of the identity of the component. Since then, a tremendous amount of research has been conducted and published on metals and ions in tobacco smoke. During the late 1950s, Cogbill and Hobbs (769) conducted pioneering work on elements found in tobacco smoke. Two reviews in 1959 by Johnstone and Plimmer (1971) and Bentley and Berry (282) documented elements found in tobacco smoke. During the late 1960s and throughout the 1970s, a tremendous amount of research was published by the Martin Brinkman Co. (2468), Celanese Fiber Marketing Co. (641), Nadkarni (2666, 20A70), Nadkarni et al. (2667, 20A71–20A79), Morie and Morrisett (2633), Jenkins (20A49), Franzke et al. (1227), John (2052), Allen and Vickroy (50), and Perinelli and Carugno (2929) on elements, isotopes, and ions in tobacco smoke. Concurrently, scientists within the tobacco industry were conducting research on metals in tobacco smoke. Much of this work was reviewed by Jenkins of Philip Morris in 1990 on the uses of nuclear radiation in tobacco and smoke research (1933). At present, eighty metal and nonmetal elements, twentyfour isotopes, and twelve ions have been identified in tobacco smoke by numerous classical and instrumental analytical techniques. It is an amazing achievement that nearly 90% of the naturally occurring elements have now been identified in tobacco and tobacco smoke. Although numerous ions in tobacco were known, research on their identity in tobacco smoke was not established until the advent of commercial application of ion

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chromatography in the late 1980s. Since then many laboratories have gathered extensive experience in the application of ion chromatography (IC) for the analysis of inorganic and organic anions, in both tobacco and tobacco smoke (250, 1273, 2931, 3160, 20A16, 20A17, 20A59, 20A85, 20A114). The presence of radioactivity, both α- and β-particles, in leaf and tobacco smoke has been reported in many publications. At earlier periods, the main concern was for β-activity found in cigars, cigarettes, and tobacco ash (113, 2657, 3367, 20A97). The α-emitting radioactive isotopes were suggested to be significant because of health concerns to smokers. The total α-activity in tobacco varies widely in green leaf, cured leaf tobacco, and tobacco smoke (2466, 3367, 3973). A very minor amount of 210Po is transferred into the mainstream smoke (MSS). Twenty-four isotopes have been identified in tobacco smoke. The discovery of elements, isotopes, and ions in tobacco smoke has only been limited by the discovery and advancement of new analytical techniques.

XX.B Methods for the Detection and Identification of Metals, Ions, and Isotopes in Tobacco and Tobacco Smoke Numerous analytical techniques with a variety of different methodologies have been employed for the analysis of metals, nonmetals, isotopes, and ions in tobacco and tobacco smoke and various other types of organic matter. The subject of the choice of analytical methodology best suited for the detection of elements, isotopes, and ions in different matter has been reviewed by Fassel (20A21), Bock (20A08), Jones and Case (20A53), Jenkins (1933), Ivanova et al. (20A48), Thompson et al. (20A103), Sigg et al. (20A94), and Jimoh (20A51). The analytical methods included classical microanalytical determination (wet methods), colorimetric determinations, various atomic absorption spectrophotometric techniques, such as classical atomic absorption spectroscopy (AAS, with single or multiple element capability), cold vapor atomic absorption (CVAA), argon-supported inductively coupled plasmas (ICP), ICP with atomization-excitation processing, graphite furnace (GF), atomic absorption spectroscopy (AAS, with or without Zeeman background correction), GF-AAS with deuterium lamp; inductively coupled plasma-atomic emission spectrometry (ICP-AES), microwave digestion, X-ray emission, competitive ligand-exchange/stripping voltammetry (CLE-SV), diffusion gradients through thin films (DGT), instrumental neutron activation analysis (INAA), ion chromatography (IC), and high performance liquid chromatography (HPLC). Hyphenated techniques are also becoming popular, such as inductively coupled plasma-mass spectrometry (ICP-MS) and IC-ICP-MS (20A51). The selection of the appropriate method depends on several factors, such as the kind of equipment available, the ease of digestion, the kind of sample, elements of interest, fume removal, contamination considerations, matrix effects, and necessary safety precautions (20A08, 20A53, 20A103).

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The inorganic components of tobacco and tobacco smoke have been determined by microanalytical techniques, classical colorimetric determinations, and modern instrumental methods. For example, Cogbill and Hobbs (769) described several colorimetric methods for the determination of metals in tobacco smoke. X-ray emission spectroscopy has been used in the determination of metals and metal isotopes in tobacco and tobacco smoke. (20A62). Atomic absorption spectroscopy is widely used and is one of the most established methods for the determination of metals in tobacco and tobacco smoke. Although quite reliable, AAS can require separate analyses and recalibrations at varying ranges for each element, with a separate lamp for each analyte (dependent on the type of AAS equipment). Concurrent determination of multiple metals is possible, while speciation is often lacking in this method. The determination of metals in tobacco smoke is often more complicated. One reason for this difficulty is the conversion of smoke samples to homogeneous solutions so that they can pass through the aspirator of the instrument. Another is that for the determination of the ultratrace quantities of metals in cigarette smoke, a preconcentration step is often required. Solvent extraction is the method of preconcentration preferred over most other methods. The choice of solvents that can provide a high degree of selectivity over a broad pH range is limited. Alternately, metal complexes that are relatively insensitive to pH changes, for example, ammonium pyrrolidinecarbodithioate, have been used successfully for a wide variety of metals (2633) in tobacco and tobacco smoke. The work of Morie and Morrisett (2633) on the use of AAS in the determination of metals in tobacco smoke serves as an excellent example. Inductively coupled plasma-atomic emission spectroscopy (ICP-AES) and mass spectrometric (ICP-MS) techniques are modern, sophisticated, very sensitive, and generally quite expensive. These methods have been used successfully for the determination of metals in tobacco and tobacco smoke (20A90, 20A112). The success of these two methods can be affected by the metal-solvent matrix employed. In many cases preseparation procedures and other special handling techniques are required. Each method for analysis of metals in tobacco and tobacco smoke has its own advantages and challenges. Instrumental neutron activation analysis (INAA) is an extremely sensitive method for the determination of metals and metal isotopes. INAA has been used successfully by Nadkarni et al. (20A73), Jenkins et al. (1934) and Kubota (2214) to determine numerous inorganic constituents (elements and several elemental isotopes) in both tobacco and tobacco smoke (1933). The use of INAA for tobacco and tobacco smoke analysis has been accepted worldwide (1933). Tobacco is ideally suited for INAA because of its large abundance and variety of inorganic components. Tobacco is a readily available, easy-to-handle solid, it produces little gas during irradiation, and is rapidly assayed by INAA. The literature on the use of INAA in tobacco is very large because tobacco is often used as a model in non-tobacco-oriented

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reactor facilities systems for INAA (1933). However, the applicability of neutron activation analyses (INAA) is limited by the availability and cost of the necessary equipment. INAA requires a neutron flux source and gamma-ray counting facilities. The most conventional laboratories are thus unlikely to pursue this approach. Further, some elements are normally not determinable by INAA (Pb and Ni), either because of low sensitivity or strong interferences from other metals [Perini (20A85)]. Jenkins (1933) noted that despite the wide-spread use of INAA for tobacco and smoke analysis, meaningful intercomparison of the INAA results published in the literature is difficult as there is a lack of descriptive experimental information on the exact types of the tobaccos or tobacco smoke tested. Many laboratories studied only tobaccos and tobacco smoke native to their own country. Many laboratories have gathered extensive experience in the application of ion chromatography (IC) for the analysis of inorganic and organic anions. Small carboxylate anions, Groups IA and IIA cations, and heavy metal ions have been identified in tobacco and tobacco smoke by this method. Several of these applications have been presented as tobacco journal (250) and tobacco conference [TCRC (2951), TSRC(1273)] papers. At the 1999 TSRC, Perini (20A85) presented a method associated with IC called transition metal IC (TMIC). TMIC can be used for specific resolution and speciation of transition metal ions in tobacco and related matrices. Perini showed that TMIC could be used to detect and speciate at least nineteen transition metal ion.

XX.C The Transference of Elements, Isotopes, and Ions from Tobacco to Tobacco Smoke Nearly all trace metals in tobacco transfer at some small level into tobacco smoke. The transfer of metals from tobacco into MSS and sidestream smoke (SSS) has been of interest for a number of years (2133, 3836–3838, 2530). Transfer of metals from filters containing metal catalysts has also been of interest as they were thought to be a source of metals entrained into the MSS (2633). For example, experimental filters with permanganate salts (20A104) and hopcalite (20A69) have been reported to remove nitrogen oxides from smoke. The percent transfer rate of metals in tobacco to tobacco smoke varies greatly but generally falls within a 0.002% to 7.0% range (20A91), although percentages as high as 19% have been reported for Sb (2666). Numerous researchers have addressed the question of metal transference employing a variety of different cigarette types, collection devices, and analytical techniques. Depending on the metal or metals of interest, the method used, and the cigarette type, the reported results cover a wide range of values. In some cases the range covers several orders of magnitude. For one to draw any significant conclusions from this mass of data would be tenuous. Some of the inadequacies associated with diversity of transfer rate reported by Morgan and Akers (20A68) are:

The Chemical Components of Tobacco and Tobacco Smoke

• Tobacco types or blends of tobaccos were often not identified, and in most cases tobacco filler types were not processed in a standard fashion. • Cigarette configurations were often varied and in many cases the cigarette configuration and materials used to construct the cigarette were not mentioned. • Often only one or two metal species were studied for a particular tobacco. • Total particulate matter (TPM) collection procedures were not uniform among studies. • Analytical methods varied widely and were often not calibrated against standard materials of known metal content. • Large analytical errors were often tolerated to obtain a numerical value. Stöber (20A99), in his review of the generation, size distribution, and composition of tobacco smoke aerosols, made the observation that more than one mechanism for the transport of metals into MSS is operative. The predominant mechanism is entrainment of small particulate matter. For the more volatile elements, however, vaporization followed by condensation into the particulate phase appears dominant. The rate of metal transfer to the smoke is dependent on the volatility, the temperature profiles in the burning cigarette, and the filter type. In cigarette smoke, element concentrations vary among brands and even within the same brand. Numerous factors influence the metal concentration found in tobacco, including soil type and pH, the atmosphere, genotype, stalk position, application of metal-containing fertilizers or agricultural chemicals, for example, herbicides and pesticides (3973). These same factors affect the concentration of elements transferred to MSS and SSS. Table XX-2 lists the percent transfer of selected metallic and nonmetallic elements between tobacco and tobacco MSS.

XX.C.1 Elements in Tobacco Smoke of Special Interest Eighty elements, twenty-four isotopes, and twelve ions have been identified in tobacco smoke. Table XX-2 contains data on the percent transfer of selected elements into tobacco smoke. Based on literature data, small portions, at most a few percent of the metals and nonmetals, transfer from the tobacco into the smoke. The predominant route of exposure of humans to metals in cigarette smoke is inhalation. The smoker will likely inhale both the mainstream vapor and particulate phase of the smoke, plus some of the smoke that is generated while the cigarette is smoldering between puffs (20A50). Nonsmokers may also be exposed to metals in cigarette smoke, through passive inhalation of environmental tobacco smoke (ETS), but these concentrations are hundreds of times more dilute (3257). Among the metals that transfer into the smoke and are thus inhaled, the International Agency for Research on Cancer (IARC) (1870) considered As, Be, Cr, Ni, and Cd as

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Table XX-2 Percent Transfer of Selected Metallic and Nonmetallic Elements between Tobacco and Tobacco Smoke CAS No.

Name (per CA Collective Index)

Transference to Smoke (%)

Reference

7429-90-5 7440-36-0 7440-38-2 7440-41-7 7726-95-6 7440-43-9 7440-70-2 7440-45-1 7440-46-2 7782-50-5 7440-47-3 7440-48-4 7440-50-8 7440-57-5 7439-89-6 7439-91-0 7439-92-1 7439-95-4 7439-96-5 7440-02-0 7440-09-7 7440-17-7 7440-19-9 7440-20-2 7782-49-2 7440-22-4 7440-23-5 7440-66-6

Aluminum Antimony Arsenic Beryllium Bromine Cadmium Calcium Cerium Cesium Chlorine Chromium Cobalt Copper Gold Iron Lanthanum Lead Magnesium Manganese Nickel Potassium Rubidium Samarium Scandium Selenium Silver Sodium Zinc

0.009-0.0014 0.003-19 [0.016] a-7.0 0-[4.0] 0.02-2.41 7-22 ND b-0.001 ND 1.27 1.2-2.2 0.43-1.74 0.5-4.2 0.71-1.7 0.002 0.014-1.3 ND-11 0.16-6.3 0.0025 0.004-0.006 <0.1-2.4 0.2-0.51 0.18-0.78 ND 0.018-2.6 2.5-5.2 0.60-1.08 0.25-1.06 0.4-2.7

1934 769, 1934,2666, 20A21, 20A67, 20A68 769, 1934, 2666, 20A21, 20A68, 20A76 3711, 20A68 769, 1933, 1934, 2666, 20A21, 20A67, 20A68 2530, 20A68 769, 1934 1934 2666, 20A21 1933, 1934 769, 2666, 1934, 20A21, 20A67, 20A68 769, 1934, 2666, 20A21, 20A67, 20A68 769, 20A68 2666 769, 1934, 2666, 20A21, 20A67, 20A68 1934, 2666 769, 2530, 20A21, 20A67, 20A68 20A67 769, 1934, 20A67 1934, 2530, 2666, 20A68 769, 20A67 1934 1934 1934, 2666, 20A21 2666, 20A21, 20A68 2666, 20A21 769, 1934 769, 2530, 2666, 20A21, 20A67, 20A68

a b

[ ] = Limit of detection ND= Not Detected

human carcinogens (1742, 20A28, 20A29) in 1985. In 1989, the U.S. Department of Health and Human Services (4012) listed chromium and lead as possible carcinogenic agents in humans. Additionally, zinc in tobacco smoke has also been a metal of concern (20A49, 20A50). Today, the list of metals classified as Group 1 (human carcinogens) has grown to include As, Be, Cd, Cr6+, Ni, 32P, 239Pu, 240Pu, α- and β-particle emitting radionuclides (in general), 222Rn, 224Ra, 226Ra, 228Ra, and 232Th. Additionally, smokeless tobacco (classified as a Group 1 mixture) and ETS, and tobacco smoke and tobacco smoking (classified as Group 1 exposure circumstances) have been classified by IARC as agents considered carcinogenic to humans (Table XX-3). IARC listed the following agents identified in tobacco smoke as Group 2A (probably carcinogenic to humans) or Group 2B (possibly carcinogenic to humans): Pb, Co, Ni, nitrates, and nitrites. Nearly all of the metals and isotopes found in tobacco that transfer to tobacco smoke are a consequence of the use of metals found naturally in the soil (some radionuclides in the soil from nuclear reactions and reactors in the area), use of fertilizer containing metals, or agrochemicals applied to the

tobacco. The radioactive compounds found in highest concentration in cigarette smoke are 210Po and 40K. Other radioactive compounds present include 226Ra, 228Ra, 232Th, and 228Th (1870). As and As compounds and Cr and some chromium compounds are causally associated with cancer in humans, while Ni and Cd and their compounds are probably carcinogenic to humans. As levels in tobacco have been elevated in the past due to the use of arsenical pesticides. Cd levels may be related to the presence of Cd in phosphate fertilizers (1870). Today, the so-called Hoffmann analytes include the following metals, isotopes, and ions: As, Be, Cd, Pb, Cr, Cr6+, Co, Hg, Ni, 210Po, and Se (3300). Despite ample scientific evidence to the contrary many in the scientific community continue to contend that many of the Hoffmann analytes represent a “clear and present danger” to smokers. The following excerpts provide information and comments to the contrary (3300). XX.C.1.a Arsenic (As) Over time, substantial decreases have been reported for As residues on tobacco and dramatic reductions in tobacco smoke.

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Table XX-3 IARC Classification and References to Agents, Groups of Agents, Mixtures and Exposure Circumstances Evaluated by IARC that are Metals, Metallic Compounds, Radioisotopes, or Tobacco or Tobacco SmokeRelated Materials Name

CAS No.

IARC Reference

7440-38-2 7440-41-7 7440-43-9 1333-82-0 1303-00-0 7440-02-0 14596-37-3 15117-48-3 and 14119-33-6

20A42, 20A36 20A27, 20A28 20A27, 20A28 20A32 20A33 20A32 20A41 20A41

Numerous isotopes in tobacco smoke Numerous isotopes in tobacco smoke 13233-32-4 13982-63-3 15262-20-1 10043-92-2 or 14859-67-7 14808-60-7

20A41 20A41 20A41 20A41 20A41 20A37, 20A41 20A39

7440-29-1

20A41

Group 1: Agents and groups of agents: Arsenic Beryllium and beryllium compounds Cadmium and cadmium compounds Chromium (VI) Gallium arsenide Nickel and nickel compounds Phosphorus-32, as phosphate Plutonium-239 and its decay products (may contain plutonium-240 and other isotopes), as aerosols Radionuclides, α-particle-emitting, internally deposited Radionuclides, β-particle-emitting, internally deposited. Radium-224 and its decay products Radium-226 and its decay products Radium-228 and its decay products Radon-222 and its decay products Silica, crystalline (inhaled in the form of quartz or cristobalite from occupational sources) Thorium-232 and its decay products Mixtures: Tobacco, smokeless

20A44, 20A36, 20A40

Exposure circumstances: Involuntary smoking (exposure to secondhand or environmental tobacco smoke, ETS) Tobacco smoking and tobacco smoke

20A45 20A45

Group 2A: Agents and groups of agents: Indium phosphide Lead compounds, inorganic Nitrate or nitrite (ingested) under conditions that result in endogenous nitrosation

22398-80-7 7439-92-1 14797-55-8 and 14797-65-0

Exposure circumstances: Cobalt metal with tungsten carbide

20A33 20A35 20A34

20A33

Group 2B: Agents and groups of agents: Antimony trioxide Carbon black Cobalt and cobalt compounds Cobalt sulfate and other soluble cobalt (II) salts Lead Nickel, metallic and alloys Titanium dioxide Vanadium pentoxide Exposure circumstances: Cobalt metal without tungsten carbide

1309-64-4 1333-86-4 7440-48-4 10026-24-1 7439-92-1 7440-02-0 13463-67-7 1314-62-1

20A43 20A38, 20A30 20A31 20A33 20A42, 20A36 20A32 20A43, 20A30 20A33 20A33

Agents, groups of agents, mixtures and exposure circumstances (associated with metals and nonmetals, or tobacco) evaluated in IARC Monographs Volumes 1-95. This list contains all agents evaluated as of November-December 2006 that are considered: Carcinogenic to humans (Group 1), probably carcinogenic to humans (Group 2A), and possibly carcinogenic to humans (Group 2B). For details of the evaluation, the relevant Monograph should be consulted, see http://monographs.iarc.fr/ENG/Classification/crthgr01.php.

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Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts

As, usually considered as As2O3 in tobacco, was removed from tobacco agronomy in 1952. Between 1917 and 1951 the As level in tobacco rose from about 12 to 57 μg/g (1459). By 1968 the As level in tobacco had decreased from the 1951 value of more than 50 μg/g to a 1968 value of 0.5 to 1.0 μg/g, a value similar to that reported by Griffin et al. (1391). Some of these chronological data were summarized by the U.S. Surgeon General in 1979 (20A107) and IARC (1871). In 1957, Cogbill and Hobbs (769) reported the transfer of As from a cigarette containing 7.1 μg of As to MSS to be 3.5%. With the tobaccos analyzed for As by Griffin et al. (1391), the As content of the MSS would range from 0.018 to 0.035 μg/cigarette. In 1968, Guthrie (1457) reported the As transfer from cigarette tobacco to its MSS varied between 4% and 12%. In 1990, Tso (3973) noted that for most tobaccos at that time the As level was around 0.1 to 0.5 μg/g (3300). XX.C.1.b Beryllium (Be) Studies on laboratory animals exposed to high Be dose and epidemiological data have indicated that Be may cause cancer, although Be has been classified as a Group 1 substance by IARC. However, IARC noted a number of limitations in the epidemiological studies, namely poor exposure characterization, relatively low excess cancer risk, and the lack of discussion of exposure to other lung carcinogens. The potential of Be to induce developmental effects has not been investigated adequately (20A02). No literature information was found on the toxicity of Be by ingestion (20A116). The level of Be reported in cigarette MSS ranges from 0 to 0.5 ng/ cigarette (1742, 1744, 3711). XX.C.1.c Chromium (Cr), Cadmium (Cd), and Lead (Pb) The possible roles of Cr, Cd, and Pb in tobacco carcinogenesis are difficult to evaluate given the present data base. In 1990, Hoffmann and Hecht (1727) stated: “Taken together, the evidence for a major role of these materials as etiologic factors in tobacco carcinogenesis is not compelling.” XX.C.1.d Chromium VI [Cr (VI)] Seventeen years have elapsed since the IARC originally evaluated the carcinogenicity of Cr and Cr compounds. In 2000 De Flora (20A12) reviewed the toxicology of Cr compounds. A wealth of results indicate that Cr metal, Cr (III), and Cr (VI) can induce a variety of genetic and related effects in vitro (20A12). But there is a lack of carcinogenicity of Cr metal and Cr (III) compounds in experimental animals and only a minority of animal carcinogenicity data with Cr (VI) compounds were positive (30 out of 70, i.e. 42.9%). Moreover, most positive studies used administration routes that do not mimic any human exposure and by-pass physiological defense mechanisms. Typically, positive results were only obtained at implantation sites and at the highest dose tested. Exposure to Cr (VI) has been known for more than a century to be associated with induction of cancer in humans (20A12).

De Flora stated: Carcinogenicity requires massive exposures, as is only encountered in well defined occupational settings, and is site specific, being specifically targeted to the lung and, in some cases, to the sinonasal cavity. Increased death rates for cancers at other sites, which were occasionally reported in some epidemiological studies, were almost invariably not statistically significant and inconsistent (being counterbalanced by other studies which apparently showed decreased rates for the same cancers) (20A12). Chromium (VI) can be reduced in body fluids and non-target cells, which results in its detoxification, due to the poor ability of chromium (III) to cross cell membranes. In target cells, chromium (VI) tends to be metabolized by a network of mechanisms leading to generation of reduced chromium species and reactive oxygen species, which will result either in activation or in detoxification depending on the site of the intracellular reduction and its proximity to DNA. When introduced by the oral route, chromium (VI) is efficiently detoxified upon reduction by saliva and gastric juice, and sequestration by intestinal bacteria. If some chromium (VI) is absorbed by the intestine, it is massively reduced in the blood of the portal system and then in the liver. These mechanisms explain the lack of genotoxicity, carcinogenicity, and induction of other long-term health effects of chromium (VI) by the oral route. Within the respiratory tract, chromium (VI) is reduced in the epitheliallining fluid, pulmonary alveolar macrophages, bronchial tree and peripheral lung parenchyma cells. Hence, lung cancer can only be induced when chromium (VI) doses overwhelm these defense mechanisms. The efficient uptake and reduction of chromium (VI) in red blood cells explains its lack of carcinogenicity at a distance from the portal of entry into the body. All experimental and epidemiological data, and the underlying mechanisms, point to the occurrence of thresholds in chromium (VI) carcinogenesis (20A12).

Although Cr (VI) has often been alleged to exist in MSS, it has never been unequivocally identified in tobacco smoke (20A95). XX.C.1.e Nickel (Ni) The USPHS (20A109) made the following statement on the occurrence of Ni in tobacco smoke: “It is not likely that nickel plays a significant role in the etiology of lung cancer in cigarette smokers.” During the 1960s the Sundermans reported that they had found Ni in MSS (3837). They speculated that Ni could possible react with CO in MSS to form nickel carbonyl. The Sundermans did not successfully induce lung cancer in rats exposed to tobacco smoke although much furor was raised as to their allegations (3837, 3838). XX.C.1.f Cobalt (Co) Co has been identified in both tobacco and tobacco smoke. Co and Co-containing compounds have been evaluated by IARC and are classified as Group 2B (possibly carcinogenic agents) (20A31). This category is used for agents for which there is limited evidence of carcinogenicity in humans and less than sufficient

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916

The Chemical Components of Tobacco and Tobacco Smoke

evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent for which there is inadequate evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals together with supporting evidence from mechanistic and other relevant data may be placed in this group. An agent may be classified in this category solely on the basis of strong evidence from mechanistic and other relevant data (IARC Preamble, see http://monographs.iarc.fr/ ENG/Preamble/CurrentPreamble.pdf).

Two large randomized trials on antioxidants (e.g., β-carotene and α-tocopherol) and Se to determine their effects on cancer risk (Chinese Cancer Prevention Study and the Selenium and Vitamin E Cancer Prevention Trial (SELECT). The Chinese study showed that a combination of β-carotene, vitamin E, and Se significantly reduced total mortality (9%), cancer mortality (13%), gastric cancer mortality (20%), and mortality of the other cancers (19%) (20A07). The SELECT is currently taking place in the United States, Puerto Rico, and Canada to determine if taking Se and/or vitamin E supplements can prevent prostate cancer in men aged fifty or older (20A82).

XX.C.1.g Mercury (Hg) Hg has been identified in both tobacco and tobacco smoke. Hg and inorganic Hg compounds (20A27) are classified by IARC as Group 3 agents (not classifiable as to carcinogenicity to humans). This category is used most commonly for agents for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents that do not fall into any other group are also placed in this category. An evaluation in Group 3 is not a determination of noncarcinogenicity or overall safety. It often means that further research is needed, especially when exposures are widespread or the cancer data are consistent with differing interpretations (IARC Preamble, see http://monographs.iarc. fr/ENG/Preamble/CurrentPreamble.pdf).

XX.C.1.i 210Polonium (210Po) For the last quarter of a century there has been a controversy over the presence and health effects of 210Po in tobacco smoke. The quantities of 210Po found in the lungs of smokers are generally about three times higher than those in nonsmokers. However, the significance of 210Po in tobaccoinduced lung cancer has been questioned upon comparison of these data with those obtained in miners (1509, 1727). In the case of 210Po, a recent in-depth study raises doubts on the significance of 210Po as a factor contributing to lung cancer in smokers (3300). 210Po is present in tobacco and tobacco smoke (0.03 to 1.0 pCi/cigarette); however, it is unlikely that these traces represent a major risk for the smoker (20A109). Rodgman and Green (3300) recently published a cancer risk assessment on toxicants in tobacco and tobacco smoke. Where there were sufficient data on carcinogenicity (animal and/or human), incremental lifetime cancer risks (ILCR) were calculated for those elements and isotopes. None of the elements (above) called Hoffmann analytes exhibited more than a low to very low ILCR (3300). For some of the elements there was insufficient cancer risk information necessary to calculate an ILRC, for example, Co, Hg, Se, and Cr. For these elements, either there were few health concerns anticipated by regulatory bodies (such as the U.S. Environmental Protection Agency or World Health Organization) or studies documenting cancer associated with these elements were not available. In view of these various uncertainties in published data and comments made by known authorities and regulatory bodies (as to either the level of these elements in smoke or their carcinogenic potency of the element) it is difficult at the present time to conclude that any of the metals and metal isotopes represents a significant hazard to the human smoker.

XX.C.1.h Selenium (Se) Se has been identified in both tobacco and tobacco smoke. The MSS yield of Se in the University of Kentucky reference cigarette 1R4F is 1.2 ng/cigarette (3300). Se and Se compounds (20A36) are classified by IARC as Group 3 agents (not classifiable as to carcinogenicity to humans). Se is not an antioxidant nutrient unto itself, but is a component of antioxidant enzymes. It possesses excellent antioxidant, antimutagenic, and anticarcinogenic properties (1177a, 3257, 3685, 20A46, 20A92, 20A93, 20A102, 20A113). El-Bayoumy (20A15) described the protective role of Se on genetic damage and on cancer. Fiökin et al. (20A22) conducted research that demonstrated a protective effect of vitamin E and Se against ETS exposure through reduction in the occurrence of lipid peroxidation. Clark et al. (20A09) reported that taking a Se supplement decreased the incidence of prostate cancer in men by more than 60% (20A09). The final analysis of the trial, published in 2002, by DuffieldLillico et al. (20A14) showed a 52% reduction of prostate cancer in men taking Se daily.

XX.D Summary To date, eighty-one elements (metals and nonmetals), fortyfive isotopes, and twenty-four ions have been identified in tobacco and tobacco smoke. As indicated in Table XX-4, 146 have been identified in tobacco, 116 have been identified in tobacco smoke, and 112 are found in both tobacco and tobacco smoke. Table XX-5 provides a tabulation of the metallic and

© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 916

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917

Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts

Table XX-4 Distribution of Metallic and Nonmetallic Elements, Isotopes and Ions between Tobacco and Tobacco Smoke Number of Identified Metallic and Nonmetallic Elements, Isotopes and Ions between Tobacco and Tobacco Smoke Component

Total

Smoke

Tobacco

Elements: 81 Metals Nonmetals

69 12

68 12

68 10

67 10

Isotopes: 45 Metal isotopes Nonmetal isotopes

39 6

20 4

39 5

20 3

Ions: 24 Totals

Smoke and Tobacco

24

12

24

12

150

116

146

112

nonmetallic elements, isotopes, and ions in tobacco, tobacco smoke, and tobacco substitute smoke. There are numerous compounds in tobacco and tobacco smoke that contain metals and nonmetals. No review articles have been published on these types of compounds in tobacco and smoke. In most papers, when they are mentioned, they are collectively called miscellaneous compounds. The compounds listed in Table XX-6 consist mainly of acid salts of sodium, potassium, magnesium, and calcium, metal oxides, hydroxides, carbonates, and carbonyl-containing compounds, halide salts of

organic compounds, a variety of organometallic compounds, for example, triphenylarsine, aluminum and magnesium phosphide, triphenylstannium hydroxide, certain agrochemicals that contain metals, such as Alloxydim-sodium®, potassium salt of gibberellic acid, and Zineb®, and several metal-containing biomolecules, such as globulins, cytochrome c6, and chlorophyll a and b. For the sake of completeness, several ammonium compounds and the acid salts and various ions of nitric, sulfuric, and phosphoric acids are included in Table XX-6. Overall, Table XX-6 lists 125 chemical components.

© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 917

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918

The Chemical Components of Tobacco and Tobacco Smoke




Table XX-5  

  

  
  



 
 
 

 
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© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 918

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919

Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts

Table XX-5 (continued) Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


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(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 919

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920

The Chemical Components of Tobacco and Tobacco Smoke

Table XX-5 (continued) Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


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© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 920

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921

Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts

Table XX-5 (continued) Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


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(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 921

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922

The Chemical Components of Tobacco and Tobacco Smoke

Table XX-5 (continued) Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


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© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 922

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923

Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts

Table XX-5 (continued) Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


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(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 923

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924

The Chemical Components of Tobacco and Tobacco Smoke

Table XX-5 (continued) Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


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© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 924

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925

Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts

Table XX-5 (continued) Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


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(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 925

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926

The Chemical Components of Tobacco and Tobacco Smoke

Table XX-5 (continued) Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke


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© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 926

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Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts

927

Table XX-6 Various Ionic and Covalently Bonded Organic and Inorganic Compounds Containing Metals and Nonmetals, Miscellaneous Ions, and Organometallic Compounds Found in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 927

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928

The Chemical Components of Tobacco and Tobacco Smoke

Table XX-6 (Continued) Various Ionic and Covalently Bonded Organic and Inorganic Compounds Containing Metals and Nonmetals, Miscellaneous Ions, and Organometallic Compounds Found in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 928

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Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts

929

Table XX-6 (Continued) Various Ionic and Covalently Bonded Organic and Inorganic Compounds Containing Metals and Nonmetals, Miscellaneous Ions, and Organometallic Compounds Found in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 929

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930

The Chemical Components of Tobacco and Tobacco Smoke

Table XX-6 (Continued) Various Ionic and Covalently Bonded Organic and Inorganic Compounds Containing Metals and Nonmetals, Miscellaneous Ions, and Organometallic Compounds Found in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C020.indd 930

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Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts

931

Table XX-6 (Continued) Various Ionic and Covalently Bonded Organic and Inorganic Compounds Containing Metals and Nonmetals, Miscellaneous Ions, and Organometallic Compounds Found in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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Table XX-6 (Continued) Various Ionic and Covalently Bonded Organic and Inorganic Compounds Containing Metals and Nonmetals, Miscellaneous Ions, and Organometallic Compounds Found in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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21

Pesticides and Growth Regulators

Since 2500 BC, farmers have used pesticides to prevent damage to their crops. The first known pesticide was elemental sulfur, used to dust crops in Sumeria about 4500 years ago. By the fifteenth century, pesticides containing arsenic, mercury, and lead were being applied to crops. In the seventeenth century, nicotine was extracted from tobacco leaves as nicotine sulfate for use as an insecticide. In the nineteenth century, two more natural pesticides were introduced: pyrethrum (extracted from chrysanthemums) and rotenone (extracted from the roots and stems of several tropical and subtropical plant species of the genus Lonchocarpus or Derris) [Miller (21A46)]. From the 1860s until the advent in 1942 of DDT (1-chloro2-[2,2,2-trichloro-1-(4-chlorophenyl)ethyl]benzene), there were numerous inorganic and naturally occurring compounds (inorganic and organic components extracted from plants and animals) developed and used for control of insects and plant diseases, particularly fungi. Little progress occurred in the discovery of natural or chemical means to control weeds. The chemistry of arsenicals was further exploited to control insects (Paris Green [copper(II) acetoarsenite]). Bordeaux mixture (copper sulfate and lime) was found to be extremely useful in the control of plant diseases, leading to its widespread usage. The invention of the pressure sprayer (both hand and power driven) made efficient large-scale application of pesticides feasible and economical. Aerial application was also invented (in the early 1920s), leading to expanded applications in agriculture. The availability of DDT, beginning in 1945 for civilian/agricultural usage, opened a new era of pest control, leading not only to its extensive usage but also to the development of numerous other synthetic organic insecticides, for example, organophosphates in 1946. About two years earlier in 1944, selective synthetic organic herbicides were discovered, starting with 2,4-D (2,4-dichlorophenoxyacetic acid), which revolutionized weed control in agriculture and elsewhere. Also, synthetic organic fungicides (metal based) were developed as effective controls of plant diseases (and for other applications). During the 1950s and 1960s, granular pesticide formulations were developed, which led to large expansions of pesticide usage on major field crops [Aspelin (21A02)]. Prior to the advent of DDT (and other organic pesticides which rapidly followed), most pesticides used in agriculture were applied to protect high value/small acreage crops, principally fruits, vegetables, and cotton. This, however, changed dramatically in the 1950s, as major field crops, for example, corn, sorghum, grains, tobacco, and soybeans, rapidly began to account for a majority of pesticide usage [Aspelin (21A02)]. By the 1960s, some very important new families of chemicals were discovered as herbicides, for example, triazines,

acetanilides, and dinitroanilines. In the 1970s, synthetic pyrethroids replaced much of the insecticide chemistry developed during the previous twenty years. During the 1980s, imidazolinone and sulfonylurea herbicides dramatically lowered application rates for weed control. During the 1990s and currently, agrochemical companies are employing new synthetic methods to produce safer pesticides (and growth regulators) for use on crops. The emphasis today in the development and use of pesticide and growth regulators is towards safer, more effective biological agents and pesticides applied at lower levels, and enhanced stewardship in use of available pesticides [Aspelin (21A02)]. Tobacco is an agricultural product processed from the leaves of plants in genus Nicotiana of the nightshade family (Solanaceae). Nicotiana is indigenous to North and South America but numerous species of Nicotiana (over sixty) are found throughout the world. The two main species cultivated and grown to produce tobacco and tobacco products worldwide are Nicotiana tabacum and Nicotiana rustica. N. tabacum is the most widely cultivated and used for production of tobacco leaf for cigarettes, cigars, chewing tobacco, snuff, snus, pipe tobacco, and other forms of tobacco products. N. rustica is the second most widely grown N. species. Its leaves are extracted for nicotine, pyridine products, and solanesol (3973). Tobacco has evolved over the centuries to be resistant to many types of pests and infections. The plants produce numerous compounds that provide for its protection. For example, the plants contain high levels of nicotine. It constitutes 0.3% to 5% in N. tabacum and up to 8% to 10% in N. rustica based on the dry weight of the tobacco leaves. Its biosynthesis takes place in the roots, and it accumulates in the leaves. It is a potent neurotoxin for many pests, with particular specificity to insects. Therefore, nicotine and salts of nicotine, for example, Black Leaf 40® (nicotine sulfate), have been widely used as insecticides in the past (21A06, 21A07, 21A39–21A42), and currently, nicotine derivatives such as Imidacloprid® [1-((6-chloro-3-pyridinyl)methyl)-N-nitroimidazolidinimine] continue to be widely used (3973). Pesticides and plant growth regulators are important parts of modern agricultural and horticultural productivity. These pesticides can be naturally occurring in the plant or synthetically produced. Although naturally produced pesticides and growth regulators are effective, their concentrations in the plant are often lower than necessary to completely eradicate harmful pests and infections. Some naturally occurring pesticides are harvested from plants and sold commercially, for example, Bacillus thuringiensis, Derris (rotenone), pyrethrum, Neem oil, and nicotine (nicotine salts) [Environmental Protection Agency (21A21)]. Over the last sixty to seventy 933

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The Chemical Components of Tobacco and Tobacco Smoke

years, hundreds of synthetic pesticides and growth regulators have been developed for application to tobacco at various stages in its development and during storage prior to use in commercial tobacco products to reduce or eradicate certain pests, for example, insects, mice, and other animals, unwanted plants (weeds), fungi, microorganisms such as bacteria and viruses, and infectious proteins. Some of the most effective pesticides and growth regulators are synthetic. Unfortunately, a number of highly effective synthetic pesticides are extremely harmful to both the environment and humans. One significant problem with synthetic insecticides is their longevity. This longevity is mostly due to the fact that many synthetic insecticides are not biodegradable. Consequently, these pesticides remain in the ecosystem for long periods of time and can have disastrous consequences on organisms that subsequently absorb the insecticide. Arsenic salts (1459, 1460) and DDT (707–709) are good examples of synthetic pesticides that remained in the ecosystem for a long time, and that have had considerable negative consequences. As a result of the possible harm to both humans and the environment associated with synthetic pesticides, worldwide regulations are now in place. These regulations vary from country to country and apply to both synthetic agrochemicals and harvested natural pesticides [Environmental Protection Agency (21A21)]. Based on a definition by the U.S. Environmental Protection Agency (EPA), a pesticide is any substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any pest. The term pesticide also applies to herbicides, fungicides, and various other substances used to control pests. Under U.S. law, a pesticide is also any substance or mixture of substances intended for use as a plant regulator, defoliant, or desiccant. Pests are living organisms that are present where they are not wanted or that cause damage to crops or humans or other animals. The EPA regulates both naturally occurring chemicals harvested or extracted from plants as pesticides and growth regulators, as well as synthetic agrochemicals [EPA (21A21)]. There are five broad chemical classifications or categories of pesticides (four for synthetic pesticides and one for natural or plant-derived pesticides). Each of the following five chemical/biological categories of synthetic and harvested/extracted natural pesticides and growth regulators includes examples of commercial pesticides: • Organochloride pesticides: Aldrin®, Chlordane®, Dieldrin®, DDT, Endosulfan®, Endrin®, Heptachlor®, Lindane®, Methoxychlor®, Mirex®, TDE. • Organophosphorus pesticides: Acephate®, Azinphosmethyl®, Chlorpyrifos®, Chlorpyriphos-methyl®, Diazinon®, Dichlorvos® (DDVP), Dicrotophos®, Dimethoate®, Disulfoton®, Ethoprop®, Fenamiphos®, Fenitrothion®, Fenthion®, Fosthiazate®, Malathion®, Methamidophos®,  Methidathion®, Methyl-parathion®, Mevinphos®, Naled®, Oxydemeton-methyl®, Parathion®, Phorate®, Phosalone®, Phosmet®, Pirimiphosmethyl®, Profenofos®, Terbufos®, Tetrachlorvinphos®, Trichlorfon®.

• Carbamate pesticides: Aldicarb®, Carbofuran®, Carbaryl®, Methom®. • Pyrethroid pesticides: Allethrin®, Bifenthrin®, Deltamethrin®, Permethrin®, Resmethrin®, ® ® Tetramethrin , Tralomethrin . • Plant derived pesticides: Azadirachtin A and B (obtained from Azadirachta indica), Bacillus thuringiensis, Derris (rotenone), Neem oil (obtained from Azadirachta indica), nicotine, pyrethrum, Spinosad (a mixture of spinosyn A and spinosyn D) derived from soil bacterium Saccharopolyspora spinosa. Not every pesticide and growth regulator example listed above may be approved for use on tobacco. This chapter provides information on pesticides and growth regulator residues (synthetic and natural occurring) identified on tobacco and identified in tobacco smoke. It also provides data on the transfer rates of these residues on tobacco to tobacco mainstream smoke (MSS) and certain examples of degradation/decomposition products from pesticides and growth regulator residues identified in MSS. Finally, a brief review of analytical methods for the analysis of pesticides and growth regulator residues on tobacco and in tobacco smoke is provided.

XXI.A Synthetic Pesticides and Plant Growth Regulator Residues on Tobacco Pesticide and growth regulator residues on tobacco and their transfer rates to MSS have been the subject of several reviews and multiple chapters in books. In the late 1960s, Guthrie and Bowery (21A25) and Guthrie (1457, 1458) reviewed the early literature dealing especially with residues of arsenic and the chlorinated hydrocarbon insecticides, as well as those of carbamates and organophosphorus compounds used on tobacco. In another publication, Guthrie (21A24) summarized legislation on pesticide residues on tobacco and tobacco products in countries around the world as of 1973. In that paper, he also included an updated account of residues in U.S. tobacco and tobacco products. Ladisch in 1973 reviewed the known chlorinated pesticides in tobacco and tobacco smoke (21A31). Two reviews published in 1979 discuss the influence of growth regulators and herbicides [Steffens (3811a)] and insecticides and nematicides [Sheets and Leidy (3634)] on the chemistry of tobacco. These reviews contained updates on residues of pesticides. Ishiguro and Sugawara (1884) reviewed the known pesticides in tobacco and smoke and literature on decomposition products from pesticides in 1980. In 1986, Wittekindt (4271a) reviewed the pesticides recommended for use of tobacco in twenty-two countries, listed the maximum residues for eleven pesticides allowed on tobacco products in Germany, and presented a list of maximum amounts recommended by the German cigarette industry for seventy-one other pesticides.

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Davis et al. (21A17) and Meyer et al. (21A45) presented a detailed analysis of maleic hydrazide (MH) residues in U.S. tobacco and discussed the toxicological implications of the residues. In 1989, the 43rd Tobacco Chemists’ Research Conference (TCRC) symposium was dedicated to the subject of regulation of insect and pathogen activity in tobacco and tobacco products. In that symposium, Benezet (21A05) reviewed chemical means to control pests in tobacco and tobacco products and their interaction. At that same symposium Danehower (21A16) and Jackson et al. (21A29) reviewed the role of natural tobacco constituents that are effective pesticides (21A30). Cousins (21A14a) published a review on herbicides and suckering agents in 1989. In 1972 and again in 1990 Tso published books on the chemistry and biology of tobacco (3972, 3973). In both books he devoted two chapters to pesticides and growth regulators (both compounds native to tobacco and applied agrochemicals). In 1991, Sheets (3633) presented a very thorough review of all known pesticides to that date. Davis and Nielsen edited a book in 1999 on tobacco production, chemistry, and technology (910a). Several chapters in that book reviewed various types of pesticides employed in the production of different types of tobacco (2483a, 2650b, 2892a, 3646a, 3661a). In 2002, Blanc et al. (21A06) reviewed the use of natural insecticides and pesticides for use on tobacco. Mueller (2650a) reviewed current approaches and tools for the management of pesticide residues on tobacco in 2005 at the 59th Tobacco Science Research Conference. Most recently in 2005, Eberhardt (21A19) prepared an extensive review of pesticides used on tobacco, the transfer rates of pesticides to MSS and sidestream smoke (SSS), and decomposition products of pesticide residues identified in MSS. The most commonly used commercial pesticides and growth regulators for tobacco, as of 1998, include: Insecticides: Acephate®, Aldicarb®, Bacillus thuringiensis, Carbaryl®, Carbofuran®, Chlorpyrifos®, Diazinon®, Disulfoton®, Endosulfan®, Ethoprop®, Fenamiphos®, Fonofos®, Imidacloprid®, Malathion®, Methidathion®, Methomyl®, Spinosad®, Trichlorfon®; Herbicides: Benefin®, Clomazone®, Diphenamid®, Isopropalin®, Napropamide®, Pebulate®, Pendimethalin®, Sethoxydim®, Sulfentrazone®; Fungicides: Dimethomorph®, Mancozeb®, Mefenoxam®, Metalaxyl®; Plant growth regulators: Ethephon®, Flumetralin®; Plant growth regulators as herbicides: maleic hydrazide; Fumigants as insecticides: Chloropicrin®; Fumigants as insecticides or herbicides: methyl bromide; Fungicides as insecticides or herbicides: 1,3-dichloropropene (1,3-D) (21A59). Worldwide pesticide use has increased 50-fold since 1950, and 2.5 million tons of industrial pesticides are now used each year [Miller (21A46)]. More than 25 million pounds of pesticides are used in tobacco production in the United States,

and tobacco ranks sixth among all agricultural commodities in the amount of pesticides applied per acre, according to the U.S. Government Accounting Office (GAO) (21A59). Tobacco farmers use a considerable quantity of pesticides and growth regulators to increase leaf yield and quality and, hence, a greater profit for their crop. Even with the greatest caution used by farmers in applying the agrochemicals, a certain level of these pesticides and growth regulators remain on the leaf after harvesting and curing. Additional pesticides are often used on tobacco that is stored to control insect populations and small but detectable levels of pesticides remain on tobacco prior to its use in manufacture of tobacco products. Therefore, certain residual pesticides are expected to be present on tobacco. Since about 1950 over 200 types of pesticides and growth regulators have been used on tobacco crops. Some are no longer used as many technological improvements have been made during that time and our knowledge of the effectiveness of different agrochemicals on pest has improved. All the newer pesticides are now regulated and strenuous testing programs exist to assure that these agrochemicals meet safety (human and environmental [soil and air]) requirements (21A21). Additionally, agricultural breeding practices have generated new varieties of tobacco plants that are often more resistant to certain plant diseases and insects (21A21). Even with all the safety measures in place residual levels of agrochemicals have been identified in both tobacco and tobacco smoke. Degradation products from the thermal degradation, pyrolysis, and combustion of these agrochemicals have also been identified on tobacco and in tobacco smoke. Generally, the level of residue tobacco pesticides and growth regulators is very small (ng/kg tobacco, ppm range). The transfer rate of these pesticides and growth regulators to MSS varies tremendously but is generally less than 30%, in many cases less than 10%, and in some cases less than 1% [Eberhardt (21A19)]. The existence of trace levels of pesticides and growth regulators in tobacco smoke was made possible by the advent of modern analytical methodologies, particularly gas capillary gas chromatography (GC/GC), gas chromatography/mass spectrometry (GC/MS) and high performance liquid chromatography (HPLC).

XXI.B Naturally Occurring Plant Growth Regulators and Pesticides in Tobacco Auxins are a class of plant growth substance (often called phytohormones or plant hormones). The most important member of the auxin family found in all plants is indole-3-acetic acid (IAA). It generates the majority of auxin effects in intact plants, and is the most potent native auxin. Naturally occurring auxins include gibberellic acid, IAA, phenylacetic acid (PAA), and indole-3-butanoic acid (IBA) (3973). Gibberellic acid and several gibberellins are sold commercially as plant growth regulators. Auxins play an essential role in coordination of many growth and behavioral processes in the plant life cycle. When stimulated during normal plant growth or when

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applied to the plant at high concentrations auxins produce ethylene. Excess ethylene inhibits elongation growth, causes leaf abscission, and can even kill the plant (21A14). Synthetic auxins and commercially available auxins are effective herbicides by their effective promotion of ethylene in plants. Synthetic auxin analogs include 1-naphthaleneacetic acid (NAA), 2,4-dichlorophenoxyacetic acid (2,4-D), indole-3 -butanoic acid, and 2-methoxy-3,6-dichlorobenzoic acid [Hobbie and Estelle (21A27), Hobbie et al. (21A28), Lomax et al. (21A35)]. Additionally, compounds such as naturally occurring pyrethrins (21A15, 21A20, 21A23, 21A32–21A34), Neem oil (a mixture from Azadirachta indica of more than 135 compounds), Azadirachtin A and B from Azadirachta indica [Akol et al. (21A01), Biswas et al. (21A05a), Cousins (21A14a)], rotenone [Chamberlin and Madden (21A11)], and Bacillus thuringiensis (B.t.) are effective naturally occurring pesticides (3973, 21A54). Of course, the most plentiful naturally occurring insecticide in tobacco is nicotine [Busbey and McIndoo (21A07, 21A08), McIndoo et al. (21A40-21A42), McIndoo (21A39), Steppuhn et al. (21A55)]. In 1989, Danehower (21A16) reviewed the field of naturally occurring tobacco growth regulators and pesticides at the 43rd TCRC. Numerous effective naturally occurring pesticides are found on the surface of tobacco leaves, including n-, iso-, and anteiso-paraffinic hydrocarbons; aliphatic alcohols and acids; wax esters; α- and β-4,8,13-duvatrien-1-ols, the α- and β-duvatrienediols (12,Z)-labda-12,14-diene-8α-ol, Z-abienol; (13,E)-labda-12-ene-8α, 15-diol, labdenediol; numerous sucrose esters (C2-C8 acids); several labdane diterpenes (sclareol-type); nicotine; nornicotine; formylnornicotine; acetylnornicotine; 3-hydroxy- acylnornicotines (C12-C16); acyl nornicotines (C12 to C13) with n-, iso-, and anteiso-methyl branching; and numerous phenolic compounds derived from shikimic acid, for example, caffeic acid, ferulic acid, gentisic acid, cichoriin, isoquercitin, rutin and their glucosides, and the mevalonic acid, for example, capsidol, solavetivone, solanascone, occidol, and numerous other sequiterpenoids created from diverse biological pathways in tobacco.

XXI.C Transfer Rates of Pesticides and Plant Growth Regulators to MSS Tobacco, because it is subject to many types of pests, can be damaged both physically and chemically. Serious infections can result and have led to total crop failures. Efforts are continually being made to breed new varieties of tobacco resistant to disease and various pests (aphids, hornworms, various nematodes, etc.). Additionally, herbicides of various types are widely used to control unwanted vegetation in the fields. As a result, the use of pesticides and various plant growth regulators is widespread and at present is the primary means used by tobacco farmers to improve tobacco quality and yield. The level of pesticide (and plant growth regulator) residues on tobacco has always been a concern to tobacco growers, the tobacco industry, and governmental regulators in terms of the safety of the resulting tobacco products. Hundreds of

The Chemical Components of Tobacco and Tobacco Smoke

tobacco pesticides and plant growth regulators have been developed and marketed in the past. Fewer than twenty-five are currently regulated and employed by farmers and the tobacco industry (3633). Regardless of the intended use of these pesticides and growth regulators, it seems inevitable that certain levels remain on the tobacco leaf. This is particularly true today, not necessarily because inordinate levels of pesticides are employed on tobacco but because tremendous advances in analytical chemistry have enabled scientists to detect extremely low levels (picogram to fentagram levels) of these residues (or their decomposition products). As certain agrochemicals used for pest control and growth regulation leave residues on cured tobacco leaves, some residual pesticides and growth regulators have been identified in tobacco smoke. An important question concerning consumer safety is whether the residual levels of pesticides (or growth regulators) represent a danger to the public. At the completion in 1976 of the study of the second set of experimental cigarettes in the National Cancer Institute (NCI) decade-long study on the “less hazardous” cigarette, it was reported that the long-chained alcohols used as suckering agents on tobacco had no adverse chemical or biological effect on cigarette MSS. In the 1976 report, Gori (1330) summarized this aspect of the NCI second study: The fatty alcohol, fatty alcohol × 100, and hand-suckered blends showed no significant difference among themselves or from the SEB II blend [see p. 2 in (1330)]. No statistically significant differences were observed among Hand-suckered, Fatty Acid-Normal, and Fatty Acid × 100 Blends (variables 60, 61, and 62) [see p. 14 in (1330)]

In the fourth NCI study completed in 1980, the chemical and biological properties of the MSSs from cigarettes made from pesticide-treated tobacco and pesticide-free tobacco were compared. Gori wrote [see p. 7 in (1333)]: No significant differences were observed between cigarettes made from pesticide-treated tobacco leaves and pesticidefree tobacco leaves.

The pesticide-treated vs. pesticide-free tobaccos used in this phase of the NCI study were those grown in Prince Edward Island, Canada. The commercial pesticides used on the tobacco included Chlorpyriphos®, Trichlorfon®, Diphenamide®, Methomyl®, DDT, Carbaryl®, maleic hydrazide, and C10 alcohol. The pesticide-treated tobacco properties were described in 1980 by Tso et al. (3973, 3977): It appears that chemicals currently registered for use on tobacco, when applied as directed, are of no significance in increasing biological activity of cigarette smoke condensate [see p. 151 in (3973)].

In 2005, Eberhardt (21A19) reported on pesticide residues on tobacco, the transfer rates of selected pesticide residues, and pyrolysis products of some pesticide residues as part

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of the CORESTA Sub-group study on pesticide residues. Information on forty agrochemicals (used from the 1950s to the present) was obtained from sixty-four literature references. The agrochemicals evaluated were insecticides, fumigants, fungicides, herbicides, and growth regulators. These represented a diverse set of compounds, including alcohols, acids, organophosphates, organohalides, carbamates, dithiocarbamates, pyrethrins, dinitro compounds, organonitrogen compounds, and heterocyclics. Prior to the work by Eberhardt (21A19), Rix (4857, 4858) evaluated the transfer of selected agrochemicals (Dicamba®, Formothion®, and Thiodan®) from tobacco to smoke. For the majority of the commercial pesticides (and plant growth regulators) reviewed by Eberhardt (21A19), only minimal information existed for their transfer into the smoke and for pyrolysis products. It must be noted that some of the agrochemicals listed, for example, Leptophos®, TDE, had only minor significance in tobacco cultivation and were added to tobacco for purely experimental reasons to study smoke transfer rates. Additionally, not all authors who provided information on transfer rates gave precise details on the pesticide concentrations in the original material used. There are only a few pesticides, such as DDT, maleic hydrazide, and several dithiocarbamates, where the transfer rates seemed to be adequately investigated, that is, in sufficient number and by different research groups [Atallah et al. (1051d, 21A03, 21A04), Chopra et al. (707, 708, 712, 714, 716), Guthrie et al. (1457, 1458), Hoffmann and Rathkamp (1756), and Hoffmann et al. (1761, 1767)]. A number of publications by these authors used labeled agrochemicals (sixteen of the sixty studies), which provided information on the fate of the original substance in tobacco MSS and SSS as well as their presence in the vapor and particulate phases of the smoke streams. As most of the naturally occurring pesticides and plant growth regulators exist in tobacco, no information on the transfer rates to tobacco smoke are available. Table XXI-3 lists the majority of known pesticides and plant growth regulators used on and identified in tobacco and tobacco smoke. Although Table XXI-3 lists a great number of natural and synthetic pesticides and growth regulators found in tobacco and tobacco smoke, there are still other pesticides and plant growth regulators that could have been used on tobacco but where no information could be found in the literature. Additionally, individual pesticides and growth regulators often have multiple common names. Therefore in reviewing Table XXI-3, pesticides and growth regulators should be searched by Chemical Abstract number or chemical name. Table XXI-3 contains only a selected number of naturally occurring pesticides and plant growth regulators found in tobacco and tobacco smoke. All of the compounds mentioned in this chapter as naturally occurring pesticides and plant growth regulators are covered in other chapters, for example, the hydrocarbons are discussed in Chapter 1, the duvatrienediols are discussed in Chapter 2, and the nicotinoids are discussed in Chapter 17. The evaluation by Eberhardt (21A19) of the available literature demonstrated that the transfer rate for all residues

studied was much less than 100%. In most studies, the transfer rate of the pesticide to MSS is stated as being <30%. For a small number of agrochemicals, for example, DDT, TDE, Lindane®, HCH-alpha®, markedly higher transfer rates were found, although it should be kept in mind that very broad ranges in transfer rates exist for many of the pesticides examined. Only in a few studies were the transfer rates of residues in plain and filtered cigarettes presented and compared. The data suggested that the presence of a filter in cigarettes slightly reduces the transfer into MSS of some pesticides, e.g., DDT, Disulfoton®, TDE (1127). Several other factors also influenced the transfer rates, for example, the type of tobacco tested, the form of the smoking article, whether cigarette, cigar, cigarillo, or pipe, the type of filter employed, the method of adding the original substance and its amount, variation in smoking conditions, such as puff volume, number of puffs, and the analytical methods employed to determine the agrochemical [Mussalo-Rauhamaa et al. (21A48), Mold and Walker (2596), Carugno (21A10), Schmid and Rastetter (21A52), Mestres et al. (21A43), Hengy and Thirion (1619), Hoffmann et al. (1761), Atallah and Dorough (21A03, 21A04), Thorstenson and Dorough (3915), Smith et al. (3724), Lorenz et al. (21A36–21A38), Guthrie (1457), Dickes et al. (21A18), Dorough and Atallah (1051d), Bowery et al. (415), Hawk et al. (1553), Ceschini and Chauchaix (644), Clark et al. (21A12), Moshy and Halter (21A47), Hengy and Thirion (1618), Meikle (2527), Sitaramaiah et al. (21A53), Thurm (21A57), Stone (21A56), Barkemeyer et al. (186), Chopra and Domanski (707), Chopra and Sherman (712), and Underwood (21A58)]. Table XXI-1 shows the percentage transfer of selected pesticides applied to tobaccos that transfer to MSS. The percentage transfers were generally taken from the publication or were calculated based on data provided in the literature [Eberhardt (21A19)].

XXI.D Decomposition Products of Agrochemicals in Mainstream Smoke The decomposition products identified in MSS of various agrochemicals added to tobacco are shown in Table XXI-2. In some of the published studies reviewed by Eberdardt (21A19), the determination and quantification of the pyrolysis products were the primary objective of the study, for example, Hoffmann et al. (1761), Mestres et al. (21A44), and Higman et al. (1645), and MSS transfer rates for the pesticide were not determined. In other studies 14C-labeled pesticides were evaluated, for example, Atallah and Dorough (21A03, 21A04), Frisch et al. (1243), and Clark et al. (21A12). In most cases the agrochemicals tested were used as purchased, for example, Comer et al. (21A13), Chopra et al. (716), and Chopra and Zuniga (717). For the majority of the pesticides reviewed by Eberhardt (21A19), only minimal information existed for their transfer into smoke and for their pyrolysis products. There are only a

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Table XXI-1 Percent Transfer of Intact Agrochemicals to Mainstream Smoke (1884, 21A19) Pesticide* Anilazine Azinphos-methyl Benomyl Captan Carbaryl Carbofuran Chlorpyrifos Cyhalothrin Cypermethrin DDT Deltamethrin Diamidofos Dieldrin Diflubenzuron Disulfoton Dithiocarbamates Endosulfan Endosulfan sulfate Endrin Fenpropathrin Fenvalerate HCH-alpha Heptachlor 3-Hydroxycarbofuran Imidacloprid Isobenzan Leptophos Lindane Linuron Malathion Maleic hydrazide Methoprene Metobromuron Mirex Monolinuron Naphthol Parathion Phosphine TDE

Percent Transfer of Intact Compound 1 0.2 - 0.27 ND ND - 2.7 1 - 11 0.3 - 20 13.5 - 15 5.2 1.51 1.2 - 83.3 2.64 ND 4 - 32 6.9 6 - 14.8 ND ND - 15.3 15.5 - 16.3 18.18 - 31.58 15.5 1.72 45 4-5 0.1 - 3.26 5.3 3.5 - 5.1 3 - 10 3.1 - 40 6.7 ND - 9.4 ND - 23 38.2 3.7 - 4 9 - 23 2.5 - 4.5 5.7 - 13.8 ND - 15.3 ND 0.007 - 63.75

few pesticides, such as DDT, maleic hydrazide, and several dithiocarbamates, where the transfer rates seem to be adequately investigated in a sufficient number of studies by different research groups [Atallah et al. (1051d, 21A03, 21A04), Chopra et al. (707, 708, 712, 714, 716), Guthrie et al. (1457, 1458), Hoffmann and Rathkamp (1756), and Hoffmann et al. (1761, 1767)].

XXI.E Methods for Analysis of Pesticides and Plant Growth Regulators Numerous analytical methods, for example, GC-GC, GC-MS and HPLC, have been published for the determination of various classes of pesticides [Haeberer and Chortyk (470, 21A26), Schmeltz et al. (3483), Sagredos and Eckert (3379– 3381), Sagredos and Moser (3382), Nesemann and Seehofer (2699), Nesemann et al. (2697, 2698), Schmid and Rastetter (21A52), Schmid (3513), Dattilo et al. (904, 905), Guhlmann et al. (1451), Cai et al. (21A09), Carpenter and Frost (606), Nowell and Resek (21A50), Zaugg et al. (21A63), Werner et al. (21A60), Yamazaki and Tomara (21A62), and many others].

XXI.F Residues of Synthetic Pesticides and Plant Growth Regulators Identified in Tobacco and Tobacco Smoke The number of pesticide, plant growth regulators, and their decomposition products identified in tobacco and tobacco smoke listed in Table XXI-3 is 298. Of these, 102 have been identified in tobacco smoke, 294 in tobacco, and 98 in both tobacco and tobacco smoke. There are more natural pesticides and growth regulators known than are listed in Table XXI-3 because only selected examples of these natural pesticides and growth regulators, described by Danehower (21A16), are given.

ND = not determined All the agrochemicals listed are sold commercially and are trademarked/registered. Each should have a ® symbol after the product name, except the following agrochemicals: DDT, 3-hydroxycarbofuran, maleic hydrazide, phosphine and TDE.

*

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939

Pesticides and Growth Regulators

Table XXI-2 Degradation Products of Pesticides in Mainstream Smoke (1884, 21A19) Pesticide* Anilazine Azinphos-methyl Captan Carbaryl Carbofuran Chlorpyrifos DDT

Diamidafos Dieldrin Diflubenzuron Dithiocarbamates Endosulfan Imidacloprid Leptophos Lindane Linuron Malathion Maleic hydrazide Methoprene Metobromuron Mirex Monolinuron Naphthol TDE (DDD)

Degradation Products of the Intact Compound

References

o-chloroaniline Oxyguthion CO2 degradation products: 7 (not further characterized), CO2 degradation products: 2 (not further characterized), CO2 decomposition into unknown fragments 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD = TDE), 1,1-dichloro-2,2-bis(pchlorophenyl)ethylene (DDE), 1-chloro-2,2-bis(p-chlorophenyl)ethylene (DDM = TDEE, 4,4’-dichlorobenzophenone (DCBP), bis(p-chlorophenyl)methane (BCPM), CO2, chloroform, methyl chloride, trans-4,4’-dichlorostilbene (DCS), DDD-olefins phenol chlorinated and dechlorinated degradation products

1457 419, 1457 21A37 1051d, 21A03, 21A04, 1051d, 1553, 21A03, 21A04 717 644, 707, 712, 714, 708, 758, 1000, 1051d, 1457, 1756, 1767, 2697, 3915, 21A18, 21A37, 21A38, 21A43

4-chloroaniline, 4-chlorophenylurea CO2, carbon disulphide, COS, ethylene thiourea, hydrogen sulfide ether CO2, CO (traces), urea compound degradation products: 4 (not further characterized), CO2 CO2 3,4-dichloroaniline CO2 acetonitrile, acrylonitrile, aminobutanoic acid, ammonia, aniline, butanoic acid, benzonitrile, CO2, CO, cyanide, 1H-pyrrole-2,5-dione, hydrazine (traces), indole, succinimide CO2, CO 4-bromoaniline degradation products: 3 (not further characterized), CO2 CO2, 4-chloroaniline degradation products: 6 (not further characterized) dechlorinated TDE, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), 1-chloro-2,2bis(p-chlorophenyl)ethylene (DDM = TDEE), 4,4’-dichlorobenzophenone (DCBP), bis(p-chlorophenyl)methane (BCPM), trans-4,4’-dichlorostilbene (DCS)

21A53 124, 186, 21A10, 21A38, 21A44, 21A51 1619 21A12 1051d, 21A03, 21A04 21A36, 21A38 822 21A38 716, 1553, 1761, 2383-2385, 3724, 3725, 4274, 21A56 1243 822 1051d, 21A03, 21A04 822, 21A37 21A03, 21A04 415, 416, 714, 758, 1457, 3915

2527 21A57

All the agrochemicals listed are sold commercially and are trademarked/registered. Each should have a ® symbol after the product name, except the following agrochemicals: DDT, 3-hydroxycarbofuran, maleic hydrazide, phosphine and TDE.

*

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940

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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Pesticides and Growth Regulators

941

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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942

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

943

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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944

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

945

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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946

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

947

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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948

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

949

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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950

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

951

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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952

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

953

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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954

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

955

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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956

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

957

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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958

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

959

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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960

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

961

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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962

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

963

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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964

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

965

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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966

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

967

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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968

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

969

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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970

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

971

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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972

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Pesticides and Growth Regulators

973

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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974

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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975

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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976

The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued) Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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22

Genes, Nucleotides, and Enzymes

Prior to discussing genes, nucleotides (DNA and RNA strands), and enzymes identified in tobacco, a general discussion of genetics, genes, nucleotides, and enzymes is appropriate (3973). There are numerous excellent reference texts that the reader can access for more detailed information on genetics [Davis and Nielsen (910a), Tso (3973), Acquaah (22A01), Bernardi (22A03), Griffiths et al. (22A12), Hartl and Jones (22A14)] and several sources of encyclopedic information (22A05, 22A17, 22A34). The general discussion will be followed by a review of work accomplished over many decades toward understanding the mysteries of tobacco genetics.

XXII.A General Discussion of Genetics Genetics is the science of heredity and variation in living organisms (22A12, 22A14, 22A17). Knowledge that desired characteristics were inherited has been used implicitly since prehistoric times for improving crop plants and animals through selective breeding. The science originated from human experience to improve crop and animals through the use of varied methods, such as domestication. However, the modern science of genetics, which seeks to understand the mechanisms of inheritance, only began with the work of Gregor Mendel in the mid-1800s (3973, 22A32). Inheritance is fundamentally a discrete process with specific traits that are passed on in an independent manner. These basic units of inheritance are now known as genes. In the cells of organisms, genes exist physically in the structure of the molecule DNA and the information contained in the genes is used to create and control the components of cells. Although genetics plays a large role in determining the appearance and behavior of organisms, it is the interaction of genetics with the environment an organism experiences that determines the ultimate outcome. For example, Nicotiana tabacum seeds planted and cultivated in different soils and under different climatic and agronomic conditions can produce different types of tobacco that have vastly different appearances and chemical composition, for example, Maryland vs. Virginia tobacco (3973). A gene is a set of segments of nucleic acid. A nucleic acid is a complex, high molecular weight biochemical macromolecule composed of nucleotide chains that convey genetic information. The most common nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Genes are arranged linearly in long chains of DNA sequences, called chromosomes. In eukaryotic organisms (which include plants and animals), each cell has its DNA arranged in multiple linear chromosomes. These DNA strands are often extremely long. The largest human chromosome, for example, is about 140 million base pairs in length (22A11).

Certain segments of nucleic acid contain the information necessary to produce a functional RNA product in a controlled manner. They contain regulatory regions dictating under what conditions this product is made, transcribed regions dictating the sequence of the RNA product, and/ or other functional sequence regions (22A23, 22A24). The physical development and phenotype, that is, a measurable characteristic, such as color or disease resistance, of organisms can be thought of as a product of genes interacting with each other and with the environment, and genes can be considered as units of inheritance. In cells, genes consist of a long strand of DNA that contains a promoter, which controls the activity of a gene, and coding sequences, which determine what the gene produces. When a gene is active, the coding sequence is copied in a process called transcription, producing an RNA copy of the gene’s information. This RNA can then direct the synthesis of proteins via the genetic code. The genetic code is the set of rules by which information encoded in genetic material (DNA or RNA sequences) is translated into proteins, that is, amino acid sequences and enzymes, by living cells. However, RNAs can also be used directly, for example, as part of the ribosome, which is a small, dense organelle in cells that assembles proteins. Molecules produced from gene expression, whether RNA or protein, are known as gene products. Most genes contain noncoding regions that do not code for the gene products, but can regulate gene expression. Additionally, there are large segments of the DNA that do not carry any genetic information. One single gene can lead to the synthesis of multiple proteins. The total complement of genes in an organism or cell is known as its genome. The estimated number of genes in the human genome has been repeatedly revised downward since the completion of the Human Genome Project, but current estimates place the human genome size at just under 3 billion base pairs and about 20000 to 25000 genes (22A15). The vast majority of living organisms encode their genes in long strands of DNA. DNA consists of a chain made from four types of nucleotide subunits: adenosine (A), cytidine (C), guanosine (G), and thymidine (T). Each nucleotide subunit consists of three components: a phosphate group, a deoxyribose sugar ring, and a nucleobase. Thus, nucleotides in DNA or RNA are typically called bases; consequently they are commonly referred to simply by their purine (adenine and guanine) or pyrimidine (cytosine and thymine) original base components. The most common form of DNA in a cell is a double helix structure, in which two individual DNA strands twist around each other in a right-handed spiral. In this structure, the base pairing rules specify that guanine pairs with cytosine and adenine pairs with thymine (each pair contains 977

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978

one purine and one pyrimidine). The base pairing between guanine and cytosine forms three hydrogen bonds, while the base pairing between adenine and thymine forms two hydrogen bonds. The two strands in a double helix must therefore be complementary, that is, their bases must align such that the adenines of one strand are paired with the thymines of the other strand, and so on. Due to the chemical composition of the pentose residues of the bases, DNA strands have directionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose; this is known as the 3’ end of the molecule. The other end contains an exposed phosphate group; this is the 5’ end. The directionality of DNA is vitally important to many cellular processes, since double helices are necessarily directional (a strand running 5’-3’ pairs with a complementary strand running 3’-5’) and processes such as DNA replication occur in only one direction. All nucleic acid synthesis in a cell occurs in the 5’-3’ direction, because new monomers are added via a dehydration reaction that uses the exposed 3’ hydroxyl as a nucleophile. The expression of genes encoded in DNA begins by transcribing the gene into RNA, a second type of nucleic acid that is very similar to DNA, but monomers of which contain the sugar ribose rather than deoxyribose. RNA also contains the base uracil (U) in place of thymine. Genes that encode proteins are composed of a series of three-nucleotide sequences called codons. A codon is a set of any three adjacent bases in the DNA or RNA. There are sixty-four different codons, of which sixty-one specify the incorporation of an amino acid into a polypeptide chain while the remaining three are stop codons that signal the end of a polypeptide. For example, the DNA codon ACG via its complementary RNA codon CGU specifies the amino acid arginine. For another example, the DNA codon TAC via its complementary RNA codon GUA specifies the amino acid valine. There are three stop codons: uracil-adenosine-adenosine (UAA), uraciladenosine-guanosine (UAG), and uracil-guanosine-adenosine (UGA). They are also called termination codons or nonsense codons. The genetic code specifies the correspondence during protein translation between codons and amino acids. The genetic code is nearly the same for all known organisms. Many molecular definitions of a gene relate to their role in directing the production of specific proteins. Production of protein itself is made possible via certain enzymes known as polymerases. Various DNAs and RNAs could not be produced without these polymerases and therefore they are of primary importance. Numerous other enzymes are produced that control metabolic and catabolic processes (enzymatically), provide structural components, and perform regulatory functions in cells. A single gene can encode multiple enzymes, and an enzyme can have multiple genes. For example, ribulose bisphosphate carboxylase-oxygenase in Nicotiana tabacum is a multimeric protein of sixteen peptides, eight small subunits (nuclear encoded) and eight large subunits (chloroplast encoded), thus two genes are responsible for this enzyme (3974c, 22A27, 22A35).

The Chemical Components of Tobacco and Tobacco Smoke

Metabolic and catabolic enzymes are specialized proteins that catalyze chemical reactions. In enzymatic catalyzed reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, or products. Almost all processes in a biological cell need enzymes in order to occur at significant rates. Since enzymes are extremely selective for their substrates and accelerate only a few reactions from among many possibilities, the set of enzymes made in a cell determines which metabolic pathways occur in that cell (3973). Each type of enzyme is generally geared to interact chemically with only one particular substance or type of substance, termed a substrate. The two parts fit together, according to a widely accepted theory introduced in the 1890s by the German chemist Emil Fischer (1852–1919), as a key fits into a lock. Each type of enzyme has a specific three-dimensional shape that enables it to fit with the substrate, which has a complementary shape. The link between enzymes and substrates is so strong that enzymes often are named after the substrate involved, simply by adding ase to the name of the substrate. For example, lactase is the enzyme that catalyzes the breakdown of lactose, while urease catalyzes the chemical breakdown of urea. Enzymes bind their reactants or substrates at special folds and clefts, named active sites, in the structure of the substrate. Because numerous interactions are required in their work of catalysis, enzymes must have many active sites, and therefore can have molecular weights as high as one million.

XXII.B Tobacco Genetics Tobacco has been used in one form or another in civilized society for nearly five centuries. Eventually in the late nineteenth century, investigations as to its composition began but they were not particularly numerous. The major driving force in the escalation in the mid-twentieth century of studies on tobacco composition was the attempt to define (1) its components that contributed to the acceptability of the taste and aroma of tobacco itself and its smoke to consumers and (2) the precursors in tobacco of the toxicants in its smoke (3973, 22A30). In 1972, Tso (22A30) remarked: The characteristics of cigarette smoke are functions of the physical and chemical properties of leaf tobacco which make the cigarette. Smoke constituents may be modified by changing leaf characteristics. The questions are: What kinds of changes are needed? and, how can these changes be achieved?

Tobacco genetics is a rather new field of study although research on tobacco to understand its physical and chemical makeup has been a goal of tobacco scientists for over a hundred years. The initial problem in undertaking the goal of trying to understand the origins of the chemical and physical essence of tobacco was that our understanding of life processes, in general, was inadequate prior to the discovery of the structure and function of DNA. Additionally, the life

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Genes, Nucleotides, and Enzymes

processing functions of numerous DNAs and RNAs in tobacco were not understood. Although scientists had an empirical knowledge of how the genetics worked via the tobacco breeding program, basic fundamental knowledge was lacking until technology was developed to execute the search for information on the genetic code for tobacco (3973). Regardless, research directed toward the ultimate goal of understanding of the fundamental life processes of tobacco began. The early genetic research was conducted in the areas of tobacco breeding (as a means to improve leaf characteristics, quality, and disease resistance) and the chemical composition of tobacco via identification of extractable material in tobacco, for example, amino acids, various proteins, and enzymes (424a, 2341a, 3972, 3973, 22A06, 22A29, 22A30). It was not until the 1970s and 1980s with the development of new analytical and genetic tools, such as HPLC and GC-MS, instrumental polymerase chain reaction (PCR), plant transformation, genetic mapping with molecular markers, gene tagging, and positional cloning, that significant progress was possible in the understanding of tobacco genetics directed towards improved pest resistance, yield, and quality (424a). The chemical composition of tobacco smoke is highly dependent on the physical and chemical properties of the leaf tobaccos used in cigarette manufacture. It is a basic tenet that the biological properties of cigarette mainstream smoke (MSS) and cigarette smoke condensate (CSC) can be improved through changes in the genetics of tobacco. Numerous types of chemical and physical modifications performed on tobacco, for example, tobacco extraction, tobacco reconstitution, tobacco expansion, inclusion of tobacco substitutes, have indicated that this tenet is possible (1375a, 1375b). Thousands of genes, nucleotides, and enzymes have been identified in tobacco. Although they do not transfer intact to MSS, hundreds of decomposition products from their combustion and pyrolysis products have been identified. Many of the combustion and pyrolysis products found in MSS and CSC have been called “Hoffmann analytes” because of their alleged adverse biological effects, for example, quinoline, HCN, and several other undesirable nitrogenous compounds, certain PAHs, aza-arenes, and phenolics (3974c). It is hoped that through genetic modifications precursors in tobacco of the toxicants in its smoke can be altered significantly to improve the safety of tobacco products (3794b, 3974c, 3975, 3984, 3976, 22A30).

XXII.C Genes, Nucleotides, and Enzymes Identified in Tobacco The sixty-five species related to Nicotiana tabacum represent sources of a divergent germplasm for biochemical and physical variations (3793, 22A19, 22A30). These species differ widely in growth habit and in chromosome numbers (3793). Tobacco breeding via interspecific hybridization has been the major tool for agricultural scientists to improve the health and quality of tobacco (22A30). Possible approaches that plant scientists can take to modify tobacco leaf have been

979

reviewed by Tso (22A31). Modifications discussed by Tso (3973, 22A31) involved genetic and cultural modification, nitrogen fertilization technology, leaf and plant population, the physiological stage of topping, and pesticide treatments. Post-harvest modifications were also discussed (22A31), as leaf composition is markedly affected by the curing process, aging, or other treatment of cured leaves (4005). The U.S. Nicotiana Germplasm Collection was initiated by the U.S. Department of Agriculture (USDA) in 1934 as a resource for tobacco breeders. The collection currently consists of approximately 1244 tobacco introductions, 656 cultivars, and 224 accessions representing fifty-nine Nicotiana species, fifty interspecific hybrids, and a newly introduced set of mutants (22A19). The gene pool of the Nicotiana Germplasm Collection represents enormous possibilities for researchers in plant pathology, plant molecular biology, and biotechnology to modify and improve the quality, yield, and safety of tobacco. It has been estimated that the genetic makeup of tobacco includes 25000 to 50000 genes (22A22). Nicotiana tabacum has a very large genome size compared with other cultivated solanaceous plants (22A13, 22A21, 22A22). At approximately 4.5 billion base pairs, it is 1.5 times the size of the human genome (22A13, 22A21, 22A22). There are at least two major (and several minor) initiatives to sequence the tobacco genome; the Tobacco Genome Initiative (TGI) and the European Sequencing of Tobacco Project (ESTobacco). Both projects have an ultimate goal of sequencing the greater part of the tobacco genome. Although tobacco has been cultivated for more than 500 years and is a crop of great economic significance, relatively little information exists on its genome structure and organization. The overall goal of the TGI is to sequence and annotate more than 90% of the open reading frames in the genome of cultivated tobacco, Nicotiana tabacum. Nicotiana tabacum is an amphiploid species (2n = 48) likely resulting from an interspecific cross between Nicotiana sylvestris (2n = 24) and Nicotiana tomentosiformis (2n = 24), and at approximately 4.5 billion base pairs has a very large genome size compared with other cultivated solanaceous plants. A complete gene catalog will provide the raw information to investigate physiological and genetic processes in the tobacco plant, a widely used model in plant biotechnology. Tobacco genomics may lead to the elucidation of genetic factors that impact constituents associated with tobacco consumption. Improving our understanding of these processes may potentially contribute to achieving the goal of reducing the harm associated with cigarette smoking. In addition, important agronomic traits such as disease and pest resistance genes could be identified, and thus could be available for use in traditional and molecular breeding projects the goal of which is to enhance the performance of tobacco as a crop in different environments. Finally, Nicotiana tabacum is a member of the agriculturally important Solanaceae family, which also includes tomato, potato, eggplant, and pepper crop plants. All of these plants may benefit from gene discovery in tobacco. The TGI is housed in the laboratories of the Plant Pathology Department of the North Carolina State University (NCSU) Centennial

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The Chemical Components of Tobacco and Tobacco Smoke

Campus, College of Agricultural and Life Sciences (Raleigh, North Carolina). NCSU will make the TGI data available to authorized academic researchers. The Tobacco Genome Initiative is supported by Philip Morris USA, Inc. (22A13, 22A21, 22A22). The TGI has identified a large percentage of genes in Nicotiana tabacum by utilizing a combination of strategies. Researchers at TGI have employed a methyl filtration approach to identify gene-rich regions in Nicotiana tabacum in order to expedite the gene discovery process. As of 2006, TGI had sequenced 1700000 lanes of methyl filtered clones and observed a dramatic increase in gene discovery in filtered vs. nonfiltered libraries. TGI has also performed expressed sequence tag (EST) sequencing from various Nicotiana libraries and to date has sequenced over 80000 ESTs. Genes tagged by these two strategies have been used as probes to identify bacterial artificial chromosome (BAC) clones for more targeted sequencing. Numerous BACs have been sequenced, revealing information about both gene structure and genome organization in Nicotiana species (22A13, 22A21). The TGI had a projected completion date in late 2007. The TGI was completed in June 2008. The second major tobacco genomic project is centered in Europe and was started in 2006. It is known as the European Sequencing of Tobacco Project or ESTobacco. This project is being conducted by Advanced Technologies (Cambridge) Ltd. (a wholly owned subsidiary of British American Tobacco) and Institut du Tabac de Bergerac (part of the Altadis Group). The aim of the ESTobacco project is to be complementary to other projects currently underway concerning the tobacco genome. The strategy of ESTobacco is to sequence only genes expressed in tobacco and not the whole genome. They believe that the size of the tobacco genome is too large to be totally sequenced. The tobacco genome is thought to be about twenty-nine times larger than that of Arabidopsis thaliana (Table XXII-1). The plan of the ESTobacco project is to investigate three commercial varieties of tobacco used throughout the world: K326 for the flue-cured type, and Burley 21 and TN86 for the burley types. To obtain the major genes, the organs of the plant (seeds, roots, stems, midribs, laminae, and flowers) prepared at different stages of development (germination, young seedlings, before and after topping, maturity) will be used as a basis for this work. A large tobacco EST dataset was obtained from eleven normalized cDNA libraries comprising 56000 clones. It is envisioned that a DNA array designed with these sequences will allow the large-scale study of Table XXII-1 Relative Size of Genomes and Number of Genes by Species Species Arabidopsis thaliana Homo sapiens Nicotiana tabacum

Genome Size (Mb)

Number of Genes

125 3000 3500 to 4500 (est.)

25500 20000 to 25000 25000 to 50000 (est.)

the genes expressed in tobacco. This new tool should lead to the acceleration of programs already underway concerning the origins of risks associated with tobacco and provide strategies for harm reduction. To encourage a wide range of initiatives on tobacco plant genetic, as with other crops, the resulting sequences obtained during the ESTobacco project will be available to the worldwide scientific community through public access databases (22A08, 22A26). As whole gene sequences and nucleotide sequences (DNA and RNA sequenced strands) become available they are being entered into GenBank (22A10). GenBank is the National Institute of Health (NIH) genetic sequence database, an annotated collection of all publicly available DNA sequences (22A02). There were approximately 65369091950 bases in 61132599 sequence records in the traditional GenBank divisions and 80369977826 bases in 17960667 sequence records in the Whole Genome Shotgun (WGS) division as of August 2006. GenBank is part of the International Nucleotide Sequence Database Collaboration, which comprises the DNA DataBank of Japan (DDBJ), the European Molecular Biology Laboratory (EMBL), and GenBank at the National Center for Biotechnology Information (NCBI). Information located in GenBank can be accessed on the Internet (1282a). Within the next few years, our understanding of the tobacco genome will be greatly improved. It is anticipated or predicted that advances in tobacco genomics will lead to the next major improvement in safety and health associated with cigarette smoking via genetic modifications of various Nicotiana species. The symposium at the 61st Tobacco Science Research Conference featured presentations from representatives from the TGI and the ESTobacco projects. Updates on both projects were given, as well as information on how new types of biotechnologies are being employed to provide both fundamental and practical information on genes that could be used to improve pest resistance, quality, yield of tobacco, and the safety of tobacco products (22A09, 22A20). In the late 1950s and through the 1960s enormous breakthroughs in DNA enzymology took place. For example, in 1955 Kornberg et al. (22A18) isolated DNA polymerase, and Weiss and Richardson (22A33) isolated DNA ligase in 1967. Smith and Wilcox (22A28) and Kelley and Smith (22A16) isolated and characterized the first sequence specific restriction nuclease in 1970. These enzymes, respectively, play roles in the synthesis of DNA molecules, the attachment of two or more DNA molecules to one another, and the breaking of DNA molecules into fragments. Importantly, these enzymes make it possible to create entirely new kinds of DNA molecules and, equally important, to manipulate the functioning of the genes located on these new molecules. The types of enzymes that Smith, Wilcox, and Kelley (22A16, 22A28) discovered are called restriction enzymes. Restriction enzymes recognize and cut specific short sequences of DNA. They are found in bacteria, which use the enzymes to digest invading DNA. The bacteria add methyl groups to their own DNA to protect them from digestion. Molecular biologists began using these enzymes, along with DNA polymerase and DNA ligase, in the early 1970s to cut, manipulate, and analyze

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Genes, Nucleotides, and Enzymes

pieces of DNA in a predictable and reproducible way. The enzymes became an important, early tool for mapping genomes. There are over 900 types of restriction enzymes that have been isolated from over 230 strains of bacteria. Some of these enzymes provide specific sequence segments of DNA and some do not. About 180 restriction enzymes are commercially available. There have been hundreds of thousands of nucleotide sequences (DNA and RNA sequenced strands) that have been produced via restriction enzymes from various forms of DNA and RNA in tobacco (22A13, 22A21). Not every DNA strand holds or is encoded with genetic information. There are considerable lengths of DNA that contain no genetic information or the function of which has yet to be identified. These segments are called “junk” or “non-coding” DNA. For example, about 97% of the human genome has been designated as “non-coding” (22A24). So, of the hundreds of thousands of nucleotide sequences that have been produced from various forms of DNA and RNA in tobacco, only a small percentage contains the essential genetic information needed to direct its life processes. However, all of these DNA and RNA strands serve a very important purpose during the construction of genomes. By employing sophisticated computer programs that can identify patterns in the bases in the DNA fragments, DNA fragments can be sequenced. “Fingerprinting” of large insert genomic fragment libraries, also known as BAC (bacterial artificial chromosomes) clones can lead to the construction of a physical map of a genome. These maps are critical to genome sequencing, positional cloning, and understanding the relative organization of genes and markers. When BAC libraries are arranged into maps that reflect the DNA sequence in a chromosome, they provide maximal information and utility. Generally, these BAC libraries are deposited in the GenBank. For example, BAC clone libraries for Nicotiana tabacum, currently being compiled as part of the TGI and ESTobacco projects, are being deposited in the GenBank. There are vast arrays of enzymes that have been identified in tobacco (429b, 429c, 3973). Plant enzymes perform valuable functions almost as soon as seeds are planted and continue to be important even through the tobacco curing process. Enzymes are in fact essential molecules that assimilate carbon dioxide from air (via photosynthesis), nitrogen by roots from the soil, and utilize hydrogen liberated by dehydrogenation from the components of the Krebs tricarboxylic acid (TCA) cycle to produce a variety of organic acids, for example, oxaloacetic and α-ketoglutaric acids. The net result of nitrogen assimilation is the utilization of a portion of newly photosynthesized carbon chains into the nitrogenous pool. When the nitrogen supply is abundant there will be more synthesis of amino acids, for example, aspartic and glutamic acids, and nicotine, and less sugars and starch. If the nitrogen supply is limited, there will be an excess accumulation of acetate in the TCA cycle, which results in higher production of carbohydrates, fats, volatile oils, resins, and polyterpenes. Tobacco enzymes efficiently and effectively control and regulate the type and level of tobacco constituents available to the plant for growth. The variations in leaf

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characteristics, texture, color, porosity, and combustibility, quality, for example, aroma and flavor based on chemical composition, and yield (poundage per acre/hectare) are a reflection of the genetic makeup of the plant, agronomic practices, soil types, and the environmental conditions (3972, 3973, 22A29, 22A30). Enzymes can either work individually or in teams. In a metabolic pathway (like the TCA cycle) several enzymes work together in a specific order, one enzyme takes the product of another enzyme as a substrate. Two sources of information on hundreds of enzymes that have been identified in tobacco are BRENDA and KEGG (429b, 429c). BRENDA: The Comprehensive Enzyme Information System is a database of enzymes and enzyme pathways. It was developed and is maintained at the Institute of Biochemistry at the University of Cologne and is available through the Internet at http://www.brenda.uni-koeln.de/. KEGG stands for the Kyoto Encyclopedia of Genes and Genomes. KEGG is a bioinformatics resource that was developed and is maintained as part of the research projects of the Kanehisa Laboratories in the Bioinformatics Center of Kyoto University and the Human Genome Center of the University of Tokyo. The phase of plant growth that extends from maturity to actual death (called senescence) is characterized by an accumulation of metabolic products, increase in respiratory rate, and a loss of dry matter (3973). At the senescence stage, enzyme activities (especially hydrolytic and other degradative enzyme systems) are intensified. These systems are responsible for breakdown of functional and structural components of the cell, such as proteins, nucleic acids, carbohydrates, and lipids. The latter stage of senescence resembles the early stage of leaf curing. Curing is a vital process which falls into the category of starvation phenomena or inanition of excised plant parts (3972, 3973). The most conspicuous chemical conversions during curing involve two phases. The first phase is dominated by hydrolytic enzymes and occurs in either flue curing or air curing. In this phase, disaccharides and polysaccharides are hydrolyzed to simple sugars; proteins are hydrolyzed to amino acids which undergo oxidative deamination; and the pectins and pentosans are hydrolyzed to pectic acid, uronic acid, and methyl alcohol. The second phase is dominated by oxidative reactions and takes place mostly in air-curing processes. Among the conversions are the following: oxidation of simple sugars to acids, oxygen and water; the increased oxidative deamination of amino acids leads to the formation of ammonia and amides, particularly asparagine; changes in organic acids, including conversion of malic to citric acid and also decarboxylations; and the oxidative and polymerization of phenols to brown products. There is a small decrease in alkaloids and some loss of dry weight (3972, 3973). Although not discussed specifically, the tobacco plant contains many thousands of different proteins that are produced by the plant to perform both structural and functional roles. The abundance and types of proteins differ according to the plant organ and cell type being considered. And at the cellular level, proteins with functional roles in chloroplasts and

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mitochondria may be encoded by the small DNA genomes of those organelles, or may be specified by nuclear genes and imported into those organelles. A significant percentage of proteins in the tobacco leaf are those involved in photosynthesis. This complex process is mediated by the action of hundreds of enzymes involved in the capture of energy from sunlight and the use of that energy to assimilate carbon dioxide from the atmosphere. A key enzyme responsible for this process is ribulose-1,5-bisphosphate carboxylase-oxygenase (sometimes referred to as RuBP carboxylase, or simply “Rubisco”) (22A35). It is an enzyme that has a dual function in that it catalyzes the carboxylation and oxygenation of ribulose-1,5-bisphosphate. Therefore, it catalyzes the crucial reactions of both photosynthesis and photorespiration, the ratio of these two processes determine plant productivity (3973, 3974c). This important enzyme is the most abundant individual leaf protein, and has been proposed as the most important and abundant single protein in nature. On the other hand, the majority of nicotine biosynthesis occurs in root tissues, so the enzymes involved in that process are expressed most abundantly in roots. Before the advent of modern plant biochemistry and molecular biology, tobacco leaves, as well as the leaves of other higher plants, were considered to possess two broad classes of proteins based on their solubility properties during extraction. Of the total tobacco leaf proteins, approximately half are “soluble” and half “insoluble.” The most abundant soluble protein came to be known as “Fraction-1 protein” (F-1 protein, shown to be primarily RuBP carboxylase), a material that can constitute as much as 50% of the total soluble tobacco leaf protein. During the 1980s, this material was considered as a potential source of food protein and for a number of other food applications due to its abundance and a number of other favorable properties. The remaining leaf protein, consisting of a multitude of smaller soluble proteins and unfractionated protein in the cytoplasm and chloroplast, was referred to as “Fraction-2 protein” (F-2 protein) (3973, 3974c). In addition to tobacco proteins having functional roles such as RuBP carboxylase, tobacco and other plants contain proteins the primary role of which is structural. For example, extensins, a family of glycoproteins rich in hydroxyproline residues, may constitute as much as 15% of the primary cell wall. Extensins are incorporated into the carbohydrate structure of cell walls and are thought to help provide structural support as cell walls develop. Contemporary research has tended to concentrate on the identification and function of individual proteins that play key roles in plant growth, development, and response to environmental cues. While much of this research has shifted from tobacco to the more easily manipulated model plant system Arabidopsis thaliana, tobacco continues to be the subject of considerable research due to the historical database of tobacco-specific information, its ease of genetic manipulation, and

The Chemical Components of Tobacco and Tobacco Smoke

its interesting biochemical pathways for alkaloid biosynthesis. This research has shown tobacco to possess an amazing diversity of proteins the roles of which continue to be elucidated. Tobacco “leaf protein” by itself contributes little to smoking quality, but it is a major precursor of hundreds of tobacco smoke components, for example, numerous nitrogenous compounds and amino acids. Similarly, other major tobacco components such as the carbohydrates, carboxylic acids, pigments, polyphenols, fatty compounds, phytosterols, and many primary or secondary compounds play a significant role in producing a myriad of tobacco smoke compounds (3972, 3973, 3974c). Plant material and smoke composition, are closely interrelated. Properties of leaf material can be modified through genetic and biochemical manipulation from seed to curing (22A30).

In dealing with an organic material as complex as tobacco, there are limitations in the range of possible changes that can be made to improve the biological interaction and metabolic balance within a plant system, and at the same time improve or alter the smoke composition and ultimately the biological activity of the smoke. The challenge that faces the tobacco industry today in light of the numerous possibilities that will come from the genetic mapping of Nicotiana tabacum is the development of new tobacco types that can satisfy farmers, manufacturers, regulators, and consumers in quality and tobacco safety. Solutions to the questions posed by Tso in 1972 (22A30) as to “what kinds of changes are needed (to produce safer tobacco products)?” And “how can these changes be achieved?” may be attainable in the future with the new-found knowledge from the genetic mapping of the tobacco genome. Table XXII-2 is a catalog of the genes, nucleotides (DNA and RNA strands), enzymes, and a few major proteins identified to date in tobacco. The format of this table differs from those in most other chapters since only one of the tobacco constituents is transferred intact to MSS (phytuberin). As a result, the Tobacco Smoke column was deleted from Table XXII-2. The catalog contains 491 entries. This number of entries represents only a very small fraction of the genes identified and nucleotides created recently during the tobacco genome projects. As more time passes, the totality of the genes and nucleotides identified in the tobacco genome will be published or made available in databases for researchers to access. The majority of the known enzymes identified in tobacco are contained in the catalog.

Acknowledgments The authors are grateful to Dr. Gary Hellmann and Dr. Lynwood Sawyer for review of this chapter.

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Genes, Nucleotides, and Enzymes

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The Chemical Components of Tobacco and Tobacco Smoke

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Genes, Nucleotides, and Enzymes

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXII-2 (Continued) Enzymes, Genes, Clones in Tobacco 



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987

Genes, Nucleotides, and Enzymes

Table XXII-2 (Continued) Enzymes, Genes, Clones in Tobacco 



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© 2009 by Taylor & Francis Group, LLC 78836_C022.indd 987

11/13/08 5:48:29 PM

988

The Chemical Components of Tobacco and Tobacco Smoke

Table XXII-2 (Continued) Enzymes, Genes, Clones in Tobacco 



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© 2009 by Taylor & Francis Group, LLC 78836_C022.indd 988

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Genes, Nucleotides, and Enzymes

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11/13/08 5:48:33 PM

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The Chemical Components of Tobacco and Tobacco Smoke

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Genes, Nucleotides, and Enzymes

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© 2009 by Taylor & Francis Group, LLC 78836_C022.indd 991

 11/13/08 5:48:37 PM

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXII-2 (Continued) Enzymes, Genes, Clones in Tobacco

© 2009 by Taylor & Francis Group, LLC 78836_C022.indd 992

11/13/08 5:48:39 PM

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Genes, Nucleotides, and Enzymes

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© 2009 by Taylor & Francis Group, LLC 78836_C022.indd 993

11/13/08 5:48:42 PM

994

The Chemical Components of Tobacco and Tobacco Smoke

Table XXII-2 (Continued) Enzymes, Genes, Clones in Tobacco

© 2009 by Taylor & Francis Group, LLC 78836_C022.indd 994

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995

Genes, Nucleotides, and Enzymes

Table XXII-2 (Continued) Enzymes, Genes, Clones in Tobacco 



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996

The Chemical Components of Tobacco and Tobacco Smoke

Table XXII-2 (Continued) Enzymes, Genes, Clones in Tobacco 



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997

Genes, Nucleotides, and Enzymes

Table XXII-2 (Continued) Enzymes, Genes, Clones in Tobacco 



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998

The Chemical Components of Tobacco and Tobacco Smoke

Table XXII-2 (Continued) Enzymes, Genes, Clones in Tobacco

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999

Genes, Nucleotides, and Enzymes

Table XXII-2 (Continued) Enzymes, Genes, Clones in Tobacco 



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23

“Hoffmann Analytes”

In essence, the terminology “Hoffmann analyte” or “Hoffmann-type analyte” or “Hoffmann list compound” had its beginning over two decades ago in 1985. Early that year, a Working Group of the International Agency for Research on Cancer (IARC) met to evaluate the carcinogenic risk of chemicals to humans, with particular emphasis on tobacco smoking. The next year, the Working Group’s assessment of tobacco smoking was published in an IARC monograph (1870). Among the twenty-eight members of the Working Group were Ernst L. Wynder and Dietrich Hoffmann from the American Health Foundation, whose participation in the discussions on the components of tobacco and particularly tobacco smoke was obviously quite extensive. The number of references cited in the various smoke component figures, tables, and appendixes in the IARC monograph (1870) reveals the extent of the Wynder-Hoffmann contribution to the Working Group study (see summary in Table XXIII-1). Nearly 44% of the citations on smoke components considered deleterious represented a Hoffmann-related publication. In all of the forty-four references listed in Table XXIII-1, Hoffmann was a co-author. A few months after the IARC 1985 Working Group meeting, Hoffmann and Wynder presented a paper on biologically active tobacco smoke components at a conference and its contents were published in 1986 (1808). Deriving their assessment of various tobacco smoke components from the conclusions of the IARC 1985 Working Group, Hoffmann and Wynder listed forty biologically active components in cigarette mainstream smoke (MSS) and sidestream smoke (SSS). Over the next decade and half, a series of articles were published with Hoffmann as a co-author of each and in each article was a listing of tobacco and/or smoke components that were classified as biologically active (1808, 1741), carcinogenic (1808, 1740, 1743, 1744), cocarcinogenic (1808), or tumorigenic (1717, 1773). Table XXIII-2 summarizes the chronology of the articles and the varied classifications of the activity of the components listed. In those publications in which the classification “biologically  active” was used, no mention was made of the fact that many biologically active components in tobacco smoke, for example, α-tocopherol and α- and β-4,8,13duvane-1,3-diol, have been demonstrated to exert anticarcinogenic or inhibitory effects on the activity of several tobacco smoke components considered potent tumorigens or mutagens [see Table 3 in (3255a), Table 6 in (3265), Table 11 in (3300)]. In contrast to the multiple listings of benz[a]anthracene (B[a] A) as a biologically active MSS component (1741, 1808) or as a tumorigen (1727, 1773) or as a carcinogen (1740, 1743, 1744), Hoffmann and Wynder (1786) reported in 1959 that, in their mouse skin-painting study, B[a]A co-administered

with benzo[a]pyrene (B[a]P) reduced the tumorigenicity of the B[a]P, that is, B[a]A was anticarcinogenic to B[a]P. Eventually the number of biologically active smoke components, primarily the tumorigens, was expanded from the forty-three listed in 1990 by Hoffmann and Hecht (1727) to eighty-two listed in 1998 by Hoffmann and Hoffmann (1740). Much of the increase was due to the inclusion of the N-heterocyclic amines and several vapor-phase components. Because of the change in its assessment concerning their tumorigenicity, chrysene and di(2-ethylhexyl) phthalate were no longer considered as tumorigens by the IARC. Several other similar lists, not co-authored by Hoffmann, were issued after 1986. They included the 1994 list by the U.S. Occupational Health and Safety Administration (OSHA) (2825) and the 2001 list by Fowles and Bates (1217). Neither of these lists differed significantly from those issued by Hoffmann and his colleagues between 1986 and 2001. Table XXIII-3 is a tabulation of the toxicants in tobacco and tobacco smoke from the IARC 1986 publication (1870) plus the seven lengthy publications co-authored from 1986 to 2001 by Hoffmann with his American Health Foundation colleagues. Examination of the various lists reveals several anomalies, none of which detracts from the meaningfulness of the publications. The anomalies include:









1. Several instances where the per cigarette yield range unit was listed as microgram in one article and nanogram in another, for example, the per cigarette yield range for quinoline listed as 1 to 2 ng in (1743) and 1 to 2 μg in (1744). 2. Several instances where the per cigarette yield range differs significantly in two different publications, for example, the per cigarette yield range for N-nitrosopyrrolidine is listed as 1.5 to 110 ng in (1727) and 3 to 60 ng in (1740). 3. Several instances where the per cigarette yield range differs in different tables in the same article, for example, the per cigarette yield range for catechol is listed as 25 to 360 µg in Table 5 in (1808), as 100 to 350 µg in Table 11 in (1808), and 140 to 500 µg in Table 13 in (1808). 4. The per cigarette yield range is listed for the wrong component, for example, the range 1.7 to 3.2 ng is listed for dibenzo[a,l]pyrene in (1741, 1743, 1744) but in each case that range should be listed for the omitted dibenzo[a,i]pyrene [see (1727, 1740, 1773)]. 5. In some instances, particularly with several PAHs, the per cigarette yield ranges include data generated from cigarettes manufactured in the 1950s 1001

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1002

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-1 Hoffmann Contributions on Smoke Components to the 1985 IARC Working Group on Tobacco Smoking

Item

No, of Hoffmann et al. References Cited

Hoffmann et al. References

Figure 5 Table 20

Some chemical constituents of tobacco smoke Concentrations of some PAHs and heterocyclic compounds in tobacco smoke

1 33

1 13

Table 21 Table 22 Table 23 Table 24

Concentrations of some phenols in tobacco smoke Concentrations of free fatty acids in cigarette smoke Concentrations of aromatic amines in cigarette smoke Concentrations of major pyridines and pyrazines in mainstream cigarette smoke Concentrations of N-nitrosamines in cigarette smoke Concentrations of N-nitrosamines in SSS of commercial cigarettes and cigars Physiochemical comparison of MSS and SSS of cigarettes Concentrations of selected compounds in nonfilter cigarette MSS and the ratio of their relative distribution in SSS Chemical compounds identified in tobacco smoke that have been evaluated for carcinogenicity in the IARC monograph series

11 1 1 2

3 1 1 1

3491 1560, 1699, 1763, 1765, 1766, 1779, 1780, 1800, 1803, 3088, 4308, 4312, 4317 497, 1703, 4332 1785 2900 512

1 2

1 2

1696 1685, 1696

2 6

2 1

1695, 1696 1720

6a

3

4332, 4348, 4348a

Table 25 Table 26 Table 30 Table 31 Appendix 2

a



Topic

No. of Specific References Cited

Three of the cited references were to IARC monographs.

1741, 1743, 1744, 1773, 1870) but an incorrect single value of 40 ng is listed in (1808); all DB[a,h] A listings in the references cited fail to take into account the reporting of a DB[a,h]A yield of 5 ng/cigarette by Van Duuren in 1958 (4020). The MSS yield of 4 ng/

and 1960s with “tar” and nicotine yields far in excess of more recently manufactured cigarettes. 6. The per cigarette yield range is incomplete, for example, a single value of 4 ng/cigarette is listed for dibenz[a,h]anthracene (DB[a,h]A) in (1727, 1740,

Table XXIII-2 Hoffmann-Related Lists of Toxicants in Tobacco and Tobacco Smoke Year

Authors

Ref. No.

1986

International Agency for Research on Cancer (IARC) Hoffmann and Wynder

1870

19

1808

5

1808

6

1808

13

1986

Table No.

1990

Hoffmann and Hecht

1727

3

1993

Hoffmann et al.

1773

1

1997 1998

Hoffmann and Hoffmann Hoffmann and Hoffmann

1740 1741

3 1

2001 2001

Hoffmann and Hoffmann Hoffmann et al.

1743 1744

5-4 4

Table Title Concentrations of biologically-active agents in nonfilter cigarette mainstream smoke Carcinogens and cocarcinogens in the smoke of a nonfilter cigarette Organ-specific carcinogens in cigarette smoke Biologically-active agents in mainstream smoke (of nonfilter cigarettes) Tumorigenic agents in tobacco and tobacco smoke Tumorigenic agents in tobacco and tobacco smoke Carcinogens in tobacco and cigarette smoke Biologically-active agents in the mainstream smoke of nonfilter cigarettes Carcinogens in cigarette smoke Carcinogens in cigarette smoke

No. of Component Listed 60 21 14 40 43 41 60 82 68 68

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1986

1986

1990

1993

1997

1998

2001

2001

IARC (1870) a

Hoffmann and Wynder (1808)

Hoffmann and Hecht (1727)

Hoffmann et al. (1773)

Hoffmann and Hoffmann (1740)

Hoffmann and Hoffmann (1741)

Hoffmann and Hoffmann (1743)

Hoffmann et al. (1744)

20-70 ng 40-70 ng b 4-76 ng c

40-70 ng g 40-60 ng j

20-70 ng

20-70 ng

20-70 ng

20-70 ng

20-70 ng

20-70 ng

Benzo[b]fluoranthene

4-22 ng 30 ng b

30 ng g

4-22 ng

4-22 ng

4-22 ng

4-22 ng

4-22 ng

4-22 ng

Benzo[j]fluoranthene

6-21 ng 60 ng b

60 ng g

6-21 ng

6-21 ng

6-21 ng

6-21 ng

6-21 ng

6-21 ng

Benzo[k]fluoranthene Benzo[a]pyrene

6-12 ng 20-40 ng 10-50 ng b 5-78 ng c

NL e

6-12 ng

6-12 ng

6-12 ng

6-12 ng

6-12 ng

6-12 ng

10-50 ng g 10-40 ng i

20-40 ng

20-40 ng

20-40 ng

20-40 ng

20-40 ng

20-40 ng

Component

Polycyclic Aromatic Hydrocarbons Benz[a]anthracene

Chrysene Chrysene, 5-methylDibenz[a,h]anthracene Dibenzo[a,e]pyrene Dibenzo[a,h]pyrene Dibenzo[a,i]pyrene

40-60 ng b 0.6 ng 4 ng Pd, NYLe Pd, NYLe 1.7-3.2 ng 2-3 ng b 17-32 ng c

40-60 ng g 0.6 ng 40 ng NLe NLe NL

40-60 ng 0.6 ng 4 ng NL NL 1.7-3.2 ng

40-60 ng 0.6 ng 4 ng NL NL 1.7-3.2 ng

NL 0.6 ng 4 ng NL NL 1.7-3.2 ng

NL 0.6 ng 4 ng P, NYLf NL NLf

NL 0.6 ng 4 ng P, NYLf NL NLf

NL 0.6 ng 4 ng P, NYLf NL NLf

Dibenzo[a,l]pyrene g Indeno[1,2,3-cd]pyrene

P, NYL 4-20 ng

P, NYL 4 ng

P, NYL 4-20 ng

P, NYL 4-20 ng

P, NYL 4-20 ng

1.7-3.2 ng f 4-20 ng

1.7-3.2 ng f 4-20 ng

1.7-3.2 ng f 4-20 ng

Pyridine

16-40 µg

NL

NL

NL

20-200 µg m

10-40 µg

20-200 µg s

Quinoline Dibenz[a,h]acridine h Dibenz[a,j]acridine

NL e 0.1 ng 2.7 ng 3-10 ng b 0.7 ng

NL 0.1 ng g 3-10 ng g

1-2 µg 0.1 ng 3-10 ng

0.2-1.3 µmg 0.1 ng 3-10 ng

1-2 µg 0.1 ng 3-10 ng

2-180 ng 0.1 ng 3-10 ng

20-200 µg p 16-40 µg r 1-2 ng x 0.1 ng 3-10 ng

0.7 ng g

0.7 ng

0.7 ng

0.7 ng

0.9 ng

0.7 ng

0.7 ng

2-20 ng 1-200 ng b 0-2.7 ng 0.1-10 ng b

1-180 ng h 2-180 ng j 1-40 ng h 0,1-40 ng j

0.1-180 ng

0.1-180 ng

0.1-180 ng

2-180 ng

2-180 ng

2-1000 ng

3-13 ng

3-13 ng

3-13 ng

3-13 ng

3-13 ng

3-13 ng

“Hoffmann Analytes”

78836_C023.indd 1003

Table XXIII-3 The Basis for the “Hoffmann Analytes”: The Lists of Toxicants Issued by HOFFMANN et al. from 1986 to 2001

Aza-arenes

7H-Dibenzo[c,g]carbazole

1-2 µg 0.1 ng 3-10 ng

N-Nitrosamines N-Nitrosodimethylamine N-Nitrosoethylmethylamine

© 2009 by Taylor & Francis Group, LLC

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(Continued)

1004

78836_C023.indd 1004

Table XXIII-3 (continued) The Basis for the “Hoffmann Analytes”: The Lists of Toxicants Issued by HOFFMANN et al. from 1986 to 2001 1986

1990

1993

1997

1998

2001

2001

Component

IARC (1870)a

Hoffmann and Wynder (1808)

Hoffmann and Hecht (1727)

Hoffmann et al. (1773)

Hoffmann and Hoffmann (1740)

Hoffmann and Hoffmann (1741)

Hoffmann and Hoffmann (1743)

Hoffmann et al. (1744)

N-Nitrosodiethylamine

0-2.8 ng 0-10 ng b 0-1 ng 0-3 ng 0-110 ng 2-42 ng b 0-9 ng 0-36 ng 0-90 ng b NL 0.2-3.0 µg 0.13-0.25 µg b 0.08-0.77 µg 0.08-0.7 µg b

0.1-28 ng

0-25 ng

0-25 ng

0-2.8 ng

0-2.8 ng

0-2.8 ng

0-2.8 ng

0-1 ng 0-3 ng 2-110 ng h 2-42 ng j 0-9 ng 0-40 ng

NL NL 1.5-110 ng

NL NL NL

NL NL 3-60 ng

0-1.0 ng 0-30 ng 3-110 ng

0-1.0 ng 0-30 ng 3-110 ng

0-1.0 ng 0-30 ng 3-110 ng

NL 0-36 ng

NL NL

NL 0-68 ng

0-9 ng 0-68 ng

0-9 ng 0-68 ng

0-9 ng 0-68 ng

NL 0.12-3.7 µg

NL 0.12-3.7 µg

NL 0.12-3.7 µg

NYL 0.12-3.7 µg

ND e 120-3.700 ng v

NL 0.12-3.7 µg v

NL 0.12-3.7 µg v

0.12-0.95 µg

0.08-0.77 µg

0.08-0.77 µg

0.08-0.77 µg

0.08-0.77 µg

0.08-0.77 µg

0.08-0.77 µg

0-150 ng 0-200 ng b NL 0-3.7 µg b NL

40-400 ng h 120 ng j NL

0.14-4.6 µg

0.14-4.6 µg

0.14-4.6 µg

0-150 ng

NL

NL

NL

NL

NL

NL

NL

NL

NL

ND k in MSS

ND in MSS

ND in MSS

ND in MSS

NL

NL

NL 32-160 ng 30-200 ng b NL NL 3-4 ng b 1.7-22 ng 1-22 ng b NL 2.4-4.6 ng 2-5 ng b

360 ng 30-160 ng

360 ng 30-200 ng

NL 30-200 ng

NL 30-200 ng

360-655 ng 30-337 ng

360-655 ng r 30-337 ng

NL 30-337 ng

NL NL

NL NL

NL NL

NL NL

NL NL

4-50 µg x NL

4-50 ng x NL

4.3-27 ng

1-22 ng

1-22 ng

1-22 ng

1-334 ng

1-334 ng

1-334 ng

NL 2.4-4.6 ng

NL 2-5 ng

NL 2-5 ng

NL 2-5 ng

NL 2-5.6 ng

NL 2-5.6 ng

NL 2-5.6 ng

N-Nitrosodi-n-propylamine N-Nitrosodi-n-butylamine N-Nitrosopyrrolidine N-Nitrosopiperidine N-Nitrosodiethanolamine N-Nitrososarcosine N’-Nitrosonornicotine 4-(N-Methylnitrosamino)1-(3-pyridyl)-1-butanone N’-Nitrosoanabasine N’-Nitrosoanatabine N-Nitrosomorpholine Aromatic Amines Aniline 2-Toluidine Aniline, 2,6-dimethyl1-Naphthylamine 2-Naphthylamine Biphenyl, 3-aminoBiphenyl, 4-amino-

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The Chemical Components of Tobacco and Tobacco Smoke

1986

NL NL NL NL NL NL NL NL NL

NL NL NL NL NL NL NL NL NL

NL NL NL NL NL NL NL NL NL

NL NL NL NL NL NL NL NL NL

25-260 ng 2-37 ng 0.37-0.89 ng 0.25-0.88 ng 11-23 ng 0.26 ng NL 0.29-0.48 ng 0.82-1.1 ng

25-260 ng 2-37 ng 6.37x-0.89 ng 0.25-0.88 ng 11-23 ng 0.3 ng NL 0.3-0.5 ng 0.8-1.1 ng

25-260 ng NL 0.37-0.89 ng 0.25-0.88 ng 11-23 ng 0.3 ng NL 0.3-0.5 ng 0.8-1.1 ng

25-260 ng 2-37 ng 0.37-0.89 ng 0.25-0.88 ng 11-23 ng 0.3 ng NL 0.3-0.5 ng 0.8-1.1 ng

70-100 µg 20-88 µg b 500-1200 µg 18-1400 µg b NL NL 10-20 µg 60-100 µg 25-140 µg b 100-250 µg NL

5-100 µg

70-100 µg

70-100 µg

70-100 µg

500-1200 µg

18-1400 µg

18-1400 µg

NL NL NL 50-100 µg

NL NL 10-20 µg NL

NL NL 10-20 µg NL

70-100 µg l 20-100 µg m 18-1400 µg l 400-1400 µg m NL NL NL 60-140 µg m

NL NL 10-20 µg 60-140 µg

70-100 µg 20-100 µg p 500-1400 µg u 400-1400 µg p NL NL NL 60-140 µg p

70-100 µg l 20-100 µg s 500-1400 µg u 400-1400 µg s NL NL NL 60-240 µg s

100-250 µg NL

NL NL

NL NL

100-650 µg m NL

NL NL

100-650 µg p NL

NL NL

20-75 µg

20-75 µg 25-40 µg p 450-1000 µg u 200-400 µg p 20-70 µg 12-50 µg p 20-60 µg p 10 µg

20-75 µg 25-40 µg s 450-1000 µg u 200-400 µg s 20–70 µg 6-70 µg s 5-90 µg s 10 µg

38-56 µg 3-15 µg P, NYL P, NYL 1.16 µg r 80-180 µg p 100-250 µg r NL

38-56 µg 3-15 µg P, NYL P, NYL

AaC MeAaC Glu-P-1 Glu-P-2 PhIP IQ MeIQ Trp-P-1 Trp-P-2

“Hoffmann Analytes”

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N-Heterocyclic Aminesk

Aldehydes and Ketones Formaldehyde Acetaldehyde Propionaldehyde Butyraldehyde Crotonaldehyde Acrolein Acetone 2-Butanone

500-1.400 µg u

Volatile Hydrocarbons 1,3-Butadiene

NL

NL

NL

NL

Isoprene

NL

NL

NL

NL

Benzene

20-50 µg

20-50 µg

12-48 µg

12-48 µg

Toluene Styrene

NL 10 µg

NL NL

NL NL

NL NL

20-75 µg l 25-40 µg m 450-1000 µg l 200-400 µg m 12–70 µg l 6-70 µg m 5-90 µg m 10 µg

38-56 µg b 3.2-15 µg b NL P, NYL NL NL

NL 3.2-15 µg NL NL NL NL

NL 3.2-15 µg NL P, NYL NL NL

NL 3.2-15 µg NL P, NYL NL NL

NL 3.2-15 µg P, NYL NYL NL 80-180 µg m

38-56 µg 3-15 µg P, NYL P, NYL 1.16 µg 100-250 µg

NL

NL

NL

NL

NL

1.5-5 µg

450-1.00 µg u 20–70 µg NL 10 µg

Miscellaneous Organic Compounds Acetamide Acrylonitrile Acrylamide Hydrazine, 1,1-dimethylMaleic hydrazide Methanol Methyl isocyanate

80-180 µg s NL (Continued)

1005

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1006

78836_C023.indd 1006

Table XXIII-3 (continued) The Basis for the “Hoffmann Analytes”: The Lists of Toxicants Issued by HOFFMANN et al. from 1986 to 2001 1986

1986

1990

1993

1997

1998

2001

2001

Component

IARC (1870) a

Hoffmann and Wynder (1808)

Hoffmann and Hecht (1727)

Hoffmann et al. (1773)

Hoffmann and Hoffmann (1740)

Hoffmann and Hoffmann (1741)

Hoffmann and Hoffmann (1743)

Hoffmann et al. (1744)

Nitromethane 2-Nitropropane

NL 0.2-2.2 µg 0.73-1.21 µg b NL 1.3-16 ng 1-16 ng b 20-38 ng NL NL NL NL

NL 0.2-2.2 µg

NL 0.73-1.21 µg

NL 0.73-1.21 µg

NL 0.73-1.21 µg

NL 0.2-2.2 µg

0.3-0.6 µg 0.7-1.2 µg

0.5-0.6 µg 0.7-1.2 µg

NL 1.3-16 ng

NL 1-16 ng

NL 1-16 ng

NL 1-16 ng

25 µg 11-15 ng

25 µg 11-15 ng

25 µg 11-15 ng

20-38 ng NL NL NL NL

20-38 ng NL NL NL NL

20-38 ng NL NL NL NL

20-38 ng 7 µg NL 20 µg 18-30 ng u

20-38 µg 7 µg 12-100 ng NL 18-37 ng u

20-38 µg 7 µg 0-100 ng NL 18-37 µg u

NL

NL

NL

NL

20-38 ng 7 µg NL 20 µg 18-30 µg l 20-40 µg m P, NYL

P, NYL

P, NYL

P, NYL

Phenol o-Cresol m-Cresol p-Cresol Catechol

60-140 µg 14-30 µg NL NL 40-350 µg

80-60 NL NL NL 200-400 µg

NL NL NL NL NL

NL NL NL NL NL

80-160 µg NL NL NL 200-400 µg

80-160 µg r NL NL NL 100-360 µg 200-400 µg r

60-180 µg t NL NL NL 90-2000 µg 100-200 µg t

Resorcinol Hydroquinone Methyleugenol Caffeic acid

8-80 µg b 88-155 µg b NL NL

60-140 µg NL NL NL 25-360 µg g 100-350 µgi 140-500 µg j NL 110-300 µg NL NL

NL NL NL NL

NL NL NL NL

NL NL NL NL

NL NL 20 ng NL

NL NL 20 ng < 3 µg

NL NL 20 ng < 3 µg

NL 0.7-1.2 µg b NL NL

NL

NL

NL

800-1200 ng

800-1.200 ng u

800-1200 µg

800-1200 µg

NL NL

NL NL

NL NL

200-370 ng NL

200-370 ng NL

200-370 µg NL

200-370 µg NL

NL

NL

NL

NL

NL

NL

NL

NL

24-43 ng NL 1-25 µg

24-43 ng NL NL

24-43 ng NL 40-120 ng

24-43 ng NL 40-120 ng

24-43 ng 20-90 µg m 40-120 ng

24-34 µg x 10-90 µg 40-120 ng

24-43 ng 20-90 µg p 40-120 µg

24-43 ng 20-90 µg s 40-120 µg

Nitrobenzene Vinyl chloride Ethyl carbamate Ethylene oxide Propylene oxide Di(2-ethylhexyl) phthalate Furan Benzo[b]furan Phenols

DDT DDE Polychlorodibenzop-dioxins Polychlorodibenzofurans Inorganic Components

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Hydrazine Hydrogen sulfide Arsenic

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The Chemical Components of Tobacco and Tobacco Smoke

Chloroaromatic Compounds

NL 9-70 ng 4-70 ng 0.2 ng 0-600 ng b NL Pc 0.03 pCi Pc

NL NL NL NL 20-3000 ng NL NL 0.03-1.0 pCi NL

NL 41-62 ng 4-70 ng NL 0-600 ng NL 35-85 ng 0.03-1.0 pCi NL

NL 41-62 ng 4-70 ng NL 0-600 ng NL 35-85 ng 0.03-1.0 pCi NL

NL 41-62 ng 4-70 ng NL 0-600 ng NL 35-85 ng 0.03-1.0 pCi NL

0.3 µg NL 4-70 ng 0.13-0.2 ng 0-600 ng 4 ng 34-85 ng 0.03-1.0 pCi NL

0.5 ng 7-350 ng 4-70 ng 0.13-0.2 ng 0-600 ng NL 34-85 ng 0.03-1.0 pCi NL

0.5 ng 7-350 ng 4-70 ng 0.13-0.2 ng 0-600 ng 34-85 ng 0.03-1.0 pCi NL

Nicotine Carbon monoxide Ammonia

1.0-2.3 mg 10-23 mg 50-130 µg

1.0-3.0 mg NL NL

NL NL NL

0.1-3.0 mg n 14-23 mg m 10-130 µg m

1.0-3.0 mg 10-23 mg 10-130 µg

1.0-3.0 mg q 14-23 mg p 10-130 µg p

0.1-3.0 mg t 14-23 mg s 10-130 µg s

Nitrogen oxides Hydrogen cyanide

100-600 µg 400-500 µg

1-2.5 mg 10-23 mg 50-170 µg i 50-130 µg j 50-600 µg 400-500 µg

NL NL

NL NL

100-600 µg m 400-500 µg m

100-600 µg 400-500 µg

100-600 µg p 400-500 µg p

100-600 µg s 400-500 µg s

“Hoffmann Analytes”

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Beryllium Cadmium Chromium (VI) Cobalt Nickel Mercury Lead Polonium-210 Selenium Additional Components

See Table 19 in (1870). See Appendix 2 in (1870). c See Table 20 in (1870) d P = present, as listed in Appendix 2 in (1870). e NL= not listed; NYL = no per cigarette MSS yield listed; ND = not detected. f The yield range listed for dibenz[a,l]pyrene is incorrect. It is the range usually listed for dibenzo[a,i]pyrene. The P, NYL designation should also apply to dibenzo[a,l]pyrene. g See Table 5 in (1808). h See Table 6 in (1808). i See Table 11 in (1808). j See Table 13 in (1808). k AaC = 2-amino-9H-pyrido[2,3-b]indole; MeAaC = 2-amino-3-methyl-9H-pyrido[2,3-b]indole; Glu-P-1 = 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole; Glu-P-2 = 2-aminodipyrido[1,2-a:3’,2’-d] imidazole; PhIP = 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine; IQ = 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline; MeIQ = 2-amino-3,4-dimethyl-3H-imidazo[4,5-f]quinoline; Trp-P-1 = 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole; Trp-P-2 = 3-amino-1-methyl-5H-pyrido[4,3-b]indole l See Table 3 in (1740). m See Table 1 in (1740). n See Table 2 in (1740). p See Table 5-1 in (1743). q See Table 5-2 in (1743). r See Table 5-3 in (1743). s See Table 2 in (1744). t See Table 3 in (1744). u Compare yield listed in Table 1 in (1741), Table 5-4 in (1743), and Table 4 in (1744). v Compare yield listed in Table 1 in (1741) with those listed in (1727, 1740, 1743, 1744).

a

b

1007

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1008







cigarette of DB[a,h]A was obtained by Hoffmann and Wynder in the late 1950s (1787, 1788) from a 1959 cigarette and reported as such in 1963 by Wynder and Hoffmann [see Table 1 in (4317)]. 7. A component with no known per cigarette yield is treated the same as a component with literally hundreds of per cigarette yield values, for example, dibenzo[a,l]pyrene vs. B[a]P. 8. For the identification of dibenzo[a,l]pyrene in MSS, IARC [see Footnote 33 in Table  20 in (1870)] cited the footnote in the 1958 publication by Van Duuren (4020). However, like many other investigators [Lyons and Johnston (2430), Rodgman and Cook (3273), Wynder and Wright (4354), Wynder et al. (4355)], Van Duuren had reported the identification of dibenzo[a,l]pyrene in MSS. However, in 1966 Lavit-Lamy and Buu-Hoï (2314) reported that the compound previously thought to be dibenzo[a,l]pyrene was actually its isomer dibenz[a,e]aceanthrylene (dibenz[a,e] fluoranthene) [see also Lacassagne et al. (2250)]. In 1983, IARC had commented that all pre-1966 studies involved with dibenzo[a,l]pyrene were actually dealing with dibenz[a,e]fluoranthene not dibenzo[a,l]pyrene (1868a). Dibenzo[a,l]pyrene was eventually identified in MSS by Snook et al. (3756) but no quantitative data were given. 9. The repetitious inclusion in the lists published by Hoffmann and colleagues (1727, 1740, 1741, 1743, 1744, 1773, 1808) of the aza-arenes dibenz[a,h] acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g] carbazole reported by Van Duuren et al. despite the failure of numerous investigators in several countries between 1970 and 2000 to confirm their presence in MSS [(3260), also see Table  12-7 in Baker (172) and Table 4 in Rodgman (3265).

These and other anomalies were described in detail by Rodgman (3265). The many publications co-authored by Hoffmann (1727, 1740, 1741, 1743, 1744, 1773, 1808), each of which contained a list of biologically active components identified in tobacco smoke, led to two interesting episodes as a result of his efforts. Because of those numerous co-authored publications and the listing of toxicants in tobacco and tobacco smoke, Dr. Dietrich Hoffmann was dubbed “The Author of the List” in 2002 (23A05). This recognition was subsequently extrapolated in numerous scientific conference presentations and journal publications in which Dr. Hoffmann’s list contributions were acknowledged by the authors in the title of many scientific conference presentations and journal publications by inclusion of the term “Hoffmann analytes” or “Hoffmann-type analytes” or Hoffmann list compounds.” In some published articles, the term “Hoffmann analytes” does not appear in the title but does appear in the headings of tables in the articles, for example, in several publications by Baker and his colleagues at British American Tobacco

The Chemical Components of Tobacco and Tobacco Smoke

(BAT), the term “Hoffmann analytes” appears in the title of several tables (174a, 174c). Table XXIII-4 catalogs some of the presentations and/or publications in which the term “Hoffmann analyte” or its equivalent was used in tobaccorelated scientific literature from the year 2000 to 2006. Table XXIII-5 catalogs the components in the various lists co-authored by Hoffmann. In an attempt at simplification, the sequence of components in Table XXIII-5 approximates the sequence in many of the articles. Also in Table XXIII-5, the various components listed by Hoffmann and colleagues (1727, 1740, 1741, 1743, 1744, 1773, 1808) are listed in the most recently accepted nomenclature, for example, benzo[b]fluoranthene is listed as benz[e]acephenanthrylene, dibenzo[a,l]pyrene is listed as dibenzo[def,p]chrysene, catechol is listed as 1,2-benzenediol. In each case, the nomenclature used in the Hoffmann articles accompanies the most recent nomenclature listing. Also included in Table XXIII-5 are several components that do not appear in any of the Hoffmann co-authored lists but recently have been included with analyses of Hoffmannlisted components, for example, 1-naphthalenamine (1-aminonaphthalene; α-naphthylamine), 3-aminobiphenyl ([1,1’-biphenyl]-3-amine), propionaldehyde (propanal), butyraldehyde (butanal), and acetone (2-propanone). Table XXIII-5 includes several tobacco smoke components that the IARC has reclassified with regard to their tumorigenicity, for example, chrysene and di(2-ethylhexyl) phthalate. Thus, chrysene no longer appears on the more recent Hoffmann lists (1740, 1741, 1743, 1744) and di(2-ethylhexyl) phthalate was omitted from (1743, 1744). One point of interest in the Table XXIII-5 catalog is the tremendous number of references that deal with some aspect of the various Hoffmann-listed components. Over the years, numerous reports have been issued in which analytical data were presented on the per cigarette yields of numerous components in the MSS of the 1R4F Kentucky Reference Cigarette. Many of the analytes were defined as “Hoffmann analytes.” Table XXIII-6 summarizes several such analyses on the 1R4F MSS reported by Baker et al. [see Table 11 in (174b)], Rustemeir et al. (3370), and R.J. Reynolds Tobacco Company (RJRT) (3190)]. Also included in Table XXIII-6 are the “Hoffmann analyte” yields reported by Chen and Moldoveanu (688) for the MSS of the 2R4F Kentucky Reference Cigarette. Similar examples of “Hoffmann analyte” data are available in Baker et al. [see Table  12 in (174b)] and Rodgman and Green (3300). Table XXIII-6 lists the MSS analytes proposed by the Department of Health (Canada) (23A06). Assessment of all the lists in Table XXIII-6 reveals that the number of analytes in each case is in the mid-40s and most of them may be considered, based on the various listings by Hoffmann and his colleagues, as “Hoffmann analytes.” The sequence of components in Table XXIII-6 parallels the component class sequence usually used in the tables in the various articles by Hoffmann and colleagues (1727, 1740, 1741, 1743, 1744, 1773, 1808). Table XXVIII-6 also indicates the many components in the Hoffmann lists that are not usually analyzed or included in the “Hoffmann analyte” list of forty-four or forty-five biologically active components.

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“Hoffmann Analytes”

Table XXIII-4 An Abbreviated Chronology of the Use of the Term “Hoffmann Analyte” or Its Equivalent in Tobacco Smoke-Related Scientific Literature Year

Author(s) and Title of Article

2000

While it did not use the term “Hoffmann analyte” in its report, the Department of Health (Canada) proposed that analytical data on the following smoke components from tobacco smoke should be a requirement (23A06): “tar”, nicotine, formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, acrolein, crotonaldehyde, acetone, benzo[a]pyrene, NNN, NNK, NAB, NAT, 1-aminonaphthalene, 2-aminonaphthalene, 3-aminobiphenyl, 4-aminobiphenyl, pyridine, quinoline, styrene, catechol, resorcinol, hydroquinone, phenol, o-cresol, m-cresol, p-cresol, eugenol, 1,3-butadiene, isoprene, benzene, toluene, acrylonitrile, NH3, CO, HCN, NO, NOx, As, Cd, Cr, Pb, Hg, Ni, Se. Examination of the Department of Health (Canada) list reveals that most of its listed components appear in the biologically-active component lists in the publications co-authored by Hoffmann (1727, 1740, 1741, 1743, 1744, 1773, 1808).

2001

In a memorandum to the Department of Health (Canada), Levine (23A10) described the results of an inter-laboratory comparison on “Hoffmann analytes” in the MSSs from three different cigarette brands.

2001

At the 55th Tobacco Science Research Conference (TSRC), Purkis et al. (3007) in their description of the reliability of measurements of smoke analytes discussed the measurement of 44 “Hoffmann analytes.” Their TSRC presentation was published in 2003.

2002

At the 56th TSRC, Baker and Willoughby (later Bishop) (172a) described the compounds generated by the pyrolysis of relatively volatile tobacco ingredients. Subsequently, the presentation was published in 2004 and linked to the “Hoffmann analyte” concept.

2002

At the 56th TSRC, Cashmore (631) presented a paper entitled: Alternative smoking regimes: Hoffmann analyte formation and prediction as a consequence of changing smoking regimes and filter vent blocking.

2003

At the 57th TSRC, Chang et al. (23A04) presented a paper entitled: Influence of tip ventilation on Hoffmann analyte deliveries.

2003

In their study of a new Kentucky Reference Cigarette 2R4F, Chen and Moldoveanu (688) described the quantitation of more than 44 analytes in smoke, including most compounds considered as biologically active and described elsewhere as “Hoffmann analytes.” They referred to the biologically-active components listed in 1998 by Hoffmann and Hoffmann (1741).

2003

At the 57th TSRC, Dimandia et al. (23A07) described the analysis of Hoffmann list compounds by comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry

2003

Also at the 57th TSRC, Ellisor et al. (23A08) described the variation in the level of Hoffmann analytes for cigarette MSS when a large volume of air passes through the collection device and Volgger et al. (23A14) described the influence of different cigarette paper properties on the formation of Hoffmann type analytes in smoke.

2003

Warren presented two papers at the 57th TSRC; both of which dealt with “Hoffmann analytes.” They were entitled: The Hoffmann analyte to ‘tar’ ratio paradox (4136) and Prediction of mainstream cigarette smoke Hoffmann analyte yields by statistical modeling (4137).

2004

Baker and Bishop (172a) in their report on the pyrolysis of tobacco ingredients noted the following: Of the approximately 4800 substances in tobacco smoke (1373), 44 are believed…to be relevant to tobacco-related diseases (23A06). These include…some volatile carbonyl compounds, tobacco-specific N-nitrosamines, aromatic amines, phenols, volatile alkenes, benzo[a]pyrene and metals. These substances are sometimes called colloquially ‘Hoffmann analytes’ since similar lists of toxicological substances have been proposed by Dietrich Hoffmann et al. of the American Health Foundation in New York since the mid 1980s. The latest compilation by Hoffmann et al. lists 82 substances (1741, 1743, 1744). From their experimental findings, BAKER and BISHOP concluded: Particular attention has been paid to assessing the generation of ‘Hoffmann analytes’, i.e., biologically-active analytes in smoke, from the pyrolysis of the ingredients. In general, the number of ‘Hoffmann analytes’ detected among the pyrolytic products of the ingredients, and their levels, are low. (Continued)

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-4 (continued) An Abbreviated Chronology of the use of the Term “Hoffmann Analyte” or Its Equivalent in Tobacco Smoke-Related Scientific Literature Year

Author(s) and Title of Article

2004

In a series of three papers on the effect of tobacco ingredients on smoke chemistry, Baker et al. (174a, 174b, 174c) did not include the term “Hoffmann analyte” or its equivalent in the three titles. However, the term “Hoffmann analyte” was used throughout each of the publications. E.g., in the abstract of Baker et al. (174a), it is stated: The studies are: pyrolysis of the ingredients; influence of the ingredients on smoke constituents believed by regulatory authorities to be relevant to smoking-related diseases (“Hoffmann analytes”)… The term “Hoffmann analytes” also appeared in the title of Table 3 in (174a). In the abstract of Baker et al. (174b), the following was stated: The effects of 450 tobacco ingredients added to tobacco on the forty-four “Hoffmann analytes” in mainstream cigarette smoke have been determined…They are based on lists published by D. Hoffmann and co-workers of the American Health Foundation… In their summary of the effect of casing ingredients on smoke composition, Baker et al. (174c) stated: The effects of 29 casing flavour ingredients and three humectants on the yields of 44 “Hoffmann analytes” in cigarette smoke have been assessed. The term “Hoffmann analytes” also appeared in the title of Table 10 in (174c).

2004

Case and Warren (23A03) were issued a European patent on a multivariate regression system for predicting “Hoffmann analytes” in tobacco smoke. While the term “Hoffmann analyte” did not appear in the title of the patent, in its text the term was used as follows: The concentration of yields of a first set of components in a particular tobacco smoke, such as the Hoffmann analytes, are predicted on the basis of a statistical model.

2004

Imperial Tobacco Co. (23A09) discussed “Hoffmann analytes” as follows: Additional information may be requested by governmental agencies. This may include measurements of large numbers of smoke constituents of regulatory interest such as the “Hoffmann analytes” (usually a list of 44 smoke constituents). We have participated in studies requested by Australian and UK agencies and have provided information to Health Canada. Our interpretation of these studies, other studies in the literature, and our own internally-produced data is that these smoke constituents are generally proportional to tar measurements for a given blend style.

2004

At the 58th TSRC, Loureau et al. (2400d) described the influence of cigarette paper and filter ventilation on the yields of “Hoffmann analytes.”

2004

At the CORESTA Congress in Japan, Röper et al. (23A11) presented a paper entitled: “Hoffmann” analytes and cigarette smoke in vitro toxicity revisited – How do the data compare?

2005

Baker and Bishop (172b) did not mention the term “Hoffmann analyte” in the title of their publication on the pyrolysis of non-volatile tobacco ingredients but did note the following: The study has concentrated on the biologically active substances produced by pyrolysis, in particular the “Hoffmann analytes.” These analytes are believed by regulatory authorities in Canada and U.S.A. to be relevant to smokingrelated diseases. They are based on lists published by Hoffmann and co-workers of the American Health Foundation in New York. For the pyrolysis of many of the non-volatile ingredients, no “Hoffmann analytes” were detected amongst the products. When they were occasionally formed, they included phenols, benzene, toluene, styrene and furfural (furfural is biologically active but it does not appear on any of the Hoffmann or regulatory authority lists).

2005

At the CORESTA Joint Study Group Meeting in Stratford-on-Avon, U.K. in 2005, BAT personnel presented the following three papers under the general heading The effect of cigarette design variables on assays of interest to the Tobacco Industry: Case et al. (23A01) presented the first paper subtitled: 1) Experimental design and some initial findings on Hoffmann analyte yields. Sheppard et al. (23A12) presented the second paper subtitled: 2) Prediction of smoke and Hoffmann analytes using two different modeling methods. Winter et al. (23A15) presented the third paper subtitled: 3) Tobacco blend types. Although the latter paper did not include the term “Hoffmann analytes” in its title, its abstract indicated it involved the examination of the potential relationships between various tobacco blend components and “Hoffmann analyte” yields across three distinct lamina tobacco blend styles, Virginia, burley, and Oriental plus a 1:1 Virginia:burley mixture.

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1011

“Hoffmann Analytes”

Table XXIII-4 (continued) An Abbreviated Chronology of the use of the Term “Hoffmann Analyte” or Its Equivalent in Tobacco Smoke-Related Scientific Literature Year

Author(s) and Title of Article

2005

At the 59th TSRC, Zemann et al. (4406a) presented a paper entitled: On-line puff-by-puff analysis of gaseous and Hoffmann analytes in cigarette smoke

2006

At the 60th TSRC, Case et al. (23A02) presented a paper entitled: The role of cigarette paper and other factors that influence Hoffmann analyte yields in sidestream smoke.

2006

Also at the 60th TSRC, Streibel et al. (23A13) presented a paper entitled: Real-time on-line characterization of selected Hoffmann analytes in inhaled and exhaled cigarette smoke (mouthspace) by photo ionisation time-of-flight mass spectrometry.

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1012

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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“Hoffmann Analytes”

1013

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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1014

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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“Hoffmann Analytes”

1015

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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1016

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1016

11/24/08 12:37:17 PM

“Hoffmann Analytes”

1017

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1017

11/24/08 12:37:18 PM

1018

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1018

11/24/08 12:37:19 PM

“Hoffmann Analytes”

1019

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1019

11/24/08 12:37:20 PM

1020

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1020

11/24/08 12:37:20 PM

“Hoffmann Analytes”

1021

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1021

11/24/08 12:37:21 PM

1022

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1022

11/24/08 12:37:22 PM

“Hoffmann Analytes”

1023

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1023

11/24/08 12:37:23 PM

1024

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1024

11/24/08 12:37:24 PM

“Hoffmann Analytes”

1025

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1025

11/24/08 12:37:25 PM

1026

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1026

11/24/08 12:37:26 PM

“Hoffmann Analytes”

1027

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1027

11/24/08 12:37:27 PM

1028

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1028

11/24/08 12:37:28 PM

“Hoffmann Analytes”

1029

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1029

11/24/08 12:37:29 PM

1030

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1030

11/24/08 12:37:30 PM

“Hoffmann Analytes”

1031

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1031

11/24/08 12:37:31 PM

1032

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1032

11/24/08 12:37:31 PM

“Hoffmann Analytes”

1033

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1033

11/24/08 12:37:32 PM

1034

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1034

11/24/08 12:37:33 PM

“Hoffmann Analytes”

1035

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1035

11/24/08 12:37:34 PM

1036

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1036

11/24/08 12:37:35 PM

“Hoffmann Analytes”

1037

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1037

11/24/08 12:37:36 PM

1038

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1038

11/24/08 12:37:37 PM

“Hoffmann Analytes”

1039

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1039

11/24/08 12:37:38 PM

1040

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1040

11/24/08 12:37:39 PM

“Hoffmann Analytes”

1041

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1041

11/24/08 12:37:42 PM

1042

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1042

11/24/08 12:37:42 PM

“Hoffmann Analytes”

1043

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1043

11/24/08 12:37:43 PM

1044

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1044

11/24/08 12:37:44 PM

“Hoffmann Analytes”

1045

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1045

11/24/08 12:37:45 PM

1046

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1046

11/24/08 12:37:45 PM

“Hoffmann Analytes”

1047

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1047

11/24/08 12:37:46 PM

1048

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued) “Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1048

11/24/08 12:37:47 PM

1049

“Hoffmann Analytes”

Table XXIII-6 Reported Yields of “Hoffmann Analytes” in 1R4F (174b, 3190, 3370) and 2R4F (688) Mainstream Smoke; Proposed MSS “Hoffmann Analyte” Yield Analyses (23A06) 1R4F 1988

Component

CAS No.

RJRT (3190)

56-55-3 205-99-2

10.5 —

205-82-3 207-08-9 50-32-8 218-01-9 3697-24-3 53-70-3 192-65-4

— — 9.2 — — — —

189-64-0

1R4F

2R4F

Proposed

2002

2004

2003

2000

Rustemeier et al. (3370)

Baker et al. [Table 11 in (174b)]

Chen and Moldoveanu (688)

Department of Health (Canada) (23A06)

Polycyclic Aromatic Hydrocarbons Benz[a]anthracene, ng/cig Benzo[b]fluoranthene, ng/cig (benzo[e]acephenanthrylene) Benzo[j]fluoranthene, ng/cig Benzo[k]fluoranthene, ng/cig Benzo[a]pyrene, ng/cig Chrysene, ng/cig Chrysene, 5-methyl-, ng/cig Dibenz[a,h]anthracene, ng/cig Dibenzo[a,e]pyrene, ng/cig (naphtho[1,2,3,4-def]chrysene) Dibenzo[a,h]pyrene, ng/cig (dibenzo[b,def]chrysene) Dibenzo[a,i]pyrene, ng/cig (benzo[rst]pentaphene) Dibenzo[a,l]pyrene, ng/cig (dibenzo[def,p]chrysene) Indeno[1,2,3-cd]pyrene, ng/cig

10.1

— —

— —

— —

— —

5.10 14.4 <7.60 <0.60 —

— — 6.51 — — — —

— — 5.51 — — — —

— — 6.96 — — — —

— — × — — — —

—

—

—

—

—

—

189-55-9

—

—

—

—

—

—

191-30-0

—

—

—

—

—

—

193-39-5

—

2.63

—

—

—

—

110-86-1 91-22-5 226-36-8 224-42-0 194-59-2

2.09 0.235 — — —

— — — <2.72 —

7.7 0.34 — — —

7.47 0.30 — — —

7.02 0.23 — — —

× × — — —

— — — — — — — — —

— — — — — — — — — 107.09 90.69

— — — — — — — — — 133.11 115.61

— — — — — — — — — × ×

 5.63 

Aza-Arenes Pyridine, μg/cig Quinoline, μg/cig Dibenz[a,h]acridine, ng/cig Dibenz[a,j]acridine, ng/cig 7H-Dibenzo[c,g]carbazole, ng/cig N-Nitrosamines N-Nitrosodimethylamine, ng/cig N-Nitrosoethylmethylamine, ng/cig N-Nitrosodiethylamine, ng/cig N-Nitrosodi-n-propylamine, ng/cig N-Nitrosodi-n-butylamine, ng/cig N-Nitrosopyrrolidine, ng/cig N-Nitrosopiperidine, ng/cig N-Nitrosodiethanolamine, ng/cig N-Nitrososarcosine, ng/cig N’-Nitrosonornicotine, ng/cig 4-(N-Methylnitrosamino)-1-(3pyridyl)-1-butanone, ng/cig N’-Nitrosoanabasine, ng/cig N’-Nitrosoanatabine, ng/cig N-Nitrosomorpholine

62-75-9 10595-95-6 55-18-5 621-64-7 924-16-3 930-55-2 100-75-4 1116-54-7 13256-22-9 16543-55-8 64091-91-4

ND ND ND — — 14.0 — — — 101.0 84.0

<4.40 — — — — 12.5 — <4.30 — 124 138

37620-20-5 71267-22-6 59-89-2

18.0 114.0 —

18.6 104.9 —

22 96 —

19.37 122.49 —

16.28 119.02 —

× × —

— — —

— — —

— — 5.1

— — 15.63

— — 15.06

— — ×

106 96

Aromatic Amines 2-Toluidine, ng/cig Aniline, 2,6-dimethyl-, ng/cig 1-Naphthylamine, ng/cig

95-53-4 87-62-7 134-32-7

(Continued)

© 2009 by Taylor & Francis Group, LLC 78836_C023.indd 1049

11/24/08 12:37:47 PM

1050

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-6 (continued) Reported Yields of “Hoffmann Analytes” in 1R4F (174b, 3190, 3370) and 2R4F (688) Mainstream Smoke; Proposed MSS “Hoffmann Analyte” Yield Analyses (23A06) 1R4F 1988

1R4F

2R4F

Proposed

2002

2004

2003

2000

Rustemeier et al. (3370)

Baker et al. [Table 11 in (174b)]

Chen and Moldoveanu (688)

Department of Health (Canada) (23A06)

Component

CAS No.

RJRT (3190)

2-Naphthylamine, ng/cig Biphenyl, 3-amino-, ng/cig Biphenyl, 4-amino-, ng/cig

91-59-8 2243-47-2 92-67-1

— — —

— — —

12.6 3.3 2.3

10.40 3.20 1.94

26148-68-5 68006-83-7 67730-11-4 67730-10-3 105650-23-5 76180-96-6 77094-11-2 62450-06-0 62450-07-1

— — — — — — — — —

— — — — — — — — —

— — — — — — — — —

— — — — — — — — —

50-00-0 75-07-0 123-38-6 123-72-8 123-73-9 107-02-8 67-94-1 78-93-3

— — — — — — —

16.5 518 — — — 46.3 — —

19.5 674 56.4 35.1 24.9 69.0 338 80.7

22.19 623.88 51.54 33.93 15.90 60.64 293.15 68.08

21.61 560.48 43.92 29.58 16.18 58.77 264.74 62.72

× × × × × × ×

106-99-0 78-79-5 71-43-2 108-88-5 100-42-5

— — 45.2 68.1 2.1

42.7 319 39.8 67.2 —

30.4 361 49.3 89.6 7.9

32.10 308.08 44.33 68.08 6.13

29.94 297.68 43.39 64.91 5.11

× × × × ×

60-35-5 107-13-1 79-06-1 57-14-7 75-52-5 79-46-9 98-95-3 75-01-4 51-79-6 75-21-8 75-56-9 117-81-7 110-00-9 271-89-6

2.2 7.6 1.1 — — — — — — — — — — —

— — — — — — — 30.0 — — — — — —

— 9.4 — — — — — — — — — — — —

— 9.51 — — — — — — — — — — — —

— 8.28

— × — — — — — — — — — — — —

108-95-2 95-48-7

6.8 1.8

11.79 3.31

9.80 3.04

9.63 2.62

10.32 2.97 1.73

× × ×

N-Heterocyclic Amines AaC, ng/cig MeAaC, ng/cig Glu-P-1, ng/cig Glu-P-2, ng/cig PhIP, ng/cig IQ, ng/cig MeIQ, ng/cig Trp-P-1, ng/cig Trp-P-2, ng/cig

— — — — — — — — —

Aldehydes and Ketones Formaldehyde, μg/cig Acetaldehyde, μg/cig Propionaldehyde, μg/cig Butyraldehyde, μg/cig Crotonaldehyde, μg/cig Acrolein, μg/cig Acetone, μg/cig 2-Butanone, μg/cig Volatile hydrocarbons 1,3-Butadiene, μg/cig Isoprene, μg/cig Benzene, μg/cig Toluene, μg/cig Styrene, μg/cig Miscellaneous Organic Compounds Acetamide, μg/cig Acrylonitrile, μg/cig Acrylamide, μg/cig Hydrazine, 1,1-dimethyl-, ng/cig Nitromethane, μg/cig 2-Nitropropane, μg/cig Nitrobenzene, μg/cig Vinyl chloride, ng/cig Ethyl carbamate, ng/cig Ethylene oxide, μg/cig Propylene oxide, ng/cig Di(2-ethylhexyl) phthalate, μg/cig Furan, μg/cig Benzo[b]furan, ng/cig Phenols Phenol, μg/cig o-Cresol, μg/cig

7.32 1.89

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1051

“Hoffmann Analytes”

Table XXIII-6 (continued) Reported Yields of “Hoffmann Analytes” in 1R4F (174b, 3190, 3370) and 2R4F (688) Mainstream Smoke; Proposed MSS “Hoffmann Analyte” Yield Analyses (23A06) 1R4F 1988

1R4F

2R4F

Proposed

2002

2004

2003

2000

Rustemeier et al. (3370)

Baker et al. [Table 11 in (174b)]

Chen and Moldoveanu (688)

Department of Health (Canada) (23A06)

Component

CAS No.

RJRT (3190)

m-Cresol, μg/cig p-Cresol, μg/cig Catechol, μg/cig Resorcinol, μg/cig Hydroquinone μg/cig Methyleugenol, μg/cig Caffeic acid, μg/cig

103-39-4 106-44-5 120-80-9 108-46-3 123-31-9 93-15-2 331-39-5

1.6 4.1 38.0 3.0 37.0 — —

2.55 6.36 53.8 0.83 43.3 — —

{8.55

{7.43

{5.84

35.3 <1.1 34.9 — —

40.57 0.94 42.77 — —

37.90 0.91 32.40 — —

× × × × × — —

50-29-3 72-55-0 — —

— — — —

— — — —

— — — —

— — — —

— — — —

— — — —

302-01-2 7440-38-2 7440-41-7 7440-48-4 7440-02-0 7440-47-3 7440-43-9 7439-97-6 7439-92-1 7782-49-2 7440-08-6

— — — — — — — — — — —

— 3.33 — — <2.63 <1.32 24.7 — 10.1 — —

— <15 — — <12 <5 47 6.5 36 <20 —

— 12.21 — — 6.44 57.74 55.09 5.43 42.51 39.81 —

— 10.39 — — 5.12 73.01 47.82 3.82 32.95 34.85 —

— × — — × × × × × × —

54-11-5 630-08-0 7664-41-7 10102-43-9

0.79 11.3 18.0 — 234 89.0 —

0.74 10.0 — — 263 80.8 —

0.74 — — — — — —

0.80 12.26 12.90 319.88 348.34 128.93 9.38

0.75 11.96 11.02 223.41 268.98 109.20 8.91

× × × × × × ×

Chloroaromatic Compounds DDT DDE Polychlorodibenzo-p-dioxins Polychlorodibenzofurans Inorganic Components Hydrazine Arsenic, ng/cig Beryllium Cobalt Nickel, ng/cig Chromium (VI), ng/cig Cadmium, ng/cig Mercury ng/cig Lead, ng/cig Selenium ng/cig Polonium-210 Additional Components Nicotine, mg/cig Carbon monoxide, mg/cig Ammonia, μg/cig Nitric oxide, μg/cig Nitrogen oxides, μg/cig Hydrogen cyanide, μg/cig “Tar”, mg/cig

74-90-8

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11/24/08 12:37:48 PM

24

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

For nearly four decades after the early 1950s an exceptional amount of information was generated on the composition of the various types of tobacco, the smoke from many of the types, and the relationship between the two. Although much of the information has been published, much has not. Exemplary in this regard was the research conducted by personnel not only at the R.J. Reynolds Tobacco Company but also at many other tobacco companies. Much information has been published in peer-reviewed journals and the remainder is available on the Internet. In the early tobacco and tobacco smoke studies, the chemical nature of one or two components was defined by means of classical chemical procedures, for example, the identification of the terpenoid alcohol solanesol in flue-cured tobacco (3359), the phenols eugenol and isoeugenol in the mainstream smoke (MSS) from Oriental tobacco (3280), and maltol in the MSS from an ingredient-free German tobacco blend (1131). However, as analytical methodology became more sophisticated and precise, many more components—sometimes several hundred newly identified in tobacco or smoke—were reported in a single publication. In 1986, each major U.S. cigarette manufacturer listed the ingredients used at that time in its cigarette products. A combined list was submitted to the U.S. Office of Smoking and Health. That list, comprising 599 additives, was subjected by a panel of eminent toxicologists not only to an extensive literature survey but also to an examination of unpublished data provided by the tobacco industry members on the chemistry and toxicology of the ingredients. The panel assessed the safety of each listed ingredient with regard to its pyrolysate components and its possible effect when added to cigarette tobacco on the chemical and biological properties of the cigarette mainstream smoke. The results were summarized in 1994 by Doull et al. (1053). Of the 599 ingredients, 460 (∼77 %) are individual compounds. The remaining items are mixtures such as natural oils, plant extracts, oleoresins, etc. Many investigators have noted in their publications that numerous compounds on the list of ingredients are tobacco and/or cigarette mainstream smoke (MSS) components. The following pages chronicle such a relationship between individual added components and their presence in untreated tobacco and/or its smoke. While Paschke et al. (2896) attempted to catalog every material ever added to tobacco and its effect on MSS chemical and/ or biological properties, this chapter deals only with those materials in the list by Doull et al. Although some of the additives cataloged by Paschke et al. did reduce the responses in specific bioassays and the levels of some MSS components

considered toxic, they also rendered the MSS unacceptable to the consumer. Obviously, the ingredients listed by Doull et al. did not suffer from such a problem since their addition was specifically designed to enhance the acceptability to consumers of the MSS from the product. As a beginning, Doull et al. (1053) in their report noted: Many of the ingredients added to cigarettes are identical or essentially similar in composition to natural leaf tobacco components.

In their 1998 report of the effect on rats of inhalation of MSS from ingredient-treated tobacco cigarettes, Gaworski et al. (24A04) expressed a similar view: The addition of flavoring ingredients to the cigarette prior to smoking did not significantly alter the type or extent of biologic changes normally seen in smoke-exposed rodents. Given the fact that many of the added flavoring ingredients are structurally similar or identical to natural constituents of tobacco leaf or of tobacco smoke itself [Lloyd et al. (2389)], these results are not totally unexpected.

Later, Rustemeier et al. (3370) in their description of the chemistry of MSS from ingredient-treated tobacco cigarettes noted: Many of these compounds or mixtures are also natural constituents of the tobacco leaf.

Rodgman (3263) concurred with the preceding statements when he wrote: Many flavorful tobacco additives listed by Doull et al. are structurally identical with or similar to highly polar, volatile components identified in the aqueous alcohol-soluble portion of cigarette MSS and tobacco.

More recently, Rodgman and Green (3300) wrote: With the capability to isolate and identify highly polar and volatile components of tobacco and its MSS, it was obvious that many were identical with or similar to ingredients of flavor formulations added to specific tobacco blends to impart unique smoking characteristics … Many “topdressing” components are structurally identical with or similar to identified tobacco components. With no evidence to the contrary, it is assumed that such an individual added flavorant would behave during the smoking process (in terms of direct transfer to smoke or degradation, reaction, etc.) much in the same manner as the naturally occurring tobacco component.

While many investigators considered many individual compounds added to cigarette tobacco filler to be tobacco and/or tobacco smoke components, it seemed worthwhile to catalog the extent to which this was true. Obviously, if 1053

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11/13/08 5:53:13 PM

1054

a specific flavorful compound is already a tobacco component, then its addition to tobacco is an attempt to enhance its flavorful effect. If it is a compound generated during the smoking process, then its addition to tobacco enhances the level in the smoke by tobacco-to-smoke transfer. The compounds added as ingredients to cigarette tobacco may fall into one of the following categories: • It is a component of one or more of the tobacco types (flue-cured, Oriental, burley, Maryland) commonly used in cigarette blends. • It is a component of cigarette MSS. • It is a component of both tobacco and tobacco smoke. • It is not a component of either the tobaccos or their smoke. An ingredient compositionally similar to but not identical with a tobacco leaf or smoke component may be categorized as an isomer or an homolog of a compound identified in natural tobacco leaf and/or its smoke. In the broad spectrum of chemistry, biochemistry, and biology, cases exist where the properties of one homolog vary significantly from those of another or where the properties of one isomer differ significantly from those of another. For example, whether classified as a “Group 2A carcinogen” by the International Agency for Research on Cancer (IARC) (1868a), or a significant carcinogen in cigarette MSS by Hoffmann and Hecht (1727), or overall as a borderline carcinogen by others, for example, Dipple et al. (983), the specific tumorigenicity of mice skin painted or subcutaneously injected with benz[a]anthracene (B[a]A) is insignificant compared to that of its homolog, 7,12-dimethylbenz[a]anthracene (DMB[a] A). The isomeric C20H12 polycyclic aromatic hydrocarbons (PAHs) benzo[a]pyrene (B[a]P) and benzo[e]pyrene (B[e] P) differ markedly in their specific tumorigenicities in studies involving mouse skin painting or subcutaneous injection (983). B[a]P under appropriate laboratory conditions is one of the most potent tumorigens known, whereas the isomeric B[e] P under the same conditions is essentially nontumorigenic. In the 1950s, the organic solvent extraction of tobacco was studied extensively with the purpose of removing PAH precursors from the tobacco. One process involved an aqueous ethanol-hexane partition to separate the polar, more flavorful tobacco components from the lipophilic PAH precursors. At that time, little was known about the nature of the polar tobacco components although it was apparent they made a considerable positive contribution to the flavor and aroma of cigarette MSS. Despite the lack of knowledge about the precise nature of the polar components, it was demonstrated they were not significant PAH precursors (3262). The lack of knowledge about the polar tobacco components was due to our inability to separate highly polar compounds in a complex mixture. This situation continued during years of intensive effort on cigarette MSS composition but was finally resolved and utilized by Schumacher et al. (3553) in the 1970s.

The Chemical Components of Tobacco and Tobacco Smoke

Among 1545 MSS components identified by Schumacher et al. (3553), Newell et al. (2769), and Heckman and Best (1587) were over 800 components new to the tobacco smoke literature, many of which were highly polar. By glass capillary gas chromatography, Grob (1416) also identified many polar components in the MSS from cigarettes containing additivefree tobacco. Later, it was shown that some of the identified polar components reported in MSS by Grob are also in the Doull et al. list (1053). With regard to tobacco, Lloyd et al. (2389) identified 275 previously unidentified components of additive-free fluecured tobacco, 132 new to all tobacco types. Many of these compounds were highly polar and considered significant contributors to MSS flavor and aroma. Similar studies were conducted on the composition of burley (3219), Oriental (3561, and Maryland (3550) tobaccos. Later, it became apparent that many of the highly polar components of tobacco and tobacco smoke were identical with or similar to many of the components used in the flavor additive formulations, that is, the “top dressing,” added to a specific tobacco blend to impart its unique smoking characteristics (1053). As previously mentioned, in the mid-1980s, each major U.S. cigarette manufacturer listed the ingredients added to its cigarette products at that time. In 1986, a combined list, comprising 599 entities, was submitted to the U.S. Office of Smoking and Health. From an extensive literature survey and examination of much unpublished data from the cigarette manufacturers on the chemistry and toxicology of the ingredients, a panel of eminent toxicologists assessed the safety of each listed ingredient with regard to its pyrolysis products and its possible effect when added to cigarette tobacco on the chemical and biological properties of cigarette mainstream smoke. Subsequently, Doull et al. (1053) listed the ingredients assessed and summarized the conclusions of the panel on their effect on the chemical and biological properties of cigarette smoke. In their assessment of available information on these ingredients variously used as cigarette tobacco ingredients, Doull et al. concluded that none of the materials used as flavorants on smoking tobacco products, particularly cigarettes marketed by U.S. manufacturers, imparted any significant adverse chemical or biological properties to the MSS from the ingredient-treated tobacco. However, Doull et al. did not publish an overview of the studies and reports they had examined or provide any details on their analysis. In their detailed assessment of reported chemical and biological properties of the MSS from cigarettes fabricated with tobacco with or without one or more additives, Paschke et al. (2895) reached a similar conclusion; namely, that in general, no significant increase in the biological activity of tobacco was reported from cigarettes containing specifically described added ingredients. In his examination of extensive laboratory data generated from additives and additive-treated cigarettes between the mid-1950s and the late 1970s, Rodgman (3263, 3264) reached a conclusion similar to that of Doull et al. (1053) and Paschke et al. (2896).

© 2009 by Taylor & Francis Group, LLC 78836_C024.indd 1054

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Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

Previously [see Table  1 in (3266)], the individual compounds listed by Doull et al. (1053) as possible U.S. cigarette ingredients were assigned a number somewhat indicative of the alphabetical order in which the 460 individual components were listed. That numerical listing is provided in Table XXIV-1A. A similar number assignment [see Table  7A in (3266)] was made in the case of individual components used as tobacco ingredients by cigarette manufactures outside of the United States. That numerical listing appears in Table XXIV-1B. In each case, a few citations on the identification of the component in tobacco and/or smoke were included in the previous publication [see Tables  1 and 7A in (3266)] to indicate that the ingredient was indeed a tobacco and/or tobacco smoke component. A more complete listing of citations on the identification of the ingredient in tobacco and/ or smoke is included in Table XXIV-2. Examination of the Reference column in Table XXIV-2 indicates that the number of references for many of the tobacco and/or tobacco smoke components used as ingredients is substantial. They not only include reports on the identification of the component in additive-free tobacco and/or its tobacco smoke but also reports on the effect of the added ingredient on MSS composition, particularly references dealing with “Hoffmann analyte” yields. In several instances, ingredients not previously included as tobacco and/or smoke components in (3266) are cataloged in Table XXIV-2 because of their identification in tobacco after the publication of (3266), for example, previously unidentified 2-hexenol and several naphthalene derivatives identified in tobacco by Peng et al. (2917a) and several esters identified in tobacco by Leffingwell and Alford (2339a). Examination of the data presented previously [see Tables 1 and 7A in (3266)] permits verification of the statements by numerous investigators that many of the ingredients in the Doull et al. list have been identified as components in untreated tobacco types and/or the MSS from cigarettes containing such tobaccos. Such an examination also permits an assessment of the effect of a number of the listed ingredients that have been reported in a variety of studies to not adversely affect the chemical or biological properties of the MSS from cigarettes containing such ingredients or the chemical properties of the pyrolysates from individual ingredients. Table XXIV-2 catalogs those individual compounds that have been identified in untreated tobacco and/or its tobacco smoke and are listed by Doull et al. (1053) as tobacco additives used by U.S. cigarette manufacturers in and prior to 1994. The references cited are pertinent not only to their tobacco/tobacco smoke identification but also to their effect on the chemical and biological properties of the MSS from cigarettes containing ingredient-treated tobacco. The components are cross-referenced to the numbers assigned to their listing in the Doull et al. (1053) and Baker et al. (174b, 174c, 24A01) articles (see Tables XXIV-1A and 1B). Over 260 of the 460 compounds (57%) listed by Doull et al. and nineteen of the fifty compounds (38%) in the Baker et al. list have been identified as components in additive-free tobacco and/ or its smoke.

1055

In 1957, Wynder (4296) proposed that reduction of the per cigarette “tar” yield by about 50% would have beneficial health-related results. By the late 1970s to the early 1980s the tobacco industry had exceeded the suggested reduction by generating the low-“tar” and ultralow-“tar” cigarette. This led to the criticisms and assertions that (1) some commercial low-“tar” brands might have additive levels much higher than those in previous high- and medium-“tar” cigarettes and (2) the fates during the cigarette smoking process of many individual added components were unknown. The criticisms and assertions of the early 1980s about tobacco additives were not new but an extension of those made earlier, for example, in 1967, Wynder and Hoffmann wrote about additives [see pp. 488 and 628 in (4332)]: The importance of flavor-enhancing agents as contributors to the tumorigenicity in the experimental animals varies for different tobacco products. For cigarettes it may be a minor factor compared to the overwhelming effects of other constituents and variables. Nevertheless, one should emphasize that further studies on the toxicity of flavorants and their combustion products could provide a scientific basis for the selection of less harmful additives … In evaluating the effect of tobacco additives, we need to consider whether such additions may contribute to the production of tumorigenic agents during the smoking of a tobacco product. If an additive increases the formation of carcinogenic substances during smoking to an analytically significant extent, it would, of course, be most undesirable. If, however, an additive should inhibit the production of tumorigenic agents during smoking and at the same time not yield other types of toxic substances, it may represent an effective and useful agent.

However, the proponents of problems with added tobacco ingredients became more vocal when the nearly 70% reduction in sales-weighted MSS “tar” yield achieved by 1985 not only answered the “tar” criticisms of the late 1950s and early 1960s but exceeded the goal that halving the “tar” yield was a means to lower lung cancer incidence in cigarette smokers (4296). In 1980, LaVoie et al. (24A07) wrote: The development of the low-tar, low-nicotine cigarette required cigarette fillers with a potential for smoke flavor contribution to make these cigarettes acceptable to the consumer. Such products can be realized either by selecting tobaccos rich in flavor or by addition of tobacco extracts or certain plant extracts, addition of synthetic flavor compounds, or a combination of several of these factors … New cigarettes should be assayed for toxicity and tumorigenicity, so that the reduction of toxic and tumorigenic effects in the smoke of low-tar, low-nicotine cigarettes is not offset by the introduction of unknown factors.

Despite their criticism of the possible increased use of flavorants in the filler of low-“tar,” low-nicotine cigarettes, the authors admitted that prior to 1980, the U.S. cigarette manufacturers had, apparently achieved a “reduction of toxic and tumorigenic effects in the smoke of low-‘tar,’ low-nicotine cigarettes.”

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1056

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-1A As Listed by Doull et al. (1053), Individual Ingredient Components Used in U.S. Smoking Products Note: The assigned numbers are those assigned by Rodgman (3266) to the individual component ingredients listed alphabetically in their more or less common name by Doull et al. (1053). Assigned No.

Name in Doull et al. (1053)

1a 2 3

Acetanisole Acetic acid Acetoin

4 5

Assigned No. 49

Name in Doull et al. (1053) 1,3-Butanediol

Assigned No. 97

50

2,3-Butanedione

Acetophenone 6-Acetoxydihydrotheaspirane

51 52 53

1-Butanol 2-Butanone 4-(2-Butylidene-3,5,5-trimethyl)2-cyclohexen-1-one

6 7 8 9 10

2-Acetyl-3-ethylpyrazine 2-Acetyl-5-methylfuran Acetylpyrazine 2-Acetylpyridine 3-Acetylpyridine

54 55 56 57 58

Butyl acetate Butyl butyrate Butyl butyryl lactate Butyl isovalerate Butyl phenylacetate

102 103 104 105 106

11

2-Acetylthiazole

59

Butyl undecylenate

107

12 13

Aconitic acid dl-Alanine

60 61

3-Butylidenephthalide Butyric acid

108 109

14

Allyl hexanoate

62

Cadinene

110

15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

Allylionone Ammonia Ammonium bicarbonate Ammonium hydroxide Ammonium phosphate dibasic Ammonium sulfide Amyl alcohol Amyl butyrate Amyl formate Amyl octanoate

63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96

Caffeine Calcium carbonate Camphene Carbon dioxide

111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144

a-Amylcinnamaldehyde Anethole transAnisyl acetate Anisyl alcohol Anisyl formate Anisyl phenylacetate l-Arginine Ascorbic acid l-Asparagine monohydrate l-Aspartic acid Benzaldehyde Benzaldehyde glyceryl acetal Benzoic acid Benzoin Benzophenone Benzyl alcohol Benzyl benzoate Benzyl butyrate Benzyl cinnamate Benzyl propionate Benzyl salicylate Bisabolene Borneol Bornyl acetate

b-Carotene cis-transCarvacrol 4-Carvomenthenol 1-Carvone b-Caryophyllene b-Caryophyllene oxide Cellulose Cinnamaldehyde Cinnamic acid Cinnamyl acetate Cinnamyl alcohol Cinnamyl cinnamate Cinnamyl isovalerate Cinnamyl propionate Citral Citric acid dl-Citronellol Citronellyl butyrate Citronellyl isobutyrate Cuminaldehyde p-Cymene l-Cysteine trans, trans-2,4-Decadienal d-Decalactone g-Decalactone Decanal Decanoic acid 1-Decanol 3-Decenal Dehydromenthofurolactone

Name in Doull et al. (1053) Diethyl malonate

98 99

Diethyl sebacate Diethylpyrazine (3 isomers)

100

Dihydroanethole

101

5,7-Dihydro-2-methylthieno[3,4-d] pyrimidine m-Dimethoxybenzene p-Dimethoxybenzene 2,6-Dimethoxyphenol Dimethyl succinate 3,4-Dimethyl-1,2cyclopentanedione 3,5-Dimethyl-1,2cyclopentanedione 3,7-Dimethyl-1,3,6-octatriene 4,5-Dimethyl-3-hydroxy2,5-dihydrofuran-2-one 6,10-Dimethyl-5,9-undecadien2-one 3,7-Dimethyl-6-octenoic acid 2,4-Dimethylacetophenone a,p-Dimethylbenzyl alcohol a,a-Dimethylphenethyl acetate a,a-Dimethylphenethyl butyrate 2,3-Dimethylpyrazine 2,5-Dimethylpyrazine 2,6-Dimethylpyrazine Dimethyltetrahydrobenzofuranone d-Dodecalactone g-Dodecalactone p-Ethoxybenzaldehyde Ethyl 10-undecenoate Ethyl 2-methylbutyrate Ethyl acetate Ethyl acetoacetate Ethyl alcohol Ethyl benzoate Ethyl butyrate Ethyl cinnamate Ethyl decanoate Ethyl fenchol Ethyl furoate Ethyl heptanoate Ethyl hexanoate Ethyl isovalerate Ethyl lactate Ethyl laurate Ethyl levulinate Ethylmaltol Ethyl methylphenylglycidate Ethyl myristate Ethyl nonanoate Ethyl octadecanoate

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1057

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

Table XXIV-1A (continued) As Listed by Doull et al. (1053), Individual Ingredient Components Used in U.S. Smoking Products Assigned No.

Name in Doull et al. (1053)

Assigned No.

Ethyl octanoate Ethyl oleate Ethyl palmitate Ethyl phenylacetate Ethyl propionate Ethyl salicylate Ethyl trans-2-butenoate Ethyl valerate Ethylvanillin 2-Ethyl-3-methoxypyrazine 2-Ethyl-5-methoxypyrazine 2-Ethyl-6-methoxypyrazine 2-Methyl-3-methoxypyrazine 2-Methyl-5-methoxypyrazine 2-Methyl-6-methoxypyrazine 2-Ethyl-1-hexanol 3-Ethyl-2-hydroxy-2cyclopenten-1-one 2-Ethyl-3,5-dimethylpyrazine 2-Ethyl-3,6-dimethylpyrazine

193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209

2-Heptenal Heptyl acetate w-6-Hexadecenlactone g-Hexalactone Hexanal Hexanoic acid 2-Hexen-1-ol 3-Hexen-1-ol cis-3-Hexen-1-yl acetate 2-Hexenal 2-Hexenoic acid 3-Hexenoic acid 3-Hexenyl formate Hexyl 2-methylbutyrate Hexyl acetate Hexyl alcohol Hexyl phenylacetate

241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257

Isobutyric acid dl-Isoleucine a-Isomethylionone 2-Isopropylphenol Isovaleric acid Lactic acid Lauric acid Lauric aldehyde l-Leucine Levulinic acid Linalool Linalool oxide Linalyl acetate l-Lysine Malic acid Maltol Maltyl isobutyrate

210 211

258 259

p-Mentha-8-thiol-3-one l-Menthol; l-menthol (synthetic)

212

260

l-Menthone

165

5-Ethyl-3-hydroxy-4-methyl2(5H)-furanone 2-Ethyl-3-methylpyrazine

261

Menthyl acetate

166 167 168 169 170 171

4-Ethylbenzaldehyde 4-Ethylguaiacol p-Ethylphenol 3-Ethylpyridine Eucalyptol Farnesol

214 215 216 217 218 219

l-Histidine 5-Hydroxy-2,4-decadienoic acid d-lactone 2,5-Dimethyl-4-hydroxy-3(2H)furanone 2-Hydroxy-3,5,5-trimethyl-2cyclohex-1-one 4-Hydroxy-3-pentenoic acid lactone 2-Hydroxy-4-methylbenzaldehyde 4-Hydroxybutanoic acid lactone Hydroxycitronellal 6-Hydroxydihydrotheaspirane 4-(p-Hydroxyphenyl)-2-butanone

262 263 264 265 266 267

172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192

d-Fenchone Furfurylmercaptan 4-(2-Furyl)-3-buten-2-one Geraniol Geranyl acetate Geranyl butyrate Geranyl formate Geranyl isovalerate Geranyl phenylacetate l-Glutamic acid l-Glutamine Glycerol Glycyrrhizin, ammoniated Guaiacol 2,4-Heptadienal g-Heptalactone Heptanoic acid 2-Heptanone 3-Hepten-2-one 2-Hepten-4-one 4-Heptenal

220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240

a-Ionone b-Ionone a-Irone Isoamyl acetate Isoamyl benzoate Isoamyl butyrate Isoamyl cinnamate Isoamyl formate Isoamyl hexanoate Isoamyl isovalerate Isoamyl octanoate Isoamyl phenylacetate Isobornyl acetate Isobutyl acetate Isobutyl alcohol Isobutyl cinnamate Isobutyl phenylacetate Isobutyl salicylate 2-Isobutyl-3-methoxypyrazine a-Isobutylphenethyl alcohol Isobutyraldehyde

268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288

dl-Methionine Methoprene 2-Methoxy-4-methylphenol 2-Methoxy-4-vinylphenol p-Methoxybenzaldehyde 1-( p-Methoxyphenyl)-1-penten3-one 4-(p-Methoxyphenyl)-2-butanone 1-(p-Methoxyphenyl)-2-propanone Methoxypyrazine Methyl 2-furoate Methyl 2-octynoate Methyl 2-pyrrolyl ketone Methyl anisate Methyl anthranilate Methyl benzoate Methyl cinnamate Methyl dihydrojasmonate Methyl isovalerate Methyl linoleate Methyl linolenate Methyl naphthyl ketone Methyl nicotinate Methyl phenylacetate Methyl salicylate Methyl sulfide 3-Methylcyclopentadecanone 4-Methyl-1-phenyl-2-pentanone

145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164

213

Name in Doull et al. (1053)

Assigned No.

Name in Doull et al. (1053)

(Continued)

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1058

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-1A (continued) As Listed by Doull et al. (1053), Individual Ingredient Components Used in U.S. Smoking Products Assigned No.

Name in Doull et al. (1053)

Assigned No.

Name in Doull et al. (1053)

Assigned No.

Name in Doull et al. (1053)

337 338

9,12,15-Octadecatrienoic acid d-Octalactone

383 384

Potassium sorbate l-Proline

339 340

g-Octalactone Octanal

385 386

5-Propenylguaethol Propionic acid

341 342

Octanoic acid 1-Octanol

387 388

Propyl acetate Propyl p-hydroxybenzoate

343 344

2-Octanone 3-Octen-2-one

389 390

Propylene glycol 3-Propylidenephthalide

345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364

1-Octen-3-ol 1-Octen-3-yl acetate 2-Octenal Octyl isobutyrate Oleic acid Palmitic acid w-Pentadecalactone 2,3-Pentanedione 2-Pentanone 4-Pentenoic acid 2-Pentylpyridine a-Phellandrene 2-Phenethyl acetate Phenethyl alcohol Phenethyl butyrate Phenethyl cinnamate Phenethyl isobutyrate Phenethyl isovalerate Phenethyl phenylacetate Phenethyl salicylate

391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410

Pyridine Pyroligneous acid Pyrrole Pyruvic acid Rhodinol Salicylaldehyde Sclareolide Skatole Sodium acetate Sodium benzoate Sodium bicarbonate Sodium carbonate Sodium chloride Sodium citrate Sodium hydroxide Solanone Sucrose octaacetate Sugar alcohols Sugars b Tannic acid

365 366 367

1-Phenyl-1-propanol 3-Phenyl-1-propanol 2-Phenyl-2-butenal

411 412 413

d-Tartaric acid a-Terpineol Terpinolene

321 322 323

5-Methyl-2-phenyl-2-hexenal 5-Methyl-2thiophenecarboxaldehyde 6-Methyl-3,5-heptadien-2-one 2-Methyl-(p-isopropylphenyl)propionaldehyde 5-Methyl-3-hexen-2-one 4-Isopropyl-3-methoxy1-methylbenzene 4-Methyl-3-penten-2-one 2-Methyl-4phenylbutyraldehyde 6-Methyl-5-hepten-2-one 4-Methyl-5-thiazoleethanol 4-Methyl-5-vinylthiazole Methyl-a-ionone 4-Methylacetophenone p-Methylanisole a-Methylbenzyl acetate a-Methylbenzyl alcohol 2-Methylbutyraldehyde 3-Methylbutyraldehyde 2-Methylbutyric acid a-Methylcinnamaldehyde Methylcyclopentenolone 2-Methylheptanoic acid 2-Methylhexanoic acid 3-Methylpentanoic acid 4-Methylpentanoic acid 2-Methylpyrazine 5-Methylquinoxaline 2-Methyltetrahydrofuran-3one Methyl methylthiopyrazine 3-Methylthiopropionaldehyde Methyl 3-methylthiopropionate 2-Methylvaleric acid Myristaldehyde Myristic acid

368 369 370

4-Phenyl-3-buten-2-ol 4-Phenyl-3-buten-2-one Phenylacetaldehyde

414 415 416

324

b-Naphthyl ethyl ether

371

Phenylacetic acid

417

325

Nerol

372

l-Phenylalanine

418

326 327 328 329 330 331 332 333 334 336

Nerolidol 2,6-Nonadienal 2,6-Nonadien-1-ol g-Nonalactone Nonanal Nonanoic acid 2-Nonanone 2-Nonen-1-ol 2-Nonenal 9,12-Octadecadienoic acid

373 374 375 376 377 378 379 380 381 382

3-Phenylpropionaldehyde 3-Phenylpropionic acid 3-Phenylpropyl acetate 3-Phenylpropyl cinnamate 2-(3-Phenylpropyl)tetrahydrofuran Phosphoric acid

419 420 421 422 423 424 425 426 427 428

a-Terpinyl acetate 5,6,7,8-Tetrahydroquinoxaline 1,5,5,9-Tetramethyl-13oxatricyclo[8,3,0,0(4,9)]tridecane 2,3,4,5Tetramethylethylcyclohexanone 3,4,5,6Tetramethylethylcyclohexanone 2,3,5,6-Tetramethylpyrazine Thiamine hydrochloride Thiazole l-Threonine Thymol a-Tocopherol o-Tolualdehyde m-Tolualdehyde p-Tolualdehyde p-Tolyl 3-methylbutyrate

289 290 291 292 293 294 295 296 297 298 299 300 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320

a-Pinene b-Pinene d-Piperitone Piperonal

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1059

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

Table XXIV-1A (continued) As Listed by Doull et al. (1053), Individual Ingredient Components Used in U.S. Smoking Products Assigned No.

Name in Doull et al. (1053)

Assigned No.

Name in Doull et al. (1053)

Assigned No.

2,6,6-Trimethylcyclohexa-1,3-dienylmethane 4-(2,6,6-Trimethylcyclohexa-1,3dienyl)-but-2-en-4-one 2,6,6-Trimethylcyclohexanone

452

Valencene

453

Valeraldehyde

454

Valeric acid

l-Tyrosine

455 456 457 458 459 460

g-Valerolactone Valine Vanillin Veratraldehyde Water 3,4-Xylenol

429

p-Tolylacetaldehyde

441

430

p-Tolyl acetate

442

431

p-Tolyl isobutyrate

443

433 434 435 436 437 438 439

Triacetin 2-Tridecanone 2-Tridecenal Triethyl citrate 3,5,5-Trimethyl-1-hexanol p,a,a-Trimethylbenzyl alcohol 4-(2,6,6-Trimethylcyclohex-2enyl)-but-2-en-4-one 2,6,6-Trimethylcyclohex-2ene-1,4-dione

445 446 447 448 449 450 451

440

d-Undecalactone g-Undecalactone Undecanal 2-Undecanone 10-Undecenal Urea

Name in Doull et al. (1053)

A number in bold print indicates the component has been identified as a tobacco and/or a tobacco smoke component (see Table XXIV-2).

a

Sugars include glucose, fructose, sucrose, galactose, and mannose

b

Table XXIV-1B As Listed by Baker et al. (174a), Individual Ingredient Components Not Used in U.S. Smoking Products but Used Outside of the U.S. Assigned No.

Name In

Assigned No.

Name In

Assigned No.

Name In

1A 2A 3A 4Ab 5A 6A 7A 8A 9A 10A 11A

Ambroxide Ammonium glycyrrhizinatea Amyl hexanoate Anisole Anisyl propionate Benzyl formate Benzyl isobutyrate Benzyl isovalerate Bornyl isovalerate Butyl valerate d-Carvone

18A 19A 20A 21A 22A 23A 24A 25A 26A 27A 28A

Ethyl isobutyrate Hexen-2-al 2-Hexenol 2-Hexenyl acetate Ionone Isoamyl propionate Isoamyl salicylate Isobutyl butyrate dl-Isomenthone Isopropyl myristate Linalyl benzoate

35A 36A 37A 38A 39A 40A 41A 42A 43A 44A 45A

12A

Cinnamyl isobutyrate

29A

Linalyl isobutyrate

46A

13A

Citronellal

30A

Methional

47A

14A

Citronellyl acetate

31A

48A

15A 16A 17A

Cyclamen aldehyde Dextrin 3-Ethyl-4-hydroxy-5-methyl3(2H)-furanone

32A 33A 34A

5H-5-Methyl-6,7dihydrocyclopenta-[b]pyrazine Menthyl isovalerate Methyl anthranilate c 1-Methyl-2,3-cyclohexadione

Methylcyclopentenolone 6-Methyl-5-hepten-2-one Methyl 2-octynate 4-Methyl-5-thiazole ethanol Neryl acetate d-Nonalactone Pectin Pent-4-en-4-olide Potassium citrate Rose oxide Sodium ethyl 4-hydroxybenzoate Sodium methyl 4-hydroxybenzoate Sodium propyl 4-hydroxybenzoate Sorbic acid

49A 50A

Sorbitol Tetradecalactone

a

The Doull et al. list dos not include this item per se but does include glycyrrhizin, ammoniated (see Table XXIV-1A, item No. 184).

b

A number in bold print indicates the component has been identified as a tobacco and/or a tobacco smoke component (see Table XXIV-2).

c

Methyl anthranilate, a component in the Doull et al. list, was inadvertently listed in Table 7A in (3266)

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1060

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients Note: The number is square brackets [ ] is that previously assigned (3266) to the tobacco ingredient component listed by Doull et al. (1053); The number with an A in square brackets [ ] is that previously assigned (3266) to the tobacco ingredient component listed by Baker et al. (174b, 174c, 24A01) The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke.

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Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1061

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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1062

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1063

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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1064

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1065

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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11/13/08 5:53:31 PM

1066

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1067

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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11/13/08 5:53:36 PM

1068

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1069

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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11/13/08 5:53:41 PM

1070

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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11/13/08 5:53:42 PM

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1071

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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11/13/08 5:53:46 PM

1072

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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11/13/08 5:53:48 PM

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1073

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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11/13/08 5:53:56 PM

1074

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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11/13/08 5:53:59 PM

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1075

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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11/13/08 5:54:00 PM

1076

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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11/13/08 5:54:04 PM

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1077

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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11/13/08 5:54:05 PM

1078

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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11/13/08 5:54:09 PM

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1079

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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1080

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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11/13/08 5:54:16 PM

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1081

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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11/13/08 5:54:17 PM

1082

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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11/13/08 5:54:21 PM

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1083

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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1084

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1085

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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1086

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1087

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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1088

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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11/13/08 5:54:35 PM

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1089

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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1090

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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11/13/08 5:54:40 PM

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1091

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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1092

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1093

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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1094

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1095

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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1096

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1097

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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1098

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1099

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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1100

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

1101

Table XXIV-2 (Continued) Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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1102

In the U.S. Surgeon General’s 1979 report [see pp. 63–64 in (4005)] the following was written: The trend toward low-tar, low-nicotine cigarettes and toward a reduction of undesirable volatile smoke compounds has brought about major changes in the smoke flavor of cigarettes. The use of rolled stems and reconstituted tobacco sheet admixed with leaf lamina and the use of effective filter tips are major factors inducing changes in smoke flavor. All of these developments have led to increased use of flavor additives, especially for low-tar, low-nicotine cigarettes. In fact, these new cigarettes require flavor corrections by additives in order to be acceptable to the consumer. Tobacco extracts as well as nontobacco flavors, such as licorice, cocoa, fruit, spices, and floral compositions, are used … At present, the selection of tobacco flavor additives from the GRAS (Generally Regarded As Safe) List or from natural extract and the screening of their smoke decomposition products for toxicity or other biological activity are not required by law and are done voluntarily by manufacturers.

Temperatures to which flavorants added to tobacco are exposed and the duration of the exposure during the smoking process range from 500 to 700ºC and the few seconds of the puff duration, respectively. Many of the flavor additives listed by the Surgeon General are used in cooking and/ or baking where the exposure temperatures are lower than in the smoked cigarette but the exposure time to the elevated temperature is much longer. This raises the question: Will more toxic compounds be formed from a given flavorant during food preparation or during cigarette smoking? When questioned about the need to determine the generation of toxic substances from a GRAS list additive used in cooking and/or baking, the FDA stated such studies were not required of the foodstuff manufacturer nor could they be done by the FDA since it had neither the staff, facilities, nor funds to undertake such studies. In the U.S. Surgeon General’s 1981 report [see pp. 51–52 in (4009)] it was noted: Humectants and flavoring agents have long been used as additives in cigarette manufacture … In recent years, cigarette manufacturers’ advertisements have focused on the flavor of new lower “tar” and nicotine cigarettes, enhanced presumably by the addition of tobacco constituents or by the addition of new flavoring materials, such as natural and synthetic chemicals. The identities and amounts of the additives actually used in the manufacture of U.S. cigarettes are not known. Systematic information has not been published or made available on the influence of these additives on the composition or biological activity of cigarette smoke.

A similar comment was made in the 1982 Surgeon General’s report [see pp. 217–218 in (4010)]: The development of the low-tar cigarette required enrichment of smoke flavors in order to make the product acceptable to the consumer. The flavor is enhanced by addition of undescribed materials that may include concentrates of flavor precursors obtained from tobacco, licorice, extracts from other plants, or semisynthetic or fully synthetic flavor components. Because these additives have not been identified, no

The Chemical Components of Tobacco and Tobacco Smoke judgment can be made as to whether they result in new compounds or higher concentrations of hazardous components in the smoke. The practice of flavor enrichment requires detailed toxicological studies that are not available at present for scientific evaluation of their impact [LaVoie et al. (2314c); USPHS (4005)].

In the 1994 report by Doull et al. (1053) and the 2000 report by Paschke et al. (2895) on their analysis of reports on the effects of added cigarette tobacco ingredients on the chemical and biological properties of its MSS, both groups essentially reached the same conclusion: The added ingredients under the conditions of use contributed no adverse chemical or biological properties to the MSS. In their 1997 review of the “changing cigarette,” Hoffmann et al. (1716) did not discuss low-“tar” cigarettes or the presumed use of additional flavoring materials, identity unknown. In a second 1997 article on cigarette design changes implemented between 1950 and 1995, Hoffmann and Hoffmann [see pp. 345–346 in (1740)] discussed the casing additives sugars and humectants (glycerol, propylene glycol, diethylene glycol) but did not mention that some cigarette manufacturers do not use diethylene glycol. The transfer of humectants to cigarette MSS and their significant contribution to FTC “tar” yield were ignored. On flavor additives, they wrote: In April 1994, the major U.S. cigarette companies released a list of 599 additives used at that time for the manufacture of cigarette [Doull et al. (1053)]. However, in the past, additional reactive flavor additives have been used (such as angelica lactone and linalool oxide; Leffingwell (2336)). An exception is menthol, which amounts to less than 2.5 mg in U.S. mentholated cigarette [Perfetti and Gordin (2923)]. Menthol is not carcinogenic in rodents [National Cancer Institute (24A10)], nor does this readily volatilized compound give rise to measurable amounts of carcinogenic hydrocarbons during smoking of cigarettes [Jenkins et al. (1936)]. Yet it is possible that the spraying of tobacco with menthol affects the burning characteristics of a cigarette and thus changes the concentration of toxic and/or tumorigenic agents in the smoke.

The Hoffmanns obviously ignored what Wynder and Hoffmann [see p. 527 in (4332)] wrote about the findings of Bock et al. (355) on the specific tumorigenicity of the MSS from menthol cigarettes: The results of Bock et al. [355] suggest no difference in tumorigenic activity of heptane-soluble “tar” from a mentholated cigarette compared with a plain cigarette when tested on a gram-to-gram basis.

Over the years it has been repeatedly asserted that cigarette ingredients added at normal levels to pre-1980 cigarettes or at slightly increased levels to more recent lower-“tar” cigarettes might adversely modify the chemistry and biology of the MSSs from such cigarettes. However, despite these repeated assertions, no chemical or biological evidence has been presented by those authorities making such assertions in support of their assertions. Table XXIV-3 summarizes many of the chemical and biological studies conducted since 1994 on the effect of tobacco

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1103

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

Table XXIV-3 A Summary of Tobacco Ingredient Studies Conducted from 1997 to Date

Analysis

Date

Number of Ingredients Studied

Detailed literature survey of ingredients added to U.S. tobacco products

1994

599

It was concluded that there was no evidence that any ingredient added to commercial cigarette tobacco produces harmful effects under the conditions of use in cigarettes.

Doull et al. (1073)

Effect of added tobacco ingredients on cigarette MSS chemistry

2002

333

Carmines (603); Rustemeier et al. (3370)

2002

482

2004

450

The smoke chemistry data revealed changes towards both higher and lower amounts of various smoke constituents…This suggests that the addition of 333 commonly used ingredients to cigarettes in three groups did not add to the toxicity of the smoke, even at the exaggerated levels tested… An overall assessment of our data suggests that these ingredients, when added to the tobacco, do not add to the toxicity of smoke, even at the elevated levels used in this series of studies. In most cases, the flavour mixtures had no statistically significant effect on the smoke yields relative to the control cigarette. In a few cases, the small increases or decreases were observed for some analytes relative to the control cigarette. The smoke yields of the experimental cigarettes were well within the ranges observed in the three reference cigarettes. The significances of differences between the test and control cigarettes were determined using both the variability of the data on the specific occasion of the measurement, and also taking into account the long-term variability of the analytical measurements over the one-year period in which analyses were determined in the present study. This long-term variability was determined by measuring the levels of the 44 “Hoffmann analytes” in a reference cigarette MSS on many occasions over the one-year period of this study. The effects of 450 tobacco ingredients (many were individual compounds listed in Tables XXIV-IA and IB) added to tobacco as seven different mixtures on the yields of 44 “Hoffmann analytes” in cigarette MSS were determined. In most cases, the flavoring ingredient mixtures had no significantly statistical effect on the MSS “Hoffmann analyte” yields vs. those from the control cigarette. Occasionally, with some mixtures, differences would be observed in some “Hoffmann analyte” yields. The effects of 29 casing ingredients and three humectants added to tobacco as eight different mixtures on the yields of 44 “Hoffmann analytes” were determined. Many of the ingredient mixtures had no statistically significant effect on the MSS “Hoffmann analyte” yields vs. those from the control cigarette. An increase in one “Hoffmann analyte”, formaldehyde, was reported when the ingredient mixture contained sugar.

2004

32

Reported Findings/ Conclusions

Reference

Baker and Smith (24A01)

Baker et al. (174b)

Baker et al. (174c)

(Continued)

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1104

The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-3 (CONTINUED) A Summary of Tobacco Ingredient Studies Conducted from 1997 to Date

Analysis

Date

Number of Ingredients Studied

1997, 2002

≈152

2002

333

2002

482

1997, 2002

2 (glycerol, propylene glycol)

1997

1 (menthol)

1998

170

2002

333

c) MSS CSC and skin painting

1999

150

Pyrolysis of tobacco ingredients under conditions simulating those in the cigarette burning zone

2002/2004

291

Effect of added tobacco ingredients on cigarette MSS biology: a) in vitro genotoxicity and cytotoxicity

b) MSS smoke inhalation

Reported Findings/ Conclusions

Although the mutagenic activities appeared to be similar, there were statistically significant differences in mutagenic activities among the samples. [The differences were primarily due to the increase in mutagenicity of the CSC when the humectants (glycerol, propylene glycol) were not added to the cigarette tobacco and thus were not present as diluents in the CSC]. Within the sensitivity and specificity of the test systems, the in vitro mutagenicity and cytotoxicity of the cigarette smoke were not increased by the addition of the ingredients. The data has been analyzed and demonstrates no additional activity from the flavored cigarettes above that of the control products. It was concluded that addition of the tested humectants singly or in combination had no meaningful effect on the site, extent or frequency of respiratory tract changes associated with smoke exposure in rats. The results of this 13-week inhalation study indicated that the addition of 5000 ppm menthol to tobacco had no substantial effect on the character or extent of the biological responses normally associated with inhalation of mainstream cigarette smoke in rats. The results indicate that the addition of flavoring ingredients to cigarette tobacco had no discernible effect on the character or extent of the biologic responses normally associated with inhalation of mainstream cigarette smoke in rats. The data indicate that the addition of these 333 commonly used ingredients, added to cigarette in three groups, did not increase the inhalation toxicity of the smoke, even at the exaggerated levels used. While tumor incidence, latency and multiplicity data occasionally differed between test and comparative reference CSC groups, all effects appeared to be within normal variation for the model system. Furthermore, none of the changes appeared to be substantial enough to conclude that the tumor promotion capacity of CSC obtained from cigarettes containing ingredients was discernibly different from the CSC obtained from reference cigarettes containing tobacco processed without ingredients. The results are compatible with parallel studies in which the ingredients are added to tobacco and the effect on cigarette smoke constituents are measured. In general, the number of “Hoffmann analytes” detected among the pyrolysis products of the ingredients, and their levels, are low…Of the 291 tobacco ingredients pyrolyzed, almost a third transfer out of the pyrolysis zone intact, and almost two thirds transfer at least 95% intact.

Reference

Bioresearch [for RJRT] (24A02); Rodgman (3263, 3264)

Carmines (603); Roemer et al. (24A11)

Massey et al. (24A09)

Heck et al. (24A06)

Gaworski et al. (24A03)

Gaworski et al. (24A04)

Carmines (603) ; Vanscheeuwijck et al. (24A12) Gaworski et al. (24A05)

Baker and Bishop (172a)

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1105

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

Table XXIV-3 (CONTINUED) A Summary of Tobacco Ingredient Studies Conducted from 1997 to Date

Analysis

Date

Number of Ingredients Studied

2003

2004

482

2004

1 (glycerol)

2005

159 non-volatile and complex ingredients (these ingredients were not individual compounds)

2006

1(sugar)

Reported Findings/ Conclusions

A review of the pre-2003 studies on the effect of added ingredients on the chemical and biological properties of cigarette MSS with emphasis on the yields of the “Hoffmann analytes.” Their discussion included various published (603, 1053, 3263, 3264, 3266, 24A03, 24A04, 24A05, 24A06) and prepublished (172a, 174a, 174b, 3314a, 3370, 24A09, 24A11, 24A12) manuscripts on tobacco ingredients. This publication summarized the reported findings on the 482 tobacco ingredients studied by Baker et al. (174b, 174c). The major conclusion: Many of the added tobacco ingredient mixtures produced no significant effect on the yields of many of the “Hoffmann analytes” in the cigarette MSS. In a series of three biological studies on genotoxicity and cytotoxicity, the response due to MSS exposure was not distinguishable between the ingredient-treated cigarette and the control. A study to determine the effect of different levels of added glycerol on cigarette MSS yields: The glycerol transfer was proportional to that added to the tobacco blend. With a system simulating cigarette combustion conditions, pyrolysis of many of the non-volatile ingredients gave no “Hoffmann analytes.” When occasionally formed, the “Hoffmann analytes” included phenols, benzene, toluene, and styrene. Biologically-active furfural, never listed as a significant biologically-active smoke component by Hoffmann and his colleagues (1727, 1740, 1741, 1743, 1744, 1773, 1808), was occasionally formed. This study was an extension of the previously reported effect (174c) of sugar ingredients on the MSS yield of formaldehyde.

Reference

Baker and Smith (174e)

Baker et al. (174a)

Liu (2380)

Baker and Bishop (172b)

Baker et al. (172c)

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1106

ingredients on the chemical and biological properties of the MSS from cigarette containing a particular added ingredient or ingredient mixture. Many of the scientific criteria suggested by the Life Sciences Research Office (LSRO) personnel (24A08) are incorporated in the tabulated investigations. It is interesting that the LSRO in its 2004 monograph [see p. 50 in (24A08)] wrote about the Doull et al. list of 460 individual compounds: “However, the fate of very few of these chemicals has been studied in cigarettes.” This statement was made about the “very few” chemicals despite the listing by LSRO [see pp. 45–46 in 24A08)] of the studies by Baker et al. (174b, 174c), Massey et al. (24A09), and Baker and Smith (24A01) on 482 ingredients, the studies by Gaworski et al. (24A03, 24A04, 24A05) and Heck et al. (24A06) on over 170 ingredients, the studies by Carmines (603), Roemer et al. (24A11), Rustemeier et al. (3370), and Vanscheeuwijck et al. (24A12) on 333 ingredients. In the latter studies (603, 3370, 24A11, 24A12), over 210 of the 333 ingredients (63%) were listed by Doull et al. as individual tobacco ingredients. Can more than 210 vs. 333 be considered “very few” agents in the smoke? LSRO is probably correct in its assessment of the number of individual components with a precise fate study but examination and understanding of the pyrolysis data and effect of many of them on MSS chemical and biological properties provide much significant data on

The Chemical Components of Tobacco and Tobacco Smoke

their behavior in a smoked cigarette. To date, there is much more known on the effect of added tobacco ingredients on MSS properties than there is on the effect of foodstuff additives on the properties of cooked foodstuffs. Despite the wealth of information now available from the studies outlined in Table XXIV-3 that indicate that the ingredients—whether tobacco compounds or nontobacco compounds—added to cigarette tobacco do not significantly alter the MSS chemical or biological properties, none of the critics of tobacco ingredients has challenged the scientific findings presented in the publications listed, provided any contradictory scientific data, or suggested any additional definitive studies. This raises the question: Is this oft-repeated assertion about the deleterious effect of added tobacco ingredients like the many other anti-tobacco-smoking assertions that have no supporting data or for which contradictory data or equivocal data have been generated [see Table 1 in Rodgman et al. (3307)]?

ACKNOWLEDGMENT The authors are extremely grateful to the late Richard R. Baker for his meaningful contributions to several sections of this chapter that were included in part in previous ingredient publications.

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25

Pyrolysis

For many years, the fate during smoking of a compound added to cigarette tobacco was defined by its fate during pyrolysis as an individually pyrolyzed compound. The stimulus for this assertion was twofold: (1) many publications were available that indicated the pyrolysis of a large number of compounds—from relatively low molecular weight ones, such as acetylene, to much higher molecular weight ones, such as the sterols—yielded tumorigenic polycyclic aromatic hydrocarbons (PAHs); (2) the ingredients to improve the smoking quality of a cigarette were added at such a low level that analytical data on their effect on smoke composition was almost impossible to generate. Because of this analytical problem with additives to the cigarette filler, many investigators utilized pyrolysis of individual tobacco components or additives in an attempt to define the spectrum of products and their influence on tobacco smoke composition and properties. The assertion of the equivalence of the fate of a compound on pyrolysis vs. its fate in a cigarette tobacco filler during smoking persisted for over twenty years after the mid-1950s. As proponents of this equivalence, Wynder and Hoffmann [see pp. 346–347 in (4332)] wrote: Most pyrolysis studies with tobacco, tobacco extracts, extract fractions, individual components, and tobacco additives are performed in a nitrogen atmosphere. This procedure has often been criticized on the grounds that many of the toxic constituents formed during smoking of tobacco products occur as a result of combustion in air rather than in a nitrogen atmosphere. This criticism, however, cannot be maintained in view of studies by Newsome and Keith (2780) which demonstrated that a reducing rather than an oxidizing atmosphere exists at the cone region of a burning cigarette.

Consideration of the effect of pyrolysis and the cigarette smoking process reveals the following: in both cases, a given compound may undergo a variety of reactions. In the case of pyrolysis, fragments produced from the compound during pyrolysis only have the opportunity to react with the unchanged compound itself or with each other. In the case of a smoked cigarette, the compound, either inherent in tobacco or added, generates fragments during the smoking process which have the opportunity not only to react with intact volatilized tobacco components (over 5300 of which have been identified) but also to react with the reaction fragments produced from them. If it is assumed that a given compound X during pyrolysis is not only transferred in part to the pyrolysate but also yields three pyrosynthetic fragments (A, B, and C), then these four entities (X, A, B, and C) may transfer to the pyrolysate intact or interact in a variety of ways to form a mixture of pyrolysate components.

entities interact with one another

X

X + A + B + C



pyrolysate plus transfer of intact X

If it is assumed not only that the same type of reaction occurs in a cigarette during the smoking process in the case of compound X, either added (Xa) to or inherent (X) in the tobacco blend, but also that similar degradation reactions occur with the other tobacco components (X1, X2, X3, … Xn) the situation described in the following equations could exist, where n could be as high as or higher than 5300, the approximate number of identified tobacco components. In the study of the addition of compound X to a cigarette tobacco filler, the added compound is designated as Xa. The inherent tobacco compound X and its fragments A, B, and C plus the added compound Xa and its fragments Aa, Ba , and Ca have the opportunity not only to react with each other but also to interact with X1, X2, X3, … Xn, A1, A2, A3, … An, B1, B2, B3, … Bn, and C1, C2, C3, … Cn, the fragments from hundreds of other tobacco components. In both the pyrolysis case and the cigarette smoke formation case, the number of fragments may, of course, be many more than the three designated as A, B, and C. X + A + B + C X Xa Xa + Aa + Ba + Ca X1 X1 + A1 + B1 + C1 X2 X2 + A2 + B2 + C2 X3 X3 + A3 + B3 + C3 … . . . . . … . . . . . … . . . . . Xn Xn + An + Bn + Cn

  entities interact with one another    cigarette smoke plus transfer of intact X and Xa, as well as intact X1, X2, X3,...Xn

Obviously, pyrolysis of an individual compound (X) at a specific temperature and during the smoking process in a machine-smoked cigarette whose blend contains inherent compound X and added compound Xa, are entirely different situations and will yield qualitative and quantitative differences between the compositions of the pyrolysates and the cigarette smoke. Qualitatively there may be some similarities in the two compositions. Quantitatively, the probability of any similarity is extremely low. It should be noted that during the pyrolysis of compound X, a specific temperature such as 700°C or 600°C is usually maintained. During the smoking process occurring in the compound X- and (X + Xa)containing cigarette, compound X and Xa and their pyrogenetically generated fragments are exposed to a range of temperatures varying from nearly 1000°C at the fire cone to 1107

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50 to 60°C near the butt. In addition, Britt et al. (435) noted that the residence time during most pyrolysis studies of tobacco components was much longer than that encountered by the tobacco components during the smoking process. The reactions depicted above in pyrolysis of a component vs. those in the cigarette smoking process with a component added to the tobacco exist despite the assertion that the pyrolysis procedure has been specifically designed to simulate the smoking process (172b, 1648, 3616). In 1979, Schmeltz et al. (3512) reported on the fate of radiolabeled nicotine during pyrolysis and its fate during actual smoking of a cigarette containing the radiolabel nicotine reveals at least two of the co-authors (Hoffmann and Schmeltz) had changed their long-held view on the supposed equivalence of compound behavior during pyrolysis and actual smoking. Schmeltz et al. wrote: Products obtained from the thermal degradation of [14C] nicotine in a combustion tube (under pyrolytic conditions) and in a cigarette (undergoing machine smoking) were examined by gas-liquid chromatography (GLC), by GLCmass spectrometry, and by radiochromatography. Under pyrolytic conditions in a combustion tube, nicotine underwent extensive degradation to pyridines, quinoline, arylnitriles, and aromatic hydrocarbons. In contrast, in a burning cigarette, a substantial portion of nicotine remained intact (≈41%), 12.5% underwent oxidation to CO2, up to 11% was degraded to volatile pyridine bases, and negligible amounts were converted to neutral or acidic particulate components. A major portion of nicotine and its degradation products was also diverted to sidestream smoke. These results suggest to us that pyrolysis experiments may be limited for establishing the fate of nicotine and possibly other tobacco components in a burning cigarette.

On the basis of numerous pyrolysis studies, it has been postulated that a number of tobacco leaf components are the major precursors of components in tobacco smoke. Throughout this chapter, smoke components alleged by some investigators to play a role in the smoking-health issue have

been emphasized, particularly those smoke components supposedly involved in the causation of lung cancer or other respiratory tract disorders. Carbon monoxide and nicotine have been proposed as cigarette mainstream smoke (MSS) components involved in cardiovascular problems. Nicotine occurs in cigarette smoke as a result of its transfer from the cut tobacco leaf where it is considered to be present in the so-called “bound” form as a variety of nicotine salts with organic acids (citric, malic, oxalic, palmitic, stearic, etc.). As noted by Perfetti (2918a, 25A47), these nicotine salts may have various structures, depending on the nature of the acid, for example, the molar ratio of acid to nicotine may be 3:1, 2:1, or 1:1. During the cigarette smoking process, these salts, depending on their composition, are considered to decompose to yield products ranging from mainly nicotine plus the acid in the salt to traces of nicotine plus various nicotine reaction and degradation products plus the acid. It has been proposed that the nicotine in the smoke again “binds” with acidic components of the smoke and is considered to be present primarily in the mainstream particulate phase as “bound” nicotine, but the binding in cigarette MSS is different from that in the tobacco. In cigarette smoke, the “binding” or salt formation is considered to be primarily with the stronger aliphatic organic acids such as formic, acetic, etc., whose levels in smoke are substantial compared to those of palmitic acid, stearic acid, etc. Table XXV-1, modified and updated from similar tables by Chortyk and Schlotzhauer (722) and Baker (171a), summarizes the major precursor relationships proposed and/or demonstrated for tobacco leaf components and tobacco smoke components. These proposals are based in part on the results of numerous pyrolysis studies. In some cases, the validation of the proposals is based on results obtained by addition of leaf components to tobacco and assessing the effect on the yields of specific MSS components when the “spiked” tobacco is smoked as a cigarette. As noted previously, equivalence of the reaction mechanisms involved in pyrolysis and those involved in the tobacco smoking process was debated for many years, with the current

Table XXV-1 Precursor Relationships between Tobacco Leaf Components and Tobacco Smoke Components Smoke Component

Leaf Component

References

Monocyclic Aromatic Hydrocarbons Benzene, toluene, xylenes, etc.

tobacco extracts paraffin hydrocarbons aliphatic acids sugars amino acids

Polycyclic Aromatic Hydrocarbons Naphthalenes, anthracenes,

solanesol

Schlotzhauer and Schmeltz (3465, 3466), Schlotzhauer et al. (3456) Schlotzhauer and Schmeltz (3466) Schlotzhauer and Schmeltz (3466) Schlotzhauer and Schmeltz (3466) Patterson et al. (2902), Schlotzhauer and Schmeltz (3466), Higman et al. (1647) Severson et al. (3616), Rodgman and Cook (3269, 3291)

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Table XXV-1 (Continued) Precursor Relationships between Tobacco Leaf Components and Tobacco Smoke Components Smoke Component phenanthrenes, pyrenes, chrysenes, fluoranthenes, benzopyrenes, etc.

Leaf Component terpenes tobacco extracts

paraffin hydrocarbons

polysaccharides (pectin, cellulose, starch)

phytosterols

long-chained esters amino acids sugars Polycyclic Aromatic Hydrocarbons (cont.)

triglycerides

Phenols Phenol, cresols, xylenols,   dihydroxybenzenes, etc.

lignin

sugars polysaccharides (cellulose, pectin, starch) protein amino acids tobacco extracts extracted tobacco

chlorogenic acid Aldehydes and Ketones Formaldehyde, acetaldehyde, acrolein, acetone, α,β-dicarbonyls, quinolines, carbolines, etc.

sugars

polysaccharides (cellulose, pectin)

triglycerides glycerol

References Schlotzhauer and Schmeltz (3466), Severson et al. (3616) Rodgman and Cook (3269, 3291), Rodgman (3246), Schlotzhauer and Schmeltz (3465), Schlotzhauer et al. (3466), Severson et al. (3615, 3616) Rodgman and Cook (3269, 3291), Rodgman (3246), Lam (2255, 2257), Schlotzhauer and Schmeltz (3466), Severson et al. (3616) Wright (4281), Gilbert and Lindsey (1289), Higman et al. (1647) Rodgman and Cook (3269, 3291), Wynder et al. (4355), Rodgman (3246), Severson et al. (3616), Schlotzhauer and Schmeltz (3466) Severson et al. (3616) Patterson et al. (2902); Higman et al. (1647) Gilbert and Lindsey (1289), Higman et al. (1647) Rodgman and Cook (3269) Rodgman and Mims (3305), Schlotzhauer et al. (3468), Higman et al. (1647), Schlotzhauer et al. (3466) Bell et al. (246), Spears et al. (3767), Higman et al. (1647), Schlotzhauer et al. (3466) Higman et al. (1647) Higman et al. (1647) Schlotzhauer et al. (3466) Rodgman and Cook (3277), Rodgman and Mims (3305), Severson et al. (3616) Schlotzhauer et al. (3462) Gager et al. (1264, 1265), Houminer and Patai (1835d), Johnson et al. (1960), Higman et al. (1647) Zamorani et al. (4398d), Fredrickson (1228), Fredrickson et al. (1238) Kitamura (2111a) Doihara et al. (1023, 1024), Kröller (2192, 2196)

Hydrogen Cyanide amino acids

Patterson et al. (2902, 2905), Higman et al. (1647), Johnson et al. (1967) (Continued)

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Table XXV-1 (Continued) Precursor Relationships between Tobacco Leaf Components and Tobacco Smoke Components Smoke Component Aliphatic Nitrogen Compounds Aliphatic amines, volatile   N-nitrosamines

Leaf Component

amino acids protein nicotine nicotine + nitrate

References

Smith et al. (3729) Higman et al. (1647) Kaburaki et al. (2006), Schmeltz et al. (3512) Tso et al. (3985), Hecht et al. (1564), Hoffmann et al. (1696)

Monocyclic Nitrogen Compounds amino acids Anilines, pyrazines, pyridines,   pyrroles, tobacco-specific N- nitrosamines, etc.

amino acids + sugars protein nicotine

Polycyclic Nitrogen Compounds Indoles, carbazoles, acridines, quinolines, carbolines, etc.

nicotine

amino acids

protein N-Heterocyclic Amines Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, IQ, AaC, MeAaC, etc.

amino acids

protein

Patterson et al. (2902), Higman et al. (1647) Green et al. (1369) Higman et al. (1647), Schmeltz et al. (3499) Schmeltz et al. (3512) Van Duuren et al. (4027), Kaburaki et al. (2006), Schmeltz et al. (3512) Patterson et al. (2902), Higman et al. (1647), Yamamoto et al. (4365a), Sugimura (3828c) Higman et al. (1647) Chortyk et al. (726), Patterson et al. (2902), Akimoto (25A01), Dong et al. (1041), Sugimura et al.(3829a), Kosuga et al. (2178a), Sugimura (3828a, 3828b), Takeda et al. (3863a, 25A73), Yasuda et al. (4382a), Yoshida and Matsumoto (4387a, 4387b, 4388), Yamazoe et al. (4370a), Conner and Dominguez (25A17), Coleman and Perfetti (25A14), Coleman et al. (25A15) Yoshida et al. (4389A, 4390)

Sulfur-Containing Compounds

Acids, Aliphatic Formic to nonanoic Acids, Aliphatic Decanoic and higher

sulfur-containing amino acids

Fujimaki et al. (25A23), Kato et al. (2048, 2049), Smith et al. (3729)

esters of mono- and disaccharides and aliphatic and terpenoid alcohols

Wynder and Hoffmann (4332)

esters of phytosterols, aliphatic alcohols, and terpenoid alcohols

Wynder and Hoffmann (4332), Severson et al. (3616)

lignin

Wynder and Hoffmann (4332)

Acids, Aromatic

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consensus being that these processes are not equivalent. Also included are the results of research in the mid-1950s on the major tobacco and cigarette paper component, cellulose, either smoked in cigarette configuration [Fredrickson (1228), Fredrickson et al. (1238)] or burned or pyrolyzed in bulk. When the primary focus of the early research was on the pyrogenesis of PAHs, Wright (4281) demonstrated that the amount of benzo[a]pyrene (B[a]P) generated during bulk burning or bulk pyrolysis of cellulose was much greater than that generated during the burning of the cellulose (cigarette paper) in a cylindrical form, simulating its configuration in the cigarette.

XXV.A Individual Tobacco Types In the early 1930s, Roffo (3320, 25A50, 25A51, 25A52) reported the production of skin tumors in laboratory animals by the repeated application of a “tar” obtained by the “destructive distillation” of tobacco. This “destructive distillate” from tobacco, as noted by Wynder and Hoffmann (4319, 4332), is in no way comparable to the smoke condensate generated from cigarettes during a smoking procedure simulating that used by the human smoker in terms of puff duration, puff frequency, and puff volume. Despite the fact that the puff volume, puff duration, and puff frequency were usually set at 35 ml, 2 sec, and 1 puff/min, respectively, after the 1937 publication by Bradford et al. (1937) on human smoking parameters, Wynder et al. (1953a, 1953b) elected to use a puff frequency of 3 puff/min for the generation of cigarette smoke condensate (CSC) for their mouse skin-painting studies, despite their assertion that the smoking regime simulated that of the human smoker. In addition, the destructive distillation procedure used by Roffo is not comparable to the pyrolysis procedures used several decades later by other investigators, for example, Lam (2255, 2257) and Wynder et al. (4355). Roffo’s work is presented here for the sake of historical completeness. In later reports, Roffo (3323, 3325) and his son (3316, 3318) claimed the identification of B[a]P in the destructive distillate of tobacco, but these claims were subsequently challenged by Wynder et al. (4306a) who noted: Roffo … claimed to have identified benzpyrene in tobacco tar, but this could not be confirmed by Hirst and his coworkers (813), and more recently that substance could not be detected by Waller (25A81). An examination by Eby (25A21) of the tobacco tar used in this study [the mouse skin-painting study by Wynder, Graham, and Croninger (4306a)] did not reveal any spectroscopic evidence of the known carcinogenic hydrocarbons.

Roffo (25A60) also claimed that the biological results in his painting results with the effect on the levels of “destructive distillate” from tobacco were the same no matter which type of tobacco was subjected to his destructive distillation process. That his destructive distillation was not comparable to the actual cigarette smoking process was demonstrated

in later studies by Wynder and Hoffmann (4317, 4332), who reported that the different types of tobacco (flue-cured, burley, Maryland, and Oriental) generated CSCs whose specific tumorigenicities were different, as were their contents of B[a] P and phenol. The specific tumorigenicities and phenol levels per milligram of CSC were found to be in the sequence

flue-cured = Oriental > Maryland > burley

whereas the B[a]P levels per milligram of condensate were found to be in the sequence

flue-cured > Oriental > Maryland > burley.

More recent confirmation of the differences among tobacco types in another bioassay has been obtained with regard to the specific mutagenicities (as measured in the Ames test with Salmonella typhimurium) of their smoke condensates generated under standard conditions. Results of both in-house studies [Smeeton et al. (3707)] and external studies [Mizusaki et al. (2568), Yoshida and Matsumoto (4388), DeMarini (933)] indicate the response of different strains of Salmonella typhimurium in the Ames test to smoke condensates from cigarettes fabricated with different tobacco types not only are dissimilar but also are in a sequence opposite that found for specific tumorigenicities determined in mouse skin-painting studies, that is, the mutagenicities based on an equivalent weight of smoke condensate were found to be in the sequence

flue-cured < Oriental < Maryland < burley.

Critical reviews of the Roffo work have been published by Wynder et al. (4306a), Wynder and Hoffmann (4332), and Larson et al. (2264). All three groups asserted that the “destructive distillate” from tobacco, as prepared by Roffo, is not comparable to CSC generated under conditions more closely approximating those in the human smoking of a cigarette. Larson et al. also noted that the number of malignant tumors produced in all of the Roffo skin-painting studies with the destructive distillate from tobacco was so few (three malignant tumors, two carcinomas and one sarcoma, in nearly 1000 treated animals) as to be almost within experimental error. Over the years, pyrolysis studies with tobaccos under a variety of conditions have provided diverse results with regard to the level of B[a]P found in the pyrolysate, for example, Kröller (2196), Green and Best (1357), and Severson et al. (3616). The phenol:B[a]P ratios were also much compared in pyrolysates and MSSs and they too provided diverse results, for example, Wynder and Hoffmann (4319, 4332), R.J. Reynolds Tobacco Company (3190). Adams et al. (31) used catechol rather than phenol as an “indicator” for phenols and provided MSS and SSS B[a]P and catechol data on four different types of commercial cigarettes. From these data, the calculated catechol:B[a]P ratios for the combined MSS and SSS were widespread, ranging from 1074:1 to 2680:1. The data reported by Severson et al. on the yields of phenol and

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benzopyrenes in the pyrolysates (and the ratios derivable from their data) demonstrated that the process involved in the generation of a tobacco pyrolysate is not comparable to the process involved in the generation of CSC from cigarettes made with the same tobacco and smoked under conditions simulating the human smoking process.

XXV.B Extracts from Tobacco The 1953 report of the successful production of carcinomas in mice repeatedly painted for their life span with daily doses of CSC generated by a smoking process supposedly simulating that used by human cigarette smokers [Wynder et al. (4306a)] led to a search for the smoke component(s) responsible for the biological response. No carcinogenic, cocarcinogenic, or promoting compound identified in CSC, when considered at its concentration in CSC, can explain the biological response obtained in mouse skin-painting studies nor can it be explained when the carcinogenic, cocarcinogenic, and promoting components at their CSC concentrations are considered to be acting in concert. The finding in 1913 by Staudinger et al. (25A68) that pyrolysis of isoprene yielded a “tar” was utilized a decade later by Kennaway (2073–2076). He reported that heating organic compounds (acetylene, isoprene, cholesterol, foodstuffs) at high temperatures (in air or an inert atmosphere) yielded “tars” or “pyrolysates” which were tumorigenic to the skin of laboratory animals. After the discoveries of the tumorigenicity of dibenz[a,h]anthracene (DB[a,h]A) and B[a]P, many such generated pyrolysates were shown to contain various tumorigenic PAHs [Rodgman (3233, 25A48)]. In the early 1950s, a controversy arose about the presence of such PAHs in CSC, a material generated by the exposure of tobacco—a mixture of many organic compounds—to temperatures ranging from slightly above ambient to over 900°C. By the late 1950s, this controversy was resolved by the identification in CSC of a variety of PAHs, including several [B[a]P, chrysene, benz[a]anthracene (B[a]A), 7,12-dimethylbenz[a]anthracene (DMB[a]A), DB[a,h]A] reported to give positive responses in skin-painted laboratory animals, albeit at dose levels far in excess of their levels in CSC. Wynder and Hoffmann (4332) reviewed much of the early research on the identification of PAHs in CSC. Demonstration that PAHs were present in CSC then led to research on their source(s). Cigarette paper [Wright (4281)], the lighting source (matches, flammable organic solventcharged cigarette lighters), and PAHs in environmental pollutants to which tobacco might be exposed during growth, harvesting, and transportation [Campbell and Lindsey (583), Lyons (2426), Bentley and Burgan (285)] were eliminated as sources or precursors of PAHs in cigarette smoke. Extensive research subsequently determined that tobacco itself and/or its components were precursors of the PAHs in CSC. As noted previously, in the 1930s, Roffo (3320, 25A50) claimed the production of malignant tumors in laboratory animals skin painted with a “destructive distillate” from tobacco. Roffo (3323, 3325) and his son [Roffo (3316, 3318)] also

The Chemical Components of Tobacco and Tobacco Smoke

claimed identification of a benzopyrene or a “benzopyrenelike” substance in the distillate. Subsequently, Roffo reported that organic-solvent extraction of tobacco yielded an organic solvent-insoluble tobacco residue whose “destructive distillate” was less tumorigenic in skin-painting studies than the “destructive distillate” prepared from the unextracted (control) tobacco (3327). Roffo postulated that the major tobacco precursor of the “distillate” component responsible for the tumorigenicity observed in laboratory animals was the phytosterols. Coincident with general acceptance of biologically active PAHs in CSC were extensive pyrolysis studies not only on organic solvent-extractable materials from tobacco but also individual components and classes of components in the solvent-extracted materials. The organic solvent (pentane, hexane, heptane, petroleum ether) used as extractant removed wax-like organic components from the tobacco. These waxy materials comprised several series of long-chained saturated (1308, 3807) and unsaturated aliphatic hydrocarbons (3247, 3345) and alcohols (812, 3276), phytosterols and their longchained fatty acid esters (3247), terpenoid alcohols such as solanesol (3344, 3359) and the duvanediols (3195, 3220, 3221, 3283, 3351, 3361), solanesyl esters with long-chained fatty acids (3296, 3358, 3616), and a series of esters of longchained alcohols and long-chained fatty acids (3294). Contradictory results were obtained on the yields of the allegedly tumorigenic PAHs and the biological properties of the CSCs from cigarettes fabricated from organic solventextracted tobaccos. With relatively nonpolar solvents such as pentane, hexane, and heptane, from 5% to 10% of the tobacco weight was removed by extraction with these solvents. Reductions in per cigarette PAH yields were reported for the MSSs from solvent-extracted tobaccos by numerous investigators, for example, Campbell and Lindsey (583), Neukomm and Bonnet (2716), Rodgman (3241–3243, 3246, 3251), and Wynder and his co-workers [Wynder (4294), Wright (4282), Wynder et al. (4355), Wynder and Hoffmann (4307, 4309)] on solvent extractions of tobaccos and their effect on the PAH yields in the CSC. Initially, the reductions in the MSS yields of the PAHs, particularly those with four or more fused rings, were reported as being significant when considered on a per cigarette yield basis. Subsequently, the same investigators (Wynder and colleagues) claimed that the reductions in PAH yields should be viewed as only marginal when the PAH yields were considered on a per gram of CSC basis. The percent reduction in tumorigenicity (expressed as % tumor-bearing animals [TBA] in skin-painting experiments) of the mainstream CSCs from cigarettes fabricated with solvent-extracted tobaccos was usually less than the percent reduction in the levels of PAHs (with B[a]P, expressed in micrograms per gram or nanograms per gram of CSC, used as an “indicator” for the levels of PAHs with four or more fused rings). It was obvious from data already in the literature describing tobacco smoke and tobacco pyrolysate compositions that B[a]P was not a valid “indicator” for the tetracyclic and higher PAHs demonstrated to be tumorigenic to mouse skin.

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American investigators [Rayburn and Wartman (3091), Rayburn et al. (3092)] as well as French investigators [Cuzin et al. (885)] reported slight to no reductions in the levels of mainstream CSC PAHs, particularly B[a]P, as a result of organic solvent-extraction of tobacco. Much of the early research on organic solvent extraction of tobacco to reduce the yields of PAHs in mainstream CSCs was reviewed by Wynder and Hoffmann (4319, 4332) and Hoffmann and Wynder (1798). Organic-solvent extraction of tobacco to control PAH levels in MSS fell from grace around 1960 when it was described by its early proponents, Wynder and Hoffmann (4309), as a process “impractical both technically and economically” and later was classified as “only of academic interest” by Wynder and Hecht (4306d), a view reported by the U.S. Surgeon General [see Table 26, p. 14: 114 in (4005)]. Pyrolysis studies have been conducted not only on the material extracted from the tobacco but also on the unextracted (control) tobaccos and the residual extracted tobaccos in attempts to define the precursor(s) of PAHs (and phenols) in cigarette MSS. In some respects, the differences between the compositions of the pyrolysates from solvent-extracted tobacco and from unextracted tobacco paralleled the differences between the compositions of the MSSs from cigarettes fabricated with solvent-extracted tobacco and with unextracted tobacco. In 1958, Wynder et al. (4355) described the effect of varying the pyrolysis temperature on the yield of pyrolysate from an n-hexane extract from tobacco. The extracted material constituted 5.4% of the original tobacco weight and consisted of long-chained saturated and unsaturated aliphatic hydrocarbons, glycerides and other esters, solanesol and phytosterols and their esters, long-chained aliphatic esters, and α-tocopherol. Major findings from their study included (see also Table XXV-2): The pyrolysate yields varied inversely as the pyrolysis temperature, that is, the pyrolysate yield decreased as the temperature of pyrolysis was increased. Presumably, this is due to less decomposition of the extracted components to vapor-phase components

(water, carbon monoxide, carbon dioxide, methane, etc.) at the lower pyrolysis temperatures. The percent conversion of the extracted components to PAHs decreased as the pyrolysis temperature decreased. The specific tumorigenicities of the pyrolysates, applied as 1% and 5% solutions in acetone in skin-painting studies involving both mice and rabbits, decreased as the pyrolysis temperature was lowered. Pyrolysis of the extract in either an inert atmosphere (nitrogen) or an oxygenated atmosphere (air) at 880°C did not markedly affect the findings with respect to the yield of pyrolysate, the generation of PAHs, or the specific tumorigenicity (mouse skinpainting bioassay) obtained with a solution of 1% pyrolysate in acetone. Studies on organic-solvent extraction of tobacco conducted from the mid- to-late 1950s by Rodgman (3241, 3242, 3246, 3251), Ashburn (116, 117), and Ashburn and Rodgman (121) provided analytical data on the PAHs in mainstream CSC that in some ways paralleled the findings reported by Wynder (4294). Rodgman (3251) summarized the RJRT R&D findings: Organic-solvent extraction of various tobacco types (fluecured, burley, Oriental) and blends reduced the yields of both total and individual PAHs, e.g., B[a]P in mainstream CSC both on a per cigarette basis and on a weight of tobacco consumed basis. The per cigarette “tar” yields were also reduced in every instance.

Partition of the organic-solvent extractables between a solvent system consisting of a polar solvent (aqueous ethanol) and a nonpolar solvent (hexane or pentane) and returning each partition fraction separately to the organic solvent-extracted tobacco residue indicated: Addition of the nonpolar solvent-soluble material (which contained the bulk of the tobacco waxes)

Table XXV-2 Pyrolysis Studies on n-Hexane Extract from Tobacco Pyrolysis Conditions

a

Temp. °C

Medium

Pyrolysate, % of Extract

Tumorigenic PAHs

560 640 720 800 880

N2 N2 N2 N2 N2

50 35 32 28 28

present

880

air

30

Tumorigenicity Studies, % Tumor-Bearing Animalsa Painted with Pyrolysate 1% Solution

5% Solution 0 17 60 97

present

0 0 0 60 77

present

67

67

% Tumor-bearing animals (mice) with carcinoma at skin-painted site; similar percentages were found with skin-painted rabbits

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to the extracted tobacco residue returned the CSC PAH yield almost to that of the CSC from the unextracted (control) tobacco. Addition of the polar solvent-soluble material (which consisted primarily of oxygen- and/or nitrogencontaining flavor-contributing tobacco components) to the extracted tobacco produced very little change in the PAH (both total and individual) level of the CSC. These results were interpreted as an indication that the relatively high molecular weight, nonvolatile tobacco wax components were the major precursors in tobacco of the PAHs in smoke, whereas the moderate to low molecular weight and volatile flavorful components in tobacco did not contribute significantly to the PAH levels in smoke. Addition of the organic solvent-soluble tobacco components, for example, long-chained aliphatic hydrocarbon fraction, solanesol, or β-sitosterol, to unextracted (control) tobacco increased the levels of the total and some individual PAHs in the CSC. Thus, removal of tobacco wax components reduced the levels of both the total and individual PAHs in CSC, whereas addition of tobacco wax components increased the levels of both the total and individual PAHs in CSC (3251, 3269). Examination of the relationship of the level of B[a]P to that of other individual PAHs in the various CSCs from the solventextracted tobaccos or from the component-“spiked” tobaccos confirmed what was already obvious from other literature data: B[a]P is not a valid “indicator” for either total PAHs or other individual PAHs with fewer than four fused rings, with four fused rings, or with more than four fused rings. From the mid-1960s to the early 1970s, the USDA group described the pyrolysis of organic-solvent extractables from tobacco. In the earlier studies, the pertinence of the pyrolysis results in defining the precursors in tobacco of the PAHs in the CSC was emphasized (3465, 3455), but subsequent research dealt with the precursors in tobacco of the simple phenols in cigarette smoke (3456, 3468). In 1968, Schlotzhauer and Schmeltz (3465) noted that hexane extractables from tobacco constituted about 6% of the original tobacco weight, whereas the extracted tobacco residue constituted about 94% of the original tobacco weight. Pyrolysis of the hexane extractables and the extracted tobacco residue indicated that, of the total B[a]P determined in these two pyrolysates, about 60% was found in the hexane extractables pyrolysate (6% of the original tobacco) and 40% in the pyrolysate of the extracted tobacco residue (94% of the original tobacco). Schlotzhauer and Schmeltz (3466) also demonstrated by pyrolysis of individual components isolated from the hexane extract that the following were precursors of the PAHs in the pyrolysates: n-dotriacontane, stearic acid and linoleic acid, phytol, squalene, and β-sitosterol. In 1973, Chortyk and Schlotzhauer (722) reviewed the pyrogenesis of tobacco smoke components. They discussed the extraction/pyrolysis results described above plus results of their studies on the pyrolysis (800°C) of fractions sequentially extracted from tobacco with a series of increasingly

The Chemical Components of Tobacco and Tobacco Smoke

polar solvents (hexane, acetone, ethanol, water) (3458). Chortyk and Schlotzhauer (722) noted: The sources of about 70% of the aromatic hydrocarbons ranging from benzene to BaP, in the pyrolysates, were due to leaf components extractable with hexane and acetone: these extracts amounted to less than 25% of dry leaf weight. The hexane extractables (7.2% of leaf weight) accounted for 33% of the neutral products. The hexane-soluble material of cured leaf tobacco is known to include aliphatic and cyclic paraffins, fatty acids, phytosterols, steryl esters, and terpenes, all preferred precursors of aromatic hydrocarbons. The acetone extract (17.5% of leaf weight) contributed another 35% of aromatic hydrocarbons to the pyrolysate, indicating a further extraction of similar polycyclic aromatic hydrocarbons precursors. Together, these two extracts contributed 86% of the BaP content of the tobacco pyrolysate. The disproportionate contribution of these fractions to BaP formation becomes apparent from the following data: the hexane and acetone fractions, containing hydrocarbons and lipids, yielded about 700 mg BaP per gram of material pyrolyzed, while the residual tobacco, consisting mostly of cellulose materials, yielded less than 34 mg of BaP per gram pyrolyzed.

They also demonstrated that the major volatile phenols (phenol, cresols) were produced primarily by pyrolysis of the alcohol extractable and the final tobacco residue. These fractions accounted for 38% and 44%, respectively, of the total phenols yield. The alcohol extractables included polyphenolic tobacco pigment and low molecular weight sugars, whereas the final tobacco residue contained the polysaccharides celluloses, starch, pectins, and lignin. All these yield the simple phenols on pyrolysis or during tobacco smoking (248, 2043, 3277, 3305, 3453, 3468, 3767). In 1978, Severson et al. (3616) revisited the organicsolvent extraction of tobacco. They noted [see p. 277 in (3616)]: Numerous pyrolytic studies have shown that the hexane or petroleum ether … extract of tobacco contains the major precursors of smoke polycyclic aromatic hydrocarbons [Wynder et al. (4355), Schlotzhauer et al. (3468), Schlotzhauer and Chortyk (3451)]. However, many of these studies were made under conditions which produced optimum PAH yields [Schmeltz and Hoffmann (3489)]; thus, the PAH distributions were not comparable to those in [CSC] and the data obtained could not be exactly correlated with PAH production during the smoking process.

Severson et al. (3616) determined the pyrolytic conditions that gave the PAH profiles of tobacco pyrolysates that they claimed “could be correlated with [CSC] PAH profiles.” Examination of their data indicates that this claim is not valid. Severson et al. conducted two major experiments. They examined: The effect of petroleum ether extraction on the PAH levels in the pyrolysates from the petroleum ether extractables, PEE (8% of the original tobacco weight), the extracted tobacco residue, RES (92% of the original tobacco weight), and the original tobacco.

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Table XXV-3 Comparison of Polycyclic Aromatic Hydrocarbon Fraction Levels, Phenol Yields, and Acid Yields in 700°C Pyrolysates from Tobacco, Petroleum Ether Extractables (PEE), and the Tobacco Residue (RES) after Extraction Amount From Pyrolysate Components

Tobacco μg/1000 mg

PEE μg/80 mg

RES μg/920 mg

Total PEE + RES μg/1000 mg

% Diff., Total vs. Tobacco

PAH Group Naphthalene Fluorene Phenanthrene Pyrene Chrysene Benzopyrene

3200 1100 1600 630 180 190

3900 1100 1500 820 260 140

1300 860 780 350 80 50

5200 1960 2280 1170 340 190

63 78 43 86 89 0

Totals

6900

7720

3420

11140

61

Phenol Group Phenol o-Cresol m- + p-Cresol Ethyl-/dimethylphenols 1-Naphthol 2-Naphthol

3610 750 1620 910 160 140

50 50 50 130 30 20

2620 630 1180 700 110 110

2670 680 1230 830 140 130

26 20 24 -9 -13 -7

Totals

7190

330

5350

5680

-21

Acids Volatile acids (C1-C7) Nonvolatile acids (C11-C34)

330 12

140 11

230 4

370 15

12 25

Totals

342

151

234

385

13

The effect of chromatography of the petroleum ether extractables PEE with eight increasingly polar solvent systems, ranging from petroleum ether to an acetone:methanol solution, on the composition of each of the eight chromatographic fractions, and on the PAH levels in the pyrolysates from each of the eight fractions. Table XXV-3, adapted from (3616), indicates that, at the optimum pyrolysis conditions specified (700°C, N2), the totals of the PAH groups (except for the benzopyrene group) in the pyrolysates from the PEE and the RES are substantially higher (42% to 89%) than the levels of the same PAH groups in the pyrolysate from unextracted tobacco. Table XXV-3 also shows that the sum of the total PAHs in the pyrolysates from the two fractions was 61% greater than the total PAHs in the control tobacco pyrolysate. Similar studies on individual and total acids and individual and total phenols in the same pyrolysates reveal that the sum of the total phenols in the pyrolysate of the PEE and RES was 21% less than the total phenols in the control tobacco pyrolysate, for acids, the sum of total acids in the pyrolysates from the two fractions (PEE plus RES) was 13% greater than the total acids in the control tobacco pyrolysate. If this situation prevails in the relatively simple situation (petroleum ether extractables, extracted tobacco residue, and unextracted control tobacco) described above, then it is highly

likely that the discrepancy will be enhanced when individual compounds are considered, that is, there will be substantial uncertainty in any attempt to extrapolate from pyrolysis data on a specific compound, either present in or proposed to be added to tobacco, to what will actually happen to that compound during the smoking of a cigarette. Since Severson et al. (3616) defined the composition of the eight chromatographic fractions, the remainder of their research findings will be discussed in the following section.

XXV.C Individual Tobacco Components The research conducted from the early 1950s to the mid1960s on the organic solvent-soluble precursors in tobacco of the PAHs in cigarette MSS has been described in detail by Wynder and Hoffmann [see pp. 345–351, 518 in (4332)] and Hoffmann and Wynder (1798). Despite the fact that the tumorigenic PAHs at their levels in cigarette smoke and acting in concert with promoting and/or cocarcinogenic but nontumorigenic PAHs, phenols, acids, etc., at their levels in cigarette smoke explain only a small fraction (less than 2%) of the biological response (measured as % TBA) observed in skin-painted laboratory animals, efforts to define the major precursors in tobacco of the tumorigenic PAHs in cigarette smoke were continued into the late 1970s, particularly by the USDA group at Athens, Georgia (3616). Despite the advances during this period in the laboratory techniques for (1)

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successful fractionation of complex mixtures such as those found in cigarette MSS and in the pyrolysates from various tobaccos, tobacco fractions, and tobacco components and (2) the quantitation of the levels of individual identified PAHs, phenols, aldehydes, ketones, etc., no revolutionary new precursor in tobacco of PAHs in tobacco smoke was discovered. The organic solvent-soluble tobacco components that yielded PAHs on pyrolysis were essentially those or structurally similar to those that had been proposed several decades earlier in the 1950s. Several tobacco components, structurally similar to those proposed earlier, had not been identified as tobacco components in the 1950s, but once they were identified, logic dictated they would yield PAHs either on pyrolysis or during the tobacco smoking process. For example, in the late 1950s, Wright [(4282), see also Rodgman (3243)] theorized that the high molecular weight terpenes (other than the phytosterols) and the phytosterols themselves were major precursors in tobacco of the PAHs in tobacco smoke. These proposals were subsequently confirmed. In 1958, Rodgman and Cook (3269, 3291) demonstrated in a “spiking” experiment with solanesol, that it was an effective precursor of total and individual PAHs in cigarette MSS as indicated by the increased levels in the PAHs in the MSS from solanesol-“spiked” tobacco cigarettes vs. those in the MSS from control tobacco cigarettes. Similarly, Rodgman and Cook reported that results from phytosterol-“spiked” tobacco cigarettes indicated the phytosterol was a major precursor of PAHs in MSS. In 1979, Severson et al. (3616) demonstrated that solanesol pyrolysis generated substantial amounts of PAHs vs. other organic solvent-soluble tobacco components. In subsequent sections, pyrolysis studies on various tobacco components categorized as follows will be discussed: Nicotine Organic solvent-soluble components: long-chained aliphatic saturated and unsaturated hydrocarbons; terpenoid alcohols such as the duvanediols, phytosterols, phytol, and solanesol; normal long-chained aliphatic alcohols; esters of these groups of alcohols with long-chained aliphatic acids (palmitic, stearic, oleic, etc.) Structural components of tobacco (the biopolymers such as lignin and the polysaccharides cellulose, starch, and pectins and their constituent monosaccharides such as glucose and fructose) Acids Proteins and amino acids Nicotine (as well as the other nicotine-related alkaloids in tobacco, usually present in trace amounts) is the one tobacco component whose level in tobacco is sometimes controlled by removal in a denicotinization process. In contrast to the removal or reduction of its level in the case of nicotine, materials such as simple sugars, glycerol, and some flavorants are added to the tobacco blend to augment their existing levels in the tobacco and to enhance certain consumer acceptable organoleptic properties of the MSS. Materials such as

The Chemical Components of Tobacco and Tobacco Smoke

licorice, cocoa, and other flavorants are added to impart other consumer acceptable organoleptic properties to the smoke (2341).

XXV.C.1  Nicotine Over the years, the results of numerous studies on the pyrolysis of nicotine have been published. Many of them, for example, those of Frank et al. (25A22) and Woodward et al. (4275a, 25A84, 25A85) in the early 1940s, preceded the escalation in the 1950s of the interest in the cigarette smoke-health issue. Other early studies of nicotine pyrolysis in air or nitrogen included those in the early 1960s by Jarboe and Rosene (1923a) and Kobashi et al. (25A37, 25A38). In 1964, pyrolysis products generated from nicotine during the tobacco smoking process were summarized by Kuhn (2228). In 1960, Van Duuren et al. (4027) extended their studies on tumorigenic PAHs in mainstream CSC to identify three tumorigenic N-heterocyclic compounds: the aza-arenes dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo [c,g]-carbazole. Their yields were 0.1, 2.7, and 0.7 ng/cigarette, respectively, substantially less than that of the nanogram per cigarette yield reported for B[a]P in the early 1960s. These three N-heterocyclics had also been reported as mouse-skin tumorigens [see tabulation in Hartwell (1544)]. Dibenz[a,h]acridine and dibenz[a,j]acridine were also identified by Van Duuren et al. in pyrolysates from nicotine and pyridine (750°C, N2). However, the presence of these aza-arenes in tobacco smoke or nicotine pyrolysate has been questioned. Of the numerous reports on this class of compound in tobacco smoke, only one report describes the identification of one of the three, dibenz[a,j]acridine: Wynder and Hoffmann (4319, 4332) reported that their group, Candeli et al. (587), was able to confirm the presence of dibenz[a,j]acridine but not dibenz[a,h]acridine in mainstream CSC. The per cigarette yield for dibenz[a,j]acridine reported by Candeli et al. (587) was almost four times that reported by Van Duuren et al. Since 1963, no other investigator has reported these three compounds in tobacco smoke or a nicotine pyrolysate. In 1970, Kaburaki et al. (2006) reported the results of their pyrolysis of nicotine at various temperatures in air and in N2. The two tumorigenic benzacridines reported in a nicotine pyrolysate by Van Duuren et al. as components of their nicotine pyrolysate were not found by Kaburaki et al. Schmeltz et al. (3499) described the results of their pyrolysis of several nitrogenous tobacco components, including nicotine: We could not detect benzo(a)pyrene in nicotine pyrolyzates, nor could we confirm the presence of the physiologically active dibenzacridines and dibenzcarbazole reported in tobacco smoke and in nicotine and pyridine pyrolyzates by Van Duuren [4027].

In their review of the pyrogenesis of tobacco smoke components, Chortyk and Schlotzhauer (722) emphasized the

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failures of several investigators to confirm the two dibenzacridines and 7H-dibenzo[c,g]carbazole in nicotine pyrolysates: Since nicotine is the most abundant and best known tobacco alkaloid, its pyrolysis has been thoroughly studied [Woodward et al. (4275a), Jarboe and Rosene (1923a)]. More recent work [Kaburaki et al. (2006)] on the pyrolysis of nicotine and various alkylpyridines has resulted in a proposed mechanism for the thermal degradation of nicotine … Schmeltz [Schmeltz et al. (3499)] also studied nicotine and identified a number of previously unreported compounds in the nicotine pyrolysates … These included pyrrole, acenaphthene, indole, skatole, and anthracene and/or phenanthrene. However, the presence of dibenzacridines and dibenzcarbazole, previously reported in nicotine and pyridine pyrolysates, could not be confirmed [Van Duuren et al. (4027)].

In 1977, Schmeltz and Hoffmann (3491) in their review of N-containing components of tobacco and tobacco smoke discussed the generation of various pyridines from nicotine during both the actual smoking process and pyrolysis. Schmeltz and Hoffmann (3491) did report the identification by Van Duuren et al. (4027) of the two dibenzacridines in cigarette smoke and nicotine pyrolysate. They did not, however, comment on the inability of other investigators (587, 2006, 3499) to confirm the findings of Van Duuren et al. In 1979, Schmeltz et al. (3512) reported their major findings from a study of the fate of radiolabeled nicotine during pyrolysis and during the actual smoking of a radiolabeled nicotine-treated cigarette: Under combustion tube pyrolysis conditions, nicotine in either silica gel matrix (pyrolysis temperature = 600°C, 750°C, or 900°C) or tobacco matrix (600°C) underwent extensive degradation to pyridines, quinolines, arylnitriles, and aromatic hydrocarbons. In a burning cigarette during actual smoking, a substantial portion of the nicotine (about 41%) remains intact, 12.5% is oxidized to carbon dioxide, as much as 11% is degraded to volatile alkylpyridines, and negligible amounts are converted to neutral or acidic components of the particulate phase. Dibenz[a,h]acridine and dibenz[a,j]acridine reported nearly two decades earlier by Van Duuren et al. (4027) were not identified in this study.

Schmeltz et al. (3512) noted: In ongoing studies we are now identifying those compounds that are formed from nicotine only as minor compounds (<0.1%) which nevertheless can contribute to the toxicity of the smoke. To this group of minor smoke constituents having nicotine as a precursor belong the dibenzacridines.

From their experimental results, Schmeltz et al. (3512) concluded: “These results suggest to us that pyrolysis experiments may be of limited value for establishing the fate of nicotine and possibly other tobacco components in a burning cigarette.” The pyrolysis system in this study [see Higman et al. (1648)] was designed to be the optimum simulation of the

smoking process. Obviously, nicotine did not behave in this pyrolysis system as it did in the burning cigarette during actual smoking. Examination of the 1979 Schmeltz et al. publication on the fate of nicotine during pyrolysis vs. actual smoking reveals at least two of the authors (Hoffmann and Schmeltz) definitely changed their opinion on their long-held view on the equivalence of compound behavior during pyrolysis and actual smoking, for example, Wynder and Hoffmann (4332) earlier wrote: Most pyrolysis studies with tobacco, tobacco extracts, extract fractions, individual components, and tobacco additives are performed in a nitrogen atmosphere. This procedure has often been criticized on the grounds that many of the toxic constituents formed during smoking of tobacco products occur as a result of combustion in air rather than in a nitrogen atmosphere. This criticism, however, cannot be maintained in view of studies by Newsome and Keith [2780] which demonstrated that a reducing rather than an oxidizing atmosphere exists at the cone region of a burning cigarette.

With regard to the dibenzacridines and dibenzocarbazole from nicotine during pyrolysis and the smoking process, Table XXV-4 summarizes the state of knowledge. None of the investigations conducted from 1963 through 2000 on the levels of these three aza-arenes in mainstream CSC confirmed the 1960 findings of Van Duuren et al. (4027). Another aspect of the involvement of nicotine (and related tobacco alkaloids) in the generation of allegedly harmful tobacco and/or smoke components is the formation of tobacco-specific N-nitrosamines (TSNAs).* It is claimed by Hoffmann and his co-workers that TSNAs such as N’-nitrosonornicotine (NNN) and 4-(N-methylnitrosamino)1-(3-pyridyl)-1-butanone (NNK) are formed from nicotine and other minor nicotine-related alkaloids during various stages of tobacco development and treatment (growing, curing, and aging) [Hecht et al. (1563, 1564), Adams et al. (22)]. TSNAs appear in cigarette MSS as a result of two mechanisms: (1) direct transfer of the TSNAs from the tobacco to the smoke, and (2) pyrogenesis during the smoking process. For example, Hoffmann et al. (1734) and Adams et al. (29) estimated that 40% to 46% of the NNN in MSS was a result of its transfer from the tobacco blend. The remainder, 54% to 60%, in MSS was due to pyrogenesis of NNN from nicotine and nornicotine during the smoking process. Similar data were generated for NNK: 26% to 37% by direct transfer; 63% to 74% by pyrogenesis. The levels in MSS of TSNAs such as NNN can presumably be reduced by reduction in the level of nicotine and/or nitrate in the tobacco blend (499). However, Brunnemann et al. (511) have presented contradictory data on the significance of the correlations among the levels of nitrate, nicotine, and TSNAs in tobacco. *

TSNAs include N’-nitrosonornicotine (NNN) from nicotine and nornicotine, 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) from nicotine, N’-nitrosoanatabine (NAT) from nicotine and anatabine, and N’-nitrosoanabasine (NAB) from anabasine.

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-4 Dibenz[a,h]acridine, Dibenz[a,j]Acridine, and 7H-Dibenzo[c,g]Carbazole in Nicotine Pyrolysates (Pyr) and Mainstream Cigarette Smoke Condensate (CSC) Dibenz[a,h]Acridine

Dibenz[a,j]Acridine

7H-Dibenzo[c,g]Carbazole

Investigators

Pyr

CSC

Pyr

CSC

Pyr

CSC

Van Duuren et al. (4027) Candeli et al. (587), Wynder and Hoffmann (4319, 4332) Kaburaki et al. (2006) Schmeltz et al. (3499) Schmeltz et al. (3512) Snook (3733) Snook et al. (3750) Grimmer et al. (1409) Kamata et al. (2021) Sasaki and Moldoveanu (3414) Rustemeier et al. (3370)

yes NE no no no NE NE NE NE NE NE

yes no NE NE no no no no no no no

yes NE no no no NE NE NE NE NE NE

yes yes NE NE no no no no no no yes

No NE NE No No NE NE NE NE NE NE

yes NE NE NE no no no no NE NE NE

yes = Compound identified. no = Compound not found or identified. NE = Substrate not examined for compound in question.

Since the TSNAs are components of the MSS particulate phase, control of their levels in smoke is also possible by any means that controls the yield of the MSS particulate matter. These include: • • • •

Use of reconstituted tobacco sheet; Expanded tobacco; High filtration efficiency; Air dilution by increased paper porosity and/or ventilated filter tips (Hoffmann et al., 1984).

Unlike the volatile N-nitrosamines such as dimethylnitrosamine (DMNA), the TSNAs are not amenable to selective filtration by use of plasticized filter tips.

XXV.C.2 Organic Solvent-Soluble Components (Long-Chained Aliphatic Hydrocarbons, Phytosterols, Solanesol, High Molecular Weight Esters, etc.) The tobacco smoke components “known” in 1954 numbered fewer than 100 (2170). At that time, the chemical composition of tobacco was as equally ill-defined as that of its smoke. Pyrolyses conducted throughout the 1950s involved the organic solvent-soluble material from tobacco and were limited either to the total extractables or to a few classes of known tobacco components, for example, phytosterols and longchained saturated aliphatic hydrocarbons. These relatively high molecular weight compounds were present in tobacco at levels usually exceeding 0.5% and presented little problem in collecting sufficient material for study. Subsequent research on tobacco (and tobacco smoke) composition resulted in the isolation and elucidation of the structures of numerous classes of organic solvent-soluble compounds, including those listed in Table XXV-5.

The early work of Roffo (3327) on the reduction of tumorigenicity of a “destructive distillate” from a solvent-extracted tobacco (ethyl alcohol), his claim that alcohol extraction removed the tumorigen precursor from the tobacco, and his proposal of the phytosterols as the tumorigen precursor(s) were described previously. Despite the fact that the “destructive distillate” from tobacco was not equivalent to cigarette smoke particulate matter, the proposal of the phytosterols as precursors in tobacco of PAHs was based on sound reasoning and previous experimental findings. Nearly two decades earlier, Kennaway (2073–2075) had demonstrated that pyrolysis of isoprene, acetylene, and cholesterol yielded pyrolysates tumorigenic to mouse skin. Cholesterol was once considered unique to animal tissue but subsequently, trace amounts were found in plant tissue, including tobacco [Stedman (3797), Grunwald et al. (1434)]. Of the tobacco and tobacco smoke sterols, the two present at the highest level are stigmasterol and β-sitosterol. These differ from each other and cholesterol in the structure and configuration of the side chain on the cyclopentane ring. They occur in tobacco as free phytosterols and phytosteryl derivatives (esters, glycosides). Pyrolysis of sterols generates high levels of chrysene. Its four rings are configurationally similar to that of the sterol ring system. In the mid-1920s, Kennaway and others were concerned about the fate of cholesterol when animal tissue was heated during roasting and broiling. Cholesterol pyrolysis experiments were crude attempts to duplicate what happened to it during the cooking process. Here again, the presence of other tissue components (amino acids, proteins, lipids, and carbohydrates) with cholesterol during cooking would certainly have affected the results when compared to the results obtained from pyrolysis of cholesterol alone. In 1928, Kennaway and Sampson (2080) also demonstrated that the specific tumorigenicities of pyrolysates from cholesterol and other organic compounds increased as the

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Table XXV-5 Organic Solvent-Soluble Components of Tobacco Identified Post-1955 Compound

Reported in Tobacco by

Reported in Tobacco Smoke By

Solanesol

Rowland et al. (3359)

Neophytadiene α-Tocopherol Squalene Solanesenes Solanesyl esters

Rowland (3345) Rowland (3347) Fredrickson (1229) — Rowland and Latimer (3358)

Phytosteryl esters Long-chained aliphatic alcohols Long-chained aliphatic esters

Rowland and Latimer (3358) Cook et al. (812) Rodgman et al. (3294), Arrendale et al. (103) Roberts (3195), Roberts and Rowland (3220, 3221), Rowland and Roberts (3360), Rowland et al. (3361) Severson et al. (3616)

Duvanediols

Phytyl esters

Mold and Booth (2590), Wynder and Wright (4354)a, Rodgman and Cook (3270) Rodgman (3247) Rodgman and Cook (3271) Van Duuren and Schmitt (4033), Rodgman et al. (3297) Rodgman et al. (3297) Rodgman and Cook (3270), Rodgman et al. (3296) Rodgman et al. (3296) Cook et al. (812) Rodgman et al. (3294) Rowland et al. (3361)

Rodgman and Cook (3287)

Wynder and Wright (4354) reported geraniol as a cigarette smoke constituent. However, the infrared spectrum of the isolate was identical with that of solanesol, not geraniol (Wright, private communication to Rodgman).

a

pyrolysis temperature was increased. This observation was later confirmed with saturated aliphatic hydrocarbons (2257) and phytosterols [Wynder et al. (4355, 4356)] isolated from tobacco. In the latter two studies, the yield of PAHs generated during pyrolysis of the compounds in question increased as the pyrolysis temperature increased. Wynder et al. (4355) and Wynder and Hoffmann (4332) reported that pyrolyses of a hexane extract of tobacco gave decreasing yields of pyrolysate “tar” as the pyrolysis temperature increased: 560°C, 50%; 640°C, 35%; 720°C, 32%; 800°C, 28%; and 880°C, 28%. They also reported that pyrolysis at 880°C of the hexane extractables in air vs. their pyrolysis in N2 gave pyrolysates whose yields were essentially the same (30% in air vs. 28% in N2) and whose specific tumorigenicities were comparable in skin-painting studies with the mouse and rabbit. Similar findings were reported for aliphatic tobacco hydrocarbons pyrolyzed either in air or in N2 at 800°C with regard to PAH composition and specific tumorigenicity in skin-painting studies. Table XXV-6, adapted from Lam (2257), demonstrates the relationship between PAH generation and pyrolysis temperature for aliphatic tobacco hydrocarbons pyrolyzed in air at several temperatures. Calculation of the yield ratios [PAH, mg/g: B[a]P, mg/g] of the other PAHs vs. B[a]P reveals significant information: In this case of pyrolysis, there was no consistency between the change in ratios of PAH/B[a]P as the temperature was increased from 700°C to 800°C, for example, in the case of the tetracyclic PAHs, the PAH/B[a]P ratio decreased for pyrene and chrysene but increased for fluoranthene; for the pentacyclic PAHs, the ratio decreased for both perylene and B[e]P; for the hexacyclic PAH dibenzo[def,mno]chrysene, the ratio increased. These same trends existed whether PAH/B[a]

P ratios were calculated as molar yields or, as in Table XXV-6, as absolute quantities (micrograms of PAHs generated per gram of aliphatic tobacco hydrocarbons pyrolyzed). The significance of these data and calculations is their demonstration in 1956 that in even the simplest pyrolysis situation, B[a]P is not a valid “indicator” for the PAHs with four or more rings and their supposed relationship to tumorigenic activity [Wynder and Hoffmann (4317, 4319, 4332)]. In addition to these data by Lam, other contrary data that demonstrated the invalidity of the concept of B[a]P as an “indicator” for PAHs with four or more rings and the tumorigenicity of the substrate (CSC, pyrolysate) containing them were generated not only by Wynder et al. (4355, 4356) but also by Campbell and Lindsey (583), Rodgman and Cook (3286), Gori (1329, 1330, 1332, 1333), National Cancer Institute (2685), and Severson et al. (3616). The lack of correlation between CSC content of B[a]P and specific tumorigenicity was demonstrated by Lazar et al. (2320), who reported that a 30-fold increase in B[a]P content by its addition to CSC produced no increase in the specific tumorigenicity to mouse skin of the B[a]P-enhanced CSC vs. the control CSC applied at equal dose levels. This lack of correlation between the B[a]P concentration in CSC and its specific tumorigenicity was also recognized by the U.S. Surgeon General, who wrote in 1981 [see p. 36 in (4009)]: The contribution of BaP or PAH in general to mouse skin carcinogenesis by cigarette smoke condensate cannot be fully measured at this time. Wynder and Hoffmann [4332] found a correlation between BaP levels and carcinogenic activity of smoke condensates from several types of cigarettes. A much larger series of experimental cigarettes was studied in the smoking and health program of the National

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-6 Polycyclic Aromatic Hydrocarbons from Aliphatic Tobacco Hydrocarbons Pyrolyzed in Air at Various Temperatures Quantity (µg) of PAH Formed on Pyrolysis (in air) of Aliphatic Tobacco Hydrocarbons (1.0 gram) Polycyclic Aromatic Hydrocarbon

At 800°C

At 700°C

PAH, µg/g

PAH/B[a]Pa

Naphthalene Acenaphthene Acenaphthylene Phenanthrene Anthracene Pyrene Fluoranthene Chrysene Perylene Benzo[a]pyrene Benzo[e]pyrene Dibenzo[def,mno]chrysene

14260 0 3520 3840 580 960 1700 400 34 340 400 42

41.94 [2/5]b 0 [3/5]c 10.35 [3/5]c 11.29 [3/5]c 1.71 [3/5]c 2.82 [4/5]d 5.00 [4/5]d 1.18 [4/5]d 0.10 [5/5]e 1.00 1.18 [5/5]e 0.12 [6/5]f

Totals

26076

86.87

B[a]P = benzo[a]pyrene [3/5] = tricyclic/pentacyclic B[a]P e [5/5] = pentacyclic/pentacyclic B[a]P

PAH, µg/g

At 600°C PAH/B[a]Pa

PAH, µg/g

4760 0 480 580 110 320 24 86 4 30 80 <1

158.7 0 16.00 19.33 3.67 10.67 0.80 2.87 0.13 1.00 2.67 <0.03

0 0 0 0 0 0 0 0 0 0 0 0

6474

21.47

0

[2/5] = bicyclic/pentacyclic B[a]P [4/5] = tetracyclic/pentacyclic B[a]P f [6/5] = hexacyclic/pentacyclic B[a]P

a

b

c

d

Cancer Institute. No significant dependence of carcinogenic potency on BaP content was observed [Gori (1329, 1330, 1332, 1333), National Cancer Institute (2683].

The post-1930 stimulus for PAH research was provided by the following events: the independent syntheses of DB[a,h]A in 1929 by Clar (760) and Fieser and Dietz (1184); the demonstration of its mouse-skin tumorigenicity by Kennaway and Hieger (2078); the early 1930s reports by Cook et al. (726, 727) on several PAH isolates from coal tar, known to be tumorigenic to the skin of mice and rabbits; identification of two coal tar isolates as B[a]P and B[a]A; and the demonstration of the tumorigenicity to mouse skin of B[a]P (194, 726). In addition to Kennaway and Sampson (2080), numerous investigators after 1932–1933 examined the pyrolysates from sterols in conjunction not only with the alleged tumorigenicity and PAH content of “destructive distillates” from tobacco, CSCs, and pyrolysates of tobacco, tobacco extractables, and individual tobacco components but also with the alleged tumorigenicity and PAH content of heated foodstuffs and their role in digestive tract cancer. For example, Roffo, in addition to his tumorigenicity studies with “destructive distillates” from various tobaccos types (3320, 3324, 25A51) and organic solvent-extracted tobaccos (3327), investigated the tumorigenicity of heated or oxidized fats (25A53, 25A55, 25A59) and the “tars” and phenanthrene derivatives from cholesterol pyrolyzed (25A56, 25A57, 25A58) or irradiated in air (25A54). Other investigators who examined the chemical and biological properties of cholesterol pyrolysates included Steiner et al. (25A69), Falk et al. (1171), and Bischoff and Rupp

(25A10). Previously, Veldstra (4042a) had demonstrated that 3,5-cholestadiene, produced pyrolytically from cholesterol, was tumorigenic to skin-painted laboratory animals. Subsequently, cholesten-4-one was found to be both tumorigenic to mouse skin and a component of the pyrolysate from cholesterol and/or its derivatives. These and other pyrolysate findings on composition (PAHs in the pyrolysate) and properties (tumorigenicity of pyrolysate and/or the components of pyrolysates generated from cholesterol or its naturaloccurring derivatives) were summarized by Rodgman (3233, 3242). Although the pentacyclic PAH 1,2-dihydro-3methylbenz[j]aceanthrylene (previously known as 3-methylcholanthrene or 20-methylcholanthrene), a potent mouse-skin tumorigen, may be prepared by a series of chemical reactions from a sterol-derived compound structurally related to cholesterol, it has never been identified in a sterol pyrolysate. Although Kröller (2191) claimed the identification of 1,2-dihydro-3-methylbenz[j]aceanthrylene (3-methylcholanthrene) in mainstream CSC, his identification of it was questioned by Wynder and Hoffmann (4332), who asserted that it and other alkylated PAHs had never been reported as a combustion or pyrolysis product. Wynder and Hoffmann (4332) also questioned the reports by Pietzsch (2962) and Kröller (2191) of the presence in CSC of the methylated PAH DMB[a] A. It and other methylated PAHs in mainstream CSC were reported in 1960 by Rodgman and Cook (3273). In addition, in 1963 Grossman et al. (1431, 1432) reported alkylated naphthalenes in the pyrolysate from solanesol, a major tobacco component. In the 1970s, Snook et al. reported not only several dimethylbenz[a]anthracenes in CSC (3756) but also a great number of alkylated PAHs in CSC (3757). Thus, the

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Table XXV-7 Total, Free, and Bound Sterols in Cigarette Tobacco Total Free, µg/g Tobacco

Bound, µg/g Tobacco

Stigmasterol β-Sitosterol Campesterol Cholesterol

326 185 129 79

262 366 173 86

588 551 302 165

37 34 19 10

Total

719

887

1,606

100

Sterol

µg/g Tobacco

%

Wynder-Hoffmann assertion about the presence of alkylated PAHs in MSS was incorrect. Campesterol, stigmasterol, β-sitosterol, and cholesterol have been identified both free and/or bound (as esters, etc.) in tobacco and CSC [see Grunwald et al. (1434) for a summary of the early research on tobacco sterols and their derivatives]. In their study, Grunwald et al. found that these four sterols constituted about 0.16% of the tobacco weight and about 15% of them were transferred to MSS. According to Grunwald et al., the remainder of the sterols were “lost in the smoke sidestream, pyrolyzed during the smoking process and/or deposited in the butt.” Thus, a cigarette containing 1.0 g of the tobacco studied by Grunwald et al. would contain 1600 µg of these sterols and deliver about 240 µg to MSS. About 82 µg of the 240 µg would be β-sitosterol, a compound reported to be anticarcinogenic to several N-nitrosamines [Wattenberg (4149a)} and PAHs [Yasukawa et al. (25A86)]. Table XXV-7, adapted from Grunwald et al. (1434), indicates the relative proportions of these four sterols in tobacco: cholesterol is the least plentiful of the four tobacco sterols in Table XXV-7. Except for minor differences in the side-chain structure, the cholesteryl oleate studied by Veldstra (4042a) is structurally similar to the phytosteryl ester fraction isolated from tobacco by Rowland and Latimer (3358) and from CSC by Rodgman et al. (3296). It was subsequently identified as a mixture of esters of stigmasterol and β-sitosterol with longchained saturated (palmitic, stearic) and unsaturated (oleic, linoleic) acids. In the late 1950s to the early 1960s, Rodgman and Cook were unsuccessful in their CSC study to identify the stigmasterol- or β-sitosterol-derived dienes or ketones corresponding to the tumorigenic 3,5-cholestadiene and cholesten-4-one generated during pyrolysis of cholesterol or its esters. However, Benner et al. (273) subsequently identified 3,5-campestadiene (VIb) and 3,5-stigmastadiene (VId] in tobacco smoke, [see Eatough et al. (1099, 1100)]. The following paragraphs summarize the relationships, both known and proposed, between a sterol such as cholesterol and its various pyrolysis products. Because of the results of the studies by Kennaway (2073– 2076), Kennaway and Sampson (2080), and Roffo (25A56, 25A57, 25A58) on the generation of tumorigenic pyrolysates from cholesterol or cholesterol-containing foodstuffs, the

question was raised: What is the relationship between these observations on tumorigenic cholesterol pyrolysates and the incidence of stomach and digestive tract cancers? When many studies, beginning in 1934 [see summary in Hartwell (1544)], revealed that 1,2-dihydro-3-methylbenz[j]aceanthrylene (3-methylcholanthrene) was a potent tumorigen equivalent in potency in mouse skin-painting bioassays to B[a]P and DB[a,h]A, extensive research was conducted in attempts to determine whether it was generated from cholesterol during various cooking processes. Examination of the entries in the catalogs by Hartwell (1544) and Shubik and Hartwell (3664) for the four PAHs considered to be potent tumorigens revealed 474 studies involving 1,2-dihydro-3-methylbenz[j] aceanthrylene (3-methyl-cholanthrene) between 1934 and 1953, 410 studies involving B[a]P between 1932 and 1953, 275 studies involving DB[a,h]A between 1930 and 1953, and 91 studies involving DMB[a]A between 1938 and 1953. One of the most potent PAHs in mouse skin-tumor induction is 1,2-dihydro-3-methylbenz[j]aceanthrylene (3-methylcholanthrene) which theoretically could be formed pyrogenetically from sterols such as cholesterol {Ia}. In addition to the trace level of cholesterol present in tobacco, tobacco usually contains substantial levels of several phytosterols [campesterol {Ib}, β-sitosterol {Ic}, stigmasterol {Id}, and ergosterol {Ie}] structurally similar to cholesterol. These phytosterols differ from cholesterol {Ia} in the structure of the long side chain. Stigmasterol {Id} is structurally similar to β-sitosterol {Ic} except for a double bond at the C22 carbon. The legend to Figure XXV-1 indicates the differences among cholesterol, campesterol, β-sitosterol, ergosterol, and stigmasterol. These sterols, present in tobacco in both the free and bound form (as glycosides and esters), are transferred intact to MSS. These sterols constitute about 0.2% of the tobacco weight. Table XXV-7 illustrates the relative proportions of these sterols in tobacco. These data indicate that cholesterol and cholesteryl derivatives are the least plentiful of the free and bound sterols in tobacco. These levels are similar to those of the standard and reference cigarettes in the National Cancer Institute (NCI) “Less Hazardous” Program (1329, 1330, 1332 1333, 2683). As shown in Figure XXV-1, pyrolysis of cholesterol {Ia} yields chrysene {III} and a Diels’ hydrocarbon {IV}, a methylcyclopentaphenanthrene. Both PAHs have also been isolated from pyrolysates of the major tobacco phytosterols. While cholesterol {Ia} and the tobacco phytosterols [campesterol {Ib}, β-sitosterol {Ic}, and stigmasterol {Id}] have not been shown to generate 3-methylcholanthrene {II} on pyrolysis, cholesterol {Ia} and its esters with long-chained acids do generate the mouse-skin tumorigens 4-cholesten-3-one {Va} and 3,5-cholestadiene {VIa} (1171). Veldstra (4042a) reported that the pyrolysis of cholesteryl oleate also yielded 3,5-cholestadiene {VIa}. Cholesteryl oleate was probably a component of the mixture of steryl esters described in fluecured tobacco by Rowland and Latimer (3358) and in tobacco smoke by Rodgman et al. (3296). The steryl esters included sterols esterified with a series of saturated (palmitic, stearic, etc.) and unsaturated (oleic, linoleic, etc.) acids.

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1122

The Chemical Components of Tobacco and Tobacco Smoke

R

CH3

CH3

CH3

CH3 H3C IV

CH3

R CH3

O CH3

CH3

II

HO

V

R CH3

CH3

CH3

I

VI

III LEGEND Sterol,

R=

Ia Ib Ic Id Ie

cholesterol campesterol β-sitosterol stigmasterol ergosterola

II

1,2-dihydro-3-methylbenz[j]aceanthrylene (3-methylcholanthrene)

III

chrysene

IV

Diels´ hydrocarbon

Va Vb Vc Vd Ve

4-cholesten-3-one 4-campesten-3-one β-4-sitosten-3-one stigmasten-3-one ergostadien-3-one

VIa VIb VIc VId VIe

3,5-cholestadiene 3,5-campestadiene β-3,5-sitostadiene 3,5-stigmastadiene 3,5,7-ergostatriene

a

-(CH2)3-CH(CH3)2 -(CH2)2-CH(CH3)-CH(CH3)2 -(CH2)2-CH(C2H5)-CH(CH3)2 -CH=CH-CH(C2H5)-CH(CH3)2 -CH=CH-CH(CH3)-CH(CH3)2

Ergosterol has a double bond at the 7-position

Figure XXV-1  Possible sterol degradation products.

In the late 1950s, Rodgman proposed that on thermal degradation during the smoking process, campesterol, stigmasterol, and β-sitosterol and their esters might generate the ketones {Vb, Vc, Vd} and dienes {VIb, VIc, VId} analogous to 4-cholesten-3-one {Va} and 5-cholestadiene {VIa} and they might also be mouse-skin tumorigens like their cholesterol counterparts. Several PAHs other than chrysene and Diels′ hydrocarbon (Figure XXV-1) were subsequently identified in sterol pyrolysates. In 1959, Wynder et al. (4355, 4356) reported that PAHs were generated at both temperatures when tobacco sterols were pyrolyzed in air at 720°C and 850°C. At these temperatures, the pyrolysates constituted 28% and 22%, respectively, of the phytosterols pyrolyzed; B[a]P constituted

0.1% and 1.0%, respectively, of the pyrolysates. These results with phytosterols pyrolyzed at two different temperatures are similar to those reported for the pyrolyses of aliphatic tobacco hydrocarbons (2255–2258). In 1962, Van Duuren (4022) described the identification of pyrene and B[a]P in a stigmasterol pyrolysate. Badger et al. (142) in their pyrolysis study of tobacco phytosterols reported the identification of some thirty PAHs, all previously reported as CSC components. They also noted the accentuated production of chrysene vs. its generation by pyrolysis of aliphatic tobacco hydrocarbons. Chrysene, reported to be tumorigenic to mouse skin, is a sterol pyrolysis product characteristically generated at a high level compared to that for other PAHs in the pyrolysate. The four-ring arrangement in chrysene is

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similar to that of the sterol rings. The International Agency for Research on Cancer (IARC) eventually removed chrysene from the tumorigen list. From a precursor “spiking” experiment involving addition to tobacco of aliphatic tobacco hydrocarbons, a phytosterol (β-sitosterol), or solanesol, it was noted that the increase in the chrysene yield in the CSC was much more pronounced with phytosterol-treated tobacco than with aliphatic hydrocarbonor solanesol-treated tobacco (3251, 3269, 3291). Doubling the levels of solanesol, aliphatic tobacco hydrocarbons, and phytosterols by addition of each to a control tobacco blend resulted in increases in the B[a]P yields in the mainstream CSCs of 13%, 13%, and 16%, respectively. However, the chrysene yields were increased by 16%, 28%, and 183%, respectively. Tripling the addition levels increased the B[a]P levels in the mainstream CSCs by 18%, 20%, and 28%, respectively, and the chrysene levels by 22%, 50%, and 239%, respectively. In their study of the petroleum ether-extractable material (8% of tobacco weight) from tobacco which was chromatographically separated into eight fractions (see Table XXV-8), Severson et al. (3616) identified PAHs in the pyrolysates from fractions F-2 and F-3 (containing phytosterol derivatives) and from fractions F-5 and F-6 (containing unbound phytosterols). Their PAH data for these four pyrolysates from phytosterol-rich tobacco fractions showed high yields of chrysene vs. those in the pyrolysates from the essentially phytosterolfree fractions (F-1, F-2, F-7, and F-8). Although their study dealt with pyrolysis of tobacco phytosterols, Schmeltz et al. (3511) did determine the percent conversion of phytosterols (and other components) to MSS PAHs by use of radiolabeled phytosterols generated by growing tobacco in an atmosphere containing radiolabeled CO2, isolating radiolabeled tobacco components, and adding them individually to cigarettes which were then smoked and the MSS analyzed. Their data are summarized in Table XXV-9. Their 1978 finding with radiolabel techniques (<1% conversion to PAHs) for the tobacco phytosterols is comparable to

Table XXV-8 Component Distribution in Eight Subfractions from a Petroleum Ether Extract of Tobacco (8% of Tobacco Weight) Chromatographic Fraction No.

%

Major Component(s)

F-1

5.3

F-2 F-3 F-4 F-5 F-6 F-7 F-8

4.3 8.9 29.2 6.6 20.3 15.8 9.6

Long-chained saturated hydrocarbons, neophytadiene Esters of sterols and terpenoid alcohols Esters of sterols and solanesol Solanesol Solanesol, sterols, and long-chained fatty acids Sterols and long-chained fatty acids Polar esters of fatty acids Polar esters of fatty acids

Table XXV-9 Conversion of Tobacco Leaf Constituents to Total Mainstream Smoke Polycyclic Aromatic Hydrocarbons Leaf Constituent Phytosterols Palmitic acid Neophytadiene Polar fraction Alkaloids

% Conversion to Mainstream PAHs <1.0 <1.0 0.10 0.15 0.10

the 1958 data of Rodgman and Cook (3269, 3291) who, using classical chemical techniques in a “spiking” experiment, reported the conversion of β-sitosterol to PAHs to be about 0.6%. As noted by Wynder and Hoffmann (4319, 4332), the first group of tobacco components studied by pyrolysis was the “tobacco paraffins.” Subsequently, these were shown to consist of a mixture of n- (normal), iso- (2-methyl-), and anteiso(3-methyl-) saturated hydrocarbons CnH2n+2, the bulk of which comprised hydrocarbons ranging from ten or twelve to more than forty carbon atoms. These hydrocarbons were also extractable from tobacco by pentane, hexane, or petroleum ether. Pyrolysis studies in air or an inert atmosphere (N2, He) with either the tobacco-derived saturated aliphatic hydrocarbon fraction or individual components of the fraction [see Lam (2255, 2256, 25A39), Wynder et al. (4356)] or individual hydrocarbons [see Lam et al. (2260) for n-pentacosane, Haefele and Giles (1480) for n-hentriacontane, Badger and Novotny (151) for n-decane, Badger et al. (142) and Lam (2256) for n-dotriacontane (dicetyl)] indicated that these tobacco components yielded pyrolysates reported to be tumorigenic in mouse skin-painting bioassays and to contain many PAHs, several of which were tumorigenic in long-term mouse skin-painting bioassays. The PAHs identified in the various pyrolysates ranged in complexity from bicyclic (naphthalenes), tricyclic (acenaphthenes, anthracenes, phenanthrenes), tetracyclic (pyrenes, fluoranthenes, chrysenes, benzanthracenes), pentacyclic (perylenes, benzopyrenes, dibenzanthracenes, benzofluoranthenes), hexacyclic (dibenzochrysenes), and heptacyclic (coronene). Eventually, all the PAHs identified in the various pyrolysates were identified in mainstream CSC. In every case where the pyrolysis temperature was lowered, the yields of the PAHs in the pyrolysate also decreased (see Table XXV-6). From data they generated, Rayburn and Wartman (3091) and Rayburn et al. (3092) challenged the concept that the saturated aliphatic hydrocarbons in tobacco were precursors of the PAHs in mainstream CSC. Wynder and Hoffmann (4319, 4332), in turn, criticized the experimental procedures that provided the data upon which Rayburn et al. based their argument: The experimental findings (of Rayburn et al.) are partially based on total polycyclic hydrocarbons of similar ultraviolet

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1124 spectra and not on analytical data. The report did not mention counting techniques for C14-labeled paraffins nor their quenching effects. These, as well as other factors, appear to weaken considerably the challenge of a concept based on extensive experimental data.

In 1979, Severson et al. (3616), in their study of the petroleum ether extractables (8% of tobacco weight) chromatographically separated into eight fractions (see Table XXV-8), reported the identification of PAHs in the pyrolysate from fraction F-1, the fraction containing the saturated aliphatic hydrocarbons extracted from the tobacco. As recently as 1985, Lam et al. (2260) identified numerous PAHs in the pyrolysate from n-pentacosane, a known component of the saturated aliphatic hydrocarbon fraction present in tobaccos. In 1958, Rodgman and Cook (3269, 3291) added tobaccoderived saturated aliphatic hydrocarbons to a tobacco blend in a “spiking” experiment and determined the effect of the addition on the PAH levels in mainstream CSC. They reported the added saturated hydrocarbons increased the yield of PAHs in cigarette MSS and thus were precursors of the smoke PAHs. The structure of the unsaturated C45 polyisoprenoid alcohol, solanesol, was established in 1956 by Rowland et al. (3359). Despite the fact that solanesol was one of the major individual components of the extractable waxes from tobacco, its pyrolysis was not reported until 1962. While Lam (2255) favored the saturated hydrocarbons as the major precursors in tobacco of PAHs in smoke, Wynder (4294) considered both the saturated hydrocarbons and the phytosterols to be the major precursors. Wright (4282) proposed that the phytosterols and other terpenoids such as solanesol were the major precursors in tobacco of PAHs in smoke. In spite of their differences of opinion on the relative importance of these tobacco components in their contribution to smoke PAHs, they collaborated on several studies in the late 1950s (4355, 4356). Subsequently, the saturated hydrocarbons, the phytosterols, and other terpenoids such as solanesol were shown to be important in the formation of PAHs in tobacco smoke (3251, 3269, 3291, 3616). In the early 1960s, Grossman et al. (1431, 1432) examined the pyrolysate from solanesol and reported the identification of monocyclic hydrocarbons (benzene and cyclopentene derivatives) (1431) and bicyclic aromatic hydrocarbons (naphthalenes) (1432). No tricyclic PAHs were reported. In 1963, Gil-Av and Shabtai (1286) postulated that solanesol in tobacco was a source of tobacco smoke PAHs and proposed a mechanism for their generation from solanesol. Solanesol and other similarly configured terpenoid compounds, for example, neophytadiene, squalene, and duvane derivatives, depolymerized during the smoking (or pyrolytic) process to produce isoprene which, in turn, reacted with itself and subsequent reaction products to generate a tumorigenic “tar” such as that described in the mid-1920s by Kennaway (2073–2075). This “tar” derived from solanesol via isoprene would contain the requisite tumorigenic PAHs such as B[a]P.

The Chemical Components of Tobacco and Tobacco Smoke

Although Gil-Av and Shabtai (1286) demonstrated the presence of B[a]P in an isoprene pyrolysate, they did not study the pyrolysis of solanesol. Severson et al. (3616) described the pyrogenesis of PAHs from solanesol in their study of the petroleum ether tobacco extractables (8% of tobacco weight) which they chromatographically separated into eight fractions (see Table XXV-8). Fraction F-4 was primarily solanesol. Fraction F-3 contained solanesyl esters. Severson et al. (3616) summarized the contribution of solanesol to PAHs in its pyrolysate (and in CSC): The carotenoids and solanesol are most like responsible for the high levels of the multialkylated PAH found in the [petroleum ether]-extract pyrolyzate and, by analogy, in CSC. Because of its relative abundance in leaf, solanesol may contribute as much as 40% of the benzopyrenes produced on pyrolysis of the [petroleum ether] extract of tobacco.

As noted previously, 1958 precursor experiments (3251, 3269, 3291), in which solanesol was added at several levels in a “spiking” experiment and the effect of this addition on the levels of total and individual PAHs in cigarette MSS were determined, demonstrated that solanesol in tobacco was indeed a precursor of PAHs in cigarette MSS. Phytol, a terpenoid alcohol, is a known component of tobacco leaf. It and its structurally similar dehydration product, neophytadiene, probably occur in tobacco leaf through the degradation of chlorophyll whose structure includes phytol (3345). Neophytadiene (3247), phytol (3285), and phytyl esters (3287) are present in tobacco smoke (see Table XXV-5). Schmeltz et al. (3511), in their 1978 radiolabel study, determined the contribution of neophytadiene to PAHs in cigarette MSS. They estimated that about 0.1% of the tobacco neophytadiene is converted during the smoking process to PAHs in the MSS (see Table XXV-9). The pyrolysis products of neophytadiene and phytol were examined in 1985 by Lam et al. (2260). Numerous PAHs were identified in both pyrolysates. Normal long-chained aliphatic alcohols, known minor components of tobacco (614, 615, 25A18, 25A80) and tobacco smoke (812), may not play a significant role as PAH precursors. In fact, Carruthers and Johnstone (614, 615), who identified 1-docosanol in tobacco, found little of its dehydration product, 1-docosene, in tobacco smoke. They postulated that long-chained primary alcohols such as 1-docosanol were little affected by pyrolysis. Severson et al. (3616) cataloged the major components in eight chromatographic fractions of the petroleum ether extractables from tobacco (see Table XXV-8). Each fraction was subjected to pyrolysis. Surprisingly, Severson et al. did not list long-chained primary alcohols in any of the eight chromatographic fractions!

XXV.C.3 Structural Components of Tobacco (Cellulose, Lignin, Pectins, etc.) Since cellulose, the pectins, starch, lignin, and proteins— the so-called structural components of tobacco—are organic compounds, that is, contain carbon, with one or more of the

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Table XXV-10 Polycyclic Aromatic Hydrocarbons from Tobacco Components Pyrolyzed in a N2 Atmosphere at 650°C Quantity (ng) of PAH Formed on Pyrolysis of Tobacco Componenta (1.0 mg) at 650°C (in N2) PAHb

Cell

Lign

Pect

Star

Sucr

Gluc

Fruc

Mal

Citr

Oxal

Acenaphthylene Fluorene Anthracene Pyrene Pyrene, 3-methylFluoranthene Benz[a]anthracenec Benzo[a]pyrenec Benzo[e]pyrenec Dibenzo[def,mno]chrysene Coronene

1.60 5.84 3.37 1.29 1.31 1.64 1.86 0.78 0.85 0.10 0.44

0.80 80.00 5.44 0.33 0 0.58 0.44 0.47 0.22 0 0

0.20 2.87 5.39 1.33 0.29 1.52 2.73 0.45 0.34 0.09 0.15

0.56 0.32 1.04 0.35 0.11 0.94 1.16 0.17 0.04 0.01 0.03

0.24 0.12 0.70 0.24 0.15 0.35 0.41 0.10 0.02 0 0.03

0.27 0.07 0.36 0.66 0.01 0.45 0.43 0.29 0.11 0.05 0.01

1.04 1.18 1.39 0.35 0.11 1.06 1.20 0.33 0.02 0.05 0.05

0.16 6.32 0.70 1.66 1.19 1.36 1.30 0.35 0.08 0.01 0.06

0.50 1.73 0.98 0.24 0.89 0.06 0.05 0.17 0.37 0.02 0.11

0.15 0.03 0.30 0.20 0.01 0 0 0.01 0 0.003 0.02

a

b

c

Cell = cellulose; Lign = lignin; Pect = pectin; Star = starch; Sucr = sucrose; Gluc = glucose; Fruc = fructose; Mal = malic acid; Citr = citric acid; Oxal = oxalic acid. Several other PAHs were found in some, but not all, of the pyrolysates, namely, azulene, naphthalene, alkylnaphthalenes, acenaphthene, phenanthrene, and perylene. Tumorigenic to mouse skin in skin-painting studies.

carbons linked to hydrogen,* they will generate PAHs during high-temperature pyrolysis much in the same manner as the compounds studied in the mid-1920s and early 1930s by Kennaway (2073–2076). In his studies, Kennaway demonstrated that pyrolysis of various organic compounds—from simple ones such as acetylene or isoprene to more complex ones—would generate pyrolysates tumorigenic to mouse skin. Subsequently, these and similar organic compound-derived pyrolysates were shown to contain a variety of PAHs (1286, 2264b), some of which were potent mouse-skin tumorigens. Obviously, PAHs should be generated from the structural components of tobacco during the reactions occurring when tobacco is smoked in a cigarette. Interest in the major precursors in tobacco of the PAHs in MSS eventually led to the conclusion that the major precursors in tobacco of cigarette MSS PAHs in cigarette MSS were the organic solvent-extractable, high molecular weight tobacco components, such as the saturated aliphatic and unsaturated aliphatic hydrocarbons, the phytosterols, and terpenoid alcohols such as solanesol (3251, 3269, 3291, 3616, 4332). During the search for the major PAH precursors in tobacco, all of the above-mentioned organic solvent-soluble tobacco components (see Table XXV-5) that were examined by pyrolysis were shown to yield PAHs. In 1957, Gilbert and Lindsey *

Examination of the data reported by Gilbert and Lindsey (1289) on the pyrogenesis of PAHs from various tobacco constituents would appear to contradict this statement. Gilbert and Lindsey reported the generation of a series of PAHs in the pyrolysate (see Table XXV-10) from the dicarboxylic acid oxalic acid [(COOH)2] which obviously has no carbon-hydrogen bond. However, it is known that a major product of the thermal decomposition of oxalic acid is formic acid [H-COOH] via decarboxylation. Formic acid does have the requisite carbon-hydrogen bond.

(1289) reported their results on the amounts of various PAHs in the pyrolysates (650°C, N2) from the major structural components from flue-cured tobacco. These included cellulose, pectins, starch and lignin, the simple sugars sucrose, glucose, and fructose, and the acids malic acid, citric acid, and oxalic. Their data, modified to indicate nanograms of individual PAHs generated per milligram of tobacco component pyrolyzed,† are summarized in Table XXV-10. Numerous pyrolysis experiments were conducted from the mid-1950s to the mid-1980s on tobacco components and tobacco fractions and residues obtained by solvent extraction of tobacco. However, meaningful comparison of the results has been difficult because of the lack of uniformity in the pyrolysis conditions employed in the studies. Even when some similarity existed between experimental conditions used in two separate experiments, precise comparison was confounded by the fact that different tobaccos or blends were used in the experiments, for example, Gilbert and Lindsey (1289) examined the PAH yields in the pyrolysates (650°C, N2) from the structural components of a flue-cured tobacco grown a year or two prior to their 1957 study; Severson et al. (3616) examined the pyrolysates (produced at a variety of temperatures including 650°C, N2) from a flue-cured tobacco probably grown a few years before their 1979 publication and from a tobacco blend. In their detailed study, Severson et al. (3616) examined the following pyrolysates: a flue-cured tobacco; its petroleum ether extractables (8% of the tobacco weight), PEE; the tobacco †

Nanogram of PAH generated per milligram of tobacco component pyrolyzed = microgram of PAH generated per gram of tobacco component pyrolyzed = parts per million (ppm) of PAH from the tobacco component pyrolyzed.

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-11 Conversion of Components in Tobacco to Benzo[a]pyrene during Pyrolysis Theoretical Contribution toa Level in Tobacco Tobacco Component of Fraction

%

Pyrolysis

Benzo[a]pyrene

Total Benzopyrenesb

mg/g

T, °C

Atmos

ng/mg

ng

ng/mg

650 650 650 650 650 650 650 650 650 650

N2 N2 N2 N2 N2 N2 N2 N2 N2 N2

0.78 0.47 0.45 0.17 0.10 0.29 0.33 0.35 0.17 0.01

70.2 16.5 48.2 6.8 4.2 31.9 25.7 35.4 1.0 0.1

1.43 0.69 0.79 0.21 0.12 0.40 0.35 0.43 0.54 0.01

ng

Flue-Cured Tobacco Components (1289) Cellulose Lignin Pectin Starch Sucrose Glucose Fructose Malic acid Citric acid Oxalic acid

9.0 3.5 10.7 4.0 4.2 11.0 7.8 10.1 0.6 1.0

90 35 107 40 42 110 78 101 6 10

Total

61.9

619

240.0

128.7 24.2 84.5 8.4 5.0 44.0 27.3 43.4 3.2 0.1 368.8

Fractions From Flue-Cured Tobacco (3616) F-1 Aliphatic hydrocarbons F-4 Solanesol F-6 Phytosterols

0.42 2.34 1.62

42 234 162

650 650 650

N2 N2 N2

29 930 670

122 21762 10854

320 380 1140

25600 30400 91200

0 110 740

0 550 700

Fractions From University of Kentucky 1R1 Tobacco Blend (3616) Petroleum ether extractables Petroleum ether extractables Petroleum ether extractables 1R1 tobacco blend Petroleum ether extractables Petroleum ether extractables

8.0 8.0 8.0 100.0 8.0 92.0

80 80 80 1000 80 920

650 700 800 700 700 700

N2 N2 N2 N2 N2 N2

190 1750 54

190000 140000 50000

5 5 5

600 700 800

Air Air Air

0 30 340

0 30 1700

Other Studies with Tobacco Components (2257) Saturated aliphatic hydrocarbons c Saturated aliphatic hydrocarbons c Saturated aliphatic hydrocarbons c

0.5 0.5 0.5

Flue-Cured Cigarette Smoke Condensate (4317)

90 d

It is assumed that 1 g of tobacco is consumed during the cigarette smoking. Total BP = B[a]P + B[e]P c Saturated aliphatic hydrocarbons isolated from flue-cured tobacco. d Estimated total of B[a]P in MSS (4317) plus SSS from an all-flue cured tobacco cigarette is 45 ng in MSS plus an estimated 45 ng in SSS. a

b

residue after petroleum ether extraction, RES; and eight chromatographic fractions (F-1 through F-8) derived from the PEE. Unfortunately, Severson et al. conducted several key pyrolysis experiments at 700°C only. It should also be noted that tobaccos, such as the flue-cured tobaccos used by Gilbert and Lindsey and by Severson et al., would not be identical because of the differences in agronomic conditions and practices for the tobaccos grown in the mid-1950s vs. the mid-1970s. Table XXV-11 summarizes pyrolysis data from Lam (2257), Gilbert and Lindsey (1289), and Severson et al. (3616) with particular emphasis on the somewhat similar experimental conditions (pyrolysis temperature, atmosphere) and on the yields of B[a]P and B[e]P from the pyrolysis of different tobaccos, blend, components, and/or fractions. The data in Table XXV-1l, plus additional data in the publications cited, indicate that the structural components as well as other components and fractions (organic solvent-soluble

or insoluble) from tobacco yielded a variety of PAHs on pyrolysis, but the structural components—the biopolymers— such as cellulose, pectins, starch, lignin, etc., on a per unit weight pyrolyzed basis generated much lower yields of PAHs than did the organic solvent-soluble components and/or fractions. Even in the cases where tobacco components are not only soluble in organic solvents but also are relatively highly oxygenated, they show a low propensity to generate PAHs on pyrolysis. This fact was demonstrated by Severson et al. (3616) in their study of the pyrolysates from the eight chromatographic fractions from the petroleum ether extractables from flue-cured tobacco. They noted: Extraction fractions F-1 and F-8 yielded relatively low yields of PAH on pyrolysis, the former because of its thermally stable hydrocarbon content, and the latter because of its polar oxygenated constituent content. Such oxygenated compounds, having a relatively low carbon content yield low

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Pyrolysis amounts of the alkyl residues essential for PAH formation [see Badger et al. (148), Schmeltz and Hoffmann (3489)].

The F-8 components that Severson et al. in their pyrolysis studies demonstrated to have a low propensity to yield PAHs on pyrolysis are similar both structurally and property-wise (molecular weight, volatility) to some of the compounds used in “top dressing” formulations for tobacco smoking products [see tabulations in Doull et al. (1053), Leffingwell et al. (2341)]. Presumably, “top dressing” components applied to tobacco products on pyrolysis would behave similarly during pyrolysis to the F-8 oxygenated tobacco components described by Severson et al. [see pp. 284–285 in (3616)]. Even though the structural components of tobacco on pyrolysis did yield PAHs, albeit at a much lower level than other classes of tobacco components, their contribution to tobacco smoke composition became important from another point of view: when only a small portion (about 2% to 3%) of the biological response observed in mice (or other rodents) skin-painted with CSC could be explained by its content of the PAHs reported to be tumorigenic to mouse skin [see pp. 14–52 in (4005), Wynder et al. (4303)] additional explanations for the observed biological response were sought. The concepts of promotion and co-carcinogenesis were introduced into the theory of CSC tumorigenicity in an attempt to explain the observed biological response in the mouse skin-painting studies. In the 1950s, Boutwell et al. (414) and Boutwell and Bosch (414) reported that low molecular weight phenols such as phenol itself and the cresols, nontumorigenic per se in skinpainting experiments, enhanced the tumorigenicity in mouse skin-painting studies of PAHs reported to be tumorigens. In 1959, Roe et al. (3314) reported the promoting effect of a phenolic fraction from cigarette MSS. Two years later, Wynder and Hoffmann (4313) examined phenol as a promoter of several PAHs (B[a]P, DMB[a]A) and concluded: Promoting substances present in tobacco smoke can increase and accelerate the tumor yield of carcinogenic polynuclear hydrocarbons that by themselves are not present in sufficient concentration to yield any tumors or yield them only after a prolonged latent period.

The low molecular weight phenols are extremely low-level components of tobacco but are present in cigarette MSS at levels many times those in tobacco. This led to the search in the late 1950s and early 1960s for precursors in tobacco of the alleged biologically active phenols in tobacco smoke. Studies by Rodgman and Cook (3277), Rodgman and Mims (3305), and Rodgman (3251) on the effect of tobacco components (lignin, pectin) added to a cigarette tobacco blend on low molecular weight phenols levels in MSS and similar studies [Spears et al. (3767), Bell et al. (248)] on the effect of tobacco carbohydrates (glucose, sucrose, starch, cellulose, or pectin) added to cigarette tobacco filler on phenols levels in MSS demonstrated that these tobacco components were major precursors of the simple phenols in cigarette MSS. From 1962 through 1971, Newell and Best conducted studies with radiolabeled components isolated from tobaccos

Table XXV-12 Conversion of Pectins, Starch, and Cellulose to Specific Polycyclic Aromatic Hydrocarbons and Phenols during Smoking Percent of Added Tobacco Component Converted during Smoking to Smoke Component Smoke Component

Pectins

Polycyclic Aromatic Hydrocarbons Pyrene NDb Benzo[a]pyrene 0.0000014 Benz[e]acephenanthrylene a 0.0000018 Benzo[k]fluoranthene 0.0000032 Phenols Phenol o-Cresol m-Cresol + p-Cresol Guaiacol 2,5-Xylenol

0.00125 0.0010 0.00077 0.00115 ND

Starch

Cellulose

ND 0.0000136 0.0000017 ND

0.0000546 0.0000021 0.0000060 ND

0.0034 0.0030 ND ND ND

0.0036 0.0046 0.0048 0.0024 0.0022

Benz[e]acephenanthrylene was formerly known as benzo[b]fluoranthene b ND = not determined a

grown in a radiolabeled CO2 atmosphere. Among these radiolabeled components studied were the cell-wall components or biopolymers [pectin (2764), starch (2764), α-cellulose (2764] of the tobacco. Each component was added individually to cigarette tobacco and their contributions to various classes of MSS components, particularly the PAHs and the phenols, were determined. Table XXV-12 summarizes the Newell-Best findings on the percent conversion during smoking of these three structural components to specific PAHs and phenols. Examination of these data indicates that the percent conversion of these structural components to phenol ranges from one (0.0013%) to about four (0.0036%) one-thousandths of a percent, whereas the conversion of these three components to benzo[a]pyrene ranges from about one (0.0000014%) to about fourteen (0.0000136%) one-millionth of a percent. Such data may be used to estimate the conversion to PAHs and phenols of a flavorant (structurally similar to but of lower molecular weight and higher volatility than these biopolymers) added to the tobacco blend. Numerous pyrolysis studies were conducted on these precursors of phenols. In each case, the generation of simple phenols (phenol, cresols, and numerous xylenols) was observed. Kato et al. (2043) reported the pyrolysis of tobacco lignin yielded phenol, cresols, xylenols, and guaiacol—all known components of cigarette MSS. Examination of the structure of lignin reveals why it would readily yield these phenols as well as other substituted phenols such as vanillin [Ball (176a)]. From the mid-1960s to the early 1980s, the USDA tobacco research group—initially at Philadelphia, Pennsylvania, and subsequently at Athens, Georgia—described the pyrolysis of

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various tobacco components and the yield of phenols in the pyrolysates. Tobacco components examined for their propensity to generate the simple phenols during pyrolysis included: • Cellulose, pectin, lignin, and the so-called tobacco pigment (3468). • The major tobacco polycarboxylic acids—malic, citric, and fumaric plus the sodium salts of citric and lactic acids (3486). In the late 1950s, a mixture of sodium and potassium citrates was used as an additive on cigarette paper to control its combustion properties.* • Tobacco and tobacco extracts [Kennedy and Riehl (25A35), Schlotzhauer et al. (3456), Severson et al. (3616)]. • Cellulose, glucose, and fructose [Higman et al. (1647)]. The latter two sugars† are used in casing materials applied to cigarettes during manufacture [Leffingwell et al. (2341)]. With regard to the generation of phenols by the tobacco acids, Schmeltz et al. (3486) noted: The data show that citric, malic and related acids give rise to phenols on pyrolysis. The yields, however, are lower than those from other phenol-forming materials present in tobacco leaf.

Despite the repeated assertions of the promoting potency for PAHs of the CSC phenolic fraction [Roe et al. (3314)] and the simple phenols, particularly phenol itself [Wynder and Hoffmann (4313, 4332)], contradictory evidence was reported. In 1962, Bock and Moore (25A11) challenged the concept that the weakly acidic portion of CSC was a tumor promoter. In fact, Wynder and Hoffmann (4319), strong proponents in 1964 of the promoting effect of the phenols in smoke, wrote “Definite tumor-promoting activity for a variety of phenols may be regarded as established.” However, this statement was omitted from their 1967 book in which Wynder and Hoffmann [see p. 626 in (4332)] wrote: Phenol and some of its derivatives have been shown to possess tumor-promoting activity … However, a reduction of phenols in tobacco smoke condensate has not led to a concomitant reduction of tumorigenicity in the corresponding “tars.” A mixture of sodium and potassium salts of citric acid was used as a cigarette paper additive, initially at RJRT and subsequently throughout the U.S. tobacco industry since the late 1950s. This additive ensured that the cigarette paper combustion char line slightly preceded the tobacco combustion char line. In the late 1950s, Rodgman (3246) demonstrated that inclusion of sodium and potassium citrates in the cigarette paper additive system reduced the levels of PAHs in the MSS. † Glucose and fructose are naturally occurring components present at relatively high levels (10% to 25%) in Oriental and flue-cured tobaccos but at relatively low levels (usually less than 2%) in burley and Maryland tobaccos, for example, see Wynder and Hoffmann (4332). For many years, the two simple sugars glucose and fructose were added as such or in the form of “invert sugars” to the cigarette blend as part of the casing materials formulation. Low levels of the disaccharide sucrose, a known naturally occurring component of tobacco, were also added. *

The Chemical Components of Tobacco and Tobacco Smoke

In 1971, Van Duuren et al. (4035), in a discussion of tumor promoters and the complexity of CSC and its potential role in carcinogenesis, reported: “Phenol, which is a weak tumor-promoting agent, is indeed an inhibitor of tumorigenesis when applied simultaneously with benzo[a]pyrene.” Two years later, Van Duuren et al. (4029) concluded from their cocarcinogenesis research: “Phenol has been regarded as an important ‘tumor promoter’ in [cigarette smoke condensate] … [but our] work indicates that it is inactive in cocarcinogenesis and, indeed, has a slight inhibitory effect on benzo[a]pyrene carcinogenesis.” Chortyk and Schlotzhauer (722) reviewed the studies reported during the preceding two decades on pyrolysis of tobacco components and the relationship of the pyrolysis results to the pyrogenesis of tobacco smoke components. In 1979, Martin et al. (2468a) not only reported the results of their own research on the generation of a variety of phenols during the pyrolysis of lignin derived from several sources but also reviewed the results of their own and earlier studies by other investigators on lignin pyrolysis. From their 1981 and 1982 studies on pyrolysis, Schlotzhauer and Chortyk (3453) and Schlotzhauer et al. (3452) reported the pyrogenesis of phenols not only from cellulose and lignin but also from chlorogenic acid and other polyphenols. Cellulose was defined as a major precursor of cresols and xylenols in smoke; lignin as a major precursor of guaiacol, eugenol, and catechol in smoke; the polyphenols, such as chlorogenic acid, as major precursors of the catechols in smoke. In 1975, Schlotzhauer and Chortyk (3452), emphasizing the toxicants in tobacco smoke, reported that the yields of PAHs and phenols in the pyrolysate from reconstituted tobacco sheet (RTS) were significantly lower than those from flue-cured tobacco leaf when generated under the same experimental conditions. Extrapolating their pyrolysis results to the formation of specific components of tobacco smoke, Schlotzhauer and Chortyk noted that “the continued use of reconstituted tobacco sheet in tobacco products appears warranted.” Comparison of data obtained under different pyrolysis conditions with cellulose, glucose, and fructose with data generated under actual smoking conditions reveals the problem of attempting such a comparison. In Table XXV-13 are summarized data from Gilbert and Lindsey (1289), Higman et al. (1647), and Newell and Best (2764) on the conversion (ppm or μg/g) of such tobacco components to B[a]P during pyrolysis under two different conditions (650°C and 840°C, N2) and when smoked in a cigarette under actual smoking conditions (35-ml puff, 2-sec puff duration, 1 puff/min). The degree of conversion of tobacco components such as cellulose to B[a] P under different pyrolysis conditions parallels the degree of conversion of other tobacco components such as the saturated aliphatic hydrocarbons to B[a]P under different pyrolysis conditions; for example, Lam (2257) and his findings summarized in Table XXV-11. The conversion of cellulose to B[a] P increases several hundredfold as the pyrolysis temperature increased nearly 200°C (from 650°C to 840°C). Under actual smoking conditions, the cellulose-to-B[a]P conversion was

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Pyrolysis

Table XXV-13 Pyrolysis vs. Actual Smoking Conditions: Conversion of Glucose, Fructose, and Cellulose to Benzo[a]pyrene Conversion (ppm or µg/g) of Tobacco Component to Benzo[a]pyrene Experimental Conditions Pyrolysis (650°C, N2) [Gilbert and Lindsey (1289)] Pyrolysis (840°C, N2) [Higman et al. (1647)] Actual smoking conditions (35-ml puff, 2-sec duration, 1 puff/min) [Newell and Best (2764)] a

Glucose

Fructose

Cellulose

0.29

0.33

0.78

47.5 NDa

98.4 ND

288.8 0.21

ND = not determined

less than 30%* of the conversion at 650°C. Similarly, under actual smoking conditions, the conversion of cellulose to B[a] P was only 0.073% of the conversion at 840°C. Thus, these data from several sources indicate that the fate of a tobacco component on pyrolysis is not equivalent to its fate under actual smoking conditions [see the conclusion of Schmeltz et al. (3512) on the fate of nicotine on pyrolysis vs. its fate during actual smoking]. As noted in reviews of the thermal degradation products from tobacco carbohydrates (cellulose, pectins, starch, and sugars) by Roberts et al. (3225) and by Schumacher (3551), pyrolysis of the carbohydrate components of tobacco results in generation of several classes of compounds other than PAHs and phenols. Among these were aldehydes and ketones, considered significant in smoking-respiratory tract issues. It was asserted during the 1960s that aldehydes and ketones, shown to be ciliastatic in vitro to ciliated tissue, were important because of their significant impairment (by extrapolation) of the action of human respiratory tract cilia. Such impairment was considered part of the mechanism of lung cancer causation by cigarette smoke. However, their importance diminished after the reported findings of Dalhamn et al. (892) that these cigarette smoke-derived, water-soluble in vitro ciliastats were removed in large part by the “scrubbing action” of the fluids coating the surfaces of the oral cavity and laryngeal area, a phenomenon demonstrated several years earlier by Rodgman et al. (3306). Early studies (1955–1959) on carbonyl components included those of Fredrickson (1228), who examined the volatile MSS components from all-cellulose cigarettes. Many were identified as aldehydes and ketones (1238, 1239). In 1959, Laurene et al. (2310) reported the unequivocal identification of acrolein *

Conversion of cellulose to B[a]P under actual smoking conditions = 0.21 mg/g; conversion of cellulose to B[a]P at 650°C = 0.78 mg/g. Percent ratio for 650°C pyrolysis = 100 × 0.21/0.778 = 27%; for 840°C pyrolysis = 100 × 0.21/288.8 = 0.073%.

in cigarette smoke and cellulose in tobacco was a major precursor of it in smoke. Grob (1413) subsequently demonstrated in 1962 that, during smoking, cellulose generated high levels not only of acrolein but also the ketone 3-buten-2-one. In 1966, Latimer (25A40) reported several aldehydes (acetaldehyde, acrolein) and ketones (acetone, 2-butanone) in the pyrolysate from tobacco-derived starch. At Philip Morris R&D, Gager et al. (1264, 1265) noted from their study with radiolabeled sugars added to cigarette tobacco that acetaldehyde and acetone were formed during the smoking process in the highest yields from added sugars but their levels were reduced because of the levels generated from other major tobacco components, such as cellulose, pectins, and starch. In their 1976 literature review of pyrolysis products from carbohydrates, Roberts et al. (3225) noted that, of the more than 140 compounds identified in the pyrolysates from glucose, fructose, sucrose, cellulose, and starch, twenty-one were aldehydes and thirty were ketones. Of these fifty-one pyrolysis products identified at that time, forty had been identified as cigarette MSS components. In 1977, Ohnishi and Kato (2850) described the identification of several carbonyl compounds in the pyrolysates from the tobacco cell-wall polysaccharides cellulose, hemicellulose, and pectins. They noted that these biopolymeric polysaccharides constituted 30% to 50% of the dry weight of the tobacco they were studying. Sakuma et al. pyrolyzed tobaccoderived cellulose (3401), chlorogenic acid, and rutin (3400) and reported various aldehydes and ketones plus numerous phenols in the pyrolysates. Many of the pyrolysate components identified have also been identified in cigarette MSS.

XXV.C.4 Acids The research findings of Gilbert and Lindsey (1289) on the generation of a variety of PAHs during the pyrolysis of major components of tobacco, including several polycarboxylic acids (oxalic, malic, and citric acids), were discussed previously (see Table XXV-10). These acids may constitute from 3% to 12% of dry tobacco weight (1289, 1329, 1330, 1332, 1333). At RJRT R&D, the fate of these acids during smoking in a cigarette was determined by Newell and Best in studies with radiolabeled acids added individually to cigarette tobacco (2763). In 1967, Schmeltz et al. (3486), in their attempt to define precursors in tobacco of several classes of compounds in cigarette smoke, studied the nature and levels of phenols generated in the pyrolysates of malic, citric, aconitic, and fumaric acids or their sodium salts. Thus, pyrolysis of tobacco leaf acids yielded phenols (3486) and PAHs (1289). Although direct comparison is somewhat difficult because of the 50°C pyrolysis temperature difference in the GilbertLindsey vs. Schmeltz et al. studies, the PAHs appeared to be generated in much lesser amounts per gram of tobacco leaf acid pyrolyzed than were the phenols. Table  XXV-14 summarizes data obtained from the studies. Pyrolysate products obtained from several short-chained aliphatic acids or their sodium salts were examined. Schmeltz and Schlotzhauer (3498) pyrolyzed sodium acetate at 500°C

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-14 Pyrolysis of Leaf Acids: Generation of Selected Phenols and Polycyclic Aromatic Hydrocarbons Compound Generated, ng/mg of Acid Pyrolyzed

Pyrolysis Conditions T, °C

Atm.

Acid Pyrolyzed Malic

Citric

Oxalic

Polycyclic Aromatic Hydrocarbons [Gilbert and Lindsey (1289)] Benz[a]anthracene Benzo[a]pyrene

650 650

N2 N2

1.30 0.33

0.35 0.17

 0 0.01

N2 N2 N2

89 79 79

25 38 51

NDa ND ND

Phenols [Schmeltz et al. (3486) Phenol o-Cresol m-Cresol + p-Cresol a

700 700 700

ND = not determined

and 800°C. The 800°C pyrolysate was much more complex than that produced at 500°C. This was true for the numbers of pyrolysate components generated and those with aromatic structures. Among the latter were several alkylbenzenes and phenols. Rudenko and Konsinska (25A61) reported similar findings from their pyrolysis of propionic acid, present in tobacco in bound form. At the USDA, Geisinger et al. (1279) demonstrated that pyrolysis of malic and lactic acids at temperatures from 500°C to 900°C (in 100°C increments) yielded both aromatic hydrocarbons and phenols. With malic acid, the aromatic hydrocarbon complexity increased (increased methylation) as the temperature increased. Bicyclic indene was the only PAH detected in the 500°C and 600°C pyrolysates. Indene and naphthalene were detected in the 700°C pyrolysate. Tricyclic acenaphthylene, anthracene, phenanthrene, and fluorene were detected in the 800°C pyrolysate, tetracyclic pyrene and chrysene in the 900°C pyrolysate. Pyrolytic products from several aromatic acids present either free or bound in tobacco were investigated, for example, Zane and Wender (4403) demonstrated in 1963 that pyrolysis of rutin, quercetin, and chlorogenic acid (tobacco polyphenols with bound caffeic acid) yielded catechol as the major product, alkylcatechols, resorcinol plus several furancarboxaldehydes. Similar results were reported by the USDA group (3462) at Athens, Georgia. In 1969, Jones and Schmeltz reported catechol as the major pyrolysis product (32%) from free caffeic acid (1981) and stilbene as the major pyrolysis product from trans-cinnamic acid (1983). trans-Cinnamic acid pyrolysate also contained low yields of several bicyclic and tricyclic PAHs. The results of these and similar pyrolysis studies with tobacco acids were reviewed by Chortyk and Schlotzhauer (722). Indirect evidence that major leaf acids such as malic, citric, and oxalic acids in tobacco contributed low PAH levels to pyrolysates from tobacco fractions was provided by Severson et al. (3616). When tobacco was extracted with hexane or petroleum ether, the bulk of these acids did not appear in

the extract but remained in the insoluble tobacco residue. Severson et al. reported that the pyrolysate from the extractables (8% of tobacco weight) contained more than twice the amount of total PAHs than did the pyrolysate from residual tobacco (92% of tobacco weight). In the same study, Severson et al. (3616) examined the levels of various PAHs (bicyclic to pentacycylic) in the pyrolysates of eight chromatographic fractions from the petroleum ether extractables. Several fractions consisted primarily of free fatty acid mixtures, such as myristic, palmitic, stearic, oleic, and linoleic acids (fractions F-5 and F-6) and esters of long-chained saturated and unsaturated alcohols with these acids (fractions F-7 and F-8, see Table XXV-8). As described previously, Schmeltz et al. (3511) demonstrated that less than 1% of radiolabeled palmitic acid, isolated from tobacco grown in a radiolabeled-CO2 atmosphere and added to cigarette tobacco filler, was converted to PAHs during the smoking process. Pyrolysis products from esters such as ethyl acetate and isobutyl acetate, both possible flavorants for tobacco smoking products, have been reported [Leffingwell et al. (2341), Miyagawa (2563)]. The principal pyrolysis products from both acetates were CO, CO2, methane, acetic acid, and acetone. Isobutyl acetate yielded isobutylene as a major product. Products from pyrolysis of the esters formed from long-chained fatty acids* and glycerol (triglycerides) were described by Higman et al. (1646) (tripalmitin, tristearin) and Kitamura (2111a) (trilaurin, tripalmitin). In the early 1970s, Halaby and Fagerson (25A28) pyrolyzed palmitic, oleic, and linoleic acids plus their triglycerides. Numerous PAHs were identified in the pyrolysates. They reported that B[a]P was generated from each acid and from each triglyceride at about 100 ppm of the compound pyrolyzed. In their studies on precursors in tobacco of PAHs in tobacco smoke, Rodgman and Cook (3269) demonstrated that addition of 0.4% (4.0 mg/g of tobacco) of trimyristin to tobacco produced, under actual smoking conditions, a 6% increase in total PAHs in the MSS. The changes in individual PAH yields are shown in Table XXV-15. These changes are also expressed in Table XXV-15 in terms of the conversion (ng/mg or ppm) of the added trimyristin to individual PAHs. The changes observed in the levels of individual PAHs are well within the experimental error for PAH analyses in the late 1950s.

XXV.C.5 Proteins and Amino Acids Amino acids, both as free acids and as acids bound within protein molecules, are present in all of the tobacco types (flue-cured, burley, Oriental, and Maryland). The diversity and levels of amino acids in various tobaccos have been *

The major long-chained fatty acids, either free or bound, in tobacco are lauric acid (C12), myristic acid (C14), palmitic acid (C16), stearic acid (C18), oleic acid (C18, 1 carbon-carbon double bond), linoleic acid (C18, 2 carboncarbon double bonds), and linolenic acid (C18, 3 carbon-carbon double bonds). However, bound and free acids in tobacco (and in tobacco smoke) are not limited to acids with even-numbered carbon chains [Bellin (258, 259), Rodgman et al. (3294), Swain and Stedman (3842, 25A72), Wynder and Hoffmann (4332)].

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Table XXV-15 Conversion of Trimyristin Added to Tobacco to Polycyclic Aromatic Hydrocarbons during Actual Cigarette Smoking (3269) Mainstream Smoke Delivery of PAH, µg/cig, at Trimyristin Addition Level to Tobacco Blend, mg/g Polycyclic Aromatic Hydrocarbon Naphthalenes a Anthracene Pyrene Fluoranthene Chrysene Benzo[a]pyrene

PAH Increase

0

4.0

In ng/4.0 mg of Trimyristin Added

15.8 b 0.247 0.051 0.213 0.018 0.081

17.7 b 0.255 0.045 0.207 0.018 0.086

1900 8c 6c (6) c 0c 5c

In ng/mgd of Trimyristin Added 475 2 1.5 0 0 1.25

Naphthalenes represent a mixture of naphthalene plus several methyl-, dimethyl-, and trimethylnaphthalenes. Micrograms produced per gram of tobacco burned. c Within experimental error of analytical procedure. d ng/mg = parts per million (ppm) a

b

presented by Gori (1329, 1330) and Tso and Chaplin (3975). The amino acids occurring free and/or bound in tobaccos include alanine, α-aminobutyric acid, arginine, aspartic acid, cystine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. The presence in cigarette MSS of numerous free amino acids and amino acid-derived compounds was demonstrated in the mid-1950s. This occurred soon after the publication of the results of several cigarette smoke-related epidemiological and biological studies led to a massive escalation in tobacco smoke composition studies; for example, Buyske et al. (562) identified glutamic acid and its derivative glutamine (glutamic acid 5-amide) in tobacco smoke. Other amino acids identified in tobacco smoke [see Ishiguro and Sugawara (1884)] include alanine, aspartic acid (and asparagine), cysteine, glycine, leucine, ornithine, phenylalanine, proline, serine, threonine, and valine. In the early 1960s, pyrocoll (dipyrrolo[a,d]pyrazine-5, 10-dione) was identified in cigarette MSS by Mold et al. (2592), who proposed that either free or bound proline was its precursor. During their study of the isolation and identification of N-heterocyclic components (the indoles and carbazoles) in cigarette MSS, Rodgman and Cook (3279) confirmed the presence of pyrocoll. Two decades earlier, Van Order and Linwall (25A78) had demonstrated that dry distillation of tryptophan yielded indole and 3-methylindole (skatole), both of which were subsequently identified in tobacco smoke (3279) and in burley tobacco by Roberts [see citation in Rodgman and Cook (3279)]. From their pyrolysis studies (850°C, N2) with lysine, leucine, and tryptophan, Patterson et al. (2902) reported that each yielded the N-heterocyclic compounds indole, quinoline, isoquinoline, several nitriles, and PAHs ranging from bicyclic to tetracyclic (see Table XXV-16). B[a]P was found

only in the leucine pyrolysate. From their own findings and from a previous report by Jarboe and Rosene (1923a) that quinoline and isoquinoline were components of a nicotine pyrolysate, Patterson et al. suggested that the precursors in tobacco of quinoline and isoquinoline in tobacco smoke might be nicotine and/or the amino acids. They also reported that tryptophan, per mole pyrolyzed, yielded a phenol fraction weighing about five times that generated from lysine and about thirty times that from leucine. Patterson et al. (2903) reported the effect of temperature on the pyrolysate composition from phenylalanine, with emphasis on PAHs yields, and the effect of tryptophan or pyrrole on the pyrolysate composition when equimolar quantities of phenylalanine + tryptophan or phenylalanine + pyrrole were pyrolyzed (see summary of results in Table XXV-17). The difference between the pyrogenesis of PAHs from phenylalanine and equimolar quantities of phenylalanine + tryptophan mixture prompted Patterson et al. (2903) to propose amino acid addition to tobacco to control the PAH content of the CSC: These results suggest the possibility that aromatic hydrocarbon content of tobacco “tar” may be affected by the amino acid composition of the tobacco and that it might be possible to affect deliberately the amount of aromatics and bases formed by adding suitable additives, such as amino acids, to the tobacco.

In 1971 when Patterson et al. made this suggestion, the presence in amino acid pyrolysates of the N-heterocyclic amines and the inordinately high mutagenicity of several of them were unknown. Higman et al. (1647) reported the generation of PAHs, phenols, pyridines, indole, quinoline, and other aromatic bases during pyrolysis of tobacco amino acids and proteins [see the review on pyrogenesis of smoke components by Chortyk and

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Table XXV-16 Components in Pyrolysates from Lysine, Leucine, and Tryptophan (2902) Yield, mg/mole of Amino Acid Pyrolyzed Lysine a

Leucine

Tryptophan

Nitrogen Compounds Hydrogen cyanide Aniline Quinoline Isoquinoline Benzonitrile o-Tolunitrile m-Tolunitrile p-Tolunitrile Phenylacetonitrile Indole 1-Naphthonitrile 2-Naphthonitrile

+b 60 160 80 470 30 30 20 6 20 10 —

+ 5 8 6 40 + 30 + — + 30 —

+ — 17.7 2.4 1370 610 + + 400 610 350 170

Cyclic Hydrocarbons Styrene Biphenyl Bibenzyl Indene Naphthalene Naphthalene, 1-methylNaphthalene, 2-methylAcenaphthene Acenaphthylene Fluorene Anthracene/phenanthrene Fluoranthene Pyrene Pyrene, methylBenzofluorene Chrysene Criphenylene Benz[a]anthracene Benzopyrene

5 10 2 40 210 10 10 20 30 10 30 10 10 2 10 10 + + —

20 30 — 70 620 40 50 — 19 80 250 90 110 20 30 50 + + 30

— + + — 1100 + — — 3 140 7900 210 270 — 150 110 + + —

Pyrolysate Component

a b

Pyrolyzed as lysine monohydrochloride + indicates the presence of compound; — indicates the absence of the compound.

Schlotzhauer (722)]. The results reported by Higman et al. are summarized in Table XXV-18. Tryptophan was found to be the precursor in tobacco of harman (1-methyl-9H-pyrido[3,4-b]indole) and norharman (9H-pyrido[3,4-b]indole) in tobacco smoke, compounds originally identified in tobacco and tobacco smoke by Poindexter and Carpenter (2972). That tryptophan was indeed a precursor in tobacco of the harmans in smoke was demonstrated by addition of radiolabeled tryptophan to tobacco and identification of radiolabeled harman and norharman in the MSS. More recent amino acid pyrolysis studies led to the isolation and identification of several N-heterocyclic amines reported not only to be tumorigenic to mouse skin but also to show inordinately high mutagenicity [Ames bioassay

(Salmonella typhimurium]. Initial impetus for amino acid pyrolyses was not the definition of the relationship between tobacco precursors and smoke components but the observation that extracts of broiled, fried, or roasted foodstuffs were highly mutagenic (Ames bioassay). These N-heterocyclic amines, derived from amino acids and/or proteins in heated foodstuffs, were defined as “cooked food” mutagens. These studies in the 1970s on the tumorigenicity and mutagenicity of extracts of cooked foodstuffs are reminiscent of the studies in the 1920s by Kennaway (2073–2076), who reported the tumorigenicity of extracts of heated foodstuffs or pyrolysates from compounds such as cholesterol, and by Roffo (25A56, 25A57, 25A58), who reported the tumorigenicity of pyrolyzed cholesterol. Subsequently, pyrolysates from many foodstuffs and cholesterol were shown to contained various PAHs, including B[a]P. Identification of highly mutagenic N-heterocyclic compounds in amino acid pyrolysates was followed by their identification not only in heated foodstuffs but also in mainstream CSC. In 1977, Sugimura et al. (3829) reported the identification of the potent mutagens 3-amino-1-methyl-5H-pyrido[4,3-b] indole (Trp-P-2) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b] indole (Trp-P-1) in tryptophan pyrolysate. The next year, Yamamota et al. (4365a) identified two potent mutagens in glutamic acid pyrolysate: aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2) and 2-amino-6-methyldipyrido[1,2-a:3’,2’-d] imidazole (Glu-P-1). Table XXV-19 lists several N-heterocyclic amines that exhibit high mutagenicity in the Ames bioassay, are amino acid pyrolysis products, and have been identified in heated foodstuffs and CSC (3828c). On a per microgram basis, B[a] P in the Ames bioassay with Salmonella typhimurium (TA 98 strain) shows about 200 revertants/µg. Several of the amino acid-derived compounds in Table XXV-19 exceed the B[a] P effect (TA 98 strain) by factors ranging from about 10 to over 2100. Yoshida and Matsumoto (4387a) reported the identification of two α-carbolines in CSC: 2-amino-9H-pyrido[2,3-b] indole (AαC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC). These and several other compounds were reported in CSC by Yamashita et al. (4367, 4368). The quantitative levels of the possibly amino acid-derived, mutagenic N-heterocyclics in CSC are shown in Table XXV-19. In their studies they emphasized in particular the identification and quantitation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) because of its inordinately high mutagenicity (433000 and 490000 revertants/µg in the Ames bioassay, Salmonella typhimurium strain TA 98). Demonstration of the mutagenicity of the compounds in Table XXV-19 was followed by demonstration of their tumorigenicity in laboratory animals. Ohgaki et al. (2849a) demonstrated the tumorigenicity of IQ in mice. Takayama et al. (3862c) and Tanaka et al. (3865c) reported its tumorigenicity in rats. Trp-P-1 and Trp-P-2 were reported to be tumorigenic in mice by Matsukura et al. (2491a) and in rats by Hosaka et al. (1835a) and Takayama et al. (3862d). Ohgaki et al. (2849b) reported that Glu-P-1, Glu-P-2, AαC, and MeAαC were

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Table XXV-17 Pyrolysis of Phenylalanine. A. Effect of Pyrolysis Temperature B. Effect of Equimolar Addition of Tryptophan (Try) or Pyrrole (Pyr) (2903) Material Pyrolyzed Phenylalanine (Phe) Pyrolyzed at Pyrolysate Component a

450°C

Monocyclic Aromatic Hydrocarbons Biphenyl — Bibenzyl 10300

650°C

850°C

950°C

Phe

Phe + Try b

Phe + Pyrc

850°C

850°C

850°C

1270 12000

10300 2550

4360 +

10300 2550

2980 —

2240 345

Polycyclic Aromatic Hydrocarbons Indene — Naphthalene 120 Naphthalene, 1-methyl— Naphthalene, 2-methyl— Acenaphthene — Acenaphthylene — Fluorene 425 Phenanthrene/anthracene 4120 Benzofluorene — Fluoranthene — Pyrene — Pyrene, methyl— Chrysenes —

360 1450 + — 485 1700 1330 9700 485 485 3500 — 485

2,730 3500 — — 1940 2550 4500 20000 1940 1270 3200 3200 2550

— 1270 — — <180 730 850 7900 2600 600 1200 <600 1580

2730 3500 — — 1940 2550 4,500 20000 1940 1270 3200 3200 2550

— 3525 — 2980 54 400 780 1440 220 160 300 220 160

170 5600 730 345 86 990 650 2410 390 40 390 + 300

N-Containing Compounds Benzonitrile o-Tolunitrile m-Tolunitrile p-Tolunitrile Phenylacetonitrile 1-Naphthonitrile Indole Quinoline Isoquinoline

850 360 60 180 1400 1400 2300 1800 3000

7880 2850 — 180 — — 725 12000 10900

1270 60 60 — — — — 300 180

7880 2850 — 180 — — 725 12000 10900

3800 680 1380 380 220 1140 17350 25750 1100

1465 260 260 260 130 1000 860 1300 430

1270 — — — — — — — —

Yield of pyrolysis component in µg/g of compound or mixture pyrolyzed. Pyrolysis involved equimolar quantities of phenylalanine and tryptophan (total mol. wt. = 369). c Pyrolysis involved equimolar quantities of phenylalanine and pyrrole (total mol. wt. = 232). a

b

tumorigenic in mice, and Takayama et al. (3862b) reported Glu-P-1 and Glu-P-2 to be tumorigenic in rats. Hoffmann and Hecht (1727) discussed the amino acidderived aromatic amines in cigarette smoke: Of the known carcinogenic pyrolysis products of the amino acids, so far only 2-amino-3-methylimidazo(4,5-f)quinoline has been detected in trace amounts of 0.26 ng in the smoke of a Japanese filter cigarette [Yamashita et al. (4368)].

Apparently, Hoffmann and Hecht had overlooked not only the reports of the identification in CSC of several other known “carcinogenic” pyrolysis products of amino acids, for example, AaC and MeAaC [Yoshida and Matsumoto (4387a)] or Trp-P-1 and Trp-P-2 [Yamashita et al. (4367)] but also the reports on their tumorigenicity in several animal species [Matsukura et al. (2491a), Hosaka et al. (1835a), Ohgaki et al. (2849a, 2849b), Takayama et al. (3862c, 3862d), Tanaka et al. (3865c)].

Table XXV-20 summarizes the MSS yields of N-heterocyclic amines considered to be significant tumorigens [Hoffmann and Hoffmann (1740, 1741)] plus the assessment of the IARC (1870) on their tumorigenicity in laboratory animals and humans. Table XXV-21 illustrates precursor relationships, either demonstrated or proposed, between N-containing components such as the amino acids and proteins and tobacco smoke components. The tabulation of possible flavorants for tobacco smoking products by Leffingwell et al. (2341) included contributions to tobacco smoke taste and aroma of twenty-three amino acids added individually to the cigarette filler. During tobacco growth, curing, aging, and/or the smoking process, tobacco sugars may react with ammonia and/ or amino acids to yield Amadori compounds which, when heated during the smoking process, will generate a variety of pyrazines [Green et al. (1369)]. Many pyrazines identified in tobacco smoke are highly flavorful and contribute uniquely

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Table XXV-18 Components in Pyrolysates from Amino Acids (Proline and Glycine) and Proteins (Casein and Collagen) (1647) Pyrolysate Component

Amino Acid or Protein Casein

Collagen

Proline

Glycine

Nitrogen Compounds Hydrogen cyanide Pyridine Pyridine, 2-methylPyridine, 3-methylPyridine, 4-methylPyridine, 3-vinylAniline Pyrrole Quinoline Isoquinoline Indole Benzonitrile o-Tolunitrile m-Tolunitrile

+ + + + + + + + + + + + + +

+ + + + + + + + + + + + + +

+ + + + + — + + + + + — + +

+ + + + + — — + — — — + — —

Cyclic Hydrocarbons Benzene Toluene Styrene Xylenes Indene Naphthalene Fluorene

+ + + + + + +

+ + + + + + +

+ + — — — — —

— + + + + — —

Phenols Phenol o-Cresol m-Cresol p-Cresol Phenol, ethylXylenol

+ + + + + +

+ — + + + +

— — — — — —

— — — — — —

a

 indicates the presence of compound; — indicates the absence of the + compound. In the publication by Higman et al. (1647), actual pyrolysis yield data are listed for each compound.

to the aroma and taste not only of tobacco smoke but also of a variety of consumer food products such as coffee, tea, cocoa, roasted peanuts, and roasted, broiled, or fried meats, poultry, and fish [Maga and Sizer (2439)].

XXV.D  Tobacco Additives XXV.D.1 Additives Used in Tobacco Production Much information exists in the tobacco literature on the use and levels of use of a various materials added to tobacco during growth, harvesting, and storage and on such materials that either remain unchanged on the tobacco as residual material or are chemically altered. These materials include insecticides, herbicides, fungicides, fumigants, and sucker

growth inhibitors (see Chapter XXI). Acceptable use levels of these are prescribed in the United States by appropriate government agencies. Comments, for example, see Wynder and Hoffmann* (4332), Guthrie (1457), and Guthrie and Sheets (1460) on the use of pesticides, etc., were published in increasing numbers, after the mid-1960s when smoke components or classes of components allegedly responsible for the effects of cigarette smoke in the smoke-disease association could not explain the observed effects at the levels in cigarette smoke. Two types of materials have been examined in greater detail than most of the others. These are discussed in this section because there is substantial information on their pyrolysis products, their transfer per se from cigarette tobacco to its MSS, their degradation during the actual smoking process, and/or their effect as either transferred or degraded materials on the biological activity. Even in these two cases, no attempt has been made to include all the available references. These classes of materials include: Sucker growth inhibitors: Representative sucker growth inhibitors or suckering agents include maleic hydrazide, currently used as an alkali metal salt, and the normal, even-numbered carbon chain saturated alcohols, ranging in carbon chain length from (C6) 1-hexanol through C12 (1-dodecanol) (4332). Pesticides: Particularly those pesticides that are chlorinated; for example, DDT, Aldrin®, and Dieldrin® (4332). XXV.D.1.a  Sucker Growth Inhibitors The pyrolysis of long-chained saturated alcohols such as 1-docosanol and long-chained unsaturated alcohols such as phytol and solanesol, known to be naturally occurring components of tobacco, was discussed previously. One of the most widely used and effective commercial preparations for inhibition of sucker growth is “Off-Shoot-T®,” a mixture consisting primarily of the even-numbered straightchained alcohols 1-hexanol, 1-octanol, 1-decanol, and 1-dodecanol [Collins et al. (25A16)]. Pyrolysis studies by Higman et al. (1644, 1645) with individual alcohols of “Off-Shoot-T®” revealed that much of the alcohol was transferred intact to the pyrolysate. Much of the remainder was converted to the corresponding alkene; for example, 1-decanol yielded 1-decene. Because of their volatility and low molecular weight, conversion of the alcohols to PAHs was minimal. Definitive evidence that the alcohol sucker growth inhibitors added to tobacco did not augment the tumorigenicity of cigarette MSS was provided in the second set of experimental cigarettes studied in the NCI “Less Hazardous” Cigarette *

It should be noted that, in their earlier review, Wynder and Hoffmann (4319) discussed pesticide-derived arsenic in tobacco and tobacco smoke, but they did not discuss tobacco production additives such as sucker growth inhibitors, pesticides, etc., and their effects on tobacco and tobacco smoke properties.

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Table XXV-19 Amino Acid-Derived N-Heterocylic Amines Compound Code

Mutagenicitya, rev/µg

Name

IQ

Imidazo[4,5-f]quinoline, 2-amino-3-methyl-

Trp-P-1 Trp-P-2 Glu-P-1 Glu-P-2 AaC MeAaC

5H-Pyrido[4,3-b]indole, 3-amino-1,4-dimethyl5H-Pyrido[4,3-b]indole, 3-amino-1-methylDipyrido[1,2-a:3’,2’-d]imidazole, 2-amino-6-methylDipyrido[1,2-a:3’,2’-d]imidazole, 2-amino9H-Pyrido[2,3-b]indole, 2-amino9H-Pyrido[2,3-b]indole, 2-amino-3-methyl-

a b

TA 98

TA 100

Level in CSC, ng/cig b

433000 490000 39000 104200 49000 1900 300 200

7000

0.26

1700 1800 3200 1200 20 120

0.29-0.48 0.82-1.1 0.37-0.89 0.25-0.88 25-260 2-37

Salmonella typhimurium, strain TA 98 or TA 100, with S-9 mix. See Hoffmann and Hoffmann (1740, 1741).

Program (1330, 2683). The chemical and biological properties of the MSSs from three samples (hand-suckered tobacco, tobacco treated with the recommended level of alcohol sucker growth inhibitor, and tobacco treated with 100 times the recommended level) were compared among themselves and with the Standard Experimental Blend, SEB II. Data obtained are shown in Table XXV-22. Examination of the data indicates that neither the normal use level of the alcohol nor a use level 100 times normal had any significant adverse effect on the mainstream CSC properties. The MSS phenol yields were increased from the hand-suckered and both alcohol-treated tobacco samples, but the increase elevation had no significant effect on the CSC biological properties. The results were described by Gori (1330):

In the summary report (2683) on the four sets of NCI Tobacco Working Group (TWG) experimental cigarettes, this statement was expanded: The fatty alcohol, fatty alcohol × 100, and hand-suckered blends showed no significant differences among themselves or from the SEB II blend.

It is interesting to note that biological responses (% TBA), ranging from a high of the average of 48% for the four replicate SEB II CSCs to a low of 36% for the CSC from the sample treated with alcohol at the normal use level, were considered to show “no significant difference.” Maleic hydrazide, another growth inhibitor used as a suckering agent on tobacco, is used in the United States as its potassium salt. Prior to 1982, use on tobacco involved application of maleic hydrazide as its diethanolamine salt. Such use was banned in 1981 by the

No statistically significant differences were observed among Hand-suckered, Fatty Alcohol-Normal and Fatty Alcohol x 100 Blends (variables 60, 61, and 62).

Table XXV-20 Summary of Lists of Tumorigenic N-Heterocyclic Amines Identified in Tobacco Smoke IARCa Evaluation of Evidence re Tumorigenicity in Component

Hoffmann and Hecht (1727)

OSHA (2825)

Hoffmann and Hoffmann (1740, 1741)

MSS Yield ng/ciga

Laboratory Animals

Humans

— — — — — — — — —

— — — — — — — — —

+ + + + + + + + +

0.37-0.89 ng 0.25-0.88 ng 0.29-0.48 ng 0.82-1.1 ng 25-260 ng 2-37 ng 0.26 ng 11-23 ng 0.26 ng

sufficient sufficient sufficient sufficient sufficient sufficient sufficient sufficient sufficient

— — — — — — probable possible probable

Glu-P-1 Glu-P-2 Trp-P-1 Trp-P-2 AaC MeAaC IQ PhIP IQ a

Data from Hoffmann and Hoffmann (1740, 1741)

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Table XXV-21 Precursor Relationships between N-Containing Tobacco Leaf Components and Tobacco Smoke Components Code pyrocoll

AaC MeAaC norharman harman

Trp-P-2 Trp-P-1 IQ Glu-P-1 Glu-P-2

Component

Demonstrated or Proposed Precursor

Tryptophan Dipyrrolo[a,d]pyrazine-5,10-dione 9H-Pyrido[2,3-b]indole 9H-Pyrido[2,3-b]indole, 2-methyl9H-Pyrido[2,3-b]indole, 2-pentyl9H-Pyrido[2,3-b]indole, 2-(2-methyl-propyl)9H-Pyrido[2,3-b]indole, 2-amino9H-Pyrido[2,3-b]indole, 2-amino-3-methyl9H-Pyrido[3,4-b]indole 9H-Pyrido[3,4-b]indole, 1-methyl9H-Pyrido[3,4-b]indole, 1-ethyl9H-Pyrido[3,4-b]indole, 1-propenyl9H-Pyrido[3,4-b]indole, 1-butyl5H-Pyrido[4,3-b]indole, 3-amino-1-methyl5H-Pyrido[4,3-b]indole, 3-amino-1,4-dimethylImidazo[4,5-f]quinoline, 2-amino-3-methylDipyrido[1,2-a:3’,2’-d]imidazole, 2-amino-6-methylDipyrido[1,2-a:3’,2’-d]imidazole, 2-aminoIndole

Indole, 3-acetonitrile Indole, 2,3-dimethylIndole, 1-methylIndole, 3-methylQuinoline

Isoquinoline

Biological Activity Tumorigen

Mutagen

Cocarcinogen

Anticarcinogen

trp prol trp trp trp trp trp trp trp trp trp trp trp trp trp creat (?) glut glut trp lys leuc trp trp trp trp trp lys leuc

— — — — — — yes yes — — — — — yes yes yes yes yes

— — — — — — yes yes yes yes ? ? ? yes yes yes yes yes

— — — — — — — — — — — — — — — — — —

— — — — — — — — — — — — — — — — — —

— — — — yes

a

yes — — yes

— — yes — —

yes — — — —

trp lys leuc

—

—

—

—

Acetonitrile has been designated as a mutagen precursor. Abbreviations: trp = tryptophan; prol = proline; lys = lysine; leuc = leucine; creat = creatinine; glut = glutamic acid

a

Environmental Protection Agency (EPA) (1147) soon after it was reported that tobacco treated with it generated N-nitrosodiethanolamine (NDELA) during smoking. NDELA was subsequently reported to be a potent, tissuespecific tumorigen in laboratory animals [see Hoffmann et al. (1696) and references therein]. Over the years, the pyrolysis of maleic hydrazide has been much studied, for example, by Patterson et al. (2907), Smith et al. (3728), Harke et al. (1507), and Clough et al. (25A13). Also studied has been its transfer (estimated at ≤4%) as intact maleic hydrazide from tobacco to cigarette MSS [Haeberer (1470), Liu and Hoffmann (2383, 2384)] and its generation of hydrazine during smoking (2385). However, in his 1979 report, the U.S. Surgeon General (4005) noted that maleic hydrazide was not a significant precursor of either hydrazine or 1,1-dimethylhydrazine in cigarette smoke. Smith et al. (3728) reported that the pyrolysis of maleic hydrazide at 600°C

yielded CO2 (24%), CO (2%), HCN (3%), NH3 (9%), and N2 (3%), hydrazine (trace), and a black residue (50%), structure unknown, whose empirical formula was C15H15N5O2. In the fourth set of experimental cigarettes in the NCI “Less Hazardous” Cigarette Program, the chemical and biological (mouse skin-painting bioassay) properties of mainstream CSC from a “pesticide”-treated tobacco cigarette were compared to those of the CSC from a control cigarette, SEB IV (1333, 2683). Gori (1333) listed the pesticides, sucker growth inhibitors, etc., used and described the chemical analyses and bioassays of the pesticide-treated and control tobaccos and their MSSs. Among the additives used in the treatment of the “pesticide”-treated tobacco were maleic hydrazide (MH-30), a 10-carbon alcohol (“Contak®”), and DDT. Because both maleic hydrazide and DDT were on the tobacco, the chemical and biological results from the MSSs from these samples are discussed later.

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Table XXV-22 NCI Study (Second Set of Experimental Cigarettes): Effect of Long Chained Alcohols Sucker Growth Inhibitors on Cigarette Smoke Properties (1330, 2683) Code No.

Cigarette Filler

Phenol, µg/g of CSCa

PAH, µg/g of CSC

% TBAd at Daily CSC Dose of

B[a]Ab

B[a]Pc

25 mg

50 mg

42 43 44 45

SEB II SEB II SEB II SEB II Avg. (Code Nos. 42-45)

3.83 3.66 3.90 3.81 3.80

1.08 0.89 0.90 0.86 0.93

0.58 0.82 0.79 0.65 0.71

50 52 41 47 47.5

54 40 49 50 48

60 61 62

Hand-suckered Alcohole level: normal application rate Alcohol level: 100 times normal application rate

4.42 4.46 4.83

0.89 0.73 0.79

0.73 0.50 0.51

54 43 49

45 36 41

CSC = cigarette smoke condensate B[a]A = benz[a]anthracene c B[a]P = benzo[a]pyrene d TBA = tumor-bearing animals e Alcohol = long-chained alcohols in sucker inhibiting reagent a

b

XXV.D.1.b  Pesticides As mentioned in earlier chapters, the biological response observed in mice skin painted with CSC or its fractions cannot be explained on the basis of the identified components and their levels in the CSC. In an attempt to define the biological response, Wynder and Hoffmann fractionated CSC and determined that the major part of the tumorigenicity that could be accounted for (only a few percent) arose from a PAH-rich fraction designated as fraction B [Wynder and Hoffmann (4332, 4342), Hoffmann and Wynder (1798, 1800)]. In addition to thirty-nine PAHs, totally or partially identified, among which were several known to be mouse-skin tumorigens, fraction B contained twenty-seven N-heterocyclic compounds (indoles, carbazoles, and acridans), five O-heterocyclic compounds (dibenzofurans), and six chlorinated compounds that were either insecticides (DDD, DDT) or their chlorinated derivatives (trans-4,4’-dichlorostilbene) [Hoffmann and Wynder (1800)]. According to Hoffmann and Wynder (1800), trans-4,4’-dichlorostilbene (DCS) is one of the major pyrolysis products of the most important tobacco insecticides DDT and DDD. They also stated: DCS is neither a complete carcinogen nor a tumor initiator, nor a tumor promoter, but the DCS (0.3%) can accelerate significantly the tumorigenicity of a BaP solution (0.003%) when both agents are applied concurrently.

However, it should be noted that the use in tobacco culture of chlorinated insecticides such as DDD and DDT in the United States was discontinued in the late 1960s. For example, between 1968 and 1974, the residual DDT levels per gram of U.S. flue-cured tobacco decreased rapidly and substantially (over 200-fold) as follows: 1968, 52 μg/g; 1970, 6 μg/g; 1974, 0.23 μg/g [USPHS (4005), IARC (1870)]. From 1967 through 1973, the organochlorine-containing pesticides such as DDT and TDE were subjected to detailed

examination not only for their contribution to cigarette MSS composition by direct transfer and/or degradation to simpler compounds during the smoking process but also to the composition of their pyrolysates. Investigators involved included Nesemann et al. (1968) from BAT (West Germany), Hoffmann et al. (1756, 1767) from the Sloan Kettering Institute and American Health Foundation, Carpenter and Frost (606) from Carreras Tobacco, Chopra and colleagues from North Carolina A&T [Chopra and Osborne (709, 25A12), Chopra and Domanski (707), Chopra et al. (708), Chopra and Thekkekandam (713, 714)] and Kennedy et al. (25A36) from Mississippi State. Chopra and Osborne (709) initially studied the pyrolysis of p,p′-DDT to identify degradation products. They compared the pyrolysis data with those from actual smoking studies and commented on the differences observed: There are two differences in the pyrolysis of DDT reported earlier and the degradation of DDT in tobacco smokes: the concentration of DDT is much greater in the former and hydrogen in the latter. The DDT degradation products as we have found are as would be expected from the difference in the reaction conditions. It is thus possible to predict the fate of a pesticide in tobacco smoke by studying its pyrolysis pattern. Also these investigations show that at the combustion zone hydrogen plays a very important role in the reactions taking place.

Chopra and his colleagues employed these pyrolysis data to identify the transfer and degradation products generated from pesticide-treated tobaccos during the smoking process [Chopra and Domanski (707), Chopra et al. (708), Chopra and Osborne (25A12), Chopra and Thekkekandam (713, 714)]. The results reported indicated the effect of added pesticides on MSS composition primarily in terms of the

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Table XXV-23 NCI Study (Fourth Set of Experimental Cigarettes): Effect of Pesticides Addition on Cigarette Smoke Properties (1333, 2683) PAH, µg /g of CSC Code No. 04 14 29 32 69 39

Cigarette Filler SEB IV SEB IV SEB IV SEB IV Avge (04,14,29,32) Pesticide-free control Pesticide-treated

% TBAd at Daily CSC Dose of

Phenol, µg/g of CSCa

B[a]Ab

B[a]Pc

12.5 mg

25 mg

3.79 2.98 3.95 3.19 3.48 5.33 6.21

0.99 1.11 0.96 1.55 1.15 1.05 1.21

0.72 0.79 0.71 0.60 0.70 0.83 0.79

24 36 24 27 27.8 34 27

49 56 55 55 53.8 54 43

CSC = cigarette smoke condensate B[a]A = benz[a]anthracene c B[a]P = benzo[a]pyrene d TBA = tumor-bearing animals a

b

transfer of intact pesticides from tobacco to smoke or the products generated from them during the smoking process. In the National Cancer Institute (NCI) study of the fourth set of cigarettes (1333, 2683), the effect of added pesticides on chemical and biological properties (mouse skin painting) was examined. As noted previously, the “pesticides” included the sucker growth inhibitors maleic hydrazide (MH-30) and “Contak®” (1-decanol) in addition to DDT (1333). Other compounds present in the mix used in the tobacco treatment according to government-approved procedures and treatment levels included Lorsban®, Dylox®, Enide®, Lannate®, and Carbaryl®. According to Smith et al. (3727), pyrolysis of Carbaryl® (methyl carbamic acid, 1-naphthyl ester) gave three major products in the pyrolysate: unchanged Carbaryl® (»40%), 1-naphthol, and methyl isocyanate. Some results from the NCI study of the MSS from the “pesticide”-treated tobacco are shown in Table XXV-23. The conclusions were [see p. 29 in (1333)]: Pesticide-Free and Pesticide-Treated Tobaccos: Two cigarettes tested in the fourth experiment were made from tobacco grown [in] Prince Edward Island (PEI) [Canada]. One of the tobaccos was pesticide-free and the other was pesticide-treated … There are no statistically significant differences among the [probability of survival] values at either dose level … Relative condensate yields from these cigarettes are presented … These yields confirm the [probability of survival] values, namely: there is no clear cut difference between the pesticide-free and pesticide-treated tobaccos.

It was also noted in the summary (2683) of the NCI 10-year “Less Hazardous” Cigarette Program: No significant differences were observed between cigarettes made from pesticide-treated tobacco leaves and pesticidefree tobacco leaves.

These findings, at least with respect to the maleic hydrazide added, are in agreement with the comments of Chopra

(704) in his theoretical discussion of the relationships among pyrolysis, maleic hydrazide, the actual smoking of tobacco treated with maleic hydrazide, and B[a]P: Evidence and data so far available on maleic hydrazide are not sufficient to suggest the MH [maleic hydrazide] is a health hazard to the smoker … Thus far it is reasonable to assume that there is not enough data or justification to consider the use of MH as a health hazard to the smoker.

In the late 1970s, two excellent reviews on reagents used to treat tobacco and their effects on tobacco chemistry were authored by Steffens (3911a) and by Sheets and Leidy (3634). The latter review included considerable information on the effect of such compounds added to tobacco on MSS composition. Sheets and Leidy (3634) summarized the data, which indicated the gradual decline in the levels on tobacco of insecticides such as DDT following the government’s proscription of their use on tobacco (and other crops) in the United States. Their summary is similar to that provided earlier by Guthrie (1457) on the gradual decline of the tobacco arsenic level following the discontinuance in 1952 of arsenate use on tobacco. By 1968, the arsenic level in U.S. tobacco had decreased from a 1951 level of ≈50 μg/g of tobacco (dry weight) to 0.5–1.0 μg/g [USPHS (4005), IARC (1870)]. In 1975, Griffin et al. (1391) reported arsenic values of 0.5 to 0.9 μg/g for U.S. tobaccos. A pesticide used to control cigarette beetles in stored tobaccos and tobacco products was methoprene (Altosid®) or in the formulation Kabat®. The use of the well-studied methoprene (5-isopropyl(2E,4E)-11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate) escalated markedly in the 1990s. Methoprene is also acceptable for controlling pests on various foodstuffs as well as mosquito larvae in water supplies. Using radiolabeled methoprene in a cigarette, Frisch et al. (1242, 1243) reported that 38.2% to 39.4% of the activity was found in the MSS, 52.3% to 52.4% in the sidestream smoke (SSS), and 8.1% to 8.4% in

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Pyrolysis

the 23-mm butt. Of the activity in the MSS, 96.8% was due to methoprene transferred from the treated tobacco. Of 1.3% total activity found in mainstream vapor phase, 86% consisted of radioactive CO plus CO2; the remaining 14% of the activity was distributed among ten vapor-phase components, all normally found as vapor-phase components of cigarette MSS.

XXV.D.2 Additives Used in Cigarette Manufacture The pyrolysate compositions from various tobacco additives, including casing materials and humectants, and their effect on cigarette MSS composition and properties were described by Roberts et al. (3225, 3226) and by Schumacher (3551). In this section, additional data are discussed. XXV.D.2.a  Casing Materials (Sugars, Cocoa, Licorice) Casing materials used in cigarette products in the United States are licorice, cocoa, and the sugars, including the invert sugars (glucose plus levulose) and sucrose. Although they did not discuss the topic in their 1964 review (4319), Wynder and Hoffmann (4332) did discuss the possible effects on cigarette MSS properties of inclusion of casing materials in the tobacco filler with particular emphasis on licorice because of its glycyrrhizin content. Glycyrrhizin, the potassium and calcium salt of glycyrrhizic acid, is polycyclic, with five cyclohexane rings in the picene configuration. (Figure XXV-2). Picene is a PAH identified in several pyrolysates by Badger et al. (142) and Kröller (2195) and in CSC by Snook et al. (3756). According to an assertion by Wynder and Hoffmann (4332), glycyrrhizin in licorice added to tobacco could be a precursor of PAHs in smoke. In an ill-defined experiment, Hoffmann et al. (1766) compared the B[a]P yield in the MSS from pipe tobacco (containing 30% casing materials, including licorice, level unspecified) smoked in a pipe (2 puff/min) with the B[a]P level in the MSS from cigarette tobacco (no licorice added) smoked identically, that is, in a pipe. The B[a]P levels were 27 and 10.5 μg/100 g of tobacco smoked, respectively. Later, Hoffmann and Rathkamp (1754) stated that the pyrolysis of licorice yielded PAHs. This finding was subsequently confirmed by Green and Best (1356, 1357), whose data on B[a]P generated during identical pyrolyses of licorice and flue-cured tobacco are summarized in Table XXV-24. They also identified thirty-five other compounds in the licorice pyrolysate [Green and Best (1356, 1357), all of which had previously been identified in cigarette MSS. Ten

Table XXV-24 Pyrolysis of Licorice vs. Flue-Cured Tobacco: Benzo[a]pyrene Generation Material Pyrolyzed Licorice Flue-cured tobacco

Benzo[a]pyrene

Pyrolysate wt., mg/g Pyrolyzed

Total, ng

ng/mg of Pyrolysate

117 133

24.8 70.5

0.21 0.53

of the licorice pyrolysate components were phenols; four were dimethyl- or trimethylnaphthalenes. Many of the compounds identified in licorice are the same as those identified in tobacco (3551, 3555). Thus, there will be similarities in their contributions to the composition of either pyrolysates from licorice vs. tobacco or the MSSs from a licorice-containing vs. a licorice-free tobacco blend. Differences will be reflected by the components unique to the material being investigated, for example, glycyrrhizin in licorice, theobromine in cocoa, and nicotine in tobacco. As noted by Schumacher et al. (3555), 172 (83%) of the 209 components identified in licorice by 1981 had also been identified in tobacco and/or tobacco smoke. Later, a similar situation between cocoa composition and tobacco/tobacco smoke compositions will be discussed. Sakuma et al. (25A62) reported the pyrolysis products from several naturally occurring polyphenols (chlorogenic acid, rutin). Rutin is a major polyphenol in both licorice and different tobacco types. It and chlorogenic acid yield substantial levels of catechol and substituted catechols on pyrolysis. All the identified volatile pyrolysis products from rutin have been identified in cigarette MSS. In the late 1970s, Harllee and Leffingwell (1512, 1513) cataloged cocoa components identified to that date with particular emphasis on the volatile, flavorful components common to cocoa and tobacco or its smoke. Both tobacco and tobacco smoke, as well as cocoa, contain numerous fatty acid triglycerides (1512) and many of the same fatty acids (1512). At least nineteen amino acids are common to cocoa and tobacco (1512). Of 352 volatile components identified in cocoa by 1979, 209 (59%) had also been identified in tobacco and tobacco smoke (1513). From his pyrolysis study on cocoa, Schlotzhauer (3447) reported that his results suggested: Cocoa powder added as tobacco flavorant would not significantly increase the phenol yield of smoke, but may affect the higher fatty acid content.

Figure XXV-2  The picene configuration present in glycyrrhizic acid.

In the NCI study of the third set of experimental cigarettes (1332), the cigarette MSS composition and biological properties (mouse skin-painting studies) of four cigarette samples were compared. These included three samples to each of which had been added individually a specified amount of glycerol (Code No. 80), sugar (Code No. 81), and cocoa (Code No. 82).

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Table XXV-25 NCI Study (Third Set of Experimental Cigarettes): Effect of a Humectant (Glycerol) or Casing Material (Sugar or Cocoa) on Cigarette Smoke Properties (1332, 2683) Relative to CSCa Additive, % Code No. 72 73 74 75

83 80 81 82

Filler

SEB III SEB III SEB III SEB III Avge 72-75 Avge 72-74 SEB III SEB III SEB III SEB III

µg/g

Glyc

Sugar

2.80 2.80 2.80 2.80 2.80 2.80 0 2.95 0 0

5.30 5.30 5.30 5.30 5.30 5.30 0 0 5.42 0

c

CSC = cigarette smoke condensate TBA = tumor-bearing animals c Glyc = glycerol

µg/g

Cocoa

Acr

Phenol

B[a]A

0 0 0 0 0 0 0 0 0 1.00

3.36 3.62 3.30 3.45 3.44 3.44 3.61 3.46 3.54 3.22

3.86 3.70 3.90 3.90 3.84 3.82 4.33 3.82 4.34 4.46

1.43 1.42 1.36 1.44 1.41 1.40 1.21 1.23 1.50 1.40

d

e

% TBAb at Daily Dose of B[a]P

12.5 mg

1.16 0.97 0.95 1.01 1.02 1.03 1.00 1.09 1.08 1.06

28 22 30 11(?) 23 27 22 22 19 28

f

25 mg 50 44 46 44 46 47 31 47 41 49

Acr = acrolein B[a]A = benz[a]anthracene f B[a]P = benzo[a]pyrene

a

d

b

e

The fourth sample was a control (Code No. 83) to which none of these casing materials/humectants had been added (1332, 2683). The results are summarized in Table XXV-25 together with data from four Standard Experimental Blend III samples (SEB III, Code Nos. 72–75), the controls for the third set of experimental cigarettes. Variations in the analytical and biological data among these four control samples (Code Nos. 72–75) raised questions about any attempt to compare on a one-to-one basis the data from individual samples, for example, the cocoa-treated sample (Code No. 82) vs. its control (Code No. 83), the sugar-treated sample (Code No. 81) vs. its control (Code No. 83), etc. Additional comments will be made about these data in the following section where humectants are discussed. The phenol data (Code No. 82 vs. Code No. 83) in Table XXV-25 indicate the prediction by Schlotzhauer (3447) appears to be valid: Inclusion of nominal levels of cocoa in the cigarette blend produced little change in the MSS phenol yield. Addition of 1% cocoa (Code No. 82 vs. Code No. 83) increased the phenol yield (mg/g of CSC) by 0.13 mg/g. This is about a 3% increase relative to Cigarette coded No. 83; well within the experimental error of the phenol determination. XXV.D.2.b  Humectants (Glycerol, Propylene Glycol) Humectants (glycerol, propylene glycol) are added to the tobacco blend to diminish the rate of post-cigarette-manufacture moisture loss. Cigarettes are usually manufactured with the blend at a 12% moisture content. As the cigarette loses moisture, that is, becomes “dry” during transportation and shelf storage, its yield of smoke components changes adversely, with increased yields not only of particulate-phase entities such “tar” and nicotine but also vapor-phase components such as the aldehydes (acetaldehyde, acrolein) and ketones (acetone, methyl vinyl ketone) [Green et al. (1364)].

These changes usually are perceived by the consumer to be detrimental and unacceptable [Townsend (25A76)]. The pyrolysis of humectants, including glycerol and propylene glycol, was studied in the mid-1960s by Doihara et al. (1023, 1024) and Kröller (2192, 2195, 2196). Kröller examined the pyrolysates from nine humectants (including glycerol and propylene glycol, the most commonly used in the United States) for the yields of B[a]P and other PAHs generated during the pyrolysis. His B[a]P data are summarized in Table XXV-26. In the early studies of methods to control cigarette MSS composition and yield, particularly with regard to PAHs, Bentley and Burgan (286) asserted addition of glycerol at the 3% level to the tobacco blend substantially decreased (by as much as ≈ 60%) the B[a]P yield when the CSCs from glycerol-treated cigarettes vs. untreated tobacco were

Table XXV-26 Benzo[a]pyrene in the Pyrolysates from Various Humectants Used or Proposed for Use in Cigarette Fabrication Humectant Diethylene glycol Triethylene glycol Glycerol 1,2-Propylene glycol 1,3-Propylene glycol Polyethylene glycol 400 Sorbitol Polyethylene glycol 600 Polyethylene glycol 1000 Tobacco, no additives

Benzo[a]pyrene, ng/g Pyrolyzed 15 30 60 60 80 105 130 289 420 20–40

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compared. Their finding was challenged by Wynder and Hoffmann (4332). Subsequently, with a reproducible analytical method for B[a]P determination, Scherbak et al. (3440) and de Souza and Scherbak (953) reported that such levels of added glycerol did not have the dramatic effect claimed by Bentley and Burgan on PAHs (or B[a]P) generation during smoking. Scherbak et al. (3440) reported: Addition of glycerol to flue-cured tobacco up to the 6% level does not modify the formation of 3,4-benzpyrene or smoke particulate.

The effect of glycerol added to the cigarette blend on MSS composition and properties was studied by the NCI TWG in the third set of experimental cigarettes (1332, 2683). The results were summarized in Table XXV-26. At the glycerol level (nearly 3%) used in the glycerol-treated sample (Code No. 80), it would be expected that the total particulate matter (TPM) would contain sufficient transferred glycerol to dilute other components by about 10% to 12% [Greene et al. (1382), Laurene et al. (2300), Wynder and Hoffmann (4332), Hege (1603)]. This was not observed with B[a]A and B[a]P yields but was with the phenol yield, see the data in Table XXV-26 for sample Code Nos. 80 and 83. The effect of transfer of humectants from the tobacco blend to smoke plus their dilution of the products formed during the cigarette smoking process affects the biological properties (mutagenicity in the Ames bioassay with Salmonella typhimurium) of the MSS particulate matter. In a detailed study of the effect of various casing ingredients (sugars, cocoa, humectants) on smoke chemistry, Baker et al. (174c) determined the yields of various “Hoffmann analytes” when such ingredients were added in various mixtures. They concluded: Many of the casing ingredient mixtures either had no statistically significant effect on the level of analytes investigated in smoke relative to a control cigarette or the produced decreases of up to 44% in some case.

Sugars did increase the yield in MSS of formaldehyde.

XXV.E Cigarette Construction Materials (Paper, Adhesives, etc.) Interest in cigarette MSS components possibly responsible for the epidemiological cigarette smoking-lung cancer association and the biological response observed in mice skin painted with massive CSC doses led to studies of the contribution of cigarette paper to MSS composition, primarily because as a cigarette construction factor, other than the tobacco blend, it contributed substantially (6% to 7%) to the weight of a 1.0-g cigarette. In 1954, Cooper and Lindsey (819), based on fragmentary UV data, reported the presence of several PAHs, including B[a]P, in a “tar” obtained by burning cigarette paper in bulk. Similar findings on PAHs (and B[a]P) in the combustion products of cigarette paper, tobacco, and

1141

cigarettes were reported by Lefemine et al. (2335), Cardon et al (594), and Alvord and Cardon (57). They also proposed an additive (ammonium sulfamate) for paper and/or tobacco to reduce pyrogenesis of PAHs. The ammonium sulfamate efficacy in decreasing B[a]P production in a burning cigarette was discussed by Wynder and Hoffmann [see pp. 521–523, 528 in (4322)], who noted that the additive gave discordant results in different investigations [no significant B[a]P reduction reported by Bentley and Burgan (286) or Pyriki et al. (3046) vs. substantial B[a]P reduction reported by Alvord and Cardon (57), Lindsey et al. (2370), and Candeli et al. (589]. Whether cigarette paper contributed significantly to the PAHs in cigarette MSS was finally resolved by Wright (4281), who reported that PAHs (and particularly B[a]P) were indeed generated when cigarette paper was burned in bulk or pyrolyzed, but when it was burned in a cylindrical configuration such as that encountered around the cigarette tobacco rod, the yields of PAHs (particularly B[a]P) were insignificant. Between 1963 and 1966, Kröller (2184–2195, 2200, 2203) reported the pyrolysis products from cigarette components permitted in cigarette fabrication in Germany. He estimated the amount of B[a]P generated by pyrolysis of each material at 700°C in air. In addition to tobacco itself (2191), the materials he studied included cellulose, starch, and a number of humectants, adhesives, and dyes consumed during the actual cigarette smoking process. Kröller (2191, 2192) asserted his pyrolysis and the actual cigarette smoking process were qualitatively and quantitatively identical processes. Kröller’s opinion of the equivalence of the fate of a material on pyrolysis in an inert atmosphere vs. its fate in the tobacco rod of a smoked cigarette parallels that of Wynder and Hoffmann (4332). In addition to phenanthrene, 4,5-methylenephenanthrene, and fluoranthene, Kröller reported the identification of four potent PAH mouse-skin tumorigens in his tobacco pyrolysate: DMB[a]A, 3-methylcholanthrene (now known as 1,2-dihydro-3-methylbenz[j] aceanthrylene), B[a]P, and DB[a,h]A. Despite their agreement with Kröller (2191, 2192) on the equivalence of the fate of a material in an inert atmosphere pyrolysis and the smoking process, Wynder and Hoffman were critical of several of Kröller’s findings. For example, Wynder and Hoffman (4332) questioned Kröller’s identification of the methyl derivatives (DMB[a]A, 30-methylcholanthrene) in his pyrolysates and smoke samples. However, a methylbenz[a]anthracene had been identified in CSC by Rodgman and Cook (3273) in the late 1950s and numerous methyl- and dimethylbenz[a]anthracenes were subsequently reported in CSC in the late 1970s by Snook et al. (3756, 3757). Table XXV-27, adapted from Kröller (2195), summarizes his data on the amounts of B[a]P generated during the pyrolysis of tobacco and numerous components used in cigarette fabrication. More recently, several studies on the pyrolysis of various adhesives either used or proposed for use as seam pastes in cigarette fabrication were conducted by Best (25A06, 25A07). He reported that, in contrast to a starch pyrolysate, the pyrolysate from polyvinyl acetate showed high levels of

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The Chemical Components of Tobacco and Tobacco Smoke Certain casing agents, saucing materials, and humectants are widely used in the manufacture of tobacco products. For all we know at this time, it is certainly a possibility that PAH may also be formed from these agents. One should keep in mind, however, that only small amounts of these materials are used for most smoking products.

Table XXV-27 Benzo[a]pyrene in the Pyrolysates from Various Materials Used or Proposed for Use in Cigarette Fabrication (2195) Material

Benzo[a]pyrene, ng/g Pyrolyzed

Their latter statement would also apply to cigarette fabrication materials consumed during the smoking process, such as the adhesives used on the cigarette paper seam, printing inks on the paper, etc. The data from Kröller (2195) on the B[a]P yields generated during cellulose and starch pyrolysis may be compared with those of Gilbert and Lindsey (1289), see Table XXV-28,. This provides an excellent example of the effect of changing pyrolysis conditions (pyrolysis at 650°C in air vs. pyrolysis at 700°C in N2) when two different materials are considered. The different pyrolysis conditions give a ratio of 9.75 (0.78/0.080) for the B[a]P yields from cellulose, but a ratio of 2.43 (0.17/0.070) for the B[a]P yields from starch. Cellulose was included in the Kröller studies because it constitutes the major part of cigarette paper, much of which is consumed during the smoking process. It was not included because cellulose, as wood pulp, is sometimes added by some manufacturers to their reconstituted tobacco sheet (RTS) to improve integrity and reduce fragmentation. The effect of cellulose added to cigarette filler on cigarette MSS composition and properties in a mouse skin-painting bioassay was examined in the mid-1970s in the NCI study of the first set of cigarettes (1329, 2683). The results are poorly defined because the cellulose was added (as wood pulp) at a 7.5% level to fillers made from the Standard Experimental Blend (SEB I) reconstituted into sheet material at three different densities.

Natural Dyes Logwood extract Buckthorn berry extract Madder lake Humic acid, sodium salt

< 10 20 120 270

Humectants Diethylene glycol Triethylene glycol Glycerol 1,2-Propylene glycol 1,3-Propylene glycol Polyethylene glycol 400 Sorbitol Polyethylene glycol 600 Polyethylene glycol 1000

15 30 60 60 80 105 130 289 420

Adhesives and Starches Alginic acid Carob bean flour Starch Cellulose Carboxymethylcellulose, sodium salt Methylcellulose Tragacanth Dialdehyde starch Cellulose monoacetate Carboxymethylstarch Guava gum Gum arabic Hydroxyethylcellulose Agar-agar Tobacco Tobacco (no additives)

30 60 70 80 120 180 230 235 285 300 300 320 340 470

XXV.F Flavoring Ingredients 20–40

acetic acid and B[a]P. Best also examined the pyrolysates from a variety of proposed new cigarette papers (25A04, 25A05, 25A08). In 1967, Wynder and Hoffmann [see pp. 350–351 in (4332)] noted that pyrolysis data on cigarette components should be considered carefully:

As outlined in Chapter 24 dealing with tobacco and/or smoke components used as flavorful additives, the numerous assertions about the possibly adverse effect of flavorful compounds added to tobacco were never accompanied by any supporting laboratory evidence. None of the information generated over the past decade that the added flavorants had little, if any, adverse effect on the chemical and biological properties of the smoke generated from the treated tobacco has been criticized by any investigator, governmental agency,

Table XXV-28 Pyrolysis of Cellulose and Starch: Comparison of Benzo[a]pyrene Data from Kröller with Those from Gilbert and Lindsey Pyrolysis Conditions Investigator Gilbert and Lindsey (1289) Kröller (2195)

Benzo[a]pyrene, ng/mg of Material Pyrolyzed

Temp., °C

Atmosphere

650 700

N2 air

Cellulose 0.78 0.080

Starch 0.17 0.070

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or medical institute or any contradictory data presented. In an exemplary study by Baker and Bishop (172a), 291 flavorful additives were pyrolyzed and, in each case, the yields of the major components of the pyrolysate were determined. As outlined in Chapter 24, many of the compounds used as flavor additives are already components of tobacco and/or its smoke. The behavior of such an additive will not differ from its tobacco inherent counterpart. In addition to the pyrolysis study of Baker and Bishop (172a), there are also many studies in which the effect of added flavorants on the chemical and biological properties of cigarette MSS was determined. Many were summarized in 2004 by Rodgman [see Tables 1 and 7A in (3266)] but since then much additional data have been published. Table XXV-29 lists a variety of references pertinent to the use of tobacco and/or smoke components as additives, their pyrolysis, their effect on smoke composition when added individually to tobacco, and their effect on smoke composition when added as a component of a flavorant formulation. Among the references cited is that of Paschke et al. who, in their report on the effect of ingredients on the chemical and biological properties of MSS, tabulated detailed pyrolysis data on a number of individual tobacco and/or smoke components plus detailed pyrolysis data on a variety of materials studied as tobacco additives [see pp. 226–241, Table 5 in (2896)]. Table XXV-30 lists a variety of references pertinent to compounds used as tobacco additives where the compounds are not known to be present in tobacco or its smoke. Included are references to their pyrolysis plus their effect on smoke composition when added as a component of a flavorant formulation.

1143

Although Table XXV-31 does not involve individual tobacco and/or tobacco smoke compounds, it is included because of the relationship of the entities to tobacco and/or tobacco products. The results of many of the studies cited were published in the early days of the examination of tobacco composition and the attempts to define the precursors in tobacco of various components in MSS. The studies on cocoa and licorice are included because of their level of use in tobacco products. Table XXV-29 deals with individual components that are either tobacco and/or tobacco smoke components, many of which are listed and discussed by Doull et al. (1053), Baker et al. (172a, 174a), Carmines (603), and Rodgman (3266) as additives in tobacco products. Table XXV-30 deals with compounds not identified to date in tobacco and/or tobacco smoke but listed as tobacco product additives. Since our primary concern throughout this project was the discussion of the contribution of individual tobacco components to smoke properties, neither Table XXV-29 nor Table XXV-30 includes the many complex mixtures (oils, extracts, resins, etc.) used as flavorful cigarette tobacco additives that have also been studied in detail with regard to their pyrolysates (172a, 172b) and their effect as tobacco additives on the chemical (174a, 174b, 630, 3370) and biological properties (174a, 25A24, 25A25, 25A27, 25A43, 25A49, 25A79) of cigarette smoke. Table XXV-32 [updated from Table 6 in (3266)] summarizes the specific conclusions from many of such studies conducted between 1994 and 2005. A more detailed summary of the chemical and biological studies through mid-2004 of the complex mixture additives was presented by Rodgman [see Tables 2 and 7B in (3266)].

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1144

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

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Pyrolysis

1145

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

(Continued )

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1146

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

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Pyrolysis

1147

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

(Continued )

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1148

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

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Pyrolysis

1149

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

(Continued )

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1150

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

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Pyrolysis

1151

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

(Continued )

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1152

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

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Pyrolysis

1153

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

(Continued )

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1154

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

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Pyrolysis

1155

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

(Continued )

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1156

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

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Pyrolysis

1157

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

(Continued )

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1158

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

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Pyrolysis

1159

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

(Continued )

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1160

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

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Pyrolysis

1161

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

(Continued )

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1162

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

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Pyrolysis

1163

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

(Continued )

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1164

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

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Pyrolysis

1165

Table XXV-29 (Continued) Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to Tobacco

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1166

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-30 Pyrolysis of Non-Tobacco and Non-Tobacco Smoke Components and/or Their Effect on Smoke Composition When Added to Tobacco References to

CAS No. 105-87-3 150-84-5 151-05-3 3681-71-8 140-39-6 143-13-5 2442-10-6 24851-98-7 103-54-8 76-49-3 141-97-9 53956-04-0 1336-21-6 10031-82-0 1319-88-6 698-27-1 151-10-0 1076-56-8

Name (per CA Collective Index)

104-87-0 122-43-0 102-22-7 5421-17-0 101-94-0 102-13-6 105-13-5 122-91-8 102-17-0 7549-33-9 93-92-5 104-53-0 13341-72-5 134-20-3 87-19-4 118-58-1] 120-47-8 94-13-3 121-98-2 94-46-2 126-64-7 532-32-1 125-12-2 87-69-4

Acetic acid, 3,7-dimethyl-2,6-octadien-1-yl ester {geranyl acetate} Acetic acid, 3,7-dimethyl-6-octenyl ester {citronellyl acetate} Acetic acid, 1,1-dimethyl-2-phenylethyl ester {α,α-dimethylphenethyl acetate} Acetic acid, 3-hexen-1-yl ester, (Z)- {cis-3-hexen-1-yl acetate} Acetic acid, 4-methylphenyl ester {p-tolyl acetate} Acetic acid, nonyl ester {nonyl acetate} Acetic acid, 1-octen-3-yl ester {1-octen-3-yl acetate} Acetic acid, 2-pentyl-3-oxo-1-cyclopentyl-, methyl ester {methyl dihydrojasmonate} Acetic acid, 3-phenyl-2-propenyl ester {cinnamyl acetate} Acetic acid, endo-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl ester {bornyl acetate} Acetoacetic acid, ethyl ester {ethyl acetoacetate} Ammonium glycyrrhizinate a Ammonium hydroxide Benzaldehyde, 4-ethoxy-{p-ethoxybenzaldehyde} Benzaldehyde glyceryl acetal Benzaldehyde, 2-hydroxy-4-methyl-{2-hydroxy-4-methylbenzaldehyde} Benzene, 1,3-dimethoxy-{m-dimethoxybenzene} Benzene, 3-methoxy-1-methyl-4-(1-methylethyl)- {4-isopropyl-3-methoxy-1methylbenzene} Benzeneacetaldehyde, 4-methyl- {p-tolylacetaldehyde} Benzeneacetic acid, butyl ester {butyl phenylacetate} Benzeneacetic acid, 3,7-dimethyl-2,6-octadieny-1-yl ester {geranyl phenylacetate} Benzeneacetic acid, hexyl ester {hexyl phenylacetate} Benzeneacetic acid, 4-methylphenyl ester {p-tolyl phenylacetate} Benzeneacetic acid, 2-methylpropyl ester {isobutyl phenylacetate} Benzenemethanol, 4-methoxy-{anisyl alcohol} Benzenemethanol, 4-methoxy-, formate {anisyl formate} Benzenemethanol, 4-methoxy-, phenylacetate {anisyl phenylacetate} Benzenemethanol, 4-methoxy-, propanoate {anisyl propionate} Benzenemethanol, α-methyl-, acetate {α-methylbenzyl acetate} Benzenepropanal {3-phenylpropionaldehyde} Benzofuranone, dimethyltetrahydro- {dimethyltetrahydrobenzofuranone-} Benzoic acid, 2-amino-, methyl ester {methyl anthranilate} Benzoic acid, 2-hydroxy-, 2-methylpropyl ester {isobutyl salicylate} Benzoic acid, 2-hydroxy-, phenylmethyl ester {benzyl salicylate} Benzoic acid, 4-hydroxy-, ethyl ester {ethyl p-hydroxybenzoate} Benzoic acid, 4-hydroxy-, propyl ester {propyl p-hydroxybenzoate} Benzoic acid, 4-methoxy-, methyl ester {methyl anisate} Benzoic acid, 3-methylbutyl ester {isoamyl benzoate} Benzoic acid, 3,7-dimethyl-1,6-octadien-3-yl ester {linalyl benzoate} Benzoic acid, sodium salt {sodium benzoate} Bicyclo[2,2,1]heptan-2-ol, 1,7,7,-trimethyl-, acetate {isobornyl acetate} Butanedioic acid, 2,3-dihydroxy- {l-tartaric acid}

7492-70-8 109-21-7 106-29-6 10094-34-5 539-90-2 540-18-1 106-27-4 10032-15-2 109-19-3 55066-56-3 16409-46-4

Butanoic acid, 2-butoxy-1-methyl-2-oxoethyl ester {butyl butyryl lactate} Butanoic acid, butyl ester {butyl butyrate} Butanoic acid, 3,7-dimethyl-2,6-octadien-1-yl ester {geranyl butyrate} Butanoic acid, 1,1-dimethyl-2-phenylethyl ester {α,α-dimethylphenethyl butyrate} Butanoic acid, 2-methylpropyl ester {isobutyl butyrate} Butanoic acid, pentyl ester {amyl butyrate} Butanoic acid, 3-methylbutyl ester {isoamyl butyrate} Butanoic acid, 2-methyl-, hexyl ester {hexyl 2-methylbutyrate} Butanoic acid, 3-methyl-, butyl ester {butyl isovalerate} Butanoic acid, 3-methyl-, 4-methylphenyl ester {p-tolyl 3-methylbutyrate} Butanoic acid, 3-methyl-, 5-methyl-2-(1-methylethyl)- cyclohexyl ester {menthyl isovalerate}

Pyrolysis of Individual Component

Effect on Mainstream Smoke Composition, When Component Added in a Mixture

172a 172a

174a, 174b, 603, 3370 174a, 174b 603, 3370 174b 174b, 603, 3370 603, 3370 603, 3370 174a, 174b 174a, 174b 603, 3370 174a, 174b 174a, 174b

172a 172a

172a 172a 172a 172a 172a 172a 172a 172a 172a

172a 172a 172a 172a 172a 172a 172a

174a, 174b 174a, 174b 174a, 174b 174a, 174b, 603, 3370 174a, 174b 174b 603, 3370 603, 3370 603, 3370 603, 3370 174a, 603, 3370 174a, 174b, 603, 3370 174a, 174b, 603, 3370 174a, 174b, 603, 3370 174a, 174b 174a, 174b 174a, 174b 603, 3370 603, 3370 603, 3370 603, 3370

2208, 2896 172a 172a 2208, 2896 172a 172a, 2201, 2896,

603, 3370 174a, 174b 603, 3370 174a, 174b 174a, 174b 174a, 174b 174a, 174c

172a

603, 3370 174a, 174b, 603, 3370 174a, 174b, 603, 3370 603, 3370 174a, 174b 174b, 603, 3370 174a, 174b, 603, 3370 603, 3370 174a, 174b, 603, 3370

172a

174b

172a 172a 172a 172a 172a

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1167

Pyrolysis

Table XXV-30 (Continued) Pyrolysis of Non-Tobacco and Non-Tobacco Smoke Components and/or Their Effect on Smoke Composition When Added to Tobacco References to Pyrolysis of Individual Component

Effect on Mainstream Smoke Composition, When Component Added in a Mixture

Butanoic acid, phenylethyl ester {phenethyl butyrate} 2-Butanone, 4-(4-methyoxyphenyl)- {4-(p-methoxyphenyl)-2-butanone} 2-Butenoic acid, ethyl ester; (E)- {ethyl trans-2-butenoate} 3-Buten-2-ol, 4-phenyl- {4-phenyl-3-buten-2-ol} 3-Buten-2-one, 4-(2,5,6,6-tetramethyl-2-cyclohexen-1-yl)- {α-irone} 2,3-Cyclohexanedione, 1-methyl- {1-methyl-2,3-cyclohexadione} Cyclohexanol, 5-methyl-2-(1-methylethyl)-, acetate {menthyl acetate}

172a 172a 172a

174a, 174b, 603, 3370 174a, 174b 174a, 174b ????? 174a, 174b 174a, 174b 174a, 174b

Cyclohexanone, 2-(1-mercapto-1-methylethyl)-5-methyl- {p-Mentha-8-thiol-3-one} Cyclohexanone, 2-methyl-5-(1-methylethyl)- {dl-isomenthone} Cyclohexene, 4-(1,5-dimethyl-4-hexenylidene)-1-methyl- {bisabolene} Cyclohexene, 1-methyl-4-(methylethylidene)- {terpinolene} 2-Cyclohexen-1-one, 2-methyl-5-(1-methylethyl)- {d-carvone} 5H-Cyclopenta[b]pyrazine, 6,7-dihydro-5-methyl- {5H-5-methyl-6,7dihydrocyclopenta[b]pyrazine} 2-Cyclopenten-1-one, 3-ethyl-2-hydroxy- {3-ethyl-2-hydroxy-2-cyclopenten-1-one} Decanedioic acid, diethyl ester {diethyl sebacate} Ethanol, 2,2’-oxybis- {diethylene glycol} Ethanone, 1-(2,4-dimethylphenyl)- {2,4-dimethylacetophenone} Ethanone, 1-(2-thiazolyl)-(2-acetylthiazole} Formic acid, 3,7-dimethyl-2,6-octadien-1-yl ester {geranyl formate} Formic acid, 3-hexenyl ester, (E)- {3-hexenyl formate, (E)-} Formic acid, pentyl ester {amyl formate} 2(3H)-Furanone, 2,5-dihydro-4,5-dimethyl-3-hydroxy- {4,5-dimethyl-3-hydroxy-2,5dihydrofuran-2-one} 2(3H)-Furanone, dihydro-5-heptyl- {γ-undecalactone} 2(3H)-Furanone, dihydro-5-octyl- {γ-dodecalactone} 3(2H)-Furanone, 2,5-dimethyl-4-hydroxy- {2,5-dimethyl-4-hydroxy-3(2H)-furanone} 3(2H)-Furanone, 3-ethyl-4-hydroxy-5-methyl- {3-ethyl-4-hydroxy-5-methyl-3(2H)furanone} 2(5H)-Furanone, 5-ethyl-3-hydroxy-4-methyl- {5-ethyl-3-hydroxy-4-methyl-2(5H)furanone} 2-O-β-D-Glucopyranuronysyl-α-D-glucopyranosiduronic acid (3β,20β)-20-carboxy11-oxo-30-norolean-12-en-3-yl- {glycyrrhizic acid; glycyrrhizin} Heptanoic acid, ethyl ester {ethyl heptanoate} 4-Heptenal {4-heptenal} 3-Hepten-2-one {3-hepten-2-one} ω-6-Hexadecenlactone {ω-6-Hexadecenlactone} 2,4-Hexadienoic acid, potassium salt {potassium sorbate}

172a 172a

CAS No. 103-52-6 104-20-1 10544-63-5 76-69-6 3008-43-3 16409-45-3 89-48-5 38462-22-5 491-07-6 495-62-5 586-62-9 2244-16-8 23747-48-0 21835-01-8 110-40-7 111-46-6 89-74-7 24295-03-2 105-86-2 33467-73-1 638-49-3 28664-35-9 104-67-6 2305-05-7 3658-77-3 27538-09-6 698-10-2 1405-86-3 106-30-9 6728-31-0 1119-44-4 7779-50-2 590-00-1 24634-61-5 2198-61-0 540-07-8 3452-97-9 21834-92-4 13419-69-7 551-08-6 17369-59-4 3738-00-9 7786-44-9 31502-14-4 141-12-8 107-75-5

Name (per CA Collective Index)

Hexanoic acid, 3-methylbutyl ester {isoamyl hexanoate} Hexanoic acid, pentyl ester {amyl hexanoate} 1-Hexanol, 3,5,5-trimethyl- {3,5,5-trimethyl-1-hexanol} 2-Hexenal, 5-methyl-2-phenyl- {5-methyl-2-phenyl-2-hexenal} 2-Hexenoic acid, (E)- {2-hexenoic acid, (E)-} 1(3H)-Isobenzofuranone, 3-butylidene {3-butylidenephthalide} 1(3H)-Isobenzofuranone, 3-propylidene {3-propylidenephthalide} Naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl- {ambroxide} 2,6-Nonadien-1-ol {2,6-nonadien-1-ol} 2-Nonen-1-ol {2-nonen-1-ol} 2,6-Octadien-1-ol, 3,7-dimetyyl-, acetate, (Z)- {neryl acetate} Octanal, 3,7-dimethyl-7-hydroxy- {hydroxycitronellal}

172a 172a 172a

172a 172a 172a 172a

174a, 174b 174a, 174b 603, 3370 174a, 174b, 603, 3370 174a, 174b 174a, 174b 174a, 174b 603, 3370

2192, 2896

172a

603, 3370 174a, 174b, 603, 3370 174a, 174b, 603, 3370 174b 603, 3370 174a, 174b

172a 172a 172a 172a

174a, 174b, 603, 3370 174a, 174b, 603, 3370 174a, 1974b, 603, 3370 174a, 174b

172a

174a, 174b, 603, 3370

172a 172a 172a

2896, 25A87 172a 172a 172a 2208, 2896 172a 172a 172a 3 172a 172a 172a 172a 120 172a 172a

174a, 174b, 603, 3370 174b 603, 3370 174a, 174b, 603, 3370 174a, 174b, 603, 3370 174a, 603, 3370 174a, 174b 174a, 174b 603, 3370 174b, 603, 3370 603, 3370 174a, 174b, 603, 3370 174a, 174b 174a, 174b 603, 3370 174a, 174b 174a, 174b (Continued)

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1168

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-30 (Continued) Pyrolysis of Non-Tobacco and Non-Tobacco Smoke Components and/or Their Effect on Smoke Composition When Added to Tobacco References to Pyrolysis of Individual Component

Effect on Mainstream Smoke Composition, When Component Added in a Mixture

Octanoic acid, 3-methylbutyl ester {isoamyl octanoate} 6-Octenoic acid, 3,7-dimethyl- {3,7-dimethyl-6-octenoic acid}

172a 172a

174a, 174b 174a, 174b, 603, 3370

7-Octen-1-ol, 3,7-dimethyl- {rhodinol} 2-Octynoic acid, methyl ester {methyl 2-octynoate} Pentanoic acid, butyl ester {butyl valerate} 4-Penten-3-one, 5-(2,6,6-trimethyl-2-cyclohexen-1-yl)- {methyl-α-ionone} Phenol, 2-ethoxy-5-(1-propenyl)- {5-propenylguaethol} Phenol, 4-ethyl-2-methoxy- {4-ethylguaiacol} Propanal, 2-methyl-3-[4-(1-methylethyl)]phenyl-{2-methyl-(p-isopropylphenyl)propionaldehyde; cyclamen aldehyde} Propanedioc acid, diethyl ester {diethyl malonate} 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, potassium salt {potassium citrate} 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, sodium salt {sodium citrate} 1,2,3-Propanetriol, monoacetate {monoacetin} 1,2,3-Propanetriol, triacetate {triacetin} Propanoic acid, 3-methylbutyl ester {isoamyl propionate} Propanoic acid, 2-methyl-, 3,7-dimethyl-6-octenyl ester {citronellyl isobutyrate} Propanoic acid, 2-methyl-, ethyl ester {ethyl isobutyrate} Propanoic acid, 2-methyl-, 2-methyl-4-oxo-4H-pyran-3-yl ester {maltyl isobutyrate} Propanoic acid, 2-methyl-, 4-methylphenyl ester {p-tolyl isobutyrate} Propanoic acid, 2-methyl-, 3,7-dimethyl-1,6-octadien-3-yl ester {linalyl isobutyrate} Propanoic acid, 2-methyl-, octyl ester {octlyl isobutyrate} Propanoic acid, 2-methyl-, phenylethyl ester {phenethyl isobutyrate} Propanoic acid, 2-methyl-, phenylmethyl ester {benzyl isobutyrate} Propanoic acid, 2-methyl-, 3-phenyl-2-propenyl ester {cinnamyl isobutyrate} Propanoic acid, 3-(methylthio)-, methyl ester {methyl 3-methylthiopropionate} Propanoic acid, phenylmethyl ester {benzyl propionate} 2-Propanone, 1-(4-methoxyphenyl)- {1-(p-methoxyphenyl)-2-propanone} 2-Propenal, 3-phenyl-, α-pentyl- {α-amylcinnamaldehyde} 1-Propene, 1,2,3-tricarboxylic acid {aconitic acid} 2-Propenoic acid, 3-phenyl-, 2-methylpropyl ester {isobutyl cinnamate} 2-Propenoic acid, 3-phenyl-, phenylethyl ester {phenethyl cinnamate} Pyran, 4-methyl-2-(2-methylpropen-1-yl)-tetrahydro- {rose oxide} 2H-Pyran-2-one, 6-butyltetrahydro- {δ-nonalactone} 2H-Pyran-2-one, 6-heptyltetrahydro- {δ-dodecalactone} 2H-Pyran-2-one, 6-hexyltetrahydro- {δ-undecalactone} 2H-Pyran-2-one, 6-methyltetrahydro- {δ-hexalactone} 2H-Pyran-2-one, 6-nonyltetrahydro- {tetradecalactone} 2H-Pyran-2-one, 6-pentyltetrahydro- {δ-decalactone} Pyrazine, 2-methoxy-3-methyl- {2-methyl-3-methoxypyrazine} Pyrazine, 2-methoxy-5-methyl- {2-methyl-5-methoxypyrazine} Pyrazine, 2-methoxy-6-methyl- {2-methyl-6-methoxypyrazine} Quinoxaline, 5-methyl- {5-methylquinoxaline} Quinoxaline, 5,6,7,8-tetrahydro- {5,6,7,8-tetrahydroquinoxaline} Tetradecanoic acid, 1-methylethyl ester {isopropyl myristate} 5-Thiazoleethanol, 4-methyl- {4-methyl-5-thiazole ethanol}

172a 172a 172a 172a 172a

174a, 174b, 603, 3370 174a, 174b 174a, 174b 174a, 174b 174a, 174b, 603, 3370 174a, 174b 174a, 174b

CAS No. 2035-99-6 502-47-6 6812-78-8 141-25-3 111-12-6 591-68-4 127-42-4 94-86-0 2785-89-9 103-95-7 105-53-3 866-84-2 68-04-2 26446-35-5 102-76-1 105-68-0 97-89-2 97-62-1 65416-14-0 103-93-5] 78-35-3 109-15-9 103-48-0 103-28-6 103-59-3 13532-18-8 122-63-4 122-84-9 122-40-7 499-12-7 122-67-8 103-53-7 16409-43-1 3301-94-8 713-95-1 710-04-3 823-22-3 2721-22-4 705-86-2 2847-30-5 2882-22-6 2882-21-5 13708-12-8 34413-35-9 110-27-0 137-00-8

Name (per CA Collective Index)

172a 172a

2206, 2896 172a, 2896 172a 172a 172a 172a 172a 172a 172a 172a 172a 3486 172a 172a 172a 172a 172a 172a 172a 172a 172a 172a 172a 172a 172a 172a 172a 172a

174a, 174b 174a, 174b 174a, 174b 174a, 174b, 603, 3370 174a, 174b 603, 3370 174a, 174b 603, 3370 174a, 174b, 603, 3370 174a, 174b 603, 3370 174a, 174b, 603, 3370 174a, 174b 174a, 174b 174a, 174b 603, 3370 174a, 174b 174a, 174b 603, 3370 174a, 174b, 603, 3370 174a 174a, 174b 174a, 174b 174a, 174b, 603, 3370 174a, 174b 174a, 174b 174a, 174b 174b, 603, 3370 174b, 603, 3370 174b 174b 174a, 174b 174a, 174b 174a, 174b 174a, 174b

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1169

Pyrolysis

Table XXV-31 Pyrolysis of Miscellaneous Tobacco Product Components Plus Their Effect on Smoke Composition When Added to Tobacco References to Effect on Mainstream Smoke Composition, When Component Added CAS No.

Name (per CA Collective Index)

Pyrolysis of Individual Component

Cocoa

172b, 2896, 3447

Hydrocarbons, aliphatic, tobacco-derived

2257, 3616

Individually

In a Mixture

174a, 174c, 603, 3370 3269, 3291

Licorice

172b, 743, 1356, 2204, 2896

Phytosterols, tobacco derived

4346

Polyphenol pigment, tobacco-derived

725a, 726

Tobacco

162, 163, 170, 171a, 172c, 276, 277, 369, 521, 522, 532, 536, 1357, 1651, 2071, 2072, 2196, 3190, 3468, 3616, 4150-4153, 4279, 4319, 4332, 25A35, 25A63

Tobacco extract

722, 3456, 3458, 3465-3467, 3470, 3472, 3616, 3877, 4355, 25A35

174a, 174c

Table XXV-32 Summary of Tobacco Ingredient Studies from 1994–2005

Analysis

Detailed literature survey of ingredients added to U.S. tobacco products

Date

Number of Ingredients Studied

Reported Findings/Conclusions

Reference

1994

599

“…it was concluded that there was no evidence that any ingredient added to cigarette tobacco produces harmful effects under the conditions of use in cigarettes.”

Doull et al. (1053)

Effect of added tobacco 2002 ingredients on cigarette MSS chemistry

333

“The smoke chemistry data revealed changes towards both higher Carmines (603); and lower amounts of various smoke constituents…This suggests Rustemeier et al. (3370) that the addition of 333 commonly used ingredients to cigarettes in three groups did not add to the toxicity of the smoke, even at the exaggerated levels tested… “An overall assessment of our data suggests that these ingredients, when added to the tobacco, do not add to the toxicity of smoke, even at the elevated levels used in this series of studies.”

2002

482

“In most cases, the flavour mixtures had no statistically significant effect on the smoke yields relative to the control cigarette. In a few cases, the small increases or decreases were observed for some analytes relative to the control cigarette. The smoke yields of the experimental cigarettes were well within the ranges observed in the three reference cigarettes.”

Baker and Smith (25A03)

(Continued )

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1170

The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-32 (Continued) Summary of Tobacco Ingredient Studies from 1994–2005

Analysis

Date

2004

Number of Ingredients Studied

482

Reported Findings/Conclusions

“The significances of differences between the test and control cigarettes were determined using both the variability of the data on the specific occasion of the measurement, and also taking into account the long-term variability of the analytical measurements over the one-year period in which analyses were determined in the present study. This long-term variability was determined by measuring the levels of the 44 “Hoffmann analytes” in a reference cigarette on many occasions over the one-year period of this study.

Reference

Baker et al. (174b)

“…It was found that, in most cases, the mixtures of flavouring ingredients (generally added in parts per million levels) had no statistically significant effect on the analyte smoke yields relative to the control cigarette.” Effect of added tobacco 1997, ingredients on cigarette 2002 MSS biology:

≈152

a) in vitro genotoxicity and cytotoxicity

b) MSS inhalation

“Although the mutagenic activities appeared to be similar, there were statistically significant differences in mutagenic activities among the sample.”

Bioresearch [for RJRT] (25A09); Rodgman (3263, 3264)

[Note: The differences were primarily due to the increase in mutagenicity of the CSC when the humectants (glycerol, propylene glycol) were not added to the cigarette tobacco and thus were not present as diluents in the CSC]. 2002

333

“Within the sensitivity and specificity of the test systems, the in vitro mutagenicity and cytotoxicity of the cigarette smoke were not increased by the addition of the ingredients.”

Carmines (603); Roemer et al. (25A49)

2002

482

“The data has been analyzed and demonstrates no additional activity from the flavoured cigarettes above that of the control products.”

Massey et al. (25A43)

1997, 2002

“It was concluded that addition of the tested humectants singly or 2 (glycerol, in combination had no meaningful effect on the site, extent or propylene frequency of respiratory tract changes associated with smoke exposure in rats.” glycol)

Gaworski et al. (25A27)

1997

1 “The results of this 13-week inhalation study indicated that the (menthol) addition of 5000 ppm menthol to tobacco had no substantial effect on the character or extent of the biological responses normally associated with inhalation of mainstream cigarette smoke in rats.”

Gaworski et al. (25A24)

1998

170

“The results indicate that the addition of flavoring ingredients to cigarette tobacco had no discernible effect on the character or extent of the biologic responses normally associated with inhalation of mainstream cigarette smoke in rats.”

Gaworski et al. (25A25)

2002

333

Carmines (603); “The data indicate that the addition of these 333 commonly used Vanscheeuwijck et ingredients, added to cigarette in three groups, did not increase the inhalation toxicity of the smoke, even at the exaggerate levels al. (25A79) used.”

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1171

Pyrolysis

Table XXV-32 (Continued) Summary of Tobacco Ingredient Studies from 1994–2005

Analysis

Date

Number of Ingredients Studied

Reported Findings/Conclusions

Reference

c) Mainstream CSC and skin painting

1999

150

“While tumor incidence, latency and multiplicity data occasionally differed between test and comparative reference CSC groups, all effects appeared to be within normal variation for the model system. Furthermore, none of the changes appeared to be substantial enough to conclude that the tumor promotion capacity of CSC obtained from cigarettes containing cigarettes with ingredients was discernibly different from the CSC obtained from reference cigarettes containing tobacco processed without ingredients.”

Gaworski et al. (25A26)

Pyrolysis of tobacco ingredients under conditions simulating those in the cigarette burning zone

2004

291

“The results are compatible with parallel studies in which the ingredients are added to tobacco and the effect on cigarette smoke constituents are measured. In general, the number of “Hoffmann analytes” detected among the pyrolysis products of the ingredients, and their levels, are low…Of the 291 tobacco ingredients pyrolysed, almost a third transfer out of the pyrolysis zone intact, and almost two thirds transfer at least 95% intact.”

Baker and Bishop [see pp. 245-246 in (172a)]

2005

159

“…a further 159 non-volatile and complex ingredients, as well as ingredient mixtures have been pyrolyzed…For the pyrolysis of many of the non-volatile ingredients, no “Hoffmann analytes” were detected among the products.

Baker and Bishop (172b)

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26

Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

Because of the diverse nature of this chapter, the following listing of its contents is provided: Carcinogens, Tumorigens, and Mutagens: The polycyclic aromatic hydrocarbons: Other classes of carcinogens, tumorigens, and mutagens: Aza-arenes N-Nitrosamines N-Heterocyclic amines Anticarcinogens, Inhibitors, and Antimutagens: Alternate exposure to carcinogens: Alternate exposures to polycyclic aromatic hydrocarbons Alternate exposures to aza-arenes Alternate exposures to N-nitrosamines Alternate exposures to N-heterocyclic amines Summary:

XXVI.A Carcinogens, Tumorigens, and Mutagens In 1990, the U.S. Environmental Protection Agency (EPA) issued several draft documents in which it defined environmental tobacco smoke (ETS) as a carcinogen and designated it as a “Group A Carcinogen” (1148, 1148a). Subsequently, EPA issued a final report on this topic (1148b). Data from various epidemiological studies on the incidence of lung cancer in nonsmokers exposed to ETS were interpreted by the EPA as indicating that ETS was causally related to lung cancer in the ETS-exposed nonsmokers. In addition to these epidemiological data, EPA relied on data from studies on tobacco smoke composition, particularly the many studies dealing with the composition of mainstream smoke (MSS) as well as the smaller number of studies dealing with sidestream smoke (SSS) composition. Of the limited number of SSS components for which quantitative data have been obtained on per cigarette yields, many are delivered at higher per cigarette levels in SSS than in MSS. Many of the SSS components quantified are those that have been considered as contributors to respiratory tract or other disease problems, based on results reported from laboratory animal experiments with individual compounds. EPA extrapolated these SSS (and MSS) qualitative and quantitative composition data directly to ETS with little regard for the profound quantitative differences between MSS and SSS composition and the highly diluted ETS system

and the biological implications of these differences (3255, 3255a, 3257). Of prime concern to EPA were those mss and sss components that, in one biological system or another, had been described as tumorigenic at doses far in excess of those encountered in mss and sss (1148). The cigarette MSS components of greatest concern to EPA were thirty-five MSS components listed by Hoffmann and Wynder (1808) in 1986, a list derived from the 1986 International Agency for Research on Cancer (IARC) monographs on tobacco smoking (1869, 1870) and expanded in 1990 to forty-three MSS (and tobacco) components by Hoffmann and Hecht (1727). The Hoffmann and Hecht list was the first of many lists issued from 1990 through 2001 by Hoffmann and his colleagues (1727, 1740, 1741, 1743, 1744, 1773), by the Occupational Safety and Health Administration (OSHA) in 1994 (2825), and by Fowles and Bates in 2001 (1217). These listings involved tobacco and tobacco smoke components previously reported to be tumorigenic, carcinogenic, or biologically active in various bioassays with individual components. The components of tobacco smoke were particularly emphasized (3265). Eventually, many of the listed MSS components, because of their multiple listings by Hoffmann and his colleagues, became defined as “Hoffmann analytes.” Table XXVI-1 is a tabulation of toxicants in tobacco and tobacco smoke from the IARC 1986 publication (1870) plus the seven lengthy publications co-authored from 1986 through 2001 by Hoffmann and his colleagues at the American Health Foundation (1727, 1740, 1741, 1743, 1744, 1773, 1808). In their 1990 list, Hoffmann and Hecht (1727) classified forty-three tobacco and/or tobacco smoke components as “tumorigenic agents in tobacco smoke.” It is interesting to note that they used the term “tumorigenic” rather than “carcinogenic” to define the components. A similar list was issued by Hoffmann et al. (1773) in 1993. In 1994, OSHA (2825)* tabulated forty-three tobacco smoke components for which it claimed there was “sufficient evidence” of carcinogenicity in humans or animals. For some unknown reason, the OSHA list included only forty-two items. Obviously, polonium-210 was inadvertently omitted. OSHA listed many of the same components as Hoffmann and Hecht but included several components not listed by them (1727) and vice versa. *

OSHA [see pp 15979–15980 in (2825)] presented a table entitled Table II-2. 43 chemical compounds identified in tobacco smoke for which there is “Sufficient Evidence” of carcinogenicity in humans or animals. However, Table II-2 lists only 42 items because 210Po, listed by many investigators as a hazard, was inadvertently omitted by OSHA.

1173

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1174

78836_C026.indd 1174

Table XXVI-1 Tumorigens, Carcinogens, and Toxicants Listed by Hoffmann and Colleagues 1986 Component Number of tumorigens and/or toxicants

IARC (1870)a

1986 Hoffmann and Wynder (1808)

1990 Hoffmann and Hecht (1727)

1993 Hoffmann et al. (1773)

1997 Hoffmann and Hoffmann (1740)

1998 Hoffmann and Hoffmann (1741)

2001 Hoffmann and Hoffmann (1743)

2001 Hoffmann et al. (1744)

35

43

43

60

70

68

69

40–70 ngg 40–60 ngj

20–70 ng

20–70 ng

20–70 ng

20–70 ng

20–70 ng

20–70 ng

30 ngg

4–22 ng

4–22 ng

4–22 ng

4–22 ng

4–22 ng

4–22 ng

60 ngg

6–21 ng

6–21 ng

6–21 ng

6–21 ng

6–21 ng

6–21 ng

NLe 10–50 ng g 10–40 ngi

6–12 ng 20–40 ng

6–12 ng 20–40 ng

6–12 ng 20–40 ng

6–12 ng 20–40 ng

6–12 ng 20–40 ng

6–12 ng 20–40 ng

40–60 ng g 0.6 ng 40 ng NLe NLe NL

40–60 ng 0.6 ng 4 ng NL NL 1.7–3.2 ng

40–60 ng 0.6 ng 4 ng NL NL 1.7–3.2 ng

NL 0.6 ng 4 ng NL NL 1.7–3.2 ng

NL 0.6 ng 4 ng P, NYLf NL NLf

NL 0.6 ng 4 ng P, NYLf NL NLf

NL 0.6 ng 4 ng P, NYLf NL NL f

Dibenzo[a,l]pyreneg Indeno[1,2,3-cd]pyrene

20–70 ng 40–70 ngb 4–76 ngc 4–22 ng 30 ngb 6–21 ng 60 ngb 6–12 ng 20–40 ng 10–50 ngb 5–78 ngc 40–60 ngb 0.6 ng 4 ng P d, NYLe P d, NYLe 1.7–3.2 ng 2–3 ngb 17–32 ngc P, NYL 4–20 ng

P, NYL 4 ng

P, NYL 4–20 ng

P, NYL 4–20 ng

P, NYL 4–20 ng

1.7–3.2 ngf 4–20 ng

1.7–3.2 ngf 4–20 ng

1.7–3.2 ngf 4–20 ng

Aza-arenes Pyridine

16–40 mg

NL

NL

NL

20–200 mgm

10–40 mg

20–200 mgs

NLe 0.1 ng 2.7 ng 3–10 ngb 0.7 ng

NL 0.1 ng g 3–10 ngg

1–2 mg 0.1 ng 3–10 ng

0.2–1.3 mg 0.1 ng 3–10 ng

1–2 mg 0.1 ng 3–10 ng

2–180 ng 0.1 ng 3–10 ng

20–200 mgp 16–40 mgr 1–2 ngx 0.1 ng 3–10 ng

1–2 mg 0.1 ng 3–10 ng

0.7 ng g

0.7 ng

0.7 ng

0.7 ng

0.9 ng

0.7 ng

0.7 ng

2–20 ng 1–200 ngb 0–2.7 ng 0.1–10 ngb

1–180 ngh 2–180 ngj 1–40 ngh 0,1–40 ngj

0.1–180 ng

0.1–180 ng

0.1–180 ng

2–180 ng

2–180 ng

2–1000 ng

3–13 ng

3–13 ng

3–13 ng

Polycyclic Aromatic Hydrocarbons Benz[a]anthracene

Benzo[b]fluoranthene Benzo[j]fluoranthene Benzo[k]fluoranthene Benzo[a]pyrene

Chrysene Chrysene, 5-methylDibenz[a,h]anthracene Dibenzo[a,e]pyrene Dibenzo[a,h]pyrene Dibenzo[a,i]pyrene

Quinoline Dibenz[a,h]acridineh Dibenz[a,j]acridine 7H-Dibenzo[c,g]carbazole N-Nitrosamines N-Nitrosodimethylamine N-Nitrosoethylmethylamine 11/24/08 12:38:56 PM

© 2009 by Taylor & Francis Group, LLC

3–13 ng

3–13 ng

3–13 ng

The Chemical Components of Tobacco and Tobacco Smoke

52

N-Nitrosodi-n-propylamine N-Nitrosodi-n-butylamine N-Nitrosopyrrolidine N-Nitrosopiperidine N-Nitrosodiethanolamine N-Nitrososarcosine N’-Nitrosonornicotine 4-(N-Methylnitrosamino)-1(3-pyridyl)-1-butanone N’-Nitrosoanabasine N’-Nitrosoanatabine N-Nitrosomorpholine Aromatic Amines Aniline 2-Toluidine Aniline, 2,6-dimethyl1-Naphthylamine 2-Naphthylamine Biphenyl, 3-amino Biphenyl, 4-aminoN-Heterocyclic amines k AaC MeAaC Glu-P-1 Glu-P-2 PhIP IQ MeIQ Trp-P-1 Trp-P-2

0–2.8 ng 0–10 ngb 0–1 ng 0–3 ng 0–110 ng 2–42 ngb 0–9 ng 0–36 ng 0–90 ngb NL 0.2–3.0 mg 0.13–0.25 mgb 0.08–0.77 mg 0.08–0.7 mgb 0–150 ng 0–200 ngb NL 0–3.7 mgb NL NL 32–160 ng 30–200 ngb NL NL 3–4 ngb 1.7–22 ng 1–22 ngb NL 2.4–4.6 ng 2–5 ngb NL NL NL NL NL NL NL NL NL

0.1–28 ng

0–25 ng

0–25 ng

0–2.8 ng

0–2.8 ng

0–2.8 ng

0–2.8 ng

0–1 ng 0–3 ng 2–110 ngh 2–42 ngj 0–9 ng 0–40 ng

NL NL 1.5–110 ng

NL NL NL

NL NL 3–60 ng

0–1.0 ng 0–30 ng 3–110 ng

0–1.0 ng 0–30 ng 3–110 ng

0–1.0 ng 0–30 ng 3–110 ng

NL 0–36 ng

NL NL

NL 0–68 ng

0–9 ng 0–68 ng

0–9 ng 0–68 ng

0–9 ng 0–68 ng

NL 0.12–3.7 mg

NL 0.12–3.7 mg

NL 0.12–3.7 mg

NYL 0.12–3.7 mg

ND e 120–3.700 ngv

NL 0.12–3.7 mgv

NL 0.12–3.7 mgv

0.12–0.95 mg

0.08–0.77 mg

0.08–0.77 mg

0.08–0.77 mg

0.08–0.77 mg

0.08–0.77 mg

0.08–0.77 mg

40–400 ngh 120 ngj NL

0.14–4.6 mg

0.14–4.6 mg

0.14–4.6 mg

0–150 ng

NL

NL

NL

NL

NL

NL

NL

NL

NL

NDk in MSS

ND in MSS

ND in MSS

ND in MSS

NL

NL

360 ng 30–160 ng

360 ng 30–200 ng

NL 30–200 ng

NL 30–200 ng

360–655 ng 30–337 ng

360–655 ngr 30–337 ng

NL 30–337 ng

NL NL

NL NL

NL NL

NL NL

NL NL

4–50 mgx NL

4–50 ngx NL

4.3–27 ng

1–22 ng

1–22 ng

1–22 ng

1–334 ng

1–334 ng

1–334 ng

NL 2.4–4.6 ng

NL 2–5 ng

NL 2–5 ng

NL 2–5 ng

NL 2–5.6 ng

NL 2–5.6 ng

NL 2–5.6 ng

NL NL NL NL NL NL

NL NL NL NL NL NL

NL NL NL NL NL NL

25–260 ng 2–37 ng 0.37–0.89 ng 0.25–0.88 ng 11–23 ng 0.26 ng

25–260 ng 2–37 ng 6.37x–0.89 ng 0.25–0.88 ng 11–23 ng 0.3 ng

25–260 ng NL 0.37–0.89 ng 0.25–0.88 ng 11–23 ng 0.3 ng

25–260 ng 2–37 ng 0.37–0.89 ng 0.25–0.88 ng 11–23 ng 0.3 ng

NL NL NL

NL NL NL

NL 0.3–0.5 ng 0.8–1.1 ng

NL 0.3–0.5 ng 0.8–1.1 ng

NL NL NL

NL 0.29-0.48 ng 0.82–1.1 ng

NL 0.3–0.5 ng 0.8–1.1 ng

1175

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(Continued)

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

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N-Nitrosodiethylamine

1176

78836_C026.indd 1176

Table XXVI–1 (continued) Tumorigens, Carcinogens, and Toxicants Listed by Hoffmann and Colleagues 1986 Component Aldehydes and Ketones Formaldehyde

IARC (1870)a

1986 Hoffmann and Wynder (1808)

1990 Hoffmann and Hecht (1727)

1993 Hoffmann et al. (1773)

1997 Hoffmann and Hoffmann (1740)

Volatile Hydrocarbons 1,3-Butadiene

NL

NL

NL

NL

Isoprene

NL

NL

NL

NL

Benzene

20-50 mg

20-50 mg

12-48 mg

12-48 mg

Toluene Styrene

NL

NL NL

NL NL

NL NL

20-75 mgl 25-40 mgm 450-1000 mgl 200-400 mgm 12–70 mgl 6-70 mg m 5-90 mg m 10 mg

Acetaldehyde Propionaldehyde Butyraldehyde Crotonaldehyde Acrolein

Miscellaneous Organic Compounds Acetamide Acrylonitrile Acrylamide Hydrazine, 1,1-dimethylMaleic hydrazide Methanol Methyl isocyanate Nitromethane 2–Nitropropane

11/24/08 12:38:56 PM

Nitrobenzene Vinyl chloride

© 2009 by Taylor & Francis Group, LLC

10 mg

5–100 mg

70–100 mg

70–100 mg

70–100 mgl 20–100 mgm 18–1400 mgl 400–1400 mgm NL NL NL

500–1200 mg

18–1400 mg

18–1400 mg

NL NL NL 50–100 mg

NL NL 10–20 mg NL

NL NL 10–20 mg NL

60–140 mgm

NL NL 10–20 mg 60–140 mg

100–250 mg NL

NL NL

NL NL

100–650 mgm NL

70–100 mg

2001 Hoffmann and Hoffmann (1743)

2001 Hoffmann et al. (1744)

70–100 mg 20–100 mgp 500–1400 mgu 400–1400 mgp NL NL NL

70–100 mgl 20–100 mgs 500–1400 mgu 400–1400 mgs NL NL NL

60–140 mgp

60–240 mgs

NL NL

100–650 mgp NL

NL NL

20-75 mg

20-75 mg 25-40 mgp 450-1000 mgu 200-400 mgp 20-70 mg 12-50 mgp 20-60 mg p 10 mg

20-75 mg 25-40 mgs 450-1000 mgu 200-400 mgs 20–70 mg 6-70 mgs 5-90 mg s 10 mg

38–56 mg 3–15 mg P, NYL P, NYL 1.16 mgr 80–180 mgp 100–250 mgr NL

38–56 mg 3–15 mg P, NYL P, NYL

NL

500–1.400 mgu

450-1.00 mgu 20–70 mg NL 10 mg

38-56 mgb 3.2–15 mgb NL P, NYL NL NL

NL

NL

NL

NL

3.2–15 mg NL NL NL NL

3.2–15 mg NL P, NYL NL NL

3.2–15 mg NL P, NYL NL NL

3.2–15 mg P, NYL NYL NL 80–180 mgm

38–56 mg 3–15 mg P, NYL P, NYL 1.16 mg 100–250 mg

NL NL

NL NL

NL NL

NL NL

NL NL

1.5–5 mg NL

0.2–2.2 mg 0.73–1.21 mgb NL 1.3–16 ng 1–16 ngb

0.2–2.2 mg

0.73–1.21 mg

0.73–1.21 mg

0.73–1.21 mg

0.2–2.2 mg

0.3–0.6 mg 0.7–1.2 mg

0.5–0.6 mg 0.7–1.2 mg

NL 1.3–16 ng

NL 1–16 ng

NL 1–16 ng

NL 1–16 ng

25 mg 11–15 ng

25 mg 11–15 ng

25 mg 11–15 ng

80–180 mgs

The Chemical Components of Tobacco and Tobacco Smoke

Acetone 2-Butanone

70–100 mg 20–88 mgb 500–1200 mg 18–1400 mgb NL NL 10–20 mg 60–100 mg 25–140 mgb 100–250 mg NL

1998 Hoffmann and Hoffmann (1741)

20–38 ng 7 mg NL 20 mg 18–30 ngu

20–38 mg 7 mg 12–100 ng NL 18–37 ngu

20–38 mg 7 mg 0–100 ng NL

NL

P, NYL

P, NYL

P, NYL

80–60 NL NL NL 200–400 mg

NL NL NL NL NL

NL NL NL NL NL

80–160 mg NL NL NL 200–400 mg

80–160 mg r NL NL NL 100–360 mg 200–400 mgr

60–180 mg t NL NL NL 90–2000 mg 100–200 mgt

110–300 mg NL NL

NL NL NL NL

NL NL NL NL

NL NL NL NL

NL NL 20 ng NL

NL NL 20 ng < 3 mg

NL NL 20 ng < 3 mg

NL

NL

NL

800–1200 ng

800–1.200 ngu

800–1200 mg

800–1200 mg

NL NL NL

NL NL NL

NL NL NL

200–370 ng NL NL

200–370 ng NL NL

200–370 mg NL NL

200–370 mg NL NL

24–43 ng NL NL NL NL NL NL 20–3000 ng NL NL 0.03–1.0 pCi NL

24–43 ng NL 40–120 ng NL 41–62 ng 4–70 ng NL 0–600 ng NL 35–85 ng 0.03–1.0 pCi NL

24–43 ng NL 40–120 ng NL 41–62 ng 4–70 ng NL 0–600 ng NL 35–85 ng 0.03–1.0 pCi NL

24–43 ng

24–34 mgx 10–90 mg 40–120 ng

20–38 ng NL NL NL NL

20–38 ng NL NL NL NL

20–38 ng NL NL NL NL

20–38 ng NL NL NL NL

Benzo[b]furan

NL

NL

NL

Phenols Phenol o-Cresol m-Cresol p-Cresol Catechol

60–140 mg 14–30 mg NL NL 40–350 mg

Resorcinol Hydroquinone Methyleugenol Caffeic acid

8–80 mgb 88–155 mgb NL NL

60–140 mg NL NL NL 25–360 mgg 100–350 mgi 140–500 mgj NL

Chloroaromatic Compounds DDT

NL

DDE Polychlorodibenzo-p-dioxins Polychlorodibenzofurans

0.7–1.2 mg NL NL NL

18–37 mgu

b

Inorganic Components Hydrazine Hydrogen sulfide Arsenic Beryllium Cadmium Chromium (vi) Cobalt Nickel Mercury Lead Polonium-210 Selenium

24–43 ng NL 1–25 mg NL 9–70 ng 4–70 ng 0.2 ng 0–600 ngb NL Pc 0.03 pCi Pc

20–90 mg 40–120 ng NL 41–62 ng 4–70 ng NL 0–600 ng NL 35–85 ng 0.03–1.0 pCi NL m

0.3 mg NL 4–70 ng 0.13–0.2 ng 0–600 ng 4 ng 34–85 ng 0.03–1.0 pCi NL

24–43 ng

24–43 ng

20–90 mgp 40–120 mg 0.5 ng 7–350 ng 4–70 ng 0.13–0.2 ng 0–600 ng NL 34–85 ng 0.03–1.0 pCi NL

20–90 mgs 40–120 mg 0.5 ng 7–350 ng 4–70 ng 0.13–0.2 ng 0–600 ng

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20–38 ng 7 mg NL 20 mg 18–30 mgl 20–40 mgm P, NYL

Ethyl carbamate Ethylene oxide Propylene oxide Di(2-ethylhexyl) phthalate Furan

34–85 ng 0.03–1.0 pCi NL (Continued)

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Table XXVI–1 (continued) Tumorigens, Carcinogens, and Toxicants Listed by Hoffmann and Colleagues 1986 IARC (1870)a

1986 Hoffmann and Wynder (1808)

1990 Hoffmann and Hecht (1727)

Additional Components Nicotine Carbon monoxide Ammonia

1.0–2.3 mg 10–23 mg 50–130 mg

1.0–3.0 mg NL NL

NL NL NL

0.1–3.0 mgn 14–23 mgm 10–130 mgm

1.0–3.0 mg 10–23 mg 10–130 mg

1.0–3.0 mgq 14–23 mgp 10–130 mgp

0.1–3.0 mgt 14–23 mgs 10–130 mgs

Nitrogen oxides Hydrogen cyanide

100–600 mg 400–500 mg

1–2.5 mg 10–23 mg 50–170 mgi 50–130 mgj 50–600 mg 400–500 mg

NL NL

NL NL

100–600 mgm 400–500 mgm

100–600 mg 400–500 mg

100–600 mgp 400–500 mgp

100–600 mgs 400–500 mgs

Component

1993 Hoffmann et al. (1773)

1997 Hoffmann and Hoffmann (1740)

1998 Hoffmann and Hoffmann (1741)

2001 Hoffmann and Hoffmann (1743)

2001 Hoffmann et al. (1744)

See Table 19 in (1870). See Appendix 2 in (1870). c See Table 20 in (1870) d P = present, as listed in Appendix 2 in (1870). e NL= not listed; NYL = no per cigarette MSS yield listed; ND = not detected. f The yield range listed for dibenz[a,l]pyrene is incorrect. It is the range usually listed for dibenzo[a,i]pyrene. The P,NYL designation should also apply to dibenzo[a,l]pyrene. g See Table 5 in (1808). h See Table 6 in (1808). i See Table 11 in (1808). j See Table 13 in (1808). k AaC = 2-amino-9H-pyrido[2,3-b]indole; MeAaC = 2-amino-3-methyl-9H-pyrido[2,3-b]indole; Glu-P-1 = 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole; Glu-P-2 = 2-aminodipyrido[1,2-a:3’,2’-d] imidazole; PhIP = 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine; IQ = 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline; MeIQ = 2-amino-3,4-dimethyl-3H-imidazo[4,5-f]quinoline; Trp-P-1 = 3-amino1,4-dimethyl-5H-pyrido[4,3-b]indole; Trp-P-2 = 3-amino-1-methyl-5H-pyrido[4,3-b]indole l See Table 3 in (1740). m See Table 1 in (1740). n See Table 2 in (1740). p See Table 5-1 in (1743). q See Table 5-2 in (1743). r See Table 5-3 in (1743). sSee Table 2 in (1744). t See Table 3 in (1744). u Compare yield listed in Table 1 in (1741), Table 5-4 in (1743), and Table 4 in (1744). v Compare yield listed in Table 1 in (1741) with those listed in (1727, 1740, 1743, 1744). a

b

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

In 1997, Hoffmann and Hoffmann (1740) classified sixty tobacco and/or tobacco smoke components as “carcinogens in tobacco and cigarette smoke.” Several components listed by Hoffmann and Hecht but omitted by OSHA were also omitted by Hoffmann and Hoffmann. A major addition, accounting for much of the increase from forty-three to sixty was the inclusion of the highly mutagenic N-heterocyclic amines. EPA (1148) incorrectly assessed the health consequences with regard to lung cancer of the components in the HoffmannHecht list by stating: Of the 99 compounds in tobacco smoke that have been studied in detail, at least 43 are complete carcinogens,* each able on its own to cause the development of cancer in humans or animals.

The EPA erred in its assessment of the forty-three components in the Hoffmann-Hecht list since most have been shown not to be (1) tumorigenic to any human tissue or (2) tumorigenic to lung tissue in laboratory animals. These facts are addressed by comments from Hoffmann and Hecht in the text accompanying their tabulation. In addition, the few compounds that have been reported to produce tumors in laboratory animals have done so at dose levels far in excess of those encountered in MSS, SSS, or ETS. Careful examination of the Hoffmann-Hecht list reveals significant flaws which, if they had been considered at all by the EPA, would have profoundly affected its conclusions concerning ETS. It has been known for over five decades that classifying a substance as “tumorigenic” or “carcinogenic” can be misleading. These terms should not be misinterpreted or over-interpreted. Users of tables with headings “tumorigenic” or “carcinogenic” must be aware of the meaning and limitations of the terms “tumorigenicity” and “carcinogenicity” when applied to specific compounds or elements. The misunderstanding and misinterpretation of these terms are not new. The term “carcinogenesis” and by extension derivative terms were defined precisely as early as 1923 and its original definition is still listed in various medical dictionaries: Carcinogenesis is the process whereby a carcinoma is generated. In the 27th edition (1051c) of Dorland’s Medical Dictionary, this definition of carcinogenesis is the same as that listed in the 13th edition (1051b). Some investigators incorrectly use the term “carcinogenesis” for the production of any tumor type not just a carcinoma. The correct term, if used in this manner, is “tumorigenesis.” The term “carcinogen” is often applied, again often incorrectly, to any factor that induces any type of tumor. Common in the past, but seldom used now, was the term “sarcogenesis” used to describe sarcoma production, the end-point in studies in which a compound injected subcutaneously induced a sarcoma. Within twenty-five years of the first successful experiments to produce tumors in animals by skin painting with solutions of coal tar by Yamagiwa and Ichikawa (4361) and *

OSHA cited the U.S. Surgeon General’s 1989 report (4012) which, in turn, reproduced the table subsequently presented in Hoffmann and Hecht (1727).

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within a decade of the first successful skin tumor inductions with pure compounds such as dibenz[a,h]anthracene (DB[a,h]A) [Kennaway and Hieger (2078)] and benzo[a] pyrene (B[a]P) [Cook et al. (796a, 797), Barry et al. (194)] the misuse and misunderstanding of the term “carcinogenicity” had reached such proportions that Shear, an outstanding and highly regarded U.S. investigator of chemical carcinogenesis, was invited to put the term in perspective. In 1941, Shear and Leiter (3627) published an article in which their admonitions regarding over-interpretation of these terms are as significant today as they were then: The term “carcinogenic potency”… is not to be considered as an invariable property inherent in a compound but is merely a summary of the results of particular experiments and is valid only for animals of the species, strain, sex, age, diet, etc. of the particular animal employed as well as the dose, menstruum, mode and site of application, etc., of the compound in question … Conclusions regarding the potency of any given compounds should therefore be interpreted in the light of the data upon which they are based.

In 1951, Hartwell compiled the second edition (1544) of his survey on compounds tested for carcinogenicity since the demonstrated carcinogenicity of DB[a,h]A and B[a]P in mouse skin-painting experiments. To further the understanding of the terms “carcinogen” and “carcinogenicity” and to minimize their future misuse, Hartwell quoted liberally from the Shear-Leiter publication. He added several important points, one of which was the following: There is a tendency on the part of some to consider carcinogenicity or lack of carcinogenicity as characteristic properties of chemical compounds. In other words, some researchers treat carcinogenicity as a fixed property of a compound. This is not a valid approach to thinking about “carcinogens.” Carcinogenicity is a variable property, depending on a number of factors. It differs from other properties of a compound that are fixed, for example, melting point, boiling point, refractive index, specific gravity, crystalline form. As noted by Shear and Leiter (3627), by Hartwell (1544), and by many others, a substance or factor can show a range from carcinogenicity to noncarcinogenicity to anticarcinogenicity and the response will differ in the laboratory depending on the animal used (species, strain, sex, age), route of administration (inhalation, ingestion, injection [subcutaneous, intravenous, intraperitoneal], skin painting, douching), mode of administration (single vs. multiple doses, neat, in solution, as an aerosol or as a vapor), diet supplied the animals, and cage care. Hartwell also cautioned: Another pitfall is the attempt to carry over, without reservation, to man, conclusions based on animal experiments. We do not know whether man is more or less susceptible than mice to particular carcinogens. Some animal species, such as the rat, rabbit, and dog are much more resistant than is the mouse, and vice versa, while in the monkey none of the powerful carcinogens has been shown to produce tumors.

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From an examination of Table XXVI-1, it is obvious that several classes of components account for the greatest number of tumorigens classified as significant in tobacco smoke. Further examination of the number of references cited for each of them in the pertinent chapters of this book indicates the magnitude of the research conducted on each class both within and outside the tobacco industry since the early 1950s. Sequentially, polycyclic aromatic hydrocarbons (PAHs), azaarenes, N-nitrosamines (NNAs), and N-heterocyclic amines in tobacco smoke have attracted much attention on their identification, quantitation, precursors, and reduction or elimination. Tumorigenic components in these four class account for nearly 60% of the total listed. The following pages contain brief descriptions of the history and chronology of the four classes of tobacco smoke components. The components listed in Table XXVI-1 and by OSHA (2825) and Fowles and Bates (1217) raise numerous questions as to why many of them were included. First, attempts to attribute the “carcinogenicity” of cigarette MSS to a particular component are questionable. Scores of citations over the past five decades have been issued by eminent scientists and health organizations in which it is stated that no single MSS component or class of components acting either individually or in concert can explain observations in human smokers or in laboratory animals treated with heroic doses of MSS. For example, comments on B[a]P in particular or other tumorigenic PAHs in general include those by Cook (793) [see also (796a, 797)], who wrote about B[a]P in cigarette smoke: The tarry condensates of the smoke obtained by smoking cigarettes in machines … have 3,4-benzpyrene, but the amount is exceedingly small and there is considerable doubt about whether the concentration is high enough to produce carcinogenic action.

In 1981, the U.S. Surgeon General [see p. 36 in (4009)] stated: The contribution of BaP or PAH in general to mouse skin carcinogenesis by cigarette smoke condensate cannot be fully measured at this time … In the smoking and health program of the National Cancer Institute … no significant dependence of carcinogenic potency on BaP content was observed.

The American Association for Cancer Research (26A02) in its 1984 position paper on smoking wrote: Studies have presented the profile of the known carcinogens in tobacco. At present, there is no direct method to assign priority to any of these substances as putative causal agents in human lung cancer.

That year, Peto and Doll (26A127) stated: “But 30 years of laboratory research has yet to identify reliably the important carcinogenic factors in cigarette smoke.” The U.S. Surgeon General [see p. 200 in (4010)], on the subject of N-nitrosamines in tobacco smoke, stated: “There is lack of direct evidence that these compounds are also human carcinogens.” This was also the view of Magee, who first demonstrated the tumorigenicity of N-nitrosamines in

The Chemical Components of Tobacco and Tobacco Smoke

laboratory animals. In 1983, Magee (26A89) noted, “a role for nitrosamines in the causation of human cancer has not been established.” On the basis of the data available, the aromatic amines, including b-naphthylamine, were discounted in the U.S. Surgeon General’s 1981 and 1982 reports: The presence of b-naphthylamine in cigarette smoke has been demonstrated [Hoffmann et al. (1747)], along with other carcinogenic aromatic amines [Patrianakos et al. (2900)]. The yield was so low that [the researchers] did not believe these agents contributed significantly to the risk of bladder cancer in smokers [see p. 41 in (4009)]. On the basis of quantitative data for aromatic amines in cigarette smoke, an etiological significance of these traces of carcinogenic amines in bladder cancer is questionable, even if one were to consider the total of the aromatic amines and their metabolites [see pp. 207–208 in (4010)].

Similar comments about other components on the various lists have been published: arsenic (4010), nickel (4010), polonium-210 (4009, 4010), and benzene (4005). Many of these MSS and/or tobacco components should be excluded from the lists on the basis of explicit comments in the literature by numerous knowledgeable authorities on their tumorigenicity to laboratory animals at levels determined in MSS, their lack of tumorigenicity in most instances on inhalation, and the equivocal evidence showing their tumorigenicity in humans at levels in MSS. All but four of the forty-three components have never produced respiratory tract tumors in laboratory animals exposed to the component via inhalation. Many have never been tested in an inhalation system, and one component of great interest (B[a]P) has only produced lung carcinoma via inhalation in animals at an extraordinarily massive dose. The following situation should not be overlooked: the MSS yield determined two, three, or four decades ago for a component is not relevant to the MSS yield found by analysis for the component from more recent or current cigarettes. For example, MSS values for dibenz[a,h]acridine and 7H-dibenzo[c,g] carbazole were obtained with 1959–1960 cigarettes, MSS values for dibenz[a,j]acridine from 1959–1960 and from 1963 cigarettes, the MSS value for DB[a,h]A is from 1963 cigarettes, the MSS value for 5-methylchrysene is from 1973 cigarettes, and the MSS value for N-nitrosodiethanolamine (NDELA) is from commercial cigarettes manufactured in or before 1981. It is well recognized, as indicated in Figure XXVI-1, that the variety of cigarette design technologies (efficient filtration, filter-tip additives, processed tobacco materials [reconstituted tobacco sheet, RTS, expanded tobaccos], air dilution [porous paper, filter-tip perforations], and paper additives) has progressively reduced the sales-weighted average MSS total particulate matter (TPM) by almost 70% from 40 mg/cigarette in the early 1950s to less than 12 mg/cigarette in the late 1980s. These eight cigarette design technologies have been defined, even by various opponents of cigarette smoking, as significant in the design of a “less hazardous” cigarette [Wynder and Hoffmann (4319, 4332), USPHS (4005, 4009), Gori (1333), Hoffmann and Hoffmann (1740, 1743, 1744)].

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Replacement of all-flue-cured or all-Oriental tobaccos with a blend of flue-cured, burley, and Oriental tobaccos

50.0

3.00 Filter tips Reconstituted tobacco Paper additives

40.0

2.50

Paper porosity

‘TAR,’ mg

Expanded tobacco

2.00

Ventilation

30.0

1.50 20.0

NICOTINE, mg

1913

1.00 10.0

0.0 1954

0.50 ‘TAR’ 1958

NICOTINE 1962

1966

1970 Year

1974

1978

1982

0.00 1986

Figure XXVI-1  “Tar” and nicotine deliveries, sales weighted average basis.

At the same time that the reduction of delivery of MSS TPM was accomplished, the composition of the MSS was altered. For example, for MSS TPM, the B[a]P content— expressed as ng B[a]P/mg TPM—has decreased about 33% (from 1.2 ng/mg TPM to 0.8 ng/mg TPM) during the same time period. The U.S. Surgeon General in his 1979 report (4005) summarized the B[a]P data for a commercial cigarette sold in the United States from 1954 to 1979. As noted by Rodgman and Green (3300), Gold et al., colleagues of Ames, as recently as 1998 questioned the extrapolation of laboratory animal tumorigenesis data generated by the use of a maximum tolerated dose (MTD) to a human situation. They stated (1318a):

Formaldehyde N-Nitrosodimethylamine (NDMA) N-Nitrosodiethylamine (NDEA) N-Nitrosopyrrolidine (NPYR) 2-Toluidine Benz[a]anthracene (B[a]A) N’-Nitrosonornicotine (NNN) 4-(N-Methylnitrosamino)-1(3-pyridinyl)-1-butanone (NNK) N-Nitrosodiethanolamine (NDELA) Cadmium

probable human carcinogen probable human carcinogen probable human carcinogen probable human carcinogen listed only as an irritant, not as a carcinogen listed only as an animal carcinogen listed only as an animal carcinogen no relevant information available re health effects probable human carcinogen probable human carcinogen

Extrapolation of cancer potency results from MTD studies to real-life exposures is not scientifically supportable.

Despite these and other equivocal statements, OSHA stated with great certainty:

From these considerations and the information presented later, it is obvious that many of the components could and should be removed from the various Hoffmann-co-authored lists that subsequently led to the “Hoffmann analyte” phenomenon. In its 1994 report on indoor air quality, OSHA (2825) dealt at some length with ETS. It presented a list of fortythree tobacco smoke components for which it claimed “there is sufficient evidence of carcinogenicity in humans or animals.” Comparison of the OSHA list with that of Hoffmann and Hecht (Table XXVI-1) reveals numerous similarities plus some differences. OSHA (2825) described ten of its listed tobacco smoke “carcinogens” in the following less-than-positive terms:

The corroborative evidence of the carcinogenic activity of tobacco smoke provided by animal bioassays and in vitro studies and the chemical similarity between mainstream smoke and ETS clearly establish the plausibility that ETS is … a human lung carcinogen.

Of the components in the various lists, the four classes of tobacco smoke components investigated in greatest detail during the past five decades were the PAHs, aza-arenes, NNAs, and the N-heterocyclic amines. Because of the wealth of background information available on PAHs demonstrated to be tumorigenic in laboratory animals, extensive research (isolation, identification, quantitation, precursors, removal, prevention of formation, etc.) was conducted in the 1950s and

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1960s on this compound class in tobacco smoke. The reason for selection of this class of compounds was obvious. It has been estimated that more research funds were expended since the 1930s on the study of tumorigenic PAHs in general (and B[a]P in particular) than on any other class of compounds. The results of thousands of investigations on PAHs (their synthesis, biological properties [tumorigenicity, mutagenicity], metabolism, sources [air pollutants, industrial oils and tars, tobacco smoke, foodstuffs, beverages, etc.], isolation, quantitation, reduction, etc.) have been published. Similar studies, but to a much lesser degree, have been conducted on the aza-arenes. Since the early 1950s, over 500 PAHs and slightly fewer than 300 aza-arenes have been reported as tobacco smoke components. The per cigarette yields of most of the PAHs and aza-arenes are in the subnanogram range. In the early 1950s, the discovery of the tumorigenicity by Barnes and Magee (192) of an NNA in laboratory animals initiated a flurry of research on the NNAs, initially in foodstuffs and subsequently (mid-1960s) in tobacco smoke. In contrast to the great number of PAHs and aza-arenes identified in tobacco smoke, fewer than sixty NNAs have been identified in tobacco and/or tobacco smoke to date. In the mid-1970s, Japanese investigators in their investigations of various cooked foodstuffs reported the isolation and identification of several N-heterocyclic amines derived pyrogenetically from amino acids and proteins [Sugimura et al. (3829, 3829a), Sugimura (3828b, 3828c)]. Subsequently, several of the N-heterocyclic amines were reported to possess inordinately high mutagenicities in the Ames test with Salmonella typhimurium, be tumorigenic in the mouse skin-painting bioassay, and to be present in cigarette smoke condensate (CSC) at low nanogram or subnanogram levels [Sato et al. (3415a), Yamashita et al. (4367, 4368)]. Fewer than a dozen of the highly mutagenic N-heterocyclic amines have been reported as CSC components.

XXVI.A.1 The Polycyclic Aromatic Hydrocarbons In the case of the PAHs in general and the thirteen specific PAHs listed in Table XXVI-1, many of the assertions about them in tobacco smoke since the early 1950s have either been shown to be incorrect or, in several instances, highly equivocal. Several sources of PAHs in cigarette MSS, originally considered to be the major sources of the PAHs, were shown to be either incorrect (effluents from lighting source, such as matches and butane- or hexane-fueled lighters) or insignificant (PAH-containing air pollutants deposited on the surface of the tobacco leaf during growing, harvesting, and curing) or primarily derived from cigarette paper combustion. Long-chained saturated hydrocarbons were originally defined as the major precursors in tobacco of PAHs in tobacco smoke. Subsequently, it was shown that the contributions of tobacco terpenes and phytosterols to the levels of MSS or SSS PAHs exceeded those of the saturated hydrocarbons. In the mid- to late 1950s, it was proposed (3241, 3242) that the per cigarette yields of MSS PAHs would be diminished by removal of saturated hydrocarbons, phytosterols, and terpenes

The Chemical Components of Tobacco and Tobacco Smoke

from the tobacco by extraction with nonpolar solvents such as hexane, a process dubbed the “dry cleaning” of tobacco.* It was proposed that the reduced MSS PAH level in the CSC from cigarettes fabricated with extracted tobacco would be accompanied by reduced tumorigenicity to mouse skin of the extracted tobacco CSC [Wynder and Wright (4354)]. In 1982, Brunnemann and Hoffmann, members of a research group that formerly proposed removal of wax-like compounds considered to be the precursors of the PAHs in smoke, advocated addition of such compounds to tobacco (480). Also in the late 1950s, it was proposed to use high-nitrate tobacco in the tobacco blend or add nitrate to the blend to modify the combustion process during smoking to decrease the MSS PAH yields [Hoffmann and Wynder (1797, 1798)]. In direct contrast was a 1982 proposal: Because of the involvement of nitrate and nitrogen oxides generated from it in the pyrogenesis of NNAs, use low-nitrate tobaccos in the blend or remove the nitrate from tobacco as a means to control NNAs in MSS (and SSS) (480). The proposal that high molecular weight PAHs, including B[a]P, could be removed from MSS by selective filtration was shown to be incorrect. Selective filtration from MSS is possible only with compounds that have an appreciable vapor pressure, that is, they are found in both the particulate and vapor phases of MSS. For example, the low molecular weight phenols and the volatile NNAs are sufficiently volatile to be selectively filtered from MSS, but the vapor pressures of most PAHs of interest (B[a]P, DB[a,h]A, B[a]A) are too low for selective filtration to be effective. B[a]P in MSS was proposed as an “indicator” of (a) the tumorigenicity of mainstream CSC to mouse skin, (b) the levels of PAHs with four or more rings, and (c) the levels of tumorigenic PAHs. In none of these cases is the level of B[a]P a valid “indicator.” (Similarly, phenol, proposed as an “indicator” of the level of low molecular weight promoting phenols in cigarette MSS, was shown not to be a valid “indicator.”) Assertions that the probability was extremely low that alkylated PAHs (methyl- and dimethyl-PAHs) would occur in tobacco smoke were demonstrated to be incorrect. Subsequently, even polyalkylated PAHs such as pentamethyl- and hexamethyl PAHs were identified in tobacco smoke, their major precursor being the high molecular weight tobacco terpenes such as solanesol [Snook et al. (3757)]. Assertions that cyclopentabenzanthracenes could not occur in tobacco smoke were incorrect. Numerous cyclopentabenzanthracenes were identified in MSS, their major

*

The concept of extraction of tobacco with an organic solvent to remove PAH precursors was not new. Roffo (3327) reported that extraction of tobacco with organic solvents such as ethyl alcohol, chloroform, acetone, petroleum ether, paraffin hydrocarbons, or benzene resulted in a reduction of the tumorigenicity of the tar generated by destructive distillation of the extracted tobacco compared to the tar generated by destructive distillation of the unextracted (control) tobacco. Roffo did not study the smokes from cigarettes fabricated with the extracted and unextracted tobaccos. He suggested that the extraction removed the phytosterols from the tobacco, which he considered the major precursor of the PAHs in the destructive distillate and in tobacco smoke.

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H N N

Dibenz[a,h]acridine, I

N

Dibenz[a,j]acridine, II

Dibenz[a,h]anthracene, IV

7H-Dibenzo[c,g]carbazole, III

Dibenz[a,j]anthracene, V

Figure XXVI-2  Structural similarity of several polycyclic aromatic hydrocarbons and aza-arenes.

precursor being the phytosterols [Snook et al. (3736, 3756, 3758, 3759)]. PAHs in tobacco smoke are formed by either (a) a degradation-combination mechanism or (b) an aromatization mechanism involving a single molecule. Studies showed that both mechanisms are operative. To bolster several arguments concerning PAHs in MSS, it was incorrectly asserted by some investigators that the fate of an individual tobacco component during experimental pyrolysis in an inert atmosphere and at a temperature approximating that of the cigarette coal was the same as its fate in the tobacco matrix during the cigarette smoking process. This assertion was shown to be incorrect by several investigators, including Schmeltz et al. (3512), members of the same group that originally proposed the equivalency of the fate of tobacco components during pyrolysis and the smoking process. The tumorigenicity of CSC to mouse skin is due to its content of PAHs with four or more fused rings. Even though it was claimed that the PAHs are the only initiators in CSC, the levels and tumorigenicities of the PAHs in CSC accounted for no more than 2% to 2.5% of the observed tumorigenic response in mouse or other rodent skin-painting bioassays. With so many incorrect or equivocal assertions about the MSS PAHs issued by anti-tobacco smoking investigators over the last four decades (see Table XXVI-2), it was somewhat surprising that both OSHA and EPA were so willing to accept the premise that the thirteen PAHs in the HoffmannHecht and/or the OSHA lists contributed significantly to the alleged tumorigenic effects of MSS and ETS in the respiratory tract of active and passive smokers, respectively.

XXVI.A.2 Other Classes of Carcinogens, Tumorigens, and Mutagens XXVI.A.2.a Aza-Arenes Within a few years of the discovery of the tumorigenicity to mouse skin of the PAHs DB[a,h]A (2078) and B[a]P (194, 796a, 797), investigations on the tumorigenicity of azaarenes began. The aza-arenes selected for study were those structurally related to the PAHs already demonstrated to be

tumorigenic. The first aza-arenes studied were those corresponding structurally to the dibenzanthracenes in which one meso-carbon was replaced by a nitrogen atom. From a comparison of their tumorigenicities (mouse skin-painting experiments), Barry et al. (194) reported that the tumorigenicity of several dibenzacridines was much less than the corresponding PAH, for example, dibenz[a,h]acridine {I} was reported to be much less tumorigenic than DB[a,h]A {IV} under the same experimental conditions. For the PAHs, much of the early research on their synthesis and tumorigenicity was conducted by the Kennaway group (Barry, Cook, Hewett, Hieger, Lindsey, Schoental) in the United Kingdom, by groups headed by Fieser and Newman in the United States, and by the Clar group in Germany. For the aza-arenes such as the benzacridines, much of the early research was conducted by the Lacassagne group (Buu-Hoï, Daudel, Lavit-Lamy, Zajdela) in France. It has been known for nearly six decades [see the review by Lacassagne et al. (2247a)] from the comparative tumorigenicity studies involving structurally similar PAHs and azaarenes (see Figure xxvi-2) that the aza-arenes are much less tumorigenic than the PAHs to mouse skin [compare DB[a,h] A {IV} vs. dibenz[a,h]acridine {I} and DB[a,j]A {V} vs. dibenz[a,j]acridine {I} or 7H-dibenzo[c,g]carbazole {III}]. These observations on tumorigenicity plus the reported amounts of the three aza-arenes in cigarette MSS relative to the amount of B[a]P certainly raises doubts as to the importance of the aza-arenes as significant tobacco smoke tumorigens. In Table XXVI-1, B[a]P is listed as occurring in cigarette MSS in yields ranging from 20 to 40 ng/cigarette, whereas the yields of aza-arenes I, II, and III are listed at 0.1, 3 to 10, and 0.7 ng/cigarette, respectively. Even though a more realistic range for B[a]P in the MSS of cigarettes marketed over the past two decades would be 5 to 20 ng/cigarette rather than 20 to 40 ng/cigarette, the ratios of B[a]P yield to those of dibenz[a,h]acridine and 7H-dibenzo[c,g]carbazole are substantial. This of course assumes that the yields for the three aza-arenes that were included in Table XXVI-1 are correct! It is obvious that the listed aza-arene yields are not meaningful for recently manufactured cigarettes whose design includes technologies not used in the late 1950s and

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-2 The Polycyclic Aromatic Hydrocarbon Paradoxes Assertion

Contradiction

Major source of PAHs in cigarette MSS is the lighting source (match, flammable fuel-charged lighter, gas burner in laboratory).

The PAH level in cigarette MSS was independent of lighting source: Cigarettes lit by an electric lighter gave the same PAH levels as those lit by matches, fuel-charged cigarette lighters, or a gas flame.

Because bulk pyrolysis of cigarette paper yielded PAHs, cigarette paper (representing about 5% of the cigarette weight) was defined as the major source of PAHs in cigarette MSS [Cooper et al. (817), Cardon et al. (594)].

Comparison of PAH yields, including B[a]P, produced by bulk pyrolysis of cigarette paper vs. pyrolysis of the paper in a cylindrical form approximating its configuration in the cigarette revealed that the cylindrical configuration combustion produced very little PAHs (or B[a]P) vs. bulk pyrolysis [Wright (4281)].

PAHs in cigarette MSS are the result of transfer of PAHs from the surface of air pollutant-contaminated tobacco to MSS.

MSS PAH level was not due to transfer of contaminant PAHs transfer from the tobacco rod to smoke: B[a]P injected into the tobacco rod produced very little increase in the MSS B[a]P level. Most of the injected B[a]P was destroyed during smoking process.

Since none of the factors noted above (means of cigarette lighting, cigarette paper, air pollutant contamination) was the source of PAHs in cigarette MSS, the source must be one or more of the tobacco components. However, even in 1957, the presence of B[a] P in tobacco smoke was questioned [cf. Fieser (1181)].

Because the fragmentary evidence presented, the presence of PAHs, particularly B[a]P, in tobacco smoke was questioned by such noted PAH experts as Fieser (1181) whose colleagues identified B[a]P in roasted coffee beans but were unable to identify it in tobacco smoke. Eventually, because of the isolation by Hoffmann of B[a]P in crystalline form from cigarette MSS (4307), its presence in MSS became universally accepted.

According to Wynder and Hoffmann, PAHs in cigarette smoke were the only major tumor initiators in mouse skin carcinogenesis (4332):

Mouse skin-painting studies with B[a]P solutions at concentrations much in excess of that in CSC produced no skin carcinomas in rabbits or mice [Wynder et al. (4351), Warshawsky et al. (26A180)]. Similarly, use of more reasonable doses of CSC in skin-painting studies instead of the massive doses usually used resulted in neither papilloma nor carcinoma formation [Wynder et al. (4351), Gori (1329, 1330, 1332, 1333), NCI (2683)].

The many detailed data obtained in studies of tobacco carcinogenesis on mouse skin exclude with some certainty that major tumor initiators other than the PAH type play a role in this assay system. B[a]P, because of its potency in skin-tumor carcinogenesis and level in MSS, was considered the major PAH of concern in tobacco smoke. In the 1981 Surgeon General’s report (4009), it is stated: Benzo[a]pyrene appears to be the most important single member of this class of compounds [the PAHs], taking into consideration both its concentration and its relative carcinogenic potency. Initially, Fieser did not believe the evidence was sufficient to demonstrate that B[a]P was present in tobacco smoke. He stated that if B[a]P were present, its precursor would be tobacco cellulose (1181).

Subsequent studies indicated the major precursors in tobacco of PAHs in its smoke were not cellulose and lignin but were the lipophilic tobacco components. Rodgman and Cook (3269, 3286, 3291) and Severson et al. (3616) reported that terpenoids, phytosterols, and saturated hydrocarbons were PAH precursors

Removal of lipophilic PAH precursors from tobacco by solvent extraction reduced the MSS PAH levels and the tumorigenicity (mouse skin-painting) of the CSC Wynder (4294), Wright (4282), Wynder and Wright (4354)]. This led to recommendations to remove the lipophilic tobacco components. Later, Wynder et al. (4332) minimized the effectiveness of the removal of the lipophilic tobacco components. Wynder and Hoffmann (4310) defined tobacco extraction as “impractical both technically and economically.” Wynder and Hecht (4306d) and the Surgeon General (4005) described tobacco extraction as “of academic interest.” Eventually, Wynder’s colleagues recommended addition of lipophilic compounds, e.g., n-hentriacontane, to tobacco (480) to offset effect of nitrate-derived NOx in NNA formation.

Biological activity of CSC from extracted tobacco was decreased but to a much lesser extent than decrease in MSS PAH (and B[a]P) yields. This resulted from two unanticipated effects of extraction on the tobacco and its smoke: Extracted lipophilic compounds included various inhibitors (saturated hydrocarbons) and anticarcinogens (a-tocopherol, b-sitosterol, cholesterol, D-limonene, duvanediols) which have been reported to offset the tumorigenicity of PAHs. • Residual tobacco after extraction contains higher levels of lignin, cellulose, and pectins. All of these generate promoting/ cocarcinogenic phenols during the smoking process: Levels of low molecular weight phenols in MSS were increased.

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Table XXVI-2 (Continued) The Polycyclic Aromatic Hydrocarbon Paradoxes Assertion

Contradiction

PAHs in cigarette smoke are generated by one or other of the following mechanism: • Organic compounds in tobacco are degraded to simpler molecules during the pyrolysis processes occurring in the burning cigarette and these simpler molecules recombine to PAHs (degradation-combination mechanism) [cf. Badger et al. (142, 143) and earlier papers]. • During the pyrolysis processes occurring in the burning cigarette, high molecular weight compounds in tobacco undergo unimolecular cyclization, dehydration, aromatization, ring expansion , etc. to form PAHs (aromatization reaction) [Rodgman and Cook (3269, 3286)].

The mechanism of PAH formation is not an either-or situation. Laboratory data indicated that both mechanisms were operative in PAH formation in the burning cigarette. Evidence for the unimolecular aromatization reaction was provided by pyrolysis data and cigarette “spiking” data with phytosterols. In this instance, the relatively high levels of chrysene and cyclopentaphenanthrene vs. B[a]P were more readily explained by the unimolecular aromatization of the tetracyclic sterol.

Inhaled cigarette smoke is the responsible agent for respiratory tract cancer, particularly squamous cell carcinoma of the lung, in smokers. It was implied in the late 1950s and in the 1960s that the responsible agent in MSS may be the PAHs, particularly B[a]P.

Inhalation experiments with laboratory animals exposed for their lifetime to cigarette MSS consistently failed to produce pulmonary squamous cell carcinoma [Essenberg (1161-1163), Leuchtenberger et al. (26A81, 26A82, 26A83), Henry and Kouri (1621, 1622)], the lung tumor type reported to be associated with smoking in humans. Similar exposures of laboratory animals to vehicular exhaust gases produced pulmonary squamous cell carcinoma [Mauderly et al. (2505)]. Inhalation studies with B[a]P at levels comparable to those in cigarette MSS were consistently negative. Tumor production at extremely high levels of inhalation exposure to B[a]P were described as “equivocal” [RTECS (3085)]. From a study with roofers exposed via inhalation to levels of B[a]P equivalent to the daily inhalation of MSS from over 700 cigarettes, Selikoff et al. (3584a) concluded: If a high level of exposure to benzo[a]pyrene has any relation to lung cancer, the effect must be small…If a high level of occupational exposure to benzo[a] pyrene by way of inhalation results in little if any increase in the risk of lung cancer — then it seems unlikely that the extremely small amount of benzo[a] pyrene in cigarette smoke can account for the high degree of association between cigarette smoking and lung cancer.

Since B[a]P and other known tumorigenic PAHs account for so little (< 2%) of the observed biological effect in mouse skinpainting studies, two possibilities were proposed: A PAH whose tumorigenicity was equivalent to that of B[a]P was present at a substantially higher level (25 to 50 times) than B[a]P or there was an unknown “supercarcinogenic” PAH in CSC, present at a level similar to that of B[a]P but whose activity was 25 to 50 times that of B[a]P [Wright (4282)].

After a year and a half unsuccessful search, attempts to find either the highly tumorigenic PAH present at a high level or the “supercarcinogenic” PAH were discontinued [Wright (4282)]. Neither proposal has resurfaced since the late 1950s.

Since B[a]P in CSC acting alone accounts for less than 2% and the total PAH fraction accounts for less than 3% of the observed biological response in mouse skin-painting studies and no “supercarcinogenic” PAHs is present, additional mechanisms are needed to explain the biological effect: The mechanisms of promotion and cocarcinogenesis of tobacco smoke components (phenols, etc.) may explain the observed effect in skin-painting studies with CSC.

The promoting/cocarcinogenic effect of phenols on PAH tumorigenicity was offset by the following: • Removal of the low-molecular weight phenols by selective filtration of smoke “does not change significantly the biological activity of the resulting condensate.” [Hecht et al. (1582, 1583)]. • Phenol inhibited the tumorigenicity of PAHs such as B[a]P [Van Duuren et al. (4029, 4035)]. • Inclusion of known initiators, promoters, and cocarcinogens in tobacco smoke in the calculation explained less than 5% of the observed biological effect in skin-painting studies.

Wynder and Hoffmann (4317) reported that doubling the level of tumorigenic 17 PAHs in CSC produces “a statistically significant increase in tumor yield.”

The following contradictory evidence was reported: Increasing the B[a]P level in CSC by a factor of 10 produced no increase in the tumorigenicity of CSC [Roe (3310, 3311)]. Increasing the level of B[a]P by a factor of 30 produced no increase in the tumorigenicity of the CSC in mouse skin-painting studies [Lazar et al. (2320)]. (Continued)

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Table XXVI-2 (Continued) The Polycyclic Aromatic Hydrocarbon Paradoxes Assertion

Contradiction

As proposed many times by Wynder, Hoffmann, and their colleagues (1766, 4304, 4317, 4319, 4330, 4355), the B[a]P level in CSC is an “indicator” (or “marker”) of the following: • The levels of the tetracyclic and higher PAHs, particularly those that are tumorigenic. • The tumorigenicity of the cigarette smoke condensate in mouse skin-painting studies.

Ample evidence indicated these premises are invalid: • No significant correlation between levels of B[a]P and other PAHs in pyrolysates from pyrolysis studies [Lam (2255, 2257)]. • Contradictory data provided from the studies of Wynder et al. (4355, 4356), Campbell and Lindsey (583), and Severson et al. (3616). • No significant correlation between levels of B[a]P and chrysene as reported by Rodgman and Cook (3269) or B[a]P and B[a]A [Gori (1329, 1330, 1332, 1333) in cigarette smoking studies. • No significant correlation between tumorigenicity of over 130 test and reference CSCs to mouse skin and their B[a]P and/or B[a]A content [Gori (1329, 1330, 1332, 1333), NCI (2683)]. • In non-CSC-related studies, Warshawsky et al. (26A180) found in their study of the carcinogenic potential of mixtures that the carcinogenic “activity of a mixture cannot be accounted for by the level of benzo[a]pyrene present.”

Tumorigenicity of PAHs, e.g., B[a]P, is inhibited by representative hydrocarbons (C31H64 and C35H72) in the saturated hydrocarbon (SHC) fraction of CSC at SHC:B[a]P ratios much less than that found in CSC [4314, see p. 370 in (4332)].

Inhibitors and anticarcinogens more potent in their effect against PAHs than the saturated hydrocarbon fraction in mouse skin carcinogenesis were identified in CSC (phytosterols, a-tocopherol, duvanediols, D-limonene): Their concentrations relative to that of the PAHs are far in excess of that required to elicit anticarcinogenesis.

Reports of the presence of DMB[a]A in MSS CSC [Pietzsch (2962), Kröller (2191)] were criticized because “the formation of a dialkylated benz[a]anthracene during pyrolysis appears questionable.” [Cook (796), Wynder and Hoffmann (4332)].

Snook et al. (3756, 3757) reported identification of numerous alkyl-, dialkyl-, and multialkyl-B[a]As in CSC. Subsequent research indicated a host of mono- to pentaalkyl-PAHs in the CSC. Their major precursors were tobacco terpenoid compounds, e.g., solanesol, neophytadiene.

Report of presence of 1,2-dihydro-3-methylbenz[j]aceanthrylene (3-methylcholanthrene) in CSC [Kröller (2191)] was criticized by Wynder and Hoffmann (4332):

Several benzo[a]cyclopentanthracenes, structurally similar to 1,2-dihydro-3methylbenz[j]aceanthrylene (3-methylcholanthrene, a methylbenzo[a]cyclopent[fg] anthracene) have been identified in CSC: These included an unmethylated benzocyclopentanthracenes, originally reported erroneously as 1,2-dihydrobenz[j] aceanthrylene (cholanthrene) by Rodgman and Cook (3273), 2,3-dihydro-1H-benzo[a] cyclopent[h]anthracene and 9,10-dihydro-9H-benzo[a]cyclopent[j]anthracene [Bonnet and Neukomm (394, 397-399), Ahlmann (39), Bonnet (392), Pyriki (3033), Rodgman and Cook (3273)].

Since this carcinogenic hydrocarbon has not yet been found in any other combustion product, it remains a doubtful assumption that it is present in tobacco smoke.

Dibenzo[a,l]pyrene (dibenzo[def,p]chrysene) is present in CSC and the pyrolysate from saturated tobacco hydrocarbons [Wynder et al. (4355)]. It was identified on the basis of agreement between spectral data for the isolate and those published for a synthetic PAH [Lyons and Johnston (2430), Lyons (2427, 2428), Wynder and Wright (4354), Rodgman and Cook (3273), Pyriki (3033), Bonnet and Neukomm (398, 399)].

Lavit-Lamy and Buu-Hoï (2314) demonstrated that the synthetic PAH originally defined as dibenzo[a,l]pyrene (dibenzo[def,p]chrysene) and spectrally identical with the tobacco smoke isolate was actually dibenz[a,e]aceanthrylene (dibenzo[a,e] fluoranthene), a fact accepted by Hoffmann and Wynder (1798). Dibenzo[def,p] chrysene (dibenzo[a,l]pyrene) was subsequently identified in tobacco smoke by Snook et al. (3756), but no quantitative data were reported. In citations of dibenzo[a,l]pyrene as a “tumorigenic agents in tobacco smoke,” Hoffmann and his coauthors (1727, 1740, 1741, 1743, 1744, 1773), IARC (1869, 1870), and EPA (1148) indicated only that it was “present.” Whether its “presence” was based on the erroneous dibenzo[a,l]pyrene reports from the 1950s or the authentic dibenzo[a,l]pyrene report of Snook et al. (3756) is unclear.

Addition of nitrate to the tobacco blend significantly reduced MSS yields of “tar,” PAHs, and phenols. The odd-electron compound NO generated during the smoking process interrupted the free radical mechanism of formation of PAHs [Hoffmann and Wynder (1797)]. The % tumor-bearing animals (%TBA) of the resulting CSC was also reduced by about 80%. On the basis of these results, nitrate addition or use of high-nitrate tobaccos was proposed.

Reductions in these deliveries were confirmed (3246, 3286), but they were less than those originally proposed. In fact, in the first NCI-TWG study (1329), doubling the nitrate level produced the following changes: “Tar”, -7%; phenanthrene, -9%; B[a]P, +23%; B[a]A, -17%; phenol, -10%; nitric oxide; +111%. Doubling the nitrate level decreased the %TBA by about 20%. Later data showed that adding nitrate increased volatile NNAs and tobacco-specific N-nitrosamines (TSNAs) in smoke. Nitrate removal or use of low-nitrate tobaccos was proposed (Brunnemann and Hoffmann (480). Hoffmann and colleagues included NNAs and TSNAs in their list of tumorigens or carcinogens in tobacco smoke.

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Table XXVI-2 (Continued) The Polycyclic Aromatic Hydrocarbon Paradoxes Assertion

Contradiction

According to Hoffmann and Wynder, increasing the number of cuts/inch (decreasing the cut width) for the tobacco filler reduces the delivery of CSC and B[a]P (1793).

The 1963 Hoffmann-Wynder findings were not confirmed either at RJRT or in the NCI-TWG study on the first set of experimental cigarettes [Gori (1329)]. In the latter study, the B[a]P and B[a]A yield for the normal filler cut (32 cpi) were less than those for the coarse (20 cpi) and fine (60 cpi) cuts.

PAHs are removed selectively by filters treated with reagents (chloranil, picric acid, 2,4,7-trinitrofluorenone) that form stable complexes with individual PAHs [Szent-Gyorgi (3847)].

Complexing reagents such as chloranil or 2,4,7-trinitrofluorenone did not selectively reduce MSS yields of individual PAHs [Rodgman and Cook, (3275)]. The complexing agent is unable to react with the nonvolatile individual PAHs in the milieu of thousands of compounds in the particles of the smoke aerosol.

Because of the nature of the cigarette smoke aerosol, Wynder and Hoffmann (4311) considered selective filtration of a specific smoke component or class of smoke components such to be an “impossibility.” However, the next year, they reversed their view, noting that selective filtration is not “impossible.” [Wynder and Hoffmann (4314)].

Wynder and Hoffmann (4314) reversed their view on the impossibility of selective filtration when they found that relatively volatile smoke components, e.g., low molecular weight phenols, are selectively removed from the MSS by filters incorporating certain plasticizers such as triacetin [cf. Laurene et al. (2312)]. Some years later, the same phenomenon was observed with volatile NNAs [Fredrickson (1236), Brunnemann et al. (514)].

Single compound pyrolysis at 800 °C in an inert atmosphere (N2 or He) is equivalent to the conditions existing in a smoked cigarette [Wynder and Hoffmann (4319, 4332)]. This proposal was an attempt to justify drawing conclusions on PAHs in MSS on the basis of pyrolysis data.

On the basis of numerous laboratory data, this premise was criticized by several investigators [Bell et al. (248), Benner et al. (276, 277), Schlotzhauer and Schmeltz (3466, 3467), Chortyk and Schlotzhauer (722), Baker (163, 166, 167, 171a, 171b), Baker and Robinson (174d)]. Proponents of the equivalence of inert-atmosphere pyrolysis of a tobacco component and its behavior in a burning cigarette during the smoking process misinterpreted one set of data and disregarded another: The atmosphere immediately behind the burning coal is oxygen-deficient compared to the oxygen level of the air entering the cigarette at the lit end and the smoke exiting the cigarette at the mouthend but it is not oxygen-free. The oxygen level in the tobacco rod a short distance (1-2 mm) behind the tobacco rod-fire cone interface is influenced by diluting air entering the tobacco rod through the cigarette paper and this diluting air increases as the cigarette paper porosity increases. The ultimate contradiction was provided from the laboratory of the original claimants. Schmeltz et al. (3512) reported that the fate of radiolabeled nicotine on pyrolysis was entirely different from its fate in the smoking process: These results suggest to us that pyrolysis experiments may be of limited value for establishing the fate of nicotine and possibly other tobacco components in a burning cigarette.

Severson et al. (1979) describe “the pyrolytic conditions that yielded [PAH] profiles of tobacco pyrolyzates that could be correlated with [cigarette smoke condensate] profiles…”

The anticipated correlation was not attained: When the tobacco, a tobacco extract, and the residual extracted tobacco were pyrolyzed, neither the amounts obtained for the individual PAHs other than B[a]P, the phenols, nor the acids (volatile or nonvolatile) in the tobacco pyrolysate matched the totals of the amounts in the extract pyrolysate plus the amounts in the residual tobacco pyrolysate. For the individual PAHs (except for B[a]P) and the acids, the totals of the amounts from the extract pyrolysate plus residue pyrolysate were higher than the amounts from the tobacco pyrolysate. For the individual phenols, the opposite was the case: The totals were less!

Between the early 1950s and 1984, literally hundreds of articles were published on PAHs in tobacco smoke with particular emphasis on the tumorigenicity of many of them (3262, 3306a, 3306b, 3307, 3713, 3714).

Despite the many published articles prior to 1984 on PAHs in tobacco smoke, none of the authors contributing to the Searle-edited over 1400-page American Chemical Society’s monograph on chemical carcinogens (3568) mentioned any of the tumorigenic PAHs reported in cigarette smoke.

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The Chemical Components of Tobacco and Tobacco Smoke

early 1960s when Van Duuren et al. (4027) reported their findings on aza-arenes in cigarette MSS. The listing of single delivery values rather than a range for dibenz[a,h]acridine (0.1 ng/cigarette) and 7H-dibenzo[c,g] carbazole (0.7 ng/cigarette) indicates the MSS yields cited are those reported from a single study, which appears to be that of Van Duuren et al. (4027). Wynder and Hoffmann (4319, 4332) cited their own unpublished 1963 findings [Candeli et al. (587)] that they could not detect dibenz[a,h]acridine in cigarette MSS. Such findings were never published in a peer-reviewed journal. Thus, the upper limit (10 ng/cigarette) of the range for MSS yield of dibenz[a,j]acridine is that reported by Hoffmann, co-author of all but one of the lists in Table XXVI-1. Single MSS yields for dibenz[a,h]acridine and 7Hdibenzo[c,g]carbazole in MSS based on a cigarette manufactured in 1959–1960 or 1963 are hardly representative of more recently manufactured cigarettes. It is well recognized that a variety of cigarette design technologies has progressively reduced the sales-weighted average mainstream TPM by almost 70% from 40 mg/cigarette in the early 1950s to less than 12 mg/cigarette currently. At the same time that the reduction of delivery of mainstream TPM was accomplished, the composition of the MSS was also altered. For example, for mainstream TPM, the B[a]P content—expressed as ng B[a]P/mg TPM—has decreased about 33% (from 1.2 ng/mg

TPM to 0.8 ng/mg TPM) during the same time period. The 1979 U.S. Surgeon General’s report (4005) summarized the B[a]P data for a commercial cigarette sold in the United States from 1954 to 1979. In addition to changes in the composition of mainstream TPM, changes in mainstream vaporphase composition also occurred. Nicotine and the tobacco proteins and amino acids are proposed as the major precursors of aza-arenes [Chortyk and Schlotzhauer (722)]. Thus, the decrease in cigarette nicotine content and delivery since 1960 should certainly influence the pyrogenesis of the dibenzacridines and dibenzocarbazole during the tobacco smoking process. The levels of nicotine in U.S. cigarette tobacco blends (and MSS) decreased on average more than 40% between 1960 and the late 1980s. In addition, inconsistencies among numerous isolation studies raise serious questions about the actual presence of these three aza-arenes in the MSS (or SSS) from cigarettes manufactured after the mid-1960s. Results from German, Japanese, and American groups of investigators on their search for dibenz[a,h]acridine {I}, dibenz[a,j]acridine {II}, and 7H-dibenzo[c,g]carbazole {III} in mainstream CSC and/ or nicotine pyrolysates are summarized in Table XXVI-3. Only Van Duuren et al. (4027) in their published report and Candeli et al. (587) in their unpublished report have detected any of these three aza-arenes in cigarette MSS!

Table XXVI-3 Dibenz[a,h]Acridine {I}, Dibenz[a,j]Acridine {II}, and 7H-Dibenzo[c,g]Carbazole {III} in Nicotine Pyrolysates (Pyr) and Mainstream Cigarette Smoke Condensate (CSC) Dibenz[a,h]Acridine

Dibenz[a,j]Acridine

7H-Dibenzo[c,g]Carbazole

Investigators

Pyr

CSC

Pyr

CSC

Pyr

CSC

Van Duuren et al. (4027) Candeli et al. (587), Wynder and Hoffmann (4319, 4332) Kaburaki et al. (2006) Schmeltz et al. (3499) Schmeltz et al. (3512) Snook (3733) Snook et al. (3750) Grimmer et al. (1409) Kamata et al. (2021) Sasaki and Moldoveanu (3414) Rustemeier et al. (3370)

yes NE

yes no

yes NE

yes yes

no NE

yes NE

no no no NE NE NE NE NE NE

NE NE no no no no no no no

no no no NE NE NE NE NE NE

NE NE no no no no no no yes

NE no no NE NE NE NE NE NE

NE NE no no no no NE NE NE

yes = Compound identified. no = Compound not found or identified. NE = Substrate not examined for compound in question. Examination of these results indicates that Van Duuren et al. (4027) reported the identification of the three N-heterocyclic compounds {I, II, and III} in mainstream CSC and two of them {I and II} in a nicotine pyrolysate; whereas, Candeli et al. (587) failed to identify {I} but did identify {II} in mainstream CSC. The 1963 Candeli et al. findings on {II} in mainstream CSC were not confirmed in 1979 by investigators (3512) from the same laboratory: Hoffmann participated in both the 1963 and 1979 studies. Two studies (3499, 3512) confirmed the 1960 report by Van Duuren et al. that 7H-dibenzo[c,g] carbazole {III} was not present in a nicotine pyrolysate.

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Examination of the results summarized in Table XXVI-3 indicates that Van Duuren et al. (4027) reported the identification of the three aza-arenes in mainstream CSC and two of them, {I} and {II}, in a nicotine pyrolysate. However, Candeli et al. (587) failed to identify {I} but did identify {II} in mainstream CSC. The Candeli et al. findings reported in 1963 on {II} in mainstream CSC were not confirmed in 1979 by investigators from the same laboratory [Schmeltz et al. (3512)]. Two later studies (3499, 3512) confirmed the 1960 finding by Van Duuren et al. that 7H-dibenzo[c,g]carbazole was not present in a nicotine pyrolysate. Examination of the detailed chromatograms presented in a study on aza-arenes in MSS and SSS by Grimmer et al. (1409) indicates the presence of several benzacridines (benz[a]acridine, benz[c]acridine). However, no gas chromatographic peaks corresponding to standard dibenz[a,h]acridine and dibenz[a,j]acridine peaks are visible in the chromatograms of the aza-arene fraction from either the MSS or SSS. The failures by numerous talented research groups (Table XXVI-3) to detect the two dibenzacridines, {I} and {II}, in tobacco smoke cannot be attributed to difficulties or problems in the analytical procedures. Motohashi et al. (26A113) reviewed the analytical procedures that enabled investigators to identify several benzacridines and their homologs plus dibenz[a,h]acridine and dibenz[a,j]acridine in a variety of environmental samples (urban air, gasoline engine exhaust, Diesel engine exhaust, street dust, and sediment from lake, river, and salt-water sources). Motohashi et al. (26A113) also reviewed in some detail the reports by Schmeltz et al. (3499), Snook et al. (3750), Grimmer et al. (1409), and Kamata et al. (2021) on the identification of various benzacridines in tobacco smoke, but they did not mention the reported identification of dibenz[a,h]acridine and dibenz[a,j]acridine in MSS by Van Duuren et al. (4027). In summary, the situation with regard to the four azaarenes considered to be significant “tumorigens” in tobacco smoke by Hoffmann and his colleagues, OSHA (1994), and/ or EPA (which relied on the 1990 Hoffmann-Hecht list) is: • OSHA did not list quinoline as a significant tumorigen whereas EPA did. • Only one laboratory, that of Van Duuren, reported the presence of dibenz[a,h]acridine, dibenz[a,j] acridine, 7H-dibenzo[c,g]carbazole, listed in Table XXVI-1 as tumorigens in tobacco smoke. • One other laboratory reported the presence of dibenz[a,j]acridine in MSS but not the other two aza-arenes [Candeli et al. (587), see Wynder and Hoffmann (4319, 4332)]. Candeli et al. reported the MSS yield for dibenz[a,j]acridine to be roughly four times that reported by Van Duuren et al. (4027). This disparity in per cigarette MSS yield should have triggered additional research on its presence and level in MSS. However, the 1963 finding by Candeli et al. has never appeared in a peer-reviewed journal.

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• Failure to detect the three aza-arenes dibenz[a,h] acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g] carbazole in cigarette MSS and/or in nicotine pyrolysates was reported in at least nine studies conducted periodically between 1970 and 2002 (Table XXVI-3). • In comparable tumorigenicity studies, the azaarenes are much less tumorigenic to mouse skin than their corresponding PAH analogs and much less tumorigenic than B[a]P [Barry et al. (194)]. The MSS yields of the three aza-arenes listed by OSHA and EPA, if they are present at all in MSS, are much less than that of B[a]P. Even when the repeated failure to confirm their presence in tobacco smoke is ignored, the combination of their significantly lower levels vs. that of B[a]P of the three aza-arenes in cigarette MSS plus their significantly lower tumorigenicity in the mouse skin-painting bioassay raises serious questions about their inclusion in a table listing the “significant tumorigens in tobacco smoke.” XXVI.A.2.b N-Nitrosamines Hoffmann and Hecht (1727) did not acknowledge that the MSS yields listed for both the volatile N-nitrosamines (NNAs) and the tobacco-specific N-nitrosamines (TSNAs) could be incorrect (and high) because of the artifactual formation of both types of NNAs during MSS (and SSS) collection for analysis as reported by Caldwell and Conner (573). EPA and OSHA accepted without question the mainstream volatile NNA and TSNA yields tabulated by Hoffmann and Hecht (1727) and cited by the U.S. Surgeon General in his 1989 report (4012). The artifactual formation of NNAs during the collection and analysis of MSS and SSS has been noted many times over the years and it has not been limited to the determination of NNAs in cigarette smoke. A similar problem was noted with the determination of NNAs in foodstuffs. Neurath et al. (2750) were one of the earliest groups of investigators to discuss this problem in cigarette smoke. More recently, Brunnemann et al. (457), from their study of the levels of NNAs in MSS and SSS, reported lower levels than previously reported for volatile NNAs in MSS, attributing the lower levels to the avoidance of artifactual formation of N-nitrosamines during smoke collection and analysis. They wrote: In fact, several of the cigarettes which were machine smoked earlier and analyzed without precautions, when smoked by us under the same conditions but with precautions, yielded 25 to 100% lower values for DMN [N-nitrosodimethylamine] and NPY [N-nitrosopyrrolidine] for the mainstream smoke. The nitrate content of the tobacco appears to be a determining factor for the concentration of volatile nitrosamines in the smoke. Selective removal of these nitrosamines does occur with cellulose acetate filter tips but not with charcoal filter tips.

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Guerin et al. [see p. 236 in (1445)], in their review of NNAs in ETS commented on four ETS-related studies, those of Brunnemann et al. (457), Stehlik et al. (3812), Matsushita and Mori (2495), and Klus et al. (2134a). Guerin et al. summarized the results on the determination of NNAs in natural and artificial ETS environments: The concentration of nitrosodimethylamine in commonly encountered ETS-contaminated indoor air is likely to range from <10–40 ng/m3. Nitrosodiethylamine and nitrosopyrrolidine are likely to be present at similar but lower concentrations. Extrapolating from studies of artificial environments suggest NNN and NNK concentrations in common environments will range from <1–3 ng/m3.

They also noted that occasionally, N-nitrosodimethylamine (NDMA) concentrations may show excursions to 100 ng/m3 or more.

The Chemical Components of Tobacco and Tobacco Smoke

It was noted previously (Table XXVI-1) that many claims about PAHs in tobacco smoke, particularly those demonstrated to be tumorigenic to the skin of rodents, were subsequently demonstrated to be either incorrect or equivocal. However, the points of contention about NNAs in tobacco smoke are fewer than the number listed for tobacco smoke PAHs (see Table XXVI-4). XXVI.A.2.c N-Heterocyclic Amines While many of the N-heterocyclic amine mutagens are present in tobacco smoke, the extensive research on this class of compounds was initiated and extended because of their presence in many foodstuffs consumed by many people. Table XXVI-5 summarizes some details of these N-heterocyclic amines in tobacco smoke.

Table XXVI-4 N-Nitrosamines in Tobacco Smoke Assertion

Contradiction

Druckrey and Preussmann (1057) proposed that conditions were appropriate (presence of nitrogen oxides, water, and secondary amines, pH < 7.0) in a burning cigarette for pyrogenesis of NNAs such as N-nitrosodimethylamine (NDMA). Boyland et al. (422, 423) proposed that the presence in tobacco smoke of nornicotine and anabasine, nitrogen oxides, and water made it highly likely that N’-nitrosonornicotine (NNN) and N’-nitrosoanabasine (NAB) would be formed. Serfontein and Hurter (3595, 3597) reported the identification of NNAs in cigarette MSS.

First claims by Serfontein and Hurter (3595, 3597) of identification of NNAs in cigarette MSS were challenged with counterclaims that NNAs were artifactually produced during smoke generation, collection, and analysis [cf. Neurath et al. (2751)]. Neurath et al. (2751) reported the presence of an NNA but subsequently discovered the identified compound was produced artifactually during the smoke processing.

Since volatile NNAs and TSNAs occur in tobacco, a part of the NNAs in cigarette MSS is a result of direct transfer of NNAs from tobacco to smoke, the remainder results from formation and transport during the smoking process [Adams et al. (29)]. For 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK), the transfer from tobacco to smoke ranges from 6.9 to 11.0% of the amount in the tobacco; this represents about 30% of the 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK) in MSS. The remainder in MSS is formed during the smoking process [Hoffmann et al. (1734), Hecht et al. (564)].

The premise of the pyrogenesis of NNN and NNK during the cigarette smoking process was challenged by Fischer et al. (1193, 1199) who reported that these compounds occur in cigarette MSS only by transfer from the tobacco rod.

The problem of artifactual formation of NNAs has persisted from the mid-1960s to the present [Neurath et al. (2751), Fredrickson (1236), Krull et al. (26A77), Eisenbrand et al. (26A27), Caldwell and Conner (573)]. Continual improvement in smoke collection and analytical procedures has progressively reduced the analytical error. TSNAs in CSC have little or no influence on the host response in skin-painting studies. Little of the volatile NNAs remain in the CSC after collection and preparation for the skin-painting bioassay. The only NNAs to consistently elicit a positive response at the application site in skin-painting studies are the alkyl-N-nitrosourethanes, none of which has been identified in tobacco or tobacco smoke to date.

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Table XXVI-4 (continued) N-Nitrosamines in Tobacco Smoke Assertion

Contradiction

Hundreds of rodent skin-painting studies with CSC and its fractions have been conducted since the first successful production of carcinoma in mice painted with CSC [see (4319, 4332 and references cited), Gori (1329, 1330, 1332, 1333), NCI (2683)]. Even in the massive NCI decade-long study, no attempt was made to correlate NNA content with bioassay results. It was assumed, from studies with individual NNAs, that they had little if any influence on CSC tumorigenicity to mouse skin. Millions of dollars and thousands of hours expended since 1953 in conducting bioassays – particularly mouse skin-painting studies – did not adequately define the total tumorigenicity of CSC in laboratory animals. Precursors of NNAs in both tobacco and tobacco smoke are the proteins and amino acids (plus nitrate) for the volatile NNAs [Brunnemann et al. (481, 482), Hoffmann et al. (1694)] and nicotine and nicotine-related alkaloids (plus nitrate) for the TSNAs [Boyland et al. (422, 423), Rathkamp et al. (3080), Hecht et al. (1563, 1565)]. The levels of NNAs in tobacco and its smoke parallel the tobacco nitrate level [Morie and Sloan (2635), Hecht et al. (1576, 1578), Tso et al. (3985)]. Removal of lipophilic PAH precursors from tobacco by solvent extraction reduces the PAH yield in MSS and the tumorigenicity (mouse skin-painting) of the CSC [Wynder (4294), Wright (4281), Wynder et al. (4355, 4356)]. This led to their recommendations to remove lipophilic components from tobacco. Confirmation of the reduced levels of PAHs in MSS from cigarettes fabricated with organic solvent-extracted tobaccos was provided by Rodgman (3241, 3242, 3246) and Rodgman and Cook (3286).

Personnel from Wynder’s laboratory subsequently recommended the addition of lipophilic compounds, e.g., n-hentriacontane, to tobacco [Brunnemann and Hoffmann (480)] to reduce the generation during the smoking process of nitrate-derived nitrogen oxide which was postulated as a reactant in the formation of NNAs.

NNA formation in tobacco smoke involves the reaction of methyl nitrite and secondary amines [Rodgman and Cook (3286), Wynder and Hoffmann (4332)]. NNA formation in tobacco smoke involves reaction among secondary amines, nitrogen oxides, and water.

The proposal by Rodgman and by Wynder and Hoffmann (4332) that NNAs arise by reaction of methyl nitrite with secondary amines was shown to be invalid: Methyl nitrite in MSS is zero initially but during the period of tobacco smoke generation, collection, and analysis it is formed artifactually in tobacco smoke [Vilcins and Lephardt (4058)].

Despite the contradictory evidence that precludes the involvement of NNAs either collectively or individually not only in various bioassays with laboratory animals but also in respiratory tract cancer in cigarette smokers, some investigators still maintain that the “tumorigenicity” of cigarette smoke in humans is due to its PAH content and its content of the TSNA, NNK.

Individual NNAs, particularly the TSNAs, have little or no influence on CSC tumorigenicity in the skin-painting bioassay. Millions of dollars and thousands of hours have been expended since 1953 in conducting bioassays that do not adequately define the total tumorigenicity of cigarette smoke condensate in laboratory animals.

In 1991, Hecht and Hoffmann (1571a) wrote:

Inhalation studies with NNAs at levels comparable to those in cigarette MSS were consistently negative. Lung tumor production by exposure to extremely high inhalation levels of NNAs was classified as “equivocal”’ by the Registry of Toxic Effects of Chemical Substances (RTECS) (3095).

Polynuclear aromatic hydrocarbons and NNK [4-(N-methyl-nitrosamino)1-(3-pyridyl)-1-butanone] are the major carcinogens involved in lung cancer induction by cigarette smoke… Hoffmann and Hecht (1727) also noted that NNK had not been tested in laboratory animals for tumorigenicity via inhalation.

Bioassay results in life-time inhalation studies with laboratory animals exposed to various cigarette MSSs show no relationship between tumor production and volatile NNAs and/or TSNA content.

On the basis of the following results, nitrate addition or use of high-nitrate tobaccos was proposed: Addition of nitrate to the tobacco blend significantly reduced MSS yields of “tar”, PAHs, and phenols. NO generated from nitrate during the smoking process interrupted the free-radical mechanism of formation of PAHs [Hoffmann and Wynder (1797, 1798)]. The tumorigenicity (% tumor-bearing animals) of the resulting CSC is also reduced.

Later, data showed that increasing the nitrate increases both the volatile NNAs and TSNAs in MSS. Even though an increased level of TSNAs in mainstream CSC was accompanied by decreased tumorigenicity of the CSC to mouse skin, it was subsequently proposed to remove nitrates from the tobacco or use low-nitrate tobaccos [Brunnemann and Hoffmann (480)]. However, several of the NNAs and TSNAs were included in the lists of “tumorigenic agents in tobacco and tobacco smoke.” (Continued)

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-4 (continued) N-Nitrosamines in Tobacco Smoke Assertion No volatile NNAs is considered a “marker” for other volatile NNAs in MSS; no TSNA is considered a “marker” for other TSNAs, either individual or total, in MSS. No NNAs – either a TSNA, a volatile NNA, or a nonvolatile NNA – is considered a “marker” for the tumorigenicity of CSC in the mouse skin-painting bioassay.

Contradiction As noted previously, as the level of nitrate in tobacco and subsequently the levels of the TSNAs in CSC increase, the tumorigenicity of cigarette smoke condensate to mouse skin decreases [Wynder and Hoffmann (4332), Hoffmann and Wynder (1801, 1802)] but its mutagenicity in the Ames system with Salmonella typhimurium increases [Mizusaki et al. (2569)].

The tumorigenicity of NNAs is inhibited by a variety of tobacco smoke components. For example, D-limonene is anticarcinogenic to NNK [Wattenberg and Coccia (26A187)], ethanol, n-butanol, and tert-butanol are anticarcinogenic to NNN [Waddell and Marlowe (26A178)], indole [Matsumoto et al. (26A97)], cholesterol [Cohen et al. (26A12)], b-sitosterol [Wattenberg (4149b)], 3,4,5-trihydroxybenzoic acid (gallic acid) [Mirvish et al. (2559c)] and its esters [Lo and Stich (26A87), Teel and Castonguay (26A172)] are anticarcinogenic to several of the NNAs in tobacco smoke [cf. Rodgman (3255, 3255a, 3257)]. Tobacco smoke not only contains other compounds such as long-chained fatty acids [Takeda et al. (26A171)] reported to diminish the tumorigenicity of various NNAs but also contains components structurally similar to compounds [(+)-catechin, esculetin, esculin [Liu and Castonguay (26A86), Teel and Castonguay (26A172)] that have been reported to act as antitumorigens and/or antimutagens to NNAs Various tobacco components and other compounds structurally similar to tobacco or smoke components are known to inhibit the N-nitrosation of secondary and tertiary amines to NNAs, a reaction known to occur among the nitrogen oxides, amino compounds, and water during the tobacco smoking process. These inhibitors of NNA formation include several primary amines, ascorbic acid and ascorbates [Mirvish et al. (26A112), Mirvish and Shubik (26A111), Archer et al. (26A03a), Mirvish (2559b, 26A104, 26A105)], indole, the tocopherols (particularly a-tocopherol) [Mergens et al. (26A100), Mirvish, (2559b)], the carotenes, several phenols, and polyphenolic compounds such as chlorogenic acid [cf. Brunnemann and Hoffmann (484, 486)]. NOTE: The effect of these compounds on the N-nitrosation reaction should be differentiated from the effect of some of the same compounds on the tumorigenicity or mutagenicity of various NNAs, e.g., inclusion of ascorbic acid or ascorbate in the reaction substantially reduces the yield of NNAs; administration of ascorbic acid with a tumorigenic NNA such as NNK substantially reduces the tumorigenicity in laboratory animals. Little study has been devoted to determining whether compounds such as those noted above would exert a beneficial effect on MSS properties if added to cigarette tobacco because of diminished N-nitrosation with resulting lower NNA yield or because of the simultaneous delivery of the antitumorigen or anti-mutagen together with the NNAs. Because of the nature of cigarette smoke aerosol, Wynder and Hoffmann (4311) considered selective filtration of a specific smoke component or class of smoke components such as the PAHs to be an “impossibility.”

Selective filtration is not “impossible.” Wynder and Hoffmann (4314) reversed their view on the impossibility of selective filtration when they found that relatively volatile smoke components, e.g., low molecular weight phenols, are selectively removed from MSS by filters incorporating certain plasticizers such as triacetin [cf. Laurene et al. (3211, 2312)]. Some years later, the same phenomenon was observed with volatile NNAs [Fredrickson (1236), Brunnemann et al. (514), Hoffmann et al. (1711)].

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Table XXVI-4 (continued) N-Nitrosamines in Tobacco Smoke Assertion

Contradiction

Guerin et al. (1445) estimated the exposure to NNAs in ETS-filled rooms to be low:                                        

NDMA    < 10-40 ng/m3 NDEA    3 ng/m3 NNN    < 1-3 ng/m3 NNK  < 1-3 ng/m3

Consumers are exposed daily to NNAs from a variety of non-tobacco sources. Many foodstuffs, beverages, and cosmetics contain appreciable levels of some of the volatile NNAs also identified in tobacco and/or tobacco smoke [Magee and Barnes (2442), Sebranek and Cassens (26A142), Preussmann and Eisenbrand (2990), Maga (2438), Bailey and Williams (158a)]. Daily nontobacco exposure (primarily dietary) to NNAs is estimated to exceed 1800 ng/person; daily nontobacco source exposure to NDMA is estimated to exceed 1100 ng/person [Preussmann and Eisenbrand (2990)]. NOTE: These estimates are based on analytical data that may have included values for NNAs artifactually generated during the analytical procedure.

As in the case of the tumorigens whose activity has been shown to be substantially reduced by administration of anticarcinogens [see reviews (3255, 3257, 3300)], Lee et al. (2327c) reported that the mutagenicities (Ames test) of several N-heterocyclic amine mutagens, each of which shows inordinately high mutagenicity, are substantially reduced by CSC. The compounds studied by Lee et al. were 2-amino-6 -methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1), 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ).

Table XXVI-5 Summary of Tumorigenic N-Heterocyclic Amines in Tobacco Smoke IARC Evaluation of Evidence re Tumorigenicity in

Component AaC MeAaC Glu-P-1 Glu-P-2 PhIP IQ MeIQ Trp-P-1 Trp-P-2 a

MSS Level ng/ciga 25-260 2-37 0.37-0.89 0.25-0.88 11-23 0.26 0.28-0.75 b 0.29-0.48 0.82-1.1

Laboratory Animals

Humans

sufficient sufficient sufficient sufficient sufficient sufficient sufficient sufficient sufficient

— — — — possible probable probable — —

See cigarette MSS yields listed in Table XXVI-1 (1740, 1741, 1743, 1744). MeIQ was not listed in (1740, 1741, 1743, 1744) but was listed by Smith et al. (3714)

b 

Table XXVI-6 summarizes the chronology of the studies dealing with the N-heterocyclic amines in tobacco smoke and in commonly consumed foodstuffs.

XXVI.B Anticarcinogens, Inhibitors, and Antimutagens In preceding publications and earlier chapters: (1) the listing of numerous MSS components as significant toxicants was questioned [Rodgman and Green (3300)] and (2) the assertions that ingredients added to cigarette tobacco adversely affect the chemical and biological properties of MSS were shown to be in error [Rodgman (3266)]. In this section, we discuss the identified MSS components that have been shown in bioassays to significantly diminish the adverse biological effects of a number of the listed MSS toxicants. The toxicological properties of a MSS component asserted to adversely affect the smoker have generally been defined in one or more bioassays devoted to the study of the effect of the component administered individually to a host. In most cases other than numerous studies of tumorigenesis, the effect on the toxicological property of a specific compound by other compounds such as those in the complex MSS aerosol has not been studied. The toxicological effect of a specific component in MSS is usually derived by extrapolation from the effect observed in one or more bioassays with the individual component. It is known that the complex MSS aerosol has a significant effect on the chemistry of components in it. For example, (1) the rate of conversion of NO to NO2 is significantly less in the MSS aerosol than in a system comprising only NO and O2 (816) and (2) methyl nitrite reported as an MSS component is not formed during the smoking process but is formed during ageing of the MSS during the analytical procedure (4058). If the chemistry of an MSS aerosol component is altered by the presence of thousands of other aerosol components, then logic dictates that its toxicology will also be altered.

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-6 Chronology of N-Heterocyclic Amine Studies Year

Event

1959

Only one fused ring N-heterocyclic compound was listed by Johnstone and Plimmer (1971) as a tobacco smoke component: the bicyclic compound, quinoline.

1960

Mold et al. (2592) isolated and identified the tricyclic N-heterocyclic 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) from CSC and defined its relationship to its precursor in tobacco, proline.

1961/ 1962

Poindexter and Carpenter (2972) reported the isolation and identification of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9Hpyrido[3,4-b]indole (harman) from CSC. They reported that the yield of total harmans in burley and flue-cured MSSs was between 15 and 20 mg/g of tobacco smoked, values which were 40 to 50 times that of the harmans in the unsmoked tobacco. Since the weight of tobacco in cigarettes sold at that time approximated 1 gram, the yield of these two compounds was about 15-20 mg/cig. Poindexter and Carpenter concluded from experiments with radiolabeled tryptophan that the harmans (found to be radiolabeled in the MSS) were generated pyrogenetically by a reaction between aldehydes (formaldehyde for norharman, acetaldehyde for harman) and tryptophan in tobacco.

1962

Rodgman and Cook (3279) confirmed the presence in cigarette smoke condensate of 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine5,10-dione (pyrocoll) and also reported the identification of indole, carbazole, and several alkylated indoles and carbazoles. Rodgman and Cook (3279) also reviewed the previously reported biological studies on indole, 3-methylindole (skatole), and carbazole: None of the three was reported to be tumorigenic.

1964

Schmeltz et al. (3505) reported 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) as tobacco smoke components. Testa and Testa (3886, 3887) also identified 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) as components of CSC.

1964

The Advisory Committee to the U.S. Surgeon General (3999) briefly discussed only four fused-ring N-heterocyclic compounds in tobacco smoke, quinoline and the two dibenzacridines (dibenz[a,h]acridine, dibenz[a,j]acridine) and the dibenzocarbazole (7H-dibenzo[c,g]carbazole) reported by Van Duuren et al. (4027).

1968

In his review of tobacco smoke composition, Stedman (3797) discussed the identification of tumorigenic N-heterocyclic compounds (dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g]carbazole) reported by Van Duuren et al. (4027) as well as 5H,10Hdipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) reported by Mold et al. (2592) and 9H-pyrido[3,4-b]indole (norharman), 1-methyl-9H-pyrido[3,4-b]indole (harman), and 9H-pyrido[2,3-b]indole reported by Poindexter and Carpenter (2972).

1971/ 1972

Wakeham (4103) noted the reported presence of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) in cigarette MSS and discussed their formation from a reaction product of tryptophan and an aldehyde. As noted by Rodgman (3253a), the structure of the aldehyde reacting with tryptophan ultimately dictated the structure of alkylated norharmans found in CSC.

1974

In addition to 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), Izard et al. (1899) reported the identification of methyl-5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (methylpyrocoll) in CSC.

1974/ In a 1974 in-house RJRT report, a 1975 TCRC presentation, and a 1977 publication on their study of the water-soluble portion of 1975/ CSC, Schumacher et al. (3553) reported the identifications of 1-methyl-9H-pyrido[3,4-b]indole (harman), 5H,10H-dipyrrolo[1, 1977 2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), octahydro-5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (octahydropyrocoll), and 2-ethyl-9H-pyrido[2,3-b]indole. 1977

Sugimura et al. (3829) reported the isolation and identification of the N-heterocyclic amines 3-amino-1,4-dimethyl-5H-pyrido[4,3-b] indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) from tryptophan pyrolysates.

1977

In separate studies, Levitt et al. (2355a) and Nagao et al. (2667b) demonstrated the mutagenicity of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) in the Ames test.

1978

Yamamoto et al. (4365a) reported the isolation and identification of 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1) and 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2) from glutamic acid pyrolysates.

1978/ 1981

Heckman and Best (1587) reported the identification of nearly 270 previously unidentified and over 150 previously identified N-containing components in CSC. These included several components structurally similar to the mutagenic N-heterocyclic amine: 9H-pyrido[2,3-b]indole, 2-methyl-9H-pyrido[2,3-b]indole, 2-(2-methylpropyl)-9H-pyrido[2,3-b]indole, 2-pentyl-9H-pyrido[2,3-b] indole, 1-butyl-9H-pyrido[3,4-b]indole, 9H-1-propenylpyrido[3,4-b]indole, and a partially characterized norharman isomer.

1979

In the 1979 U.S. Surgeon General’s report (4005), the aza-arenes dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g] carbazole, quinoline, and alkylated quinolines in CSC were discussed but not the presence or properties of the mutagenic N-heterocyclic amines identified in tobacco smoke.

1980/ 1981

Yoshida and Matsumoto (4388) and Matsumoto et al. (2492) reported the identification of 2-amino-9H-pyrido[2,3-b]indole (AaC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC) in CSC.

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Table XXVI-6 (continued) Chronology of N-Heterocyclic Amine Studies Year

Event

1981

Matsukura et al. (2491a) demonstrated the tumorigenicity in mice of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). Hosaka et al. (1835a) demonstrated the tumorigenicity in rats of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). In the 1982 Surgeon General report (4010), 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) were classified as “toxic and tumorigenic agents of cigarette smoke” in amounts of 3.2 to 8.1 mg/cig and 1.1 to 3.1 mg/cig, respectively, in cigarette MSS. None of the other mutagenic N-heterocyclic amines in tobacco smoke was discussed. Snook and Chortyk (3739, 3740) reported the MSS yield of 9H-pyrido[3,4-b]indole (norharman) to be 1.2 to 13.4 mg/cig; that for 1-methyl-9H-pyrido[3,4-b]indole (harman) to be 0.3 to 3.8 mg/cig. They found a linear relationship between the yield of cigarette MSS “tar” and the yields of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman). In contrast to the 1962 findings of Poindexter and Carpenter (2972), Snook and Chortyk reported that the MSS yields of these two compounds were not influenced by the tobacco type. Demarini (933) reviewed the studies on the mutagenicity of CSC. He discussed the studies of Yoshida and Matsumoto (4388) and Matsumoto et al. (2492) on the mutagens 2-amino-9H-pyrido[2,3-b]indole (AaC) (80 ng/cig) and 2-amino-3-methyl-9Hpyrido[2,3-b]indole (MeAaC) (7 ng/cig). None of the authors contributing to the Searle-edited 1400-page American Chemical Society’s monograph on chemical carcinogens (3568) mentioned the tumorigenic and mutagenic N-heterocyclic amines reported in cigarette smoke and numerous cooked foods. Ohgaki et al. (2849b) demonstrated the tumorigenicity in mice and Takayama et al. (3862b) demonstrated the tumorigenicity in rats of 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1) and 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2). Takayama et al. (3862c) demonstrated the tumorigenicity in rats of the tobacco smoke component 2-amino-3-methylimidazo[4,5-f] quinoline (IQ). Ohgaki et al. (2849, 2849a) demonstrated the tumorigenicity in mice of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), found in broiled fish, fried beef, beef extract, and CSC. Takayama et al. (3862d) demonstrated the tumorigenicity in rats of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). Tanaka et al. (3865c) demonstrated the tumorigenicity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The IARC (1870) listed several tryptophan-derived tobacco smoke isolates including 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman). The levels in cigarette MSS of these two components were listed as 9.5 to 14.1 and 2.5 to 5.8 mg/cig, respectively. No mention was made of the mutagenic N-heterocyclic amines in CSC or the degree of evidence for their carcinogenicity in animals and humans. Yamashita et al. (4367, 4368) identified and quantitated the following mutagenic N-heterocyclic amines in CSC:

1982

1982/ 1984

1983

1984 1984

1984/ 1985 1985

1985/ 1986

1985/ 1986

1986

2-amino-3-methylimidazo[4,5-f]quinoline (IQ)          0.3 ng/cig 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1)      0.3 ng/cig 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2)       0.2 ng/cig 2-amino-9H-pyrido[2,3-b]indole (AaC)            16.9 ng/cig 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC)       1.6 ng/cig Sugimura (3828c) reviewed the isolation and identification of the mutagenic N-heterocyclic amines s, their high mutagenicity in the Ames test (Salmonella typhimurium) of several of them, their tumorigenicity, and their various sources – including CSC for many. However, Sugimura did write the following about the importance of the mutagenic N-heterocyclic amines as human carcinogens: Taking various factors into consideration, it is probably impractical and not realistic to make risk estimations from the carcinogenicity data on rodents given a single carcinogen. However, for a simple extrapolation of animal data for risk estimation, TD50 values, which are the doses needed to develop cancers in 50% of animals fed on carcinogens [IQ, Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, AaC, and MeAaC] for their life time, have been calculated based on mouse experiments… If we assume the average TD50 value of heterocyclic amines should be about 8mg/kg/day, we can roughly estimate the risk of these carcinogenic heterocyclic amines for human beings. The intake of heterocyclic amines was calculated from available data on their quantities in foods. Apparently the human intake is about 0.0002% times the TD50 obtained from animal data. This means that heterocyclic amines may not be so serious for human cancer development… On the other hand, it is also true that human beings are being exposed to many heterocyclic amines and many other carcinogens with tumor promoters and/or suppressing factors for carcinogenesis. At this moment, it is honest to state that no solid information on the estimation of risk of heterocyclic amines has been obtained in any direction, either positive or negative.

1990

Felton and Knize (1177d) reviewed the results of numerous studies on the mutagenicity and tumorigenicity of the mutagenic N-heterocyclic amines. (Continued)

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1196

The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-6 (continued) Chronology of N-Heterocyclic Amine Studies Year

Event

1994

Lee et al. (2327c) reported that the condensate from cigarette MSS significantly inhibited the mutagenicity of several N-heterocyclic aromatic amines as measured in the Ames assay with Salmonella typhimurium, strain TA 98 in presence of S-9 mix. The mutagenic N-heterocyclic amines tested included: 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1) 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2) 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) The mutagenic activities of these mutagens were suppressed as much as 80% by addition of 50 to 100 mg of CSC per plate.

1997

Hoffmann and Hoffmann (1740) issued a revised list of tumorigenic components in tobacco and tobacco smoke. Their revision of the Hoffmann-Hecht (1727) list included, in addition to several vapor-phase components, eight of the mutagenic N-heterocyclic amines: 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1) 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2) 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) 2-amino-9H-pyrido[2,3-b]indole (AaC) 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC)

Except for tumorigenic effects, little has been reported on the effect of other components in the complex MSS aerosol on the toxicological properties of an individual component. The tumorigenicity of many MSS components has been discussed frequently and in great detail but little has been written about the biological activity of nontumorigenic MSS components reported to counteract the tumorigenicity in laboratory animals of the various tumorigens. Inhibitors of carcinogens or anticarcinogens are compounds that prevent tumor development. Wattenberg (26A186) divided them into three categories based on the time in the carcinogenic process when they are effective. The first category consists of compounds that prevent the formation of carcinogens from precursor substances, for example, ascorbic acid [Mirvish (26A103, 26A104)], tocopherols [Newmark and Mergens (26A116)], and phenols [Newmark and Mergens (26A116), Kuenzi et al. (2216)] which inhibit the formation of nitroso tumorigens from precursor amine and nitrite both in vivo and in vitro. The second category includes “blocking agents,” which inhibit carcinogenesis by preventing carcinogenic compounds from reaching or reacting with critical target sites in the tissues, for example, disulfiram [Wattenberg (26A183)], which inhibits the metabolism of symmetrical dimethylhydrazine to its carcinogenic metabolites [Fiala et al. (26A34)]. The last category of inhibitors, the “suppressing agents,” works by suppressing the expression of neoplasia in cells exposed to a carcinogenic agent. Retinoids are an example of this category.

In 1941, Shear and Leiter (3627) described in detail the many factors affecting tumorigenicity of a chemical. In the mid-1940s, several nontumorigenic aromatic hydrocarbons (benzene, naphthalene, anthracene) administered with B[a] P or dibenz[a,h]anthracene (DB[a,h]A) significantly diminished the B[a]P and DB[a,h]A tumorigenicity (843, 844, 26A17). In recent lists of MSS toxicants, benzene, B[a]P, and DB[a,h]A are listed as significant tumorigens. Reported many times, however, is the noncarcinogenicity of benzene in the solvent-control group when it was used as the solvent for known or suspect tumorigens in skin-painting bioassays (1544, 3665). Steiner and Falk (3814) reported that benz[a]anthracene (B[a]A), categorized as either an extremely weak or an inactive mouse-skin tumorigen (983), significantly diminishes DB[a,h]A tumorigenicity when both DB[a,h]A and B[a]A are administered simultaneously by subcutaneous injection. Despite this and similar bioassay results plus the presence of B[a]A and DB[a,h]A in MSS, both are repeatedly categorized as significant tumorigens in cigarette MSS! Similar inhibition was reported with mixtures of 7,12-dimethylbenz[a] anthracene (DMB[a]A) and several inactive PAHs (1654). In subsequent studies, other nontumorigenic PAHs (phenanthrene, fluoranthene, pyrene) were reported to be effective antitumorigens against B[a]P and DMB[a]A (976, 3686). The nontumorigenic hydrocarbons — benzene, naphthalene, anthracene, phenanthrene, fluoranthene, pyrene — are MSS components, present at per cigarette delivery levels

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

far in excess of those of B[a]P, DB[a,h]A, or any of the other PAHs classified as tobacco smoke toxicants. Much evidence collected since 1932 on the tumorigenicity of PAHs indicates their tumorigenicity is not inherent but depends on specific metabolites that comprise one or more epoxides, dihydroxy compounds, and dihydroxy epoxides. For B[a]P, more than a dozen metabolites are known and they show a range of tumorigenicities (983). Conversion of B[a]P in an inhaled MSS particle to a particular metabolite cannot be a simple process. The more than 500 PAHs in cigarette MSS range from bicyclic to decacyclic structures. In a variety of chemical reactions, the rate of reaction decreases as the molecular weight (number of rings) of the PAH increases. That is, with stoichiometric levels of the PAH and the reactant, bicyclic PAHs react faster than tricyclic PAHs, which in turn react faster than tetracyclic PAHs, etc. Diol, epoxide, and/or diol-epoxide metabolites structurally similar to those described for B[a]P have been reported for many PAHs, for example, naphthalene, anthracene, phenanthrene, B[a]A, benzo[c]phenanthrene, pyrene, chrysene, DB[a,h]A, benzo[b]triphenylene, and DMB[a]A (983). All of these and structurally similar PAHs have been reported by Snook et al. as cigarette MSS components (3756). In a situation, such as the formation of metabolites, where an equimolar mixture of bicyclic through hexacyclic PAHs is present, a pentacyclic aromatic hydrocarbon such as B[a]P will form little of its metabolite(s) compared to the levels formed by a more reactive bicyclic or tricyclic aromatic hydrocarbon. Numerous in vitro studies have demonstrated that inclusion of equimolar quantities of lower molecular weight PAHs, such as phenanthrene or anthracene, inhibits the hydroxylation-epoxidation of B[a]P in hepatic microsomes (26A192). However, PAH data from Hoffmann and Wynder (1798) and Rodgman and Cook (3273) indicate the PAH classes (bicyclic, tricyclic, etc.) in MSS are present at significantly higher molar levels than the pentacyclic PAHs, which include B[a] P and DB[a,h]A. In an in vitro study, the nontumorigenic PAHs pyrene and fluoranthene significantly inhibited the binding of a tumorigenic PAH to calf thymus DNA (enzyme source = mouse skin homogenate) [Slaga and Boutwell (3683), Slaga et al. (3688)]. The in vitro inhibition of the hydroxylation reaction is paralleled by a reduction of in vivo tumorigenicity. Because of their vapor pressure properties, tumorigenic PAHs (B[a]P, DB[a,h]A, etc.) and aza-arenes are present primarily in the MSS particulate phase. Similarly, many of the reported anticarcinogens or inhibitors occur in the MSS particulate phase (3255, 3255a, 3257), for example, high molecular weight alkanes (1099), b-sitosterol and cholesterol (1099), a-tocopherol (3271, 3347), indole (3279), indole3-acetonitrile (1898), duvatrienediols (3361), and PAHs (anthracene, phenanthrene, pyrene, fluoranthene, B[e]P) [see (3255a)]. Despite the fact that the anticarcinogenicity of certain components of tobacco (1171) and tobacco smoke (1824, 1672a) and of tobacco smoke itself (1824) has been known for over four decades, most discussions are directed at them

1197

as toxicants. Seldom is any significant discussion directed at smoke components known to possess anticarcinogenic properties. In a brief 1964 review of the possibility of anticarcinogenic agents in tobacco smoke, Wynder and Hoffmann [see 296, 330 in (4319)] discussed the findings of Steiner and Falk (3814) and Kotin and Falk [see 489–490 in (26A76)] in their studies with potent and weakly tumorigenic PAHs in the subcutaneous injection bioassay as well as their own findings in the mouse skin-painting bioassay (4314, 4316). Ignored was the discussion by Kotin and Falk (26A76) on the anticarcinogenicity vs. B[a]P or vs. DB[a,h]A of nine PAHs (anthracene, benzo[a]fluorene, B[a]A, chrysene, pyrene, B[e]P, benzo[k]fluoranthene, benzo[ghi]fluoranthene, perylene), two aza-arenes (benzo[a]carbazole, benz[c]acridine), and 2-naphthol. All but the two aza-arenes had been identified in cigarette MSS prior to their 1964 review. Subsequently, the aza-arenes noted were identified as MSS components (3339, 3750). Earlier, Wynder and Hoffmann (4311) had reported on MSS components that inhibited the action of a “tumorigen” invariably listed as significant. The finding was an outgrowth of their investigation of the effect of organic solvent extraction of tobacco on the PAH content of MSS. Cigarettes fabricated from the extracted tobacco yielded lower quantities of B[a] P and DB[a,h]A in MSS (3240, 3242, 3262). Skin-painting bioassays with MSS CSCs from the control and extracted tobaccos gave a lower percentage of tumor-bearing animals (% TBA) in the group treated with the extracted tobacco CSC. However, the decrease in % TBA was considerably less than the percent decrease in the level of tumorigenic PAHs in the CSC (4307). One explanation for the difference was that the solvent extracted almost all the alkanes from the tobacco. Thus, the alkanes were absent from the MSS from extractedtobacco cigarettes. This fraction (constituting about 3% of MSS CSC) was reported to significantly inhibit the tumorigenicity of B[a]P (4311, 4314, 26A59). Mouse skin-painting studies with B[a]P and the alkanes n-hentriacontane and n-pentatriacontane at ratios of alkane: B[a]P of 20:1 and 100:1 for each alkane showed they significantly inhibited B[a]P tumorigenicity (4311, 4314, 26A59). The MSS of a cigarette delivering 20 mg of CSC contains about 0.6 mg (600000 ng) of the alkane fraction and 10 ng of B[a]P, an alkane fraction: B[a]P ratio of 60000:1, far in excess of the ratios that produced significant inhibition of B[a]P tumorigenicity [Wynder and Hoffmann (4311, 4319, see pp. 370–371 in (4332)]. Increasing the long-chained alkane level in CSC by 1% from ~3% (C12 to C30) to 4% by addition of crystalline alkanes isolated from CSC resulted in reduction of the tumorigenicity of the CSC from 40% TBA to 24% TBA. This result was dismissed as “not statistically significant.” Wynder and Hoffmann [see 245–247, 628 in (4332)] again discussed anticarcinogenic components of tobacco smoke: Any discussion of as complex a carcinogen as tobacco smoke should at least mention the existence of anticarcinogens. These are substances that reduce or “neutralize” the effect of a carcinogen by reacting with the carcinogen or a carcinogenic metabolite, thereby deactivating it, or by competing

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1198 for reaction with cell constituents, or by interfering with the resorption of a carcinogen … The existence of anticarcinogens, however, must be considered in evaluating any complex mixture such as tobacco smoke condensate … An explanation of the tumorigenic activity of tobacco smoke condensate in terms of single constituents is made more difficult by the presence of substances that may act as anticarcinogens and/ or absorption retarders, especially for tumorigenic agents. It is known that structurally related noncarcinogenic hydrocarbons can inhibit the effect of carcinogenic hydrocarbons … Several investigators have noticed some inhibition of tumor growth by tobacco smoke condensate … [including] Hoffman and Griffin [1672a] … Falk et al. [1174] … [and] Homburger and Treger [1823b] … it should not come as a surprise that a material which has been proved to be carcinogenic may also interfere with tumor development, if not with tumor initiation.

They also noted [see pp. 370–371, 628–629 in (4332)]: An explanation of the tumorigenic activity of tobacco smoke condensate in terms of single constituents is made more difficult by the presence of substances that may act as anticarcinogens and/or absorption retarders, especially for tumorigenic agents. It is known that structurally related noncarcinogenic hydrocarbons can inhibit the effect of carcinogenic hydrocarbons. The same interrelationship may apply to tumor-promoting and nontumor-promoting phenols.

Numerous compounds demonstrated in various bioassays to be highly effective anticarcinogens against many MSS toxicants have been identified in tobacco smoke at per cigarette delivery levels far in excess of those of the alleged tumorigens. Seldom have these anticarcinogenic MSS components been discussed in the numerous reviews of the biological properties of MSS. Even though some of the earliest data on MSS components, for example, the alkanes, that inhibit B[a]P tumorigenicity in the skin-painting bioassay were provided by Wynder and Hoffmann [4314, see 370–371, 628–629 in (4332)], they more often preferred to discuss alkanes as major precursors of tumorigenic PAHs in MSS [see 496–501 in (4332), 1798, 4314, 4342] rather than inhibitors of B[a]P tumorigenicity. MSS components reported to possess significant inhibitory or anticarcinogenic action against various tumorigenic PAHs and NNAs in MSS have been cataloged (3255, 3255a, 3257). Those opposed to cigarette smoking view the complex mixture MSS differently from other complex mixtures such as raw or cooked foods, gasoline and Diesel engine exhausts, factory effluents, etc. [see (1345, 3685)]. Most are reluctant to accept the premise that a nontumorigenic component will offset the tumorigenicity of a tumorigen in animals treated with the complex mixtures CSC, MSS, SSS, or environmental tobacco smoke (ETS) containing the two (1773). Other MSS components may have also influenced the mouse skin-painting results obtained with control tobacco and extracted tobacco CSCs. Hexane extraction of tobacco not only removes alkane inhibitors, thus making impossible their transfer to MSS, but also removes substantial amounts

The Chemical Components of Tobacco and Tobacco Smoke

of b-sitosterol (4356), a-tocopherol (3271, 3347), indole (3279), duvatrienediols (3361, 3389), and D-limonene (765, 2174), thus eliminating or drastically reducing their transfer to MSS during smoking. Subsequently, it was demonstrated that: (1) these smoke components are present by transfer from tobacco to MSS during smoking and to SSS during smolder between puffs or they are generated during smoking; (2) the compounds listed are anticarcinogenic vs. several of the listed tumorigens, for example, PAHs, NNAs, and ethyl carbamate. However, in the 1950s, neither the identity of several of these tobacco or smoke components nor their anticarcinogenicity was known. Comparison of identified MSS components (1373) with lists of compounds (1177a, 3685) that possess inhibitory or anticarcinogenic action in tumorigenesis studies reveals not only that MSS contains many anticarcinogens but also that their MSS levels often exceed those of the components listed as significant tumorigens. Previously, we discussed a few inhibitory and anticarcinogenic MSS components, but they represent a small sample of the MSS components reported to exhibit such properties. From the review by Slaga and DiGiovanni (3685) and other reports (1177a), we compiled a list of MSS (and tobacco) components reported to counteract the tumorigenicity of MSS toxicants (Table XXVI-7A). From the per cigarette MSS deliveries (Table XXVI-7A), it may be calculated that the tumorigenic PAHs listed contribute from 4 to 10 mg/g of mainstream CSC. Nontumorigenic PAHs (naphthalene, anthracene, pyrene, phenanthrene, fluoranthene, benzo[e]pyrene, and benzo[b]triphenylene) total 90 to 180 mg/g of CSC. The anticarcinogenic effect of nontumorigenic PAHs and weakly tumorigenic or nontumorigenic aza-arenes vs. carcinogenic PAHs has been known since the 1940s (3685, 3814). An interesting aspect of Table XXVI-7A is that it includes the dioxins as antitumorigens. Slaga and DiGiovanni (3685) summarized the studies in which dioxins were shown to interfere with the enzyme pathways responsible for tumorigenesis of several of the most potent PAHs. The dioxins were not listed as MSS toxicants in previous tabulations similar to Table XXVI-7A (3255, 3255a, 3257). In fact, only the 2001 Fowles-Bates toxicant list issued since 1990 (1217) included the dioxins even though their presence in MSS was known in 1980 (854). Is the omission of such MSS toxicants related in any way to the fact that dioxins are significant antitumorigens vs. some of the most potent mouse-skin tumorigenic PAHs present in MSS? The 1964 Advisory Committee, in Chapter 6 of its 1964 Report, mentions that twenty-seven nontumorigenic PAHs had been identified in MSS, but none by name [see Chapter 6, p. 55 in (3999)]. Was the omission of their identities related to the fact that several were known to be antitumorigenic to several potent mouse-skin tumorigens such as B[a]P? In Table XXVI-7A are listed only the two n-alkanes (C31 and C35) shown experimentally by Wynder and Hoffmann to reduce the tumorigenicity of B[a]P to mouse skin. However, the alkane listing in Table XXVI-7A could logically be

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Table XXVI-7A Anticarcinogens, Inhibitors, and Antimutagens in Tobacco and Tobacco Smoke

CAS No.

630-04-6 630-07-9 7235-40-7 5989-27-5

Component Hydrocarbons, Aliphatic Saturated aliphatic hydrocarbons b Hentriacontane C31H64 Pentatriacontane C35H72 b,b-Carotene D-Limonene

Approximate Delivery, mg/g MSS CSC

Effective Against

AT, AMa

Representative References to Anticarcinogenicity, Inhibition, and/or Antimutagenicitye

30000

B[a]P

AT

Wynder and Hoffmann (4314)

15–50

DMB[a]A NNK

AT AT

Mathews-Roth (2486a) Wattenberg and Coccia (26A187) Homburger et al. (26A61) Crabtree (843, 844, 26A17) Crabtree (843, 844, 26A17) Crabtree (843, 844, 26A17) DiGiovanni et al. (976) DiGiovanni et al. (976) Slaga et al. (3686) DiGiovanni et al. (976) Slaga et al. (3686) Steiner and Falk (3814) Hoffmann and Wynder [unpublished data cited on pp. 246, 292 in (4332)] DiGiovanni et al. (976) Slaga et al. (3686) Slaga and Boutwell (3683) Slaga et al. (3686)

Hydrocarbons, Aromatic 71-43-2 91-20-3 120-12-7 85-01-8 206-44-0

Benzene Naphthalene Anthracene Phenanthrene Fluoranthene

480–1900 80–160 4–7 2–4 3–4

DB[a,i]P B[a]P, DB[a,h]A B[a]P, DB[a,h]A B[a]P, DB[a,h]A DMB[a]A DMB[a]A

AT AT AT AT AT AT

129-00-0

Pyrene

3–4

DMB[a]A

AT

56-55-3

Benz[a]anthracene

0.8–2.8

DB[a,h]A B[a]P

AT

192-97-2

Benzo[e]pyrene

0.2

DMB[a]A

AT

215-58-7

Benzo[b]triphenylenec

0.05

MC, DB[a,h]A, DMB[a]A

AT

64-17-5

Alcohols Ethanol

8–20

NNN NNN NNN NNN DMB[a]A

AT AM AT AT AT

Waddell and Marlowe (26A178) Farinati et al. (26A32) Waddell and Marlowe (26A178) Waddell and Marlowe (26A178) Saito et al. (3389)

12–25

DMB[a]A

AT

Saito et al. (3389)

DMB[a]A

AT

Shamberger (26A158)

NNA PAH NNA

AT AT

Wattenberg (4149b Yasukawa et al. (26A196) Cohen et al. (26A12)

NNA

AM

Takeda et al. (26A171)

NNA B[a]P

AT AT

B[a]P

AT

Mirvish et al. (2559c) Kallistratos (26A68) Kallistratos and Fasske (26A17) Wattenberg et al. (4149c)

B[a]P

AT

Wattenberg (4149b)

71-36-3 75-65-0 57605-80-8

83-46-5

1-Butanol 2-Propanol, 2-methyl- {tert-butanol} a-4,8,13-Cyclodecatriene-1,3-diol, 1,5,9trimethyl-12-(1-methylethyl)- {a-4,8,13-duvane1,3-diol} b-4,8,13-Cyclodecatriene-1,3-diol, 1,5,9trimethyl-12-(1-methylethyl)-{b-4,8,13-duvane1,3-diol} 2,4,6,8-Nonatetraen-1-ol, 3,7-dimethyl-9-(2,6,6trimethyl-1-cyclohexen-1-yl)-, (all-E)- {retinol} b-Sitosterol

57-88-5

Cholesterol

57-10-3 57-11-4 149-91-7 499-12-7

Acids Acids, long-chained aliphatic Palmitic acid C16H32O2 Stearic acid C18H36O2 Benzoic acid, 3,4,5-trihydroxy- {gallic acid} 1-Propene-1,2,3-tricarboxylic acid {aconitic acid}

57605-81-9

68-26-8

331-39-5 1135-24-6

2-Propenoic acid, 3-(3,4-dihydroxyphenyl){cinnamic acid, 3,4-dihydroxy-} {caffeic acid} 2-Propenoic acid, 3-(3-hydroxy-4methoxyphenyl)- {cinnamic acid, 3-hydroxy-4methoxy-} {ferulic acid}

400–550 120–240

(Continued)

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Table XXVI-7A (continued) Anticarcinogens, Inhibitors, and Antimutagens in Tobacco and Tobacco Smoke

CAS No. 614-60-8

Component

621-82-9

2-Propenoic acid, 3-(2-hydroxyphenyl){o-coumaric acid 2-Propenoic acid, 3-phenyl- {cinnamic acid}

50-81-7

Lactones Ascorbic acid

91-64-5 108-29-2

2H-Benzopyran-2-one {coumarin} 3H-2-Furanone, dihydro-5-methyl- {a-angelica lactone}

108-95-2

Phenols 4H-1-Benzopyran-4-one, 2-(3,4dihydroxyphenyl)-3,5,7-trihydroxy-{quercitin} Cyclohexanecarboxylic acid, 3-[[3-(3,4dihydroxyphenyl)-1-oxo-2-propenyl]oxy]-1,4,5trihydroxy-, [1S-(1a,3b,4a,5a)]- {chlorogenic acid; 3-O-caffeoylquinic acid} Phenol

88-18-6 128-37-0

Phenol, 2-(1,1-dimethylethyl)Phenol, 2,6-bis(1,1-dimethylethyl)-4-methyl-

117-39-5 327-97-9 93451-46-8

150-76-5

Phenol, 4-methoxy-

59-02-9

a-Tocopherol {vitamin E}

305-01-1 520-18-3

120-72-9

771-51-7 83-67-0 58-08-2

Approximate Delivery, mg/g MSS CSC

1000–7000

400–600

2H-1-Benzopyran-2-one, 6,7dihydroxy- {esculetin} 4H-1-Benzopyran-4-one, 3,5,7-trihydroxy-2(4-hydroxyphenyl)- {kaempferol} N-Containing Components Indole

Indole-3-acetonitrile 1H-Purine-2,6-dione, 3,7-dihydro-3,7-dimethyl{theobromine} 1H-Purine-2,6-dione, 3,7-dihydro-1,3,7trimethyl- {caffeine}

54-11-5

Nicotine

494-97-3

Nornicotine

400–600

Effective Against

AT, AMa

Representative References to Anticarcinogenicity, Inhibition, and/or Antimutagenicitye

B[a]P

AT

Wattenberg et al. (4149c)

NPYR, NNN

AT

Chung et al. (26A07, 26A08)

DMB[a]A

AT

B[a]P, DMB[a]A B[a]P

AT AT

DiGiovanni et al. (976) Slaga and Bracken (3684) Wattenberg et al. (26A189) Wattenberg et al. (26A189)

DMB[a]A

AT

Kato et al. (2046a)

B[a]P

AT

Lesca (2351a)

B[a]P NNN. NPYR B[a]P B[a]P, DMB[a]A

AT

NNA CSC NNK

AT AM AT

Van Duuren et al. (4035) Chung et al. (26A07, 26A08) Lam et al. (26A79) Slaga and Bracken (3684) Slaga et al. (3687) Wattenberg (26A182) Clapp et al. (26A11) Clapp et al. (26A10) Wattenberg et al. (4149c) Slaga et al. (3687) Shklar (3655a) Slaga and Bracken (3684) Viaje et al. (4049a) Weerapradist and Shklar (4159c) Thompson (26A175) Rosin (26A136) Teel and Castonguay (26A172)

AHR

AT

Puppala et al. (26A132)

NNA NNN, NPYR NNK B[a]P EC

AT

Matsumoto et al. (26A97) Chung et al. (26A07, 26A08) Chung et al. (26A09) Wattenberg and Loub (26A190) Nomura (26A119)

EC DMB[a]A NNA, NMOR NNK NDMA NNAL NDMA NNAL

AT

NDEA 1,2-DMH B[a]P DMB[a]A MC, DMB[a]A DB[a,i]P 1,2-DMH

AT AT

AT AT

AT AT

AT AM AM AM AM

Nomura (26A119) Perchellet and Boutwell (26A126) Mirvish et al. (2559c) Schüller et al. (26A141) Lee et al. (2327b) Brown et al. (437) Lee et al. (2327b) Brown et al. (437)

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1201

Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

Table XXVI-7A (Continued) Anticarcinogens, Inhibitors, and Antimutagens in Tobacco and Tobacco Smoke

CAS No. 486-56-6

622-78-6 121-79-4 75-15-0 52-90-4

108-31-6 7439-96-5 7782-49-2

Component

Approximate Delivery, mg/g MSS CSC

Cotinine Miscellaneous Components Benzene, (isothiocyanatomethyl)Benzoic acid, 3,4,5-trihydroxy-, propyl ester {propyl gallate} Carbon disulfide Cysteine Dioxin

Maleic anhydride Manganese Selenium Cigarette smoke condensate

Abbreviations B[a]P = benzo[a]pyrene DB[a,h]A = dibenz[a,h]anthracene DB[a,i]P = dibenzo[a,i]pyrene = benzo[rst]pentaphene DMB[a]A = 7,12-dimethylbenz[a]anthracene 1,2-DMH = 1,2-dimethylhydrazine 7-MB[a]A = 7-methylbenz[a]anthracene 12-MB[a]A = 12-methylbenz[a]anthracene 5-MeC = 5-methylchrysene EC = ethyl carbamate Glu-P-1 = 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole Glu-P-2 = 2-aminodipyrido[1,2-a:3’,2’-d]imidazole PhIP = 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine IQ = 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline

Effective Against

AT, AMa

Representative References to Anticarcinogenicity, Inhibition, and/or Antimutagenicitye

NDMA NNAL

AM AM

Lee et al. (2327b) Brown et al. (437)

DMB[a]A NNK

AT AT

1,2-DMH NDMA DMB[a]A, MC, B[a]P, 7-MB[a]A, 12-MB[a]A, 5-MeC, DB[a,h]A PAH, DMB[a]A B[a]P DMB[a]A NNA Glu-P-1, Glu-P-2, Trp-P-1, Trp-P-2, IQ, MeIQd

AT AT AT

Wattenberg (26A184, 26A185) Lo and Stich (26A87) Teel and Castonguay (26A172) Wattenberg and Fiala (26A188) Lo and Stich (26A87) Berry et al. (26A06) Cohen et al. (26A13) DiGiovanni et al. (26A23)

AT AT AT AT AM

Klein (26A74) Sunderman et al. (3836a) Shamberger (26A157) Thompson (26A175) Lee et al. (2327c)

MC = 3-methylcholanthrene = 1,2-dihydro-3-methylbenz[j]aceanthrylene NDMA = N-nitrosodimethylamine NNA = N-nitrosamine NNAL = 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol NNN = N’-nitrosonornicotine NNK = 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone NPYR = N-nitrosopyrrolidine PAH = polycyclic aromatic hydrocarbon AHR = aryl hydrocarbon receptor MeIQ = 2-amino-3,4-dimethyl-3H-imidazo[4,5-f]quinoline Trp-P-1 = 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole Trp-P-2 = 3-amino-1-methyl-5H-pyrido[4,3-b]indole

AT = test for antitumorigenicity; AM = test for antimutagenicity. This fraction consists primarily of the n-, iso- (2-methyl-), and anteiso- (3-methyl-) alkanes from C15 to C40. c Benzo[b]triphenylene was formerly known as dibenz[a,c]anthracene. d Several of the highly mutagenic N-heterocyclic amines identified in cigarette smoke (and foods) by Sugimura and his colleagues (see Chapter XVII.F). a

b

increased because the total alkane fraction consisting of n-, iso-, and anteiso-alkanes reduced the tumorigenicity of B[a] P and presumably all of the alkanes could be involved in the tumorigenicity reduction. The number of identified components in the alkane fraction in tobacco smoke approximates seventy. The complete list of the identified tobacco smoke alkanes appears in Table I.A-10 in Chapter 1. The antitumorigens and antimutagens in Table XXVI-7A are presented in a slightly different way in Table XXVI-7B. Several of the significant PAH, NNA, and N-heterocyclic amine tumorigens or mutagens are listed in the same sequence

as in Table XXVI-1 and the tobacco smoke components that reduce or nullify their tumorigenicity or mutagenicity are listed for each. It is interesting to see how many tobacco smoke components have been reported to inhibit or reduce the potent tumorigenicity of B[a]P (eighteen in all) or DB[a,h] A or DMB[a]A (twenty in all). Here again, only two of the seventy alkanes examined for their inhibition of B[a]P tumorigenicity are included. In Table XXVI-7C, references are listed on various aspects (identification, quantitation, tobacco precursors, biological results, etc.) of the tobacco and tobacco smoke

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Table XXVI-7B Anticarcinogens, Inhibitors, and Antimutagens in Tobacco and Tobacco Smoke Component Affected

Anticarcinogen, Inhibitor, Antimutagen

Polycyclic aromatic hydrocarbons

maleic anhydride b-sitosterol

Benz[j]aceanthrylene, 1,2-dihydro-3-methyl-a

dioxin

a-tocopherol {vitamin E}

Benz[a]anthracene, 7,12-dimethyl- b

ascorbic acid benzene, (isothiocyanatomethyl)benzo[e]pyrene 2H-benzopyran-2-one {coumarin} 4H-1-benzopyran-4-one, 2-(3,4-dihydroxyphenyl)-3,5,7trihydroxy- {quercitin} benzo[b]triphenylene b,b-carotene a-4,8,13-cyclodecatriene-1,3-diol, 1,5,9-trimethyl-12-(1methylethyl) {a-4,8,13-duvane-1,3-diol} b-4,8,13-cyclodecatriene-1,3-diol, 1,5,9-trimethyl-12-(1methylethyl) {b-4,8,13-duvane-1,3-diol} dioxin

fluoranthene maleic anhydride 2,4,6,8-nonatetraen-1-ol, 3,7-dimethyl-9-(2,6,6-trimethyl-1cyclohexen-1-yl)-, (all-E)- {retinol} phenanthrene phenol, 2,6-bis(1,1-dimethylethyl)-4-methyl-

phenol, 4-methoxy1H-purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl- {caffeine}

pyrene selenium a-tocopherol {vitamin E}

Benzo[rst]pentaphene {dibenzo[a,i]pyrene} Benzo[a]pyrene

D-limonene anthracene benz[a]anthracene benzene 2H-benzopyran-2-one {coumarin}

Reference Klein (26A74) Wattenberg (4149b) Yasukawa et al. (26A196) Berry et al. (26A06) Cohen et al. (26A13) DiGiovanni et al. (26A23) Shklar (3655a) Slaga and Bracken (3684) Viaje et al. (4049a) Weerapradist and Shklar (4159c) DiGiovanni et al. (976) Slaga and Bracken (3684) Wattenberg (26A184, 26A185) DiGiovanni et al. (976) Slaga et al. (3686) Wattenberg et al. (26A189) Kato et al. (2046a) Slaga and Boutwell (3683) Slaga et al. (3686) Mathews-Roth (2486a) Saito et al. (3389) Saito et al. (3389) Berry et al. (26A06) Cohen et al. (26A13) DiGiovanni et al. (26A23) DiGiovanni et al. (976) Slaga et al. (3686) Klein (26A74) Shamberger (26A158)

Slaga and Bracken (3684) Slaga et al. (3687) Wattenberg (26A182) Wattenberg et al. (4149c) Slaga et al. (3687) Nomura (26A119) Perchellet and Boutwell (26A126) Mirvish et al. (2559c) DiGiovanni et al. (976) Slaga et al. (3686) Shamberger (26A157) Shklar (3655a) Slaga and Bracken (3684) Viaje et al. (4049a) Weerapradist and Shklar (4159c) Homburger et al. (26A61) Crabtree (843, 844, 26A17) Hoffmann and Wynder [unpublished data cited on pp. 246, 292 in (4332)] Crabtree (843, 844, 26A17) Wattenberg et al. (26A189)

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Table XXVI-7B (Continued) Anticarcinogens, Inhibitors, and Antimutagens in Tobacco and Tobacco Smoke Component Affected

Anticarcinogen, Inhibitor, Antimutagen

Benzo[a]pyrene (cont.)

cyclohexanecarboxylic acid, 3-[[3-(3,4-dihydroxyphenyl)-1oxo-2-propenyl]oxy]-1,4,5-trihydroxy-, [1S-(1a,3b,4a,5a)]- {chlorogenic acid, 3-O-caffeoylquinic acid} dioxin

3H-2-furanone, dihydro-5-methyl- {a-angelica lactone} hentriacontane C31H64 manganese naphthalene pentatriacontane C35H72 phenol phenol, 2-(1,1-dimethylethyl)phenol, 2,6-bis(1,1-dimethylethyl)-4-methyl-

1-propene-1,2,3-tricarboxylic acid {aconitic acid}

Dibenz[a,h]anthracene

2-propenoic acid, 3-(3,4-dihydroxyphenyl)- {cinnamic acid, 3,4-dihydroxy-, caffeic acid} 2-propenoic acid, 3-(3-hydroxy-4-methoxyphenyl){cinnamic acid, 3-hydroxy-4-methoxy-, ferulic acid} 2-propenoic acid, 3-(2-hydroxyphenyl)- {o-coumaric acid} anthracene benz[a]anthracene benzene benzo[b]triphenylene dioxin

naphthalene phenol, 4-methoxyN-Nitrosamines

benzoic acid, 3,4,5-trihydroxy- {gallic acid} cholesterol indole palmitic acid C16H32O2 1H-purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl- {caffeine}

stearic acid C18H36O2 selenium b-sitosterol N-Nitrosodimethylamine

N-Nitrosodiethylamine N-Nitrosopyrrolidine

cotinine cysteine nicotine nornicotine phenol, 2,6-bis(1,1-dimethylethyl)-4-methyl2-propenoic, 3-phenyl- {cinnamic acid} phenol indole

Reference Lesca (2351a)

Berry et al. (26A06) Cohen et al. (26A13) DiGiovanni et al. (26A23) Wattenberg et al. (26A189) Wynder and Hoffmann (4314) Sunderman et al. (3836a) Crabtree (843, 844, 26A17) Wynder and Hoffmann (4314) Van Duuren et al. (4035) Lam et al. (26A79) Slaga and Bracken (3684) Slaga et al. (3687) Wattenberg (26A182) Kallistratos (26A68) Kallistratos and Fasske (26A69) Wattenberg et al. (4149c) Wattenberg (4149b) Wattenberg et al. (4149c) Crabtree (843, 844, 26A17) Steiner and Falk (3814) Crabtree (843, 844, 26A17) Slaga and Boutwell (3683) Slaga et al. (3686) Berry et al. (26A06) Cohen et al. (26A13) DiGiovanni et al. (26A23) Crabtree (843, 844, 26A17) Wattenberg et al. (4149c) Slaga et al. (3687) Mirvish et al. (2559c) Cohen et al. (26A12) Matsumoto et al. (26A97) Takeda et al. (26A171) Nomura (26A119) Perchellet and Boutwell (26A126) Mirvish et al. (2559c) Takeda et al. (26A171) Thompson (26A175) Wattenberg (4149b) Yasukawa et al. (26A196) Lee et al. (2327b) Lo and Stich (26A87) Schüller et al. (26A141) Lee et al. (2327b) Clapp et al. (26A11) Chung et al. (26A07, 26A08) Chung et al. (26A07, 26A08) Chung et al. (26A07, 26A08) (Continued)

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7B (Continued) Anticarcinogens, Inhibitors, and Antimutagens in Tobacco and Tobacco Smoke Component Affected N’-Nitrosonornicotine

4-(N-Methylnitrosamino)-1-(3-pyridyl)-1-butanone

N-Nitrosomorpholine N-Heterocyclic Amines Glu-P-1 Glu-P-2 IQ MeIQ Trp-P-1 Trp-P-2

Anticarcinogen, Inhibitor, Antimutagen 1-butanol ethanol

Reference

2H-1-benzopyran-2-one, 6,7-dihydroxy- {esculetin} indole D-limonene nicotine 1H-purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl- {caffeine}

Waddell and Marlowe (26A178) Waddell and Marlowe (26A178) Farinati et al. (26A32) Chung et al. (26A07, 26A08) Chung et al. (26A07, 26A08) Waddell and Marlowe (26A178) Chung et al. (26A07, 26A08) Lo and Stich (26A87) Teel and Castonguay (26A172) Teel and Castonguay (26A172) Chung et al. (26A09) Wattenberg and Coccia (26A187) Schüller et al. (26A141) Mirvish et al. (2559c)

cigarette smoke condensate cigarette smoke condensate cigarette smoke condensate cigarette smoke condensate cigarette smoke condensate cigarette smoke condensate

Lee et al. (2327c) Lee et al. (2327c) Lee et al. (2327c) Lee et al. (2327c) Lee et al. (2327c) Lee et al. (2327c)

indole phenol 2-propanol, 2-methyl- {tert-butanol} 2-propenoic, 3-phenyl- {cinnamic acid} benzoic acid, 3,4,5-trihydroxy-, propyl ester {propyl gallate}

1,2-Dihydro-3-methylbenz[j]aceanthrylene = 3-methylcholanthrene, regarded as one of the most potent tumorigens to mouse skin known. Although it does not appear in any of the lists in Table XXVI-1 by Hoffmann and his colleagues, it is a tobacco smoke component. b 7,12-Dimethylbenz[a]anthracene  is regarded as one of the most potent tumorigens to mouse skin known. Although it does not appear in any of the lists in Table XXVI-1 by Hoffmann and his colleagues, it is a tobacco smoke component. a 

components listed in Table XXVI-7A as known inhibitors, anticarcinogens, and antimutagens. For the reader’s benefit, the sequence of components in Table XXVI-7C is identical with that in Table XXVI-7A and the CAS nomenclature has been included in each case. In a review of antimutagens and inhibitors of mutagenesis, Ramel et al. (26A133) discussed the many antimutagens found naturally occurring in plants. They did not discuss tobacco specifically but did discuss the natural occurrence of the following antimutagens: a-tocopherol, 2H-1-benzopyran-2-one, 7-hydroxy-2H-1-benzopyran-2-one, and 3-phenyl-2-propenal. All four have been identified as tobacco components; all but 7-hydroxy-2H-1-benzopyran-2-one have been identified in MSS. Lee and Reed (2327d) investigated the antimutagenicity of nicotine vs. N-nitrosodimethylamine (NDMA) and nicotine vs. B[a]P in the Ames test (Salmonella typhimurium TA 100). They observed that nicotine inhibits the mutagenicity of NDMA but not that of B[a]P. Although the mechanism of this antimutagenicity was not elucidated, the report by Murphy and Heilbrun (26A115) on the inhibition of NNN metabolism by nicotine suggests nicotine inhibition of NNA activation may be involved. Lee et al. (2327b) repeated their earlier experiment and not only confirmed the antimutagenic

effect of nicotine on NDMA but also demonstrated the similar activity of nornicotine and cotinine. Brown et al. (437) reported the antimutagenicity of nicotine and cotinine vs. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Lee et al. (2327c) reported that CSC inhibits the mutagenic activity of several N-heterocyclic amines when tested in the Ames assay with Salmonella typhimurium TA 98 in the presence of the S-9 activation system. The mutagenic N-heterocyclic amines tested included Glu-P-1, Glu-P-2, TrpP-1, Trp-P-2, IQ, and MeIQ. These compounds are among the most potent mutagens known (3828c, 3829, 3829a, 4365a, 4357, 4368). Several have also been reported to be tumorigenic in mammalian bioassays (1177d). In one of the first demonstrations of antimutagens in tobacco smoke, Lee et al. (2327c) reported that 50 to 100 mg of CSC per plate suppresses the mutagenic activity of these compounds by as much as 80%. Enzymatic studies indicate that CSC is a potent inhibitor of cytochrome P-450 dependent monooxygenase. Therefore, it appears that CSC exerts its antimutagenicity by inhibiting the P-450 system. Lee et al. (2327c) subsequently reported that fractionation of CSC gave fractions that showed low mutagenicity themselves but were significantly antimutagenic. Only a few of the listed MSS tumorigens have ever been tested for tumorigenicity to lung tissue by exposure of animals

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1205

Table XXVI-7C Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7C (Continued) Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

1207

Table XXVI-7C (Continued) Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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1208

The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7C (Continued) Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

1209

Table XXVI-7C (Continued) Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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1210

The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7C (Continued) Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

1211

Table XXVI-7C (Continued) Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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1212

The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7C (Continued) Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

1213

Table XXVI-7C (Continued) Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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1214

The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7C (Continued) Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

1215

Table XXVI-7C (Continued) Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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1216

The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7C (Continued) Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

1217

Table XXVI-7C (Continued) Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7C (Continued) Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

via inhalation. The results with all but one of the four MSS components (B[a]P, NDMA, NDEA, 210Po), tested via inhalation at dose levels substantially exceeding those in MSS, were rated “equivocal” (3095). Only 210Po, administered via inhalation at massive dose levels to rats, produced squamous cell carcinoma, the lung tumor type similar to that associated statistically with cigarette smoking. However, the U.S. Surgeon General (4005, 4010) and Hoffmann and Hecht (1727) discounted the effect of 210Po in MSS in lung cancer causation in active smokers. From the type of evidence available presently, it is doubtful that many of the toxicants should be included in the various lists. Examination of data and reports on the tobacco smoke components present in one or more of the many lists sustains the premise that it is inappropriate to use such lists as evidence of any relationship between exposure to MSS and lung cancer induction in smokers or exposure to ETS and lung cancer induction in nonsmokers. Several specific components could and should be excluded from the toxicant lists for reasons other than the failure to induce lung tumors via inhalation.

1. By the early 1960s, dibenzo[a,l]pyrene had been reported in MSS by several groups [see account in (3262)]. For its identification, the investigators





relied on a published UV spectrum purportedly that of synthetic dibenzo[a,l]pyrene (dibenzo[def,p] chrysene). However, in 1966 it was demonstrated that the published spectrum was that of an isomer, dibenz[a,e]aceanthrylene (dibenzo[a,e]fluoranthene) (2314). 2. Previously noted was the failure by many research groups between 1963 and 2000 to confirm the presence in MSS of the tumorigenic aza-arenes reported by Van Duuren et al. (4027). Dibenz[a,j] acridine was reported recently by Rustemeier et al. (3370). 3. The precursors of arsenic and NDELA in MSS have been banned from U.S. tobacco agronomy since 1952 and 1981, respectively.

XXVI.B.1 Alternate Exposures to Carcinogens, Tumorigens, and Mutagens Examination of the tumorigens listed in Table XXVI-1 logically leads to the questions: What, if any, are the human exposures to the listed tumorigens other than MSS and/or ETS?

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

Is the exposure to a given tumorigen less, more, or equal to that from cigarette smoke? A detailed account of such alternate exposures requires many pages and tables. Most tumorigens in Table XXVI-1 have many alternate sources. The one obvious exception is the tobacco-specific N-nitrosamines (TSNAs) which, by definition, being tobacco specific, have no alternate. Table XXVI-8 is a brief list, with references, of alternate exposures to the major classes of tumorigens in tobacco smoke. The cited references provide tabulated details of human exposures to them. Subsequent to Table XXVI-8 are discussions and tables in which the alternate exposures to the four major tumorigen classes in tobacco smoke are presented in more detail.

XXVI.B.1.a Alternate Exposures to Polycyclic Aromatic Hydrocarbons Despite the ubiquity of PAHs in modern society, their presence in and their contribution to the alleged hazard of tobacco smoke have been repeatedly emphasized for nearly half a century but seldom are the other many sources and/or levels of exposure to PAHs currently acknowledged as they were in the 1930–1950 period. Daily exposure to PAHs by inhalation (MSS, ETS, air pollutants) may represent only a small part of the total daily exposure; other exposures to PAHs often substantially exceed exposure via inhalation. Exposures to various PAHs are summarized in two different forms in Tables XXVI-9 and XXVI-10. Results from many studies have been reported on the types and levels of PAHs, with particular emphasis on B[a]P, B[a]A, chrysene, benz[e]acephenanthrylene (benzo[b]fluoranthene), benzo[k]fluoranthene, indeno[1,2,3-cd]pyrene, DB[a,h]A, and benzo[ghi]perylene. As noted by Menzie et al. (2533), all of these PAHs have been identified in exhausts or effluents from fossil fuel combustion sources, in soils, sediments, and water, and in a variety of commonly used foodstuffs. Although concern about PAHs in foodstuffs, particularly those arising pyrogenetically during cooking (grilling, broiling, roasting, etc.) predates the major concern over their presence in tobacco smoke, efforts to identify them in foodstuffs have been much less than for tobacco smoke. The number of PAHs identified in tobacco smoke exceeds 500, including several hundred derivatives where the positions of the alkyl groups have not been precisely defined (3757, 3758). PAHs identified in foodstuffs, both cooked and uncooked, number fewer than 150. Whether one considers the overall composition in general or the PAH fraction in particular, no other commercial product has been examined as extensively as tobacco or tobacco smoke. Many PAHs are components of foodstuffs in the average diet (see Tables XXVI-9 and XXVI-10). Except for 5-methylchrysene, PAHs listed in the many reports by Hoffmann and his colleagues (1727, 1740, 1741, 1743, 1744, 1773, 1808) and OSHA (2825) as tobacco and tobacco smoke “tumorigens” have been identified in many foodstuffs. Grasso discussed

Table XXVII-8 Exposures to Tumorigens and Mutagens from Sources Other than Mainstream and Environmental Tobacco Smoke Alternate Exposure

References

Polycyclic Aromatic Hydrocarbons Foodstuffs Bailey and Williams (158a) Grasso (1345) Lijinsky and Shubik (2364a, 2364b) Maga (2438) Neukomm and Bonnet (2715) Vaessen et al. (4014) Waldman et al. (4106) Beverages (coffee, tea, cocoa, etc.) Kuratsune (2237) Kuratsune and Hueper (2238) Maga (2438) Vehicle engine exhaust Grimmer (1399-1402, 1405, 1406a, 1406b) Lyons (2428) Mauderly et al. (2505) Strach (3821) Sawicki et al. (3419b, 3419c) Williams et al. (4247a) Wynder and Hoffmann (4315, 4316) Furnace effluents Mumford et al. (26A114) Aza-arenes Vehicle engine exhaust Furnace effluents N-Nitrosamines Foodstuffs

Beverages (coffee, tea, cocoa, water, etc.) Cosmetics Industrial exposure (rubber, leather, metal, and pharmaceutical industries) N-Heterocyclic Amines Foodstuffs

Beverages (coffee, tea, cocoa, etc.)

Metals Foodstuffs

Grimmer (1407a) Grimmer (1407b) Bailey and Williams (158a) Grasso (1345) Kröller (2205, 2206) Preussmann and Eisenbrand (2990) Preussmann and Eisenbrand (2990) Mitch et al. (26A112a) Preussmann and Eisenbrand (2990) Preussmann and Eisenbrand (2990)

Bailey and Williams (158a) Jägerstad et al. (1916b) Matsumoto et al. (2492) Nagao et al. (2667f) Sugimura (3828b, 3828c, 3828e, 3828f) Sugimura and Nagao (3829b) Sugimura et al. (3829a) Tanaka et al. 3865c) Yasuda et al. (4382a) Aeschbacher and Würzner (38a) Kosugi et al. (2178b) Nagao et al. (2667d, 2667e) Grasso (1345)

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-9 Personal Exposure to Tobacco Smoke Polycyclic Aromatic Hydrocarbons Listed as Tumorigens Exposure Source Fish -Raw -Cooked -Smoked Oysters Mussels Meat -Frankfurters -Hamburgers -Bacon -Ham, smoked -Bologna -Sausage -Beef, broiled -Beef, roasted -Beef, barbecued -Poultry -Cholesterol, heated Dairy Products -Milk -Cheese

B[a]Aa

B[e]A

B[j]F

B[k]F

B[a]P

Chr

Chr, me

DB[a,h]A

NC

DB[b]C

B[rst]P

DB[d]P

IP

× × — × —

× × — — —

— — — — —

× × — — —

× × × × ×

— — — — —

— — — — —

— — — — —

— — — — —

— — — — —

— — — — —

— — — — —

— — — — —

—

—

× — — — — — — — — —

× — — — — — — — — —

× — — — — — — — — —

— — — — — — — — — — —

— — — — — — — — — — —

—

×

— — — — — — — — — — —

—

× × × — — —

— — — — — — — — — —

—

× — — — — — — — — —

× × × × × × × × × × —

—

× — — — — — — — — —

— — — — — — — — — — —

—

× — — —

× — — — — — — — — —

— —

— —

— —

— —

× ×

— —

— —

— —

— —

— —

— —

— —

— —

—

— — — — —

× —

× —

× —

— — — — —

— — — × —

— — — — —

— — — — —

— — — — —

— — — — —

— — —

×

× × ×

— — — — —

× —

Cereals -Puffed corn -Puffed oats -Puffed wheat -Barley malt -Bran Bread -Untoasted -Toasted

× ×

× × × × ×

— —

— —

— —

— —

× ×

— —

— —

— —

— —

— —

— —

— —

— —

Beverages -Tea -Coffee, regular -Coffee, instant -Water -Bourbon -Scotch

— — — — — —

— — — × — —

— — — — — —

— — — — — —

× × × × × ×

— — — — — —

— — — — — —

— — — — — —

— — — — — —

— — — — — —

— — — — — —

— — — — — —

— — — — — —

Fruits, Vegetables -Fresh -Potatoes, cooked -Potatoes, French fried -Endive -Spinach -Soybeans -Kale -Tomatoes -Apples -Prunes

× — — — — — — — — —

— — — — — — — — — —

— — — — — — — — — —

— — — — — — — — — —

× × × × × × × × × ×

— — — — — — — — — —

— — — — — — — — — —

— — — — — — — — — —

— — — — — — — — — —

— — — — — — — — — —

— — — — — — — — — —

— — — — — — — — — —

— — — — — — — — — —

× × ×

— — —

— — —

— — —

× × ×

— — —

— — —

— — —

— — —

— — —

— — —

— — —

— — —

Oils, cooking Coconut oil -Vegetable oil Mayonnaise

×

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

Table XXVI-9 (continued) Personal Exposure to Tobacco Smoke Polycyclic Aromatic Hydrocarbons Listed as Tumorigens Exposure Source

B[a]Aa

B[e]A

B[j]F

B[k]F

B[a]P

Chr

Chr, me

DB[a,h]A

NC

DB[b]C

B[rst]P

DB[d]P

IP

Margarine

×

—

—

—

×

—

—

—

—

—

—

—

—

MSS, SSS, ETS

×

×

×

×

×

×

×

×

×

×

×

×

×

Engine exhausts b, c, d

×

×

×

×

×

×

×

×

—

—

—

—

×

Tars, soots, oils, excluding ETS c

×

×

—

×

×

×

—

×

—

—

—

—

×

Oils, catalytically cracked

—

—

—

—

×

×

×

—

—

—

—

—

—

Vehicle tire carbon blacks

×

—

—

—

×

×

—

—

—

—

—

—

—

Open-fire, coal combustion e

×

×

×

×

×

×

—

×

×

—

×

×

×

Urban atmospheres

×

—

—

—

×

×

×

—

—

—

—

—

—

B[a]A = benz[a]anthracene B[e]A = benz[e]acephenanthrylene = benzo[b]fluoranthene B[j]F = benzo[j]fluoranthene B[k]F = benzo[k]fluoranthene B[a]P = benzo[a]pyrene Chr = chrysene Chr, me = chrysene, 5-methyl-

DB[a,h]A = dibenz[a,h]anthracene NC = naphtho[1,2,3,4-def]chrysene = dibenzo[a,e]pyrene DB[b]C = dibenzo[b,def]chrysene = dibenzo[a,h]pyrene B[rst]P = benzo[rst]pentaphene = dibenzo[a,i]pyrene DB[d]P = dibenzo[def,p]chrysene = dibenzo[a,l]pyrene IP = indeno[1,2,3-cd]pyrene]

The PAHs listed also occur in MSS, SSS, and ETS. Wynder and Hoffmann (4315) c Williams et al. (4247a) d Grimmer et al. (1405) e Mumford et al. (26A114) a

b

the PAHs in foods and their significance [see p. 1213 in (1345)]: The significance of these low levels of PAH carcinogens in food is difficult to assess. Undoubtedly, they are among the most potent carcinogens known, and every effort should be made to reduce their concentration in food. There are no clear indications, however, that they cause human cancer … Furthermore, there are indications that low levels of [benzo[a]pyrene], probably one of the most potent of the PAH found in food, do not produce tumors in experimental animals. The repeated application of 1.25 mg of [benzo[a] pyrene] in acetone to the skin of mice for 68 weeks failed to produce tumors [Roe (3310, 3311)]; dietary intake of 100 ppm of [benzo[a]pyrene] or less also had no effect in mice [Neal and Rigdon (2687].

His comments on the carcinogenicity to humans of PAHs in ingested foods are equally applicable to the carcinogenicity to humans of the PAHs in inhaled cigarette MSS or ETS. Grasso noted that the following five PAHs were commonly found in foods: B[a]A, B[a]P, DB[a,h]A, benz[e]acephenanthrylene (benzo[b]fluoranthene), and benzo[k]fluoranthene; all listed by Hoffmann and his colleagues (1727, 1740, 1741, 1743, 1744, 1773, 1808) and OSHA (2825) as “tobacco smoke tumorigens.” Grasso also listed the ranges of B[a]A

and B[a]P levels found in a variety of commonly consumed foodstuffs. Maga (2438) listed sixty-five common foodstuffs containing PAHs. As did the list compiled by Grasso, Maga’s list included fruits and vegetables, dairy products, cereal products, legumes, beverages (including water), cooking oils, meat products, seafood products, and miscellaneous foodstuffs such as eggs, sugar, and olives. When many foodstuffs are heated during preparation, their PAH content increases dramatically, for example, a single serving of charcoalbroiled meat contains more than 600 times the B[a]P level in the MSS from one cigarette [Lijinsky and Shubik (2364a, 2364b)]. Estimates such as this one are usually based on the Federal Trade Commission’s (FTC) listing of total particulate matter (TPM), “tar,” nicotine, and CO deliveries plus an average value for the level of the B[a]P in the MSS TPM. Such comparisons between cigarettes and foodstuffs may yield estimates that are actually too low. For a given cigarette brand, the FTC numbers are obtained via precisely defined smoking regimen and analytical methods (preconditioned cigarettes: 25°C; relative humidity, 60%; conditioning time, 24 hr; and smoking parameters: 35-ml puff volume, 2-sec puff duration, 1 puff/min; 25°C, 60% relative humidity, cigarette smoked to a defined butt length). On the other hand:

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-10 Polycyclic Aromatic Hydrocarbon Sources Polycyclic Aromatic Hydrocarbon

Tobacco Smoke

Gasoline Engine Exhausta

Cooked Fishb

Broiled Hamburgerb

Barley Maltbh

Puffed Cerealsb

Common Foodsb

× × × × × × × × × × × × × × × × × × × ×

— —

— —

— —

— —

× —

× × — —

× × — —

— — —

×

× — — — —

× — — — — — — —

—

× —

× × × × × × × × × × × × × × × × × × × ×

Benz[j]aceanthrylene, 1,2-dihydro-c Benz[j]aceanthrylene, 1,2-dihydro-3-methyl-d Benz[e]acephenanthrylenee Benz[a]anthracene Benz[a]anthracene, 7,12-dimethylBenzo[j]fluoranthene Benzo[k]fluoranthene 11H-Benzo[b]fluorene Benzo[rst]pentaphenef Benzo[ghi]perylene Benzo[c]phenanthrene Benzo[a]pyrene Benzo[e]pyrene Benzo[b]triphenyleneg Chrysene Dibenz[a,h]anthracene Dibenz[a,j]anthracene Dibenzo[e,l]pyrenei Indeno[1,2,3-cd]fluoranthene Indeno[1,2,3-cd]pyrene

× × × —

—

× —

× —

× × —

× × — — — — — — —

× × × — × ×

× × × —

× × —

× — —

— —

× × × — × — — — — × — — — — — — — —

Wynder and Hoffmann (4315) Maga (2438) c Previously known as cholanthrene d Previously known as 3-methylcholanthrene e Previously known as benzo[b]fluoranthene f Previously known as dibenzo[a,i]pyrene g Previously known as dibenz[a,c]anthracene h Also contains a high level of N-nitrosodimethylamine i Also known as dibenzo[fg,op]naphthacene a

b

• Few smokers, if any, in the smoking of a cigarette take in the TPM amount found in the FTC determination. • Few smokers smoke their cigarettes to as short a butt length as in the FTC procedure. • Because of involvement in other tasks, smokers often place their cigarette in an ash tray for a brief time, thus missing one or more puffs on the cigarette. Few smokers take the number of puffs obtained for a given cigarette brand in the FTC procedure. The smoking machine used in the method never misses a puff on the cigarette under test! • The smoking machine used in the FTC procedure does not “exhale” as do smokers. It has been determined in numerous studies that cigarette smokers exhale between 10% and 50% of the TPM inspired during the puffs needed to consume the cigarette, thus retaining between 50% and 90% of the inspired TPM. All of these factors, if taken into account for a foodstuffcigarette comparison such as the one noted previously, will

increase the calculated number of cigarettes in the B[a]P comparison. Analysis of a foodstuff as elementary as bread reveals a B[a]P level of 0.23 ng/g (mainly in the crust); light toasting raised the B[a]P level to 0.39 ng/g; darker toasting raised it to 0.56 ng/g. For an average slice of bread (weight one ounce or approximately 30 g), these values would be about 7, 12, and 17 ng/slice. Maga also reported the dietary intake of B[a]P (charcoal-broiled meat excluded) averaged about 500 ng/day. From their analysis of human exposure to B[a]P, Waldman et al. (4106) reported in 1991 that “the range and magnitude of dietary exposures to benzo[a]pyrene” ranged from 2 to 500 ng/day and “were much greater than for inhalation (10 to 50 ng/[day]).” For some subjects, however, they found a dietary maximum of 1149 ng/day, despite omission of the contribution of B[a]P-containing beverages such as coffee. These B[a]P-intake estimates [Maga (2438), Waldman et al. (4106)] were lower than that reported by Hattemeyer-Frey and Travis (1551): 2200 ng/day (97% from diet; 3% from inhalation and water contamination). If B[a]P were tumorigenic in man and its threshold limit value were “zero,” the incidence

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

Table XXVI-11 Levels of Benzo[a]pyrene and Benz[a]anthracene in Common Foodstuffs Foodstuff

Benzo[a]pyrene, ng/g

Fresh vegetables Vegetable oils Coconut oil Margarine Mayonnaise Coffee Tea Grain Oysters and mussels Smoked ham Smoked fish Smoked bonito Cooked sausage Singed meat Broiled meat Charcoal-broiled steak Broiled mackerel Barbecued beef Barbecued ribs Cigarette mainstream smoke a a

2.85-24.5 0.4-1.4 43.7 0.4-0.5 0.4 0.3-1.3 3.9 0.19-4.13 1.5-9.0 3.2 0.83 37 12.5-18.8 35-99 0.17-0.63 8.0 0.9 3.3 10.5 20-25

Benz[a]anthracene, ng/g 0.3-43.6 0.8-1.1 98.0 1.4-3.0 2.2 1.3-3.0 2.9-4.6 0.40-6.85 … 2.8 1.9 189 17.5-26.2 28-79 0.2-0.4 4.5 2.9 13.2 3.6 20-35

The total mainstream smoke (particulate phase plus vapor phase) from an 85-mm filtered cigarette smoked under FTC conditions approximates 0.5 g.

of digestive tract cancer would be substantially higher than it is. The data tabulated in Table XXVI-11 on B[a]P and B[a] A from Maga, Grasso, and other investigators of the PAHs in frequently consumed foodstuffs have been expanded in Table XXVI-12 to include the cigarette equivalents of various dietary items consumed at estimated per meal levels. The inhaled cigarette MSS particulate phase from one cigarette is assumed to deliver 10 ng of B[a]P and 12.5 ng of B[a]A to the smoker. The following situation, known to be contrary to experimentally determined fact, is also assumed: None of the MSS particulate phase, nor its B[a]P content, nor its B[a] A content is exhaled by the smoker. How do these exposures to B[a]P in the diet, etc., compare to the exposure to B[a]P in ETS? It is obvious that dietary intake of B[a]P far outweighs the intake of B[a]P via inhalation, including that inhaled in ETS. Guerin et al. (1445) of the Oak Ridge National Laboratory discussed the contribution of ETS to indoor air PAH concentrations and tabulated their assessments of the situation. They noted: The data suggest that ETS contributes between 0.5 and 1 ng/m3 of BaP to indoor environments containing measurable ETScontamination … Excursions in BaP concentrations due to

1223

ETS in such environments reach approximately 2.5 ng/m3 … The magnitude of ETS-contribution [to PAH and BaP concentration] is generally small and is often difficult to consistently detect in most environments.

The daily intake of B[a]P from ETS may be estimated if the following assumptions are made: • The average hourly intake of air is independent of whether the host is awake or asleep and is 1 m3. • The B[a]P level due to ETS is at the high end of the range estimated by Guerin et al. (1992) to be 0.5 to 1 ng/m3. • None of the daily intake of B[a]P, whether from diet, ETS, and the like, is eliminated by exhalation, etc. Table XXVI-13 shows a comparison of the intake of B[a] P from ETS vs. the other B[a]P intakes discussed previously. XXVI.B.1.b Alternate Exposures to Aza-Arenes Even though, as indicated in Table XXVI-3 and the text accompanying it, the presence of the three pentacyclic N-heterocyclic compounds in tobacco smoke is equivocal, the alternate exposure to them and similar components is discussed below. In their 1956 review of angular benzacridines and dibenzacridines and their tumorigenicity, Lacassagne et al. (2247a) made the following interesting observation, pertinent to the alleged “carcinogenicity” of benzene, frequently used as a solvent in tumorigenicity studies in the 1930s, 1940s, and 1950s: These molecules [the angular benzacridines] are very soluble in benzene and acetone (two solvents currently used for the investigations of carcinogenic activity).

In addition to the exposure to acridines and benzacridines in tobacco smoke, other exposures to various acridines and benzacridines have been cataloged in the scientific literature. Many of the sources (Table XXVI-14) comprise environmental pollutants. Unlike the PAHs and the NNAs, nontobacco smoke exposure to the acridines and benzacridines does not include foods. However, exposures other than tobacco smoke to polycyclic nitrogen compounds include exposures to the mutagenic N-heterocyclic amines in a variety of foods. XXVI.B.1.c Alternate Exposures to N-Nitrosamines Among several groups who have been involved in research on NNAs since soon after their tumorigenicity in laboratory animals was first reported by Magee and Barnes (2441a) are Barnes, Magee, and Schoental in the United Kingdom and Dontenwill, Druckrey, Preussmann, and Schmähl in Germany. From the German group, Preussmann has been a key contributor to our knowledge of N-nitrosamines. He has authored or co-authored research results and review articles continuously on NNAs since 1959. Initially, Preussmann was

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-12 Cigarette Equivalents of Benzo[a]pyrene (B[a]P) and Benz[a]anthracene (B[a]A) in Common Foodstuffs B[a]P

B[a]A

ng/g

ng/Servinga

Cigarette Equivalentb

ng/g

Fresh vegetables Vegetable oils Coconut oil Margarine Mayonnaise Coffee Tea Grain

2.85-24.5 0.4-1.4 43.7 0.4-0.5 0.4 0.3-1.3 3.9 0.19-4.13

325-2800 (4) 46-160 (4) 1245 (1) 11-14 (1) 23 (2) 17-74 (2) 222 (2) 22-471 (4)

32-280 5-16 125 1 2 2-7 22 2-47

0.3-43.6 0.8-1.1 98.0 1.4-3.0 2.2 1.3-3.0 2.9-4.6 0.40-6.85

34-4970 (4) 91-125 (40 2800 (1) 40-85 (1) 125 (2) 74-171 (2) 165-262 (2) 46-780 (4)

3-400 7-10 225 3-7 10 6-14 13-21 4-62

Bread, untoasted Bread, light toast (3 min) Bread, dark toast (5 min)

0.23 0.39 0.56

20 (3) 33 (3) 48 (3)

2 3 5

— — —

— — —

— — —

Oysters and mussels Smoked fish Smoked bonito Smoked whiting Broiled mackerel

1.5-9.0 0.83 37 6.9 0.9

171-1026 (4) 95 (4) 4218 (4) 787 (4) 103 (4)

17-103 10 422 79 10

— 1.9 189 — 2.9

— 217 (4) 21500 (4) — 330 (4)

— 17 1720 — 26

Smoked ham Cooked sausage

3.2 12.5-18.8

370 (4) 1425-2143 (4)

37 143-214

2.8 17.5-26.2

319 (4) 2000-2900 (4)

25 160-232

Singed meat

35-99

3990-11290 (4)

400-1130

28-79

3200-9000 (4)

256-720

Broiled meat Broiled hamburger, fatty Broiled hamburger, lean Charcoal-broiled steak

0.17-0.63 2.6 0 8.0

19-72 (4) 296 (4) 0 (4) 912 (4) 1824 (8)

Charcoal-broiled T-bone

50

Barbecued beef Barbecued pork Barbecued ribs Cigarette mainstream smokec

3.3 4.5 10.5 20-25

Foodstuff

2-7 30 0 9(4) 182 (8)

5700 (4) 11400 (8)

570 1140

376 (4) 513 (4) 1197 (4)

38 51 120

0.2-0.4 — — 4.5 1026 (8)

ng/Servinga

Cigarette Equivalentb

23-46 (4) — — 513 (4) 1026 (8)

2-4 — — 41 82

—

—

—

13.2 … 3.6 20-35

1500 (4) … 410 (4)

120 … 33

Number in parentheses indicate number of ounces consumed. B[a]P and B[a]A content calculated at level per ounce (28.5 g) consumed. Inhaled cigarette MSS particulate phase from one cigarette is assumed to deliver 10 ng of B[a]P and 12.5 ng of B[a]A to the smoker. The following, contrary to experimental fact, is also assumed: None of the MSS particulate phase, nor its B[a]P content, nor its B[a]A content is exhaled by the smoker. c The weight of the total MSS (vapor phase + particulate phase) from an 85-mm filtered cigarette smoked under FTC conditions approximates 0.5 g. a

b 

Table XXVI-13 Comparison of Daily Dietary and Inhalation Intake of Benzo[a]pyrenea Study Maga (2438) Hattemeyer-Frey and Travis (1551) Waldman et al. (4106) From inhaled ETS

Type

B[a]P from Diet

B[a]P via Inhalation

Total B[a]P Intake

estimated measured measured estimated

— 2130 ng/day 2-500 ng/day b —

— 70 ng/day 10-50 ng/day 24 ng/day c

500 ng/day 2200 ng/day 12-550 ng/day b

Based on assumptions listed above. Dietary intakes as high as 1149 ng/day were noted. c Even if intake were at the excursion value of 2.5 ng/m3, the daily intake from ETS would be 60 ng.

a

b

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

Table XXVI-14 Aza-Arenes Sources Other Than Tobacco Smoke Acridine/Benzacridine Source Automobile exhaust Coal-fired residential furnace emission Coal distillate

Reference Sawicki et al. (3419b), Williams et al. (4247a) Grimmer et al. (1407b)

Graebe and Caro (1334f), Kruber (2210a) Coal tar Lang and Eigen (2261a), Merli et al. (2534a) Crude oil Schmitter et al. (3519b), Grimmer et al. (1407a) High boiling petroleum distillate McKay et al. (2519a), Later et al. (26A80) Industrial stack effluent Sawicki et al. (3419a) Urban suspended particulate matter Sawicki et al. (3419c), Cautreels and van Cauwenberghe (636a), Dong et al. (1040a), Adams et al. (35)

involved with the investigation of the relationship between the structure of a NNA and its tumorigenicity [Druckrey et al. (1059)]. In 1962, Druckrey and Preussmann (1057) proposed the possibility of the formation of NNAs in tobacco smoke from the secondary amines, nitrogen oxides, and water present. For the next two decades, Preussmann investigated methods of NNA analysis [Preussmann et al. (26A129), Egan et al. (1112a)], tumorigenicity of various NNAs [Druckrey et al. (1056a, 1058), Habs et al. (1469a), Magee et al. (2443), Janzowski et al. (1921a, 1921b), Ketkar et al. (2086c, 2086d), Zerban et al. (26A197)], the involvement of nitrate and nitrite in NNA formation [Spiegelhalder et al. (26A165)], NNAs in foods [Spiegelhalder et al. (26A167)], beverages [Spiegelhalder et al. (26A166, 26A168)], and toiletries [Spiegelhalder and Preussmann (26A169)]. In the late 1980s, Preussmann returned to the study of NNAs in tobacco and tobacco smoke and the question of the possible endogenous formation of tobacco-specific NNAs in smokers [Tricker et al. (3944, 3945, 3953, 3954), Tricker and Preussmann (3946–3951), Fischer et al. (1191–1200); Spiegelhalder et al. (3773, 3774), Kumar et al. (2235)]. Discussing the escalation in publications on N-nitroso compounds, Preussmann (2989a) wrote: At present (1981), more than 1400 papers are published annually on the analysis, formation, chemistry, biochemistry, metabolism and biological effects of N-nitroso compounds. There is no equivocal and convincing evidence of carcinogenicity in humans of N-nitroso compounds. Therefore, an answer is needed to the question whether exposure to traces of these compounds from the general environment … poses a risk to human health. In this situation animal data must be extrapolated to man, with all the inherent uncertainties.

Preussmann and Stewart (2991) noted the exponential increase in publications on NNAs between 1972 and 1984 and

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estimated that about three papers were published daily on this topic in the scientific literature in 1983. They also cautioned: Patterns of investigations established with nitroso compounds are being extended to more structurally complex carcinogens. Yet the contribution of nitroso compounds to the burden of environmentally determined neoplasia in humans remains to be determined … The priority that might reasonably be placed on reducing human exposure to nitroso compounds could be better judged if the number of cancers likely to be affected by such measures were known.

Discussions in this chapter are limited primarily to the NNAs common to tobacco and tobacco smoke and the other exposures (foodstuffs, beverages, cosmetics, drugs, etc.). As described by Preussmann and Stewart (2991), various bioassays on laboratory animals have been conducted on over 220 different NNAs and 110 N-nitrosamides, over 330 in all. Fewer than sixty of these N-nitroso compounds have been identified in tobacco and/or tobacco smoke. Historically, the search for tumorigenic compounds in foodstuffs and beverages began in the early 1930s, shortly after the demonstration that the synthetic PAH DB[a,h]A [Kennaway and Hieger (2078)] and the coal tar isolate B[a]P [Cook et al. (796a, 797), Barry et al. (194)] were carcinogenic when painted on mouse skin and sarcogenic when injected subcutaneously. The initial investigations were limited to attempts to demonstrate the presence of these and similar PAHs in heated foodstuffs (meat, fish, etc.), particularly those containing cholesterol and its derivatives. Subsequent to the demonstration of the tumorigenicity in laboratory animals of NNAs such as N-nitrosodimethylamine (NDMA) [Barnes and Magee (192), Magee and Barnes (2441a)], the search for NNAs in commonly used foods and beverages began. Despite nearly half a century of study of food components tumorigenic to laboratory animals, caution was recommended as recently as 1984 in the interpretation of the laboratory findings, for example, Grasso (1345) in his review of carcinogens in food noted: Carcinogens occur at very low concentrations in food so that if any type of tumors result at all, the number is expected to be very low indeed. At present much thought is being given to the relative hazards of these levels and how they can be assessed. Certainly no firm association has been established between any human cancer and the low levels of carcinogens in food, but this problem may only reflect the imperfect state of current epidemiological investigations.

Despite hundreds of publications on the presence of NNAs in foods and beverages and the results of bioassays with NNAs in laboratory animals, Grasso also wrote: Despite intensive experimental investigations, however, the hazard to humans from small doses of nitrosamines present in our food and water are difficult to assess, and until further experimental evidence is available, no firm opinion can be given.

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This opinion is almost identical with that of Preussmann and Stewart (2991), who reviewed not only the human exposure to NNAs in foods, beverages, water, drugs, cosmetics, etc., but also exposure to the NNAs (volatile, nonvolatile, and tobacco specific) in tobacco products: Although estimates of the total human burden caused by exposure to nitroso carcinogens have been attempted …, we do not think that sufficient data exist for meaningful evaluation; therefore, estimation of nitrosamine contribution to human cancer risk is largely speculative. Premature calculations are liable to be misinterpreted by those who are not thoroughly familiar with the multitude of uncertainties and difficulties inherent in such calculations, especially when estimates of lifetime risks are based on such figures.

Table XXVI-15 lists the levels (ng/g) of several NNAs identified in commonly used foods and beverages. Table XXVI-16 summarizes the studies in which various NNAs were identified in foods and beverages. One of the earliest investigators of NNAs in foodstuffs was Kröller (2205), who identified N-nitrosodimethylamine (NDMA) in cheese. Kröller’s studies were not limited to possible tumorigens in foodstuffs. From 1963 through 1966, he also investigated the pyrosynthesis of PAHs, particularly B[a]P, in cigarette smoke and from various materials used in cigarette fabrication, for example, cigarette paper, adhesives, humectants, dyes, inks, flavorants, tobaccos [see summary in Wynder and Hoffmann (4332)]. Also included in Table XXVI-15 are data for the per cigarette deliveries of several NNAs identified in foods and beverages. From these data, comparisons of the relative exposures from foods, etc., and cigarette smoke are possible, for example, the per cigarette MSS range for NDMA has been reported as 0.1 to 180 ng (see Table XXVI-1). Since one ounce is approximately 30 g, a person eating 1 oz of fried bacon would be exposed to 3 to 840 ng of NDMA that is, 30 times 0.1 to 28 ng of NDMA. Similarly for cured meat, the per cigarette exposure of 0.1 to 180 ng should be compared to the dietary exposure of 30 to 2400 ng from eating 1 oz of cured meat. Also, compare the exposure to 30 to 60 ng/ cigarette of N-nitrosopyrrolidine (NPYR) vs. 300 to 3150 ng NPYR from eating 1 oz of sausage! Over the years, numerous reports [see Neurath et al. (2751), Fredrickson (1236), Krull et al. (26A77), Eisenbrand et al. (26A27), Caldwell and Conner (573)] on the artifactual formation of NNAs during the collection and analysis of tobacco smoke and the various remedial procedures taken to minimize this problem have been published. Similar problems were noted by Wolff and Wasserman (26A195) on inflated levels of NNAs reported in foodstuffs and beverages. They expressed reservations about the validity of pre-1972 analytical methodology since later studies demonstrated that the earlier procedures introduced both artifact and error. Thus, the levels of NNAs reported in foodstuffs were actually lower than those reported prior to 1972. In 1986, Sen et al. (26A150) proposed improvements in analytical methodology to prevent artifactual formation and subsequent inflated levels of NNAs in rubber products; propyl gallate

The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-15 N-Nitrosamines in Foods and Beverages (ng/g) Food or Beverage

NDMAa

NDEA

Meat Bacon, uncooked Bacon, fried Cured meats

1–9.5 0.1–28 1–80

≤ 40

Fish Fresh or frozen Salted or pickled Smoked, baked, or processed

3–18 1–35 6–177

Vegetables/vegetable oils Beans Vegetablesb Soybean oilc

NPYR

NPIP

≤17 3–44 10–105d

0 1

1–2 50–108

… 0–37

≤147

…

… … …

0 0 0–20

0–0.2 0 0–4

… … …

… … …

Cheeses

0.1-68

…

…

2–11

Beverages Water Alcohol beverages

0.8–3.3

0.1–1.83 … ≤0.1

…

≤10 0.1–180

ND–25

ND–9

Cigarette Mainstream Smoke (ng/cig) e

1–4

30–60

≤60d

NDMA = N-nitrosodimethylamine; NDEA = N-nitrosodiethylamine; NPYR = N-nitrosopyrrolidine; NPIP = N-nitrosopiperidine b 16 different vegetable species tested c Freshly refined d Levels in sausage e See Table XXVI-1 a

was demonstrated to be an effective inhibitor of N-nitrosation during the analytical procedure. A variety of investigations has been conducted during the past decade on exposures to NNAs, and a few will be cited here. Okieimen et al. (26A120) reported on the total NNAs content of beer, dairy products, bouillon cubes, and tobacco products. They reported that dairy products showed the lowest total value; bouillon cubes, the highest. Mandagere (2450a) reported on the high NNA levels in a variety of meats cured via a smoking process. Coker et al. (26A16) tested some 200 commercial foodstuffs for NNAs and noted the values for beverages were high, those for dairy products low. Craddock (26A18) and Sen (26A143) found NNA levels in Canadian foodstuffs and beverages to be similar to those for U.S. products. Since the review by Preussmann and Stewart (2991) on the tumorigenicity of NNAs and that by Preussmann and Eisenbrand (2990) on exposure to NNA tumorigens in the environment, numerous detailed reviews of NNA exposures (alcoholic beverages, meats, seafood, cosmetics, tobacco, rubber goods, metal cutting oils, pharmaceuticals, environment, and water) have been presented by Mejstrik et al. (26A99), Tricker and Preussmann (3946), Tricker et al. (3954), Ellen (26A30), and Matsui and Kaya (26A95).

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Table XXVI-16 Volatile and Nonvolatile N-Nitrosamines in Foodstuffs and Beverages N-Nitrosamine: Foodstuff/Beverage

Reference

Acetic acid, 2-methylnitrosamino)- [N-nitrososarcosine (NSAR)] Meat Hamburg and Kann (26A49) Beer (and malt) Pollock, (26A128), Sen et al. (26A156) 1-Butanamine, N-butyl-N-nitroso- [N-nitrosodibutylamine (NDBA)] Fish Huang et al. (26A63) Ethanamine, N-ethyl-N-nitroso- [N-nitrosodiethylamine (NDEA)] Bacon Crosby et al. (26A19), Wasserman et al. (26A181) Fish Sen et al. (26A155), Crosby et al. (26A19), Wasserman et al. (26A181), Fong and Chan (26A39, 26A40), Huang et al. (26A63) Cheese Crosby et al. (26A19), Wasserman et al. (26A181) Powdered milk Maduagwu and Bassir (26A88) Beer (and malt) Spiegelhalder et al. (26A166), Scanlan et al. (26A139), Kawabata et al. (2058) Sen et al. (26A154) Gastric juices + nitrite Methanamine, N-methyl-N-nitroso- [N-nitrosodimethylamine (NDMA)] Meat, cured meat Wasserman et al. (26A181), Panalaks et al. (26A121, 26A122), Sen (26A142a), Spiegelhalder et al. (26A167), Eisenbrand (26A26), Helgason et al. (26A58) Bacon Crosby et al. (26A19), Wasserman et al. (26A181), Vecchio et al. (26A177), Sen et al. (26A152) Fish Sen et al. (26A155), Crosby et al. (26A19), Wasserman et al. (26A181), Fong and Chan (26A39, 26A40), Iyengar et al. (26A64), Havery and Fazio (26A51), Kawabata et al. (26A71), Maki et al. (26A90), Josefsson and Nygren (26A67), Matsui et al. (26A96), Huang et al. (26A63), Pedersen and Meyland (26A123) Nieper and Etzel (26A117), Röper (26A134), Röper et al. (26A135), Squid Kawabata et al. (26A71), Matsui et al. (26A96) Cheese Kröller (2205), Crosby et al. (26A19), Wasserman et al. (26A181), Goodhead et al. (26A42), Havery et al., (26A55), Gough et al. (26A44), Eisenbrand et al. (26B16), Elgersma et al. (26A29); Danish Institute of Protein Chemistry (26A21), Spiegelhalder et al. (26A167), Eisenbrand (26A26) Powdered milk Maduagwu and Bassir (26A88), Libbey et al. (26A84), Lakritz and Pensabene (26A78), Havery et al. (26A52) , Sen and Seaman (26A147) Wheat flour Hedler and Marquardt (26A57) Beer (and malt) Sen and Dalpe (26A144), Goff and Fine (26A41), Spiegelhalder et al. (26A166, 26A167), Walker et al. (26A109), USFDA (26A176), Maki et al. (26A91, 26A92), Preussmann et al. (26A130, 26A131), Scanlan et al. (26A138, 26A139), Sen et al. (26A151), Stephany and Schüller (26A170), Eisenbrand (26A26), Havery et al. (26A54), Hotchkiss et al. (26A62), Sen and Seaman (26A146, 26A148), Slack and Wainwright (26A160), Kann et al. (26A70), Kawabata et al. (2058), Mangino et al. (26A93), Spiegelhalder (26A162), Jasinski (26A66), Scanlan et al. (26A139), Scanlan and Barbour (26A138) Scotch whiskey Goff and Fine (26A41) Brandy (French) Walker et al. (26A179) Other alcohol beverages Sen and Dalpe (26A144), Gough (26A43), Bassir and Maduagwu (26A05) Water Fine et al. (26A37, 26A38), Kimoto et al. (26A72), Mitch et al. (26A112a) Morpholine, 4-nitroso- [N-nitrosomorpholine (NMOR)] Fish Fong and Chan (26A39, 26A40) Piperidine, 1-nitroso- [N-nitrosopiperidine (NPIP)] Meat, cured meat Spiegelhalder et al. (26A167), Eisenbrand (26A26) Bacon Crosby et al. (26A19), Wasserman et al. (26A181), Vecchio et al. (26A177) Fish Crosby et al. (26A19), Wasserman et al. (26A181) Squid Kawabata et al. (26A71), Matsui et al. (26A96) Cheese Crosby et al. (26A19), Wasserman et al. (26A181) 1-Propanamine, N-nitroso-N-propyl- [N-nitrosodipropylamine (NDPA)] Fish Sen et al. (26A155), Huang et al. (26A63) Pyrrolidine, N-nitroso- [N-nitrosopyrrolidine (NPYR)] Meat, cured meat Pensabene et al. (26A124), Spiegelhalder et al. (26A167), Eisenbrand (26A26), Theiler et al. (26A173), Alldrick et al. (26A01) Bacon Hansen et al. (26A50), Sen et al. (26A145, 26A153), Gough et al. (26A45), Havery et al. (26A53), Janzowski et al. (26A65), Cross and Bharucha (26A20), Gray and Randall (26A47), American Meat Institute (26A03), Nitrite Safety Council (26A118), Webb and Gough (26A191), Josefsson and Nygren (26A67), Fazio et al. (26A33), Gray (26A46), Pensabene et al. (26A125), Alldrick et al. (26A01), Vecchio et al. (26A177) (Continued)

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Table XXVI-16 (continued) Volatile and Nonvolatile N-Nitrosamines in Foodstuffs and Beverages N-Nitrosamine: Foodstuff/Beverage Fish Cheese Beer (and malt)

Reference Crosby et al. (26A19), Wasserman et al. (26A181), Kawabata et al. (26A71), Matsui et al. (26A96) Crosby et al. (26A19), Wasserman et al. (26A181) Spiegelhalder et al. (26A166), Scanlan et al. (26A139), Kawabata et al. (2058), Jasinski (26A66)

2-Pyrrolidinecarboxylic acid, 1-nitroso-[N-nitrosoproline (NPRO)] Meat Pensabene et al. (26A124), Hamburg and Hamburg (26A48), Dennis et al. (26A22), Dunn and Stich (26A25), Helgason et al. (26A58), Sen and Seaman (26A148) Bacon Hansen et al. (26A50), Brunnemann et al. (509), Sen and Seaman (26A148), Massey et al. (26A94) Chicken Brunnemann et al. (509) Ham Brunnemann et al. (509) Toast Brunnemann et al. (509) Biscuits Brunnemann et al. (509) Cornflakes Brunnemann et al. (509) Beer (and malt) Pollock (26A128), Sen et al. (26A156), Brunnemann et al. (509) Diethanolamine, N-nitroso- [N-nitrosodiethanolamine (NDELA)] Meat, cured Coker et al. (26A15)

The daily intake of NNAs from ETS may be estimated with these assumptions: • The average hourly intake of air is independent of whether the host is awake or asleep and is 1 m3. • The NNA level due to ETS is at the high end of the range estimated by Guerin et al. (1445) for the various NNAs, that is, 40 ng/m3 for N-nitrosodimethylamine (NDMA), 3 ng/m3 for N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR), N’-nitrosonornicotine (NNN), and 4-(Nmethyl-nitrosamino)-1-(3-pyridinyl)-1-butanone (NNK). • None of the daily intake of the NNAs, whether from diet, ETS, and the like, is eliminated by exhalation, etc. • The measured values reported for NNAs in diet, ETS, etc. From the dietary NNA data of Preussmann and Eisenbrand (2990), Preussmann et al. (26A130), and Spiegelhalder et al. (26A167) and environmental tobacco smoke NNA data summarized by Guerin et al. (1445), the comparison in Table XXVI-17 was developed. It is obvious that the estimated exposure to the NNAs in diet vs. ETS differs from the B[a]P exposure case. Whereas the dietary exposure to B[a]P was between twenty and ninety times the exposure to B[a]P in ETS, the dietary exposure to NNAs is essentially the same as the exposure to NNAs in ETS. Previously, the review by Holcomb (26A60), his proportioning of male and female respiration rates during the day, his use of 11% particle retention, and his comments on the contribution of ETS to PAH exposure, were discussed. His summary of the NNA situation was:

Two studies [Stehlik et al. (3812), Hoffmann et al. (1678)] have reported the presence of … (NDEA) and … (NDMA) in smoke-filled rooms … These are not tobacco-specific nitrosamines. The lack of reported background levels and the unusually high level of smoking prevents the evaluation of ETS contribution of these substances. Other nitrosamines reported to be found in tobacco smoke have either not been monitored or not been reported in ambient air where ETS is present.

Unlike the volatile NNAs, which are found primarily in the vapor phase, TSNAs are predominantly particulate-phase components.* Thus, their intake and retention should be proportional to the intake and retention of ETS particles. If Holcomb’s assigned values for respiration rates during the day and his use of 11% retention are applied to the TSNA values in the above summary, the intake of NNN plus NNK will be much less than the 144 ng/day indicated. It probably would be less than 10 ng/day. If the more recent data of McAughey et al. (26A98) for the percent retention of particulates from aged and diluted SSS is used in the calculations (17% to 41%, depending on analytical procedure and subjects’ gender), the estimated exposure to NNN plus NNK will not be as low as if the 11% retention from the Hiller et al. (1654a, 1654b) study is used. Brunnemann et al. (460) determined the levels of several TSNAs in bars (3), restaurants (2), a car, trains (2), an office, and a smoker’s private residence. The values reported and the subsequent descriptions of the values found are shown in Table xxvi-18. In their discussion of exposure to TSNAs in ETS at various sites, Hoffmann et al. (1702)—perhaps to embellish the situation—apparently disregarded the fact that no NNN nor *

Although data are sparse, there is some evidence to indicate that TSNAs in ETS may be distributed between the vapor and particulate phases.

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Table XXVI-17 Comparison of Dietary and Environmental Tobacco Smoke Dietary Intake, ng/Day Country

NDMA

Federal Republic of Germany United Kingdom Japan The Netherlands

NDEA

1100a

NPYR

NPIP

Total

100–150

10

1210–1260 530 1780 1100

Intake from ETSb, ng/day

Estimated from German, Japanese, and American ETS studiesc

NDMA

NDEA

NPYR

960

72

72

NPIP

NNN + NNK

Total

144

1248

Because of the reduction in N-nitrosodimethylamine (NDMA) level in beer after 1979, this number is now probably closer to 700 ng/day. On basis of the assumptions listed previously. c Brunnemann et al. (457), Stehlik et al. (3812), Matsushita and Mori (2495), Klus et al. (26A75); unfortunately, the tobacco-specific N-nitrosamine results from a more recent study on ETS by Brunnemann et al. (1992) were not included in the assessment by Guerin et al. (1445) or Holcomb (26A60). a

b

N’-anatabine was detected in half the test sites! Hoffmann et al. (1702) list total TSNAs in the MSS from two different U.S. cigarettes at 979 and 670 ng/cigarette. Thus, at an exposure level of 62 ng/m3 and a respiration rate of 1 m3/hr, it would require a nonsmoker to remain for nearly 16 and 11 hours in such an atmosphere to be exposed to similar levels of TSNAs as a smoker who inhales MSS from the two cigarettes, respectively. Such a period surely exceeds the “several hours” noted by Hoffmann et al. (1702). Analysis of sixty-eight commercially available drug preparations containing aminopyrine indicated that all contained NDMA [Schoenhard et al. (26A140)]. The following ranges for the NDMA levels were reported: thirty-five samples, 1 to 10 ppb; twenty-seven samples, 11 to 50 ppb; five samples, 51 to 100 ppb; one sample, 370 ppb. More recently, Preussmann Table XXVI-18 Tobacco-Specific N-Nitrosamines in Indoor Air TSNAs in indoor air, ng/m3

Reference Brunnemann et al. (460) Hoffmann et al. (1702) a b

NNN

NAT

NNK

Total of 3 TSNAs

NDa b–22.8

NDb–9.5

1.4–29.3

1.4–61.6

1.8–23

1.5–10

1–29

4.3–62

ND = not detected Not detected in 5 of the 10 sites monitored (a restaurant, both trains, the office, smoker’s residence)

and Eisenbrand (2990), Mejstrik et al. (26A99), Lijinsky (26A85), Ellen (26A30), and Matsui and Kaya (26A95) have reviewed the studies on the detection of NNAs in pharmaceuticals as well as in other consumer products. Examination by Fan et al. (26A31) of a series of cosmetics widely used in the United States revealed that twenty-seven of twenty-nine samples contained NDELA at levels varying from 1 to 48000 ppb. From a similar study conducted several years later, Klein et al. (26A73) reported that five of ten cosmetic samples contained NDELA at levels ranging from 20 to 4113 ppb. Despite the concern about the possible tumorigenicity of NDELA, its use in cosmetics has continued since its ban as an agricultural chemical in the United States in 1981 (1147). Although none of the three has been identified in tobacco or tobacco smoke to date, N-nitrosomethyldodecylamine (in six of seven products tested), N-nitrosomethyloctadecylamine, and N-nitrosobenzylmethylamine were identified in 1981 by Hecht (26A56) in various commonly used cosmetics. Fan et al. (26A31) described an analytical method to determine NDELA in various cosmetics and shampoos; this procedure was updated by Fine (26A36). Erickson et al. (1159) reported the presence of NDELA and similar compounds in cosmetics. Preussmann and Eisenbrand (2990) commented on the rapid absorption of NDELA in rats when administered by a variety of routes (subcutaneous, oral, and intratracheal). Preussmann and Eisenbrand (2990), Mejstrik et al. (26A99), Ellen (26A30), Lijinsky (26A85), and Matsui and Kaya (26A95) have reviewed the findings on the detection of NNAs in cosmetics. Spiegelhalder and Preussmann (26A169) described the volatile and nonvolatile NNAs found in many

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The Chemical Components of Tobacco and Tobacco Smoke

samples of toiletries and cosmetics. Eisenbrand et al. (26B15) reported a series of N-nitrosodialkylamines in cosmetics. Investigations [Spiegelhalder and Eisenbrand (26A164), Spiegelhalder (26A163)] of various rubber products that come in frequent contact with human tissue revealed the presence of several NNAs. Baby-bottle nipples and pacifiers contained appreciable levels of NDMA, NDEA, N-nitrosodibutylamine (NDBA) [Thompson et al. (26A174)], and NPIP. NDMA and NDEA were found in various rubber toys. These two NNAs plus NPIP were also found in rubber gloves. In their study of NNAs in rubber products, Sen et al. (26A149), in their analysis of thirty samples, reported the detection of NMOR in various rubber products in addition to NDMA, NDEA, NDBA, and NPIP. Solenova et al. (26A161) reported the presence of NDMA and NDEA. Several NNAs have been identified in pesticides used on various vegetable crops, for example, NDMA [Ross et al. (26A137)] and N-nitrosodipropylamine (NDPA) [Zweig et al. (26A198)]. Most water supplies show little evidence of volatile or nonvolatile NNAs. However, water deionized by passage through various anion-exchange resins containing trialkylammonium compounds were reported to show NDMA levels ranging from 0.03 to 0.34 mg/liter [Fiddler et al. (26A35), Fine et al. (26A37, 26A38), Gough et al. (26A44), Cohen and Bachman (26A14), Kimoto et al. (26A72), Mitch et al. (26A112a)]. On the subject of industrial and occupational exposures to NNAs, Preussmann and Eisenbrand (2990) wrote: Data on occupational exposure to different nitrosamines are recent and not yet representative or complete. Nevertheless, the data indicate that certain industries have a serious

nitrosamine problem and that the highest known concentrations of preformed N-nitrosamines occur in the workplace, especially in the rubber and leather industries … Exposures have been shown to vary considerably in regard to amount and type of nitrosamine found in different working places in several industries and occupations.

Preussmann and Eisenbrand (2990) summarized the following situations: In the rubber industry, workers were exposed to NDMA, NDEA, NMOR, and NPIP. In their study of the atmospheres in 132 sites in twelve rubberprocessing plants in France, Ducos and Gaudin (26A24) reported the detection of NDMA, NDEA, and NMOR in 93%, 27%, and 13% of the sites surveyed, respectively. In the leather-tanning industry, exposures to NDMA [Bailey et al. (26A04), Skrabs (26A159), Wolf et al. (26A194)] and to NDEA [Skrabs (26A159), Wolf (26A193)], and NMOR [Wolf (26A193)] occur. Exposures to NDELA [Erickson et al. (1159)] in the cutting oils used in machine shops and to NDMA and NDEA [Wolf et al. (26A194), Wolf (26A193)] in foundries have been reported. In a plant producing rocket fuels, including 1,1-dimethylhydrazine by reduction of NDMA, workers were exposed to extremely high levels of NDMA. Shortly after this high exposure was recorded, the factory ceased manufacture of 1,1-dimethylhydrazine. Exposures to NDMA and NDEA have been reported in chemical and pharmaceutical factories where amines are used in production. In Table XXVI-19 is presented a simplified summary of the possible exposures to non-tobacco-specific N-nitrosamines that are known components of tobacco smoke. All ten NNAs

Table XXVI-19 Non-Tobacco Exposures to Tobacco/Tobacco Smoke N-Nitrosamines N-Nitrosaminea Consumer Good or Environment Tobacco and/or tobacco smokeb Food, beverages Rubber goods Cosmetics Pharmaceuticalsc Pesticidesc Water Industrial environments   Rubber processing plants   Leather tanneries   Foundries   Machine shops

NDMA

NDEA

NDPA

NDBA

NDELA

NPIP

NPYR

NPRO

NMOR

NSAR

× × × —

× × × — — — — — × × × —

× × — — —

× × × — — — — — — — — —

× ×

× × × — — — — — × — — —

× × — — — — — — — — — —

× × — — — — — — — — — —

× × × — — — — — — — — —

× × — — — — — — × × — —

× × × — × × × —

× — — — — — —

× — — — — — — — ×

NDMA = N-nitrosodimethylamine; NDEA = N-nitrosodiethylamine; NDPA = N-nitrosodipropylamine; NDBA = N-nitrosodibutylamine; NDELA = N-nitrosodiethanolamine; NPIP = N-nitrosopiperidine; NPYR = N-nitrosopyrrolidine; NPRO = N-nitrosoproline; NMOR = N-nitrosomorpholine; NSAR = N-nitrososarcosine b In addition to the NNAs listed, tobacco and tobacco smoke contain a variety of TSNAs and N-nitrosamino acids other than N-nitrososarcosine. c N-Nitrosamines other than those determined in tobacco and/or tobacco smoke have also been detected in various consumer goods

a 

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listed are found not only in tobacco smoke but also in a great variety of commonly consumed foodstuffs and beverages. XXVI.B.1.d Alternate Exposures to N-Heterocyclic Amines Because of their concerns about the mutagenicity of commonly consumed heated foods, many of the studies of the isolation, identification, and estimation of N-heterocyclic amines in heated foodstuffs or heated food components, particularly amine-containing components such as amino acids, proteins, and peptides, were conducted by Japanese investigators. This becomes obvious from examination of the authors and co-authors of the references listed in Table XXVI-20. With the advent of the Ames mutagenicity test with Salmonella typhimurium in the mid-1970s and the demonstration of its utility, the number of studies on potential mutagenic systems and the mutagenicity-tumorigenicity relationship virtually exploded. By highly competent application of up-to-date isolation and characterization techniques plus utilization of the Ames test, Sugimura and his staff at the Japanese National Cancer Research Institute contributed significantly to our knowledge of the structures, properties, and precursors in foods of the mutagenic N-heterocyclic amines. Although the methodologies differed, the 1977 isolation and identification of the mutagenic N-heterocyclic amines (Trp-P-1, Trp-P-2) from a tryptophan pyrolysate paralleled the historic 1932 isolation and identification of polycyclic aromatic hydrocarbons (B[a]P, B[e]P, B[a]A, perylene) from coal tar. In the 1930s, the Kennaway group in the United Kingdom used ultraviolet spectrophotometry [Hieger (1631)] to monitor coal-tar PAHs during their concentration and purification by repeated precipitations and recrystallizations of PAH-picric acid complexes [Cook et al. (796a, 797)]. In the mid-1970s, Sugimura et al. (3829) used the Ames test (Salmonella typhimurium, TA 98 strain/S-9) to monitor tryptophan pyrolysate mutagens (TrpP-1, Trp-P-2) during their concentration and purification by sequential chromatography on silicic acid, alumina, and CM-Sephadex® columns. References to several early studies on the identification of biologically active compounds in heated foodstuffs are included in Table XXVI-20, for example, the 1956 study of PAHs such as B[a]P in roasted coffee [Kuratsune, (2237)] and the similar mid-1960s studies of PAHs in broiled meat [Lijinsky and Shubik (2364a, 2364b)]. PAHs such as B[a] P were identified in both studies. The major concern of the early investigators was the possible presence of tumorigenic PAHs, particularly B[a]P, in the heated foodstuff. Another PAH of concern was the potent tumorigen 3-methylcholanthrene because of its possible pyrosynthesis during cooking from cholesterol, a component of many meats. Of course, it was subsequently demonstrated that B[a]P, in addition to its tumorigenicity to mouse skin, is also mutagenic in the Ames test. However, its specific mutagenicity is insignificant compared to that of many N-heterocyclic amines.

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From their studies of heated foods or food pyrolysates (thirty different foods, including rice, flour, soy beans, fish, meat, and eggs), Sugimura and Nagao (3828b) reported: • Mutagenicity was proportional to the protein content. • Mutagenicity was proportional to the levels of specific amino acids (tryptophan, glutamic acid, etc.) in the constituent protein. • Mutagenicity was dependent on water content and heating temperature, for example, for foods with low water content, the mutagens appear at 300°C; for those with high water content, the mutagens appear at 400°C. As noted in the sections on PAHs and NNAs in foods, estimates of daily exposures to these classes of compounds in foods, beverages, and other factors have been made by numerous investigators. Estimates of exposures to mutagenic N-heterocyclic amines are limited. Part of the reason is the difference in time span since the particular class of compounds was found to be tumorigenic and/or mutagenic. Exposures to PAHs tumorigenic in laboratory animal bioassays have been studied for more than seven decades [since the early 1930s and the identification of B[a]P in coal tar by Cook et al. (796a, 797)]. Exposures to NNAs tumorigenic in laboratory animal bioassays have been studied [Magee and Barnes (2441a)] since the mid-1950s. In contrast, exposures to mutagenic N-heterocyclic amines reported to be tumorigenic in laboratory animal bioassays have only been studied for about thirty years (since the mid-1970s and the availability of the Ames test). In his mid-1980s review, Sugimura (3828c) attempted to estimate the exposure of humans to mutagenic N-heterocyclic amines with the limited data at his disposal. He wrote: Taking various factors into consideration, it is probably impractical and not realistic to make risk estimations from the carcinogenicity data on rodents given a single carcinogen. However, for a simple extrapolation of animal data for risk estimation, TD50 values, which are the doses needed to develop cancers in 50% of animals fed on carcinogens [IQ, Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, AaC, and MeAaC] for their life time, have been calculated based on mouse experiments … If we assume the average TD50 value of heterocyclic amines should be about 8mg/kg/day, we can roughly estimate the risk of these carcinogenic heterocyclic amines for human beings. The intake of heterocyclic amines was calculated from available data on their quantities in foods. Apparently the human intake is about 0.0002% times the TD50 obtained from animal data. This means that heterocyclic amines may not be so serious for human cancer development.

Sugimura added: On the other hand, it is also true that human beings are being exposed to many heterocyclic amines and many other carcinogens with tumor promoters and/or suppressing factors for carcinogenesis. At this moment, it is honest to state that no solid information on the estimation of risk of heterocyclic amines has been obtained in any direction, either positive or negative.

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-20 Mutagenicity of Beverages, Heated Foods, and Heated Food Components Food or Food Component Foods, heated (grilled, broiled, etc.)

References

Herring, broiled Mackerel, broiled Pike, broiled Sardine, broiled

Sugimura et al. (3829a), Sugimura and Nagao (3829b), Matsumoto et al. (2492), Sugimura (3828a, 3828c, 3828f), Nagao et al (2667a), Tanaka et al. (2667a), Felton and Knize (1177d) Commoner et al (790a), Hargraves and Pariza (1501a), Hayatsu et al. (1555b), Turesky et al. (3988b), Ohgaki et al. (2849a), Takayama et al. (3862c) Lijinsky and Shubika (2364a, 2364b), Nagao et al. (2667c), Commoner et al. (790a), Yasuda et al. (4382a), Hayatsu et al. (1555a, 1555b), Kasai et al. (2037a), Jägerstad et al. (1916b), Felton et al. (1177d), Ohgaki et al. (2849a), Takayama et al. (3862c) Yamaguchi et al. (4361a), Ohgaki et al. (2849a)   Sugimura and Nagao (3829b)  Nagao et al. (2667c), Yasuda et al. (4382a), Kasai et al. (2037c, 2037d), Yamaizumi et al. (4361b)   Nagao et al. (2667c, 2667f)  

Sardine, broiled

Ohgaki et al. (2949a), Takayama et al. (3862c)

Protein pyrolysates Albumin Soybean globulin Calf thymus Egg white Serum albumin Casein; collagen; Gluten; histone; Insulin; lysozyme; Ovalbumin; zein; Tobacco protein

Nagao et al. (2667f), Yoshida and Matsumoto (4387b), Nebert et al. (2688a), Yoshida et al. (4390) Yasuda et al. (4382a) Yoshida et al. (4389a, Ohgaki et al. (2849b)   Nagao et al. (2667b)     Matsumoto et al. (2491c)  

Peptide pyrolysates Polypeptides Carnosine Glycyl glycineb Glycyl glutamic acid Glycyl proline Glycyl tryptophan Leucyl glycyl phenylalanine Tryptophanyl alanine Tryptophanyl glycine Tryptophanyl tryptophan Tryptophanyl tyrosine

Johnson et al. (1968)       Matsumoto et al. (2491c)    

Amino acid pyrolysates

Masuda et al. (2486), Kato et al. (2048, 2049), Kosuge et al. (2178a), Nebert et al. (2688a)

Phenylalanine Lysine Tryptophan

Sugimura et al. (3829) Wakabayashi et al. (4102a) Sugimura et al. (3829), Yoshida and Matsumoto (4387a), Negishi and Hayatsu (2689a), Yamazoe et al. (4379a), Hosaka et al. (1835a), Matsukura et al. (2491a), Takayama et al. (3862d) Sugimura (3828a, 4365a), Takeda et al. (3863a), Yamamoto et al. (4365a), Ohgaki et al. (2849b), Takayama et al. (3862b) Smith et al. (3722a)

Beef, extract Beef, broiled, fried, and/or charred

Cuttlefish, broiled Eggs; fish; meat Flour; rice Soy beans Fish, broiled, charred

Glutamic acid Histidine 3-Methylhistidine

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Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

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Table XXVI-20 (continued) Mutagenicity of Beverages, Heated Foods, and Heated Food Components Food or Food Component

References

Alaninec; arginine; Asparagine; citrulline; Cysteine; cystine; Glutamic acid; Glutamine; histidine; Lysine; methionine; Ornithine; Phenylalanine; serine; Threonine; tryptophan; Tyrosine; valine

     Matsumoto et al. (2491b)     

Beverages Coffee, roasted Coffee, instant Tea Brandy Sake Cigarette smoke condensate

Kuratsune b (2237), Nagao et al. (2667d, 2667e), Sugimura (3828b), Aeschbacher and Würzner (38a) Aeschbacher and Würzner (38a), Kosugi et al. (2178b) Nagao et al. (2667e), Sugimura (3828d) Sugimura (3828d) Takase and Murakami (3862a) Sugimura (3828d), Yoshida and Matsumoto (4388), Matsumoto et al. (2492), DeMarini (930, 9329, 933)

This was a PAH study, with emphasis on the generation of B[a]P. No mutagens detected in glycylglycine pyrolysate. c The pyrolysates from the various amino acids studied showed mutagenicities (Ames test) in the following sequence (revertant/mg of pyrolysate), the amino acid yielding the highest mutagenic pyrolysate listed first: Tryptophan, serine, glutamic acid, ornithine, lysine, arginine, citrulline, threonine, alanine, cystine, glutamine, methionine, cysteine, tyrosine, phenylalanine, histidine, asparagine, valine. a

b

Table XXVI-21 Mutagenicity of Common Beverages vs. Cigarette Smoke Condensate Agent Cigarette Coffee Teab Brandy

Exposure Level

ST Straina

S-9 mix

Revertants

one, inhaled 200 ml 200 ml 50 ml

TA 98 TA 100 TA 100 TA 100

yes no no no

4000 180000 mutagenic 10500

ST = Salmonella typhimurium b Japanese green tea a

Table XXVI-22 Benzo[a]Pyrene Equivalency of Extracts of Charred Fish and Meat Analyte Sardine Mackerel Beefsteak a b

Sample wt., g

B[a]P Equivalency, ng

Cigarette Equivalency Based on B[a]Pa

100 (3.5)b 60 (2.1) 190 (6.7)

35800 68200 85500

2983 5683 7125

Calculation based on assumption of MSS yield of 12 ng/cig of B[a]P Number in parentheses is weight in ounces

Sugimura (3828d) reported comparisons of the mutagenicities (Ames test) of various beverages (coffee, brandy, and tea) and CSC. His data are summarized in Table XXVI-21. In another comparison of mutagenicities toward Salmonella typhimurium TA 98, Nagao et al. (2667c) calculated the B[a]P equivalency of extracts of charred fish and meat. Their data, with additions (charred food weight in ounces, cigarette equivalents based on B[a]P), are shown in Table XXVI-22.

XXVI.C Summary It is obvious from the numerous Hoffmann co-authored lists (1727, 1740, 1741, 1743, 1744, 1773, 1808) summarized in Table XXVI-1 plus many other listings (1217, 2825) and articles that some seventy tobacco smoke components are defined as significant toxicants, with most of the seventy being defined as significant tumorigens. Forty or so have recently been defined as “Hoffmann analytes” and their cigarette MSS yield reductions are used to define a “potentially reduced exposure product” (PREP). It should be noted that the various bioassays that generated the data used to define the tumorigenicity of the various cigarette smoke components are similar to or identical with the various bioassays that generated the data to define the antitumorigenicity of various compounds to several known potent tumorigens such as B[a]P or DB[a,h]A. Many of the compounds with demonstrated antitumorigenicity have been identified in CSC and

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are present in it at much higher levels than such potent tumorigens as B[a]P, DB[a,h]A, and DMB[a]A. Why do so many of the proponents of the hazards of cigarette MSS seldom discuss in detail the many anticarcinogens, antitumorigens, or antimutagens present in MSS or the many alternate exposures to the various compound classes, the PAHs, aza-arenes, NNAs, and N-heterocyclic amines, defined as significant cigarette MSS problems? At the 1962 American Association for Cancer Research conference (4314), in their 1964 review [see pp. 330–331 in (4319)], and in their 1967 book, Wynder and Hoffmann [see pp. 370–371 in (4332)] also described the results of their experiments on the antitumorigenicity of two tobacco smoke paraffinic hydrocarbons, n-hentriacontane (C31H64) and n-pentatriacontane (C35H72), co-administered separately at two different levels with B[a]P. Subsequently, they noted [see pp. 628–629 in (4332)]: An explanation of the tumorigenic activity of tobacco smoke condensate in terms of single constituents is made more difficult by the presence of substances that may act as anticarcinogens and/or absorption retarders, especially for tumorigenic agents. It is known that noncarcinogenic hydrocarbons can inhibit the effect of carcinogenica hydrocarbons … The presence of substances such as long-chain paraffinic hydrocarbons may interfere with absorption of tumorigenica components. It is interesting to note the authors’ interchange of these two terms.

a

In their book, Wynder and Hoffmann described not only the 1951 results reported by Steiner and Falk (3814) on the antitumorigenicity of B[a]A to B[a]P when co-administered subcutaneously but also their own 1963 results of the antitumorigenicity of B[a]A to B[a]P when administered in a skinpainting bioassay [see pp. 246–247 in (4332)]. They noted: The existence of anticarcinogens, however, must be considered in evaluating any complex mixture such as tobacco smoke condensate.

The Chemical Components of Tobacco and Tobacco Smoke

Despite such a statement, neither Wynder and Hoffmann nor any of the proponents of the hazards of cigarette smoking discussed in any detail the presence of antitumorigens in cigarette MSS. The same proponents usually disregard alternate exposures to various tumorigens despite the many pre-mid-1950s articles by Kennaway and Hueper on respiratory effect of air pollutants. Because of the chronology of the discovery of the tumorigenicity of NNAs in the mid-1950s and N-heterocyclic amines in the late 1970s, it is obvious that neither Kennaway nor Hueper could discuss alternate exposures to them. Examples of more recent research are the many publications by Grimmer et al. on exposure to PAHs (1397–1402, 1405, 1406a, 1406b, 1407b) and aza-arenes (1407a) as air pollutants. In the monograph edited by Searle, comprising over 1400 pages on chemical carcinogens (3568), only one of the major classes (PAHs, aza-arenes, N-heterocyclic amines) of tumorigenic components in MSS was mentioned. The exception, the presence of NNAs in tobacco and smoke, was described briefly by Preussmann and Eisenbrand [see pp. 839–842 in (2990)]. The bulk of the material they cited on NNAs in tobacco and/or smoke included tabulated results by Hoffmann and his colleagues on NNAs and TSNAs in tobacco smoke (514, 1680) and tobacco [including snuff (1675, 1677, 1685)]. However, Preussmann and Eisenbrand cited many pre-1984 publications in which much data were presented on exposure to NNAs from many alternate sources such as food [see pp. 832–834 in (2990)], beverages [see pp. 834–839 in (2990)], cosmetics [see pp. 842–844 in (2990)], prescriptions [see pp. 844–845 in (2990)], pesticides [see pp. 845–846 in (2990)], rubber products [see pp. 846–848 in (2990)], water [see pp. 848–849 in (2990)], and occupations [see pp. 851–857 in (2990)]. In his chapter in Searle (3568), Grasso (1345) described the results of much research on PAHs and NNAs in foods but none on N-heterocyclic amines in food. Many references to alternate exposures to NNAs are presented herein but a great many more may be obtained by a search of the Internet.

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27

Free Radicals

XXVII.A Introduction Free radicals and reactive oxygen species are common to all living animals and plants, including tobacco. Reactive oxygen species in plants include hydrogen peroxide (H2O2) and singlet oxygen (1O2), as well as several free radicals and radical anions, such as nitric oxide (NO), superoxide anion radical (O2ˉ˙), hydroxyl radical (HO˙), and perhydroxyl radical (HO2˙), [Bartosz (27A06), Dat et al. (27A23), Halliwell (27A40)]. These highly reactive oxidation by-products are created by normal cell metabolism and environmental factors such as pollution and are continuously produced by living organism. Free radicals play an important role in the life processes of plants. Free radicals and reactive oxygen species are produced predominantly in plant cells during photosynthesis and photorespiration, and to a lesser extent, in respiration processes. Free radicals and reactive oxygen species play crucial roles as signaling molecules in various physiological processes. For example, during periods of environmental stress intra- and intercellular levels of H2O2 and NO tend to increase. Additionally, specific types of free radicals and reactive oxygen species interact with thiol-containing proteins and activate different signaling pathways as well as transcription factors, which in turn regulate gene expression and cell-cycle processes. Therefore, free radicals and reactive oxygen species control numerous types of cellular redox reactions (homeostasis), signaling processes (photosynthetic and respiratory metabolism), and processes that regulate plant growth, development, acclimatory and defense ´ lesak et al. (27A105)]. responses [S  The role of free radicals and reactive oxygen species in plant biochemistry and physiology have been described in many review papers [Kuz  ´niak and Urbanek (27A63), Neill et al. (27A80, 27A81), Apel and Hirt (27A02), Hung et al. (27A47)]. There are no free radicals or reactive oxygen species that are unique to tobacco. As a result there will not be an in-depth discussion of free radicals or reactive oxygen species specifically found in tobacco. In most cases the free radicals in biological systems are highly reactive and have half-lives of 10 -6 to 10 -3 seconds. Nonetheless, free radical activity has been observed in tobacco. Analytical methodologies rapid and specific enough to monitor and identify these free radicals are just emerging. It is believed that the presence of oxygen (O2) in the Earth’s atmosphere originated from photosynthetic activity. However, oxygen is involved in two very different roles in biological systems. It is a prerequisite for aerobic metabolism and consequent normal growth and development, but at the same time a reduction or an increase of molecular oxygen in biological systems very often results in the formation of reactive oxygen species that can cause deregulation of normal

cellular processes and eventually cause cell death. Therefore, in plants and in other aerobic organisms antioxidant systems have evolved. The balance of oxidants and antioxidants in plants and animals is critical for survival. The production of reactive oxygen species is normally carefully controlled by living organisms. A dynamic equilibrium exists between the formation of reactive oxygen species and the activity of the antioxidant scavenging systems [Hancock et al. (27A45), Irshad and Chaudhuri (27A49), Mittler et al. (27A74), Mittler (27A73), Vranova et al. (27A119)]. To protect themselves from reactive oxygen species, plants possess a number of free-radical scavenging enzymes, such as ascorbate peroxidase, catalase, and superoxide dismutase, and low molecular weight antioxidants, like ascorbate and tocopherols [Hancock et al. (27A45), Vranova et al. (27A119)]. Antioxidants in tobacco and tobacco smoke are discussed in Chapter 26. At the senescence stage in tobacco growth, enzyme activities (especially hydrolytic and other degradative enzyme systems) are intensified. These systems are responsible for breakdown of functional and structural components of the cell, such as proteins, nucleic acids, carbohydrates, and lipids. The latter stage of senescence resembles the early stage of leaf curing [Tso (27A114)]. During each of these processes, free radical reactions are occurring in tobacco leaf. In 1955, Frankenburg et al. reported that free radical reactions were occurring in cured tobacco leaves to form a nicotine dimer (1224, 1226). After tobacco is grown, cured, and aged there are free radicals still found in the lamina. It is believed that free radicals are present on the polyphenols, carbohydrates, and lignin present in tobacco. This is supported by evidence for the generation of free radicals in cellulose by irradiation with ultraviolet light [Kleinert (27A61)]. The existence of stable free radicals in lignin has also been demonstrated [Rex (27A98), Steelink (27A107), Steelink et al. (27A108)]. The formation of free radicals in wood by ionizing radiation has been shown, as well as the generation of free radicals in wood resulting from exposure to light [Kalnins et al. (27A57)]. Free radicals are ubiquitous. They are found in living plants and for practical purposes are essential to all life. They also exist in plant material that is dried. These types of free radicals are called persistent free radicals and are normally associated with free radicals present in the structural biomass of the plant (polyphenols, carbohydrates, and lignin). The tobacco precursors of free radicals found in the particulate phase of cigarette mainstream smoke (MSS) are also long-lived, persistent free radicals but arise from the thermolysis of the tobacco biomass to form numerous types of phenolic and quinoidal free radicals [Wooten et al. (27A120)]. Short-lived free radicals are also present in the vapor phase 1235

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of MSS. Although the types of free radical in tobacco may be similar in form to those in tobacco smoke, in some cases, for example, NO, they are generated in very different ways. Free radicals can participate in a wide variety of reactions, such as additions, substitutions, eliminations, rearrangements, reductions, electron transfers, and oxidations (27A01). From the beginning of the twentieth century, free radical chemistry has spread its influence over a wide range of research areas that impact our progress and well-being. Apart from polymer chemistry, synthetic organic chemistry, and environmental chemistry, much effort in recent times is expended on research in health and nutrition [Nagendrappa (27A78)]. There are some general features of a free radical reaction. Free radical reactions take three distinct, identifiable steps. The first is formation of the free radical that can happen by enzyme catalysis, homolysis, thermolysis, radiation, light induction, combustion and pyrolysis, or other means. The second step, called propagation, is the heart of a free radical reaction. In this step, free radicals are repeatedly regenerated and can react with neutral molecules to produce new free radicals. If there is no intervention, two free radicals can react to form a neutral molecule and the reaction is terminated, which represents the third step in the general reaction scheme. Because of this repetitive nature of the reaction, free radical reactions are called “chain reactions” and are often represented as a cyclic process [Nagendrappa (27A78)].

XXVII.B Analytical Methods for Determination of Free Radicals The instrumental method historically used for the detection of free radicals is electron spin resonance (ESR) (sometimes called electron paramagnetic resonance, ERP). ESR is a spectroscopic technique that detects species that have unpaired electrons. Free radicals can be organic compounds that have a free electron on carbon, oxygen, or nitrogen, or inorganic compounds or complexes that have a free electron, usually residing on a metal (27A31). ESR spectroscopy is the preferred and major analytical technique for the detection and quantification of free radicals [Demopoulos (27A28)]. ESR has been used in many fields of science to explore the presence and effects of free radicals in chemistry, physics, and biology. Free radicals can be gases, liquids, or solids and generally exist in very low, and in some cases, steady-state concentrations. ESR can be used to make direct measurements of free radicals that exist in steady-state concentrations [Demopoulos et al. (27A29)]. For short-lived, highly reactive free radicals, regardless of their physical and chemical form, numerous methodologies are now available to convert these free radicals into longer-lived species for analysis. Short-lived free radicals are first treated with another reagent called a spin trap. The resultant product, the spin adduct, is a more stable free radical species that can then be measured by ESR. Concentrations of free radicals are determined by measuring the spin-trap adducts. A wide variety of spin-trapping reagents have been used. Figure XXVII-1 shows the chemical structures for a

The Chemical Components of Tobacco and Tobacco Smoke

selection of these spin traps. Techniques that use ESR alone or ESR with spin-trapping methodologies have advanced tremendously over the last forty years [Janzen and Gerlock (27A54), Janzen (27A52, 27A53), Janzen et al. (27A55)]. Unlike other typical analytical techniques, such as infrared spectroscopy, ESR measurements require a high level of technical skill and expertise. ESR sample measurements are highly dependent on sample collection, sample preparation, types of solvents, temperature, choice of spin trap, and instrument calibration of electrical and magnetic fields, among other things. ESR, by itself, is considered a very specific, yet semiquantifiable, technique for the measurement of free radicals. It can be used in conjunction with other analytical techniques, such as gas chromatography, mass spectroscopy, and high performance liquid chromatography (HPLC) for the study of free radicals [Cranton and Frackelton (27A20)]. ESR used in conjunction with other analytical techniques is an emerging field. Free radicals can also be measured in biological samples. In a recent review by Sanchez-Moreno (27A103), several ESR techniques were described for the collection and determination of free radicals (superoxide, hydroxyl, and peroxyl) that occur in biological systems. These techniques include the total radical-trapping antioxidant parameter method (TRAP), the oxygen-radical absorbance capacity method (ORAC), and the Trolox equivalent antioxidant capacity method (TEAC). McAnalley et al. (27A70) have provided descriptions and applications of these (and other) methodologies for the determination of free radicals in biological media. SanchezMoreno (27A103) concludes that “in spite of the diversity of biological methods, there is a great need to standardize measurements of antioxidant activity.” Sophisticated ESR instrumentation is now becoming available that allows for the direct study of free radicals and free radical damage in living systems. In 2006, Hirata and Fujii (27A46) reviewed newly developed technologies in ESR spectroscopy and imaging equipment that are useful for the analysis of free radicals in living (biological) systems. Automatic control techniques used for a continuous-wave ESR spectrometer were discussed. Recent developments in timedomain ESR spectroscopy were also reported. Time-domain ESR spectroscopy is a technically challenging method, but can be very useful for the detection of free radicals with very short relaxation times in biological tissues. ESR imaging techniques were also reviewed which are able to visualize free radicals in animal subjects noninvasively. Applications of in vivo ESR spectroscopy and imaging for the detection of free radicals generated in biological specimens is another emerging field especially designed for the noninvasive direct detection of free radicals in biomedical applications. Shulaev and Oliver (27A104) and Tarpey et al. (27A113) have also recently written reviews on ESR methods for the detection of reactive oxygen- and nitrogen-centered free radical metabolites in in vitro and in vivo systems employing metabolic and proteomic markers for oxidative stress. Additional articles, reviews, and books on ESR and methodologies to detect and measure reactive free radicals in vitro

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Free Radicals

O

O

CH3 CH3

HC=N

HC=N

CH3 CH3

CH3

CH3 O=N

CH3

PBN

4-PBNO

N

CH3

MPN

CH3

O CH3 CH3 N N O

PNO

N O

4-methyl-PNO

O

CH3 DMPO

Figure XXVII-1  Chemical structures of 4-POBN, PBN, MNP, PNO, 4-methyl-PNO, and DMPO spin traps. (From McCormick, M.L., G.R. Buettner, and B.E. Britigan; J. Biol. Chem. 270 (1995) 29265-29269. With permission.)

and in vivo in plants and animals have been written by Khan and Swartz (27A58), Khan et al. (27A59), Bacic and Mojovic (27A03), Muckenschnabel et al. (27A75), Halliwell and Whiteman (27A43), Utsumi and Yamada (27A116), Utsumi et al. (27A117), and Halliwell and Poulsen (27A42). The newest methodologies for the detection, quantification, and identification of free radicals in cigarette smoke employ HPLC and high-resolution mass spectrometry (MS) analysis of stable radical adducts [Bartalis et al. (27A05)], hyphenated LC-MS/MS techniques with a C18 reverse phase column fitted to a triple quadrupole instrument for analysis of stable radical adducts [Rolando et al. (27A99, 27A100)], and electrospray ionization (ESI)-HPLC/MS analysis of stable radical adducts [Masselot et al. (27A68, 27A69)].

XXVII.C Free Radicals in Tobacco Smoke Tobacco smoke contains free radicals. As presented in previous chapters, tobacco smoke is a highly complex aerosol composed of more than 5000 components distributed between the vapor and the particulate phases. The enormous complexity of cigarette smoke is the result of multiple thermolytic processes that occur in heated tobacco within the confines of the burning cigarette rod. These processes involve distillation, pyrolysis, and combustion and are influenced by several factors, including the design of the cigarette [Norman (27A82)] and the composition of the tobacco blend [Bokelman and Ryan (385), Leffingwell (2338)]. As indicated in Chapters 1 through 21, numerous classes of organic compounds are represented in cigarette smoke, including saturated, unsaturated, and polycyclic aromatic hydrocarbons, alcohols, aldehydes, ketones, carboxylic acids, esters, phenols, nitriles, N-nitrosamines, terpenoids, and alkaloids [see also Baker (172), Dube and Green (1067), Hoffmann et al. (1744)]. Invariably, the combustion of tobacco, like

that of any organic matter, also produces free radicals via oxidative processes involving homolytic reactions. The high temperatures produced during the smoking process are easily capable of causing bond scissions that lead to free radical production [Badger et al. (141), Brown (27A14)]. An elaborate description of the fluctuating thermal gradients and vapor environment inside a cigarette during smoking has been given by Baker (172). The chemical complexity of cigarette smoke is strongly dependent on the heating conditions inside the lit cigarette. To summarize briefly, when a smoker lights and draws on a cigarette, the temperature of the ignited tobacco rises rapidly, and a hot coal forms at the lit end of the cigarette (the combustion zone and pyrolysis zone). Peak temperatures inside the coal can exceed 900°C. The high temperature inside the coal during a puff causes an increase in the viscosity of the air flowing through the coal and a concomitant increase in the resistance to the draw of air through the cigarette. This effect forces air to be drawn primarily into the periphery of the coal at the paper burn line rather than through the center of the coal. The depletion of oxygen due to combustion inside the coal and the flux of air around the coal results in the formation of a region immediately behind the coal that is depleted of oxygen, but where the temperatures remain high enough to promote the thermal decomposition of the unburned tobacco. This area behind the coal is known as the pyrolysis/distillation zone. Large amounts of volatile and semivolatile smoke constituents evolve from this zone. These constituents result, in part, from the pyrolysis of tobacco, and in part, from the distillation of volatile constituents native to tobacco because of the heat of the encroaching coal. Numerous types of MSS free radicals are formed in this pyrolysis/distillation zone [Wooten et al. (27A120)]. Cigarette smoke can be divided into two phases, particulate- and vapor-phase smoke, by the use of a Cambridge filter

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[Dube and Green (1067)]. The radicals in these two fractions differ greatly. The MSS particulate phase contains more than 1017 stable, long-lived radicals per gram of total particulate matter (TPM). The vapor phase of smoke contains more than 1015 short-lived radicals per puff [Baker (27A04), Wooten et al. (27A120)]. Free radicals in tobacco smoke were initially detected in whole smoke by Lyons et al. (2429). After some years, scientists became interested in examining the population of free radicals in the particulate and vapor phases of MSS. This trend has continued for nearly forty-five years. It was not until recently that it was proposed that artifacts may be forming during the separation of the whole smoke [Culcasi et al. (27A22), Bartalis et al. (27A05)].

XXVII.D Historical Review of Free Radical Research on Cigarette Smoke The following paragraphs chronologically summarize research reported on free radicals in MSS [Prier (27A84)] and important discoveries that shaped the mechanisms proposed to explain the generation of free radicals in MSS and their possible biological impact. This historical review of free radicals in cigarette smoke is not exhaustive, but attempts to capture much of the fundamental research that has shaped this field of science and gives the researcher ready sources for further examination. In 1958, Lyons et al. (2429) first observed free radicals by electron spin resonance (ESR) in whole cigarette smoke that was condensed at liquid oxygen temperature. These workers reported that whole cigarette smoke contains two populations of free radicals, an unstable population that can only be observed at -183°C and that vanishes when the condensate is warmed to 60°C, and a persistent, stable population that exists for “several days” at room temperature. They reported that the unstable population accounts for about one-sixth of the total free radical population determined at -183°C and consists of about 1015 free electrons per gram of tar. This work was repeated by Forbes et al. (1211) in 1967 with very similar results. In a second set of experiments Lyons and Spence in 1958 studied the effect of extracting benzene solutions of the stable free radicals with water, 2 N sodium hydroxide, and 2 N sulfuric acid. They reported that the ESR signal of the stable free radicals was reduced in intensity following each extraction by 20, 50, and 57%, respectively. They concluded that whole cigarette smoke contains several different types of free radicals, some of which are very stable while others exist only fleetingly. They also suggested for the first time that free radicals might be involved in the carcinogenicity of cigarette smoke (2432). In a follow-up study, Lyons and Spence in 1960 reported the detection of free radicals in sidestream smoke (SSS) as well as in MSS. They reported that dried SSS condensate contains 5 × 1014 spins per gram of tar, while MSS condensate contains 6 × 1015 spins per gram of tar. These results were compared

The Chemical Components of Tobacco and Tobacco Smoke

to chimney soot and to the condensed exhaust material from Diesel-powered automobiles that contain 5 × 1018 and 2 × 1019 spins per gram of material, respectively (2435). Ingram and Allen in 1959 (1862) and Ingram in 1961 (1861) published two further extensions of earlier work in which the pyrolysis of organic material was related to the production of free radicals detected by ESR. They demonstrated that free radical production by pyrolysis is a general phenomenon that occurs with various types of hydrocarbons and that the concentration of free radicals produced is proportional to the percent of carbon in the pyrolyzed material. A maximum free radical concentration was detected at about 90% carbon. They concluded that such a high percentage of carbon is consistent with a polycyclic aromatic hydrocarbon (PAH) and that free electrons must reside within such a structure. Ingram (1861) postulated that the stable free radicals generated from the pyrolysis of tobacco could be benzosemiquinone radicals. He also postulated that PAH free radicals would be present in tobacco smoke condensate. In 1963, Marsden and Collins (2466) reported on their results from measurements of α-activity in leaf tobacco used for cigarettes marketed in the United Kingdom, and in specially made, standard-size unblended cigarettes made from tobaccos originating from widely separated geographical locations. The origin of free radicals in tobacco smoke was discussed. They speculated on contributions of α-radiation and free radicals in cigarette smoke in the induction of lung cancer. In that same year, Westermark (4220a) suggested that free radicals generated during smoking could lead to a free radical chain reaction, which could possibly generate enough free radicals to be carcinogenic. Wynder and Hoffmann in their lengthy 1964 review of tobacco carcinogenesis (4319) discussed tobacco smoke as a “complete carcinogen” and in their evaluation of the role of tobacco smoke components in experimental carcinogenesis listed radicals with the comment that radicals are “suggested as possible carcinogens in disagreement with the experiments” [see p. 391, Table XXII in (4319)]. Takeshita and Ohe in 1964 published a paper on the effects of aging of cigarette smoke and its relation to radical concentration (3864). In their study they used the radical scavenger α,α’-diphenyl-β-picrylhydrazyl (DPPH) and were able to detect free radicals in condensed whole smoke from flue-cured tobacco after 300 hr, employing a colorimetric method. DPPH is a fluorescent stable free radical and will react with other radicals to form a neutral, nonfluorescent hydrazine species. DPPH is not considered a spin trap, which generally involves free radical addition to a nitroso function. The reaction produces stable nitroxides which build up to readily detectable concentrations in the presence of a free radical source. The usefulness of radical addition reactions with nitrones has been found to exceed that of the nitroso compound because of their greater stability in a variety of reaction conditions. Much work has been done with phenyl N-tert-butylnitrone (PBN) in solution, although many new spin adducts are now available. The free radical addition reaction is called a spin-trapping reaction. The nitrone or nitroso

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compound is called a spin trap and the radical addition product is called a spin adduct [Janzen and Gerlock (27A54)]. In 1965, Boenig (369) reported on the pyrolytic products of cigarettes irradiated with 60Co γ-radiation. ESR experiments were not conducted on the tobacco to determine the presence or extent of free radicals, although a reduction in concentration of free radicals in smoke condensate (as measured by ESR) was noted along with reductions in MSS tars and tar-like components. Later in 1975, Severson et al. (3610) conducted studies on γ irradiation of cigarettes and concluded that γ irradiation had no major effects on smoke composition. Their study negated the possibility of decreased formation of PAHs as a result of fewer free radicals and other suggested changes in smoke chemistry. Boenig reviewed the literature on free radicals and health in 1966 (370, 371). In his reports, he considered the fundamental processes involved in the pyrolysis of tobacco during smoking, that is, distillation, steam distillation, thermal oxidation, decomposition, and thermal cracking (thermal cracking apparently playing a major role in this combustion). He emphasized that thermal cracking probably is the most important step, during which free radicals are formed. Interaction of a considerable proportion of these free radicals then leads to the formation of various types of molecules including the PAHs. He proposed a mechanism that would explain the formation of PAHs from various tobacco constituents and a variety of small reactive free radicals, for example, NO, hydroxyl, and alkyl. Later that year, he authored a paper in which he proposed a unifying concept that free radical exposure and health are intimately linked (372). Browning and Patton presented a paper at the 20th Tobacco Chemists’ Research Conference in 1966 on a quantitative analytical procedure to determine stable free radicals in tobacco smoke condensate by ESR (448). Their analytical method for the determination of stable free radicals in tobacco smoke condensate was generally applicable to all types of tobacco tars. Accuracy for the method was based upon standard coal reference samples that yielded 7.52 × 1016 spins/g of tar. The experimental precision was 10%. They discussed the limitations (heating effects, sample isolation and concentration, and solvent effects) and utility of the method. In 1966, Forbes reported on the role of free radicals in tobacco smoke carcinogenesis (1210). In that publication, he concluded that tobacco smoke condensates contained a variety of free radical species that had a broad range of stability. Some of the free radicals had life-times of only a few seconds, while others are stable over long periods of time. The chemical nature of the radicals formed in tobacco smoke was not fully identified. Forbes postulated that some of the free radicals formed resembled radicals obtained from benzo[a]pyrene. In 1967, Forbes et al. further examined free radicals present in tobacco smoke condensates by ESR (1211). They prepared and examined sulfuric acid solutions of smoke condensates. They reported that the free radical species present in sulfuric acid solutions of smoke condensates corresponded to a modified benzopyrene-type cation radical and to the spectrum of a modified anthracene cation radical, with the

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latter decaying fairly rapidly. No definitive proof was given for these two cation radicals. Rowlands et al. (27A101) studied the effect of MSS free radicals on the tissue of perfused rabbit lungs in 1967. The lungs were removed from the animals and attached to bell jars that were used to simulate the breathing operation. The animal blood was circulated through the veins and arteries attached to the lung while smoke were periodically drawn into the lung. The blood was then sampled and studied by ESR. They found a three-line ESR spectrum superimposed on a second broad singlet. They theorized that a covalent, hexa-coordinated ferric hemoglobin complex explained the ESR spectra. In 1968, Rowlands et al. (27A102) published an extension of their previous work in which the reaction of cigarette smoke condensate (CSC) with hemoglobin was studied in more detail. In addition, the electron transfer properties of the smoke condensate were studied. The involvement of the oxides of nitrogen in the free radical properties of the smoke was suggested by a selective condensation experiment in which the smoke was fractionated at various temperatures and the various condensates reacted with hemoglobin. Cooper et al. published a paper (814) in the 1968 National Cancer Institute monograph Toward a Less Harmful Cigarette (4343) in which they suggested that free radicals in MSS were possible contributors to tobacco smoke carcinogenesis. They summarized research from the previous decade on free radicals in tobacco smoke and discussed the possible role of free radicals as a cause of cancer (814). It should be noted that as early as 1954, Dorn reviewed the published experimental evidence that indicated that the products formed by the combustion of tobacco may cause skin cancer in mice. He stated that compared to other known carcinogens, the combustion products of tobacco smoke are relatively weak. (27A30). In their 1967 book, Wynder and Hoffmann [see pp. 461–463 in (4332)] briefly described the studies on cigarette smoke free radicals conducted up to that time. Summing up the available evidence, they wrote: Several facts seem to exclude an importance of radicals in tobacco smoke condensate carcinogenesis. Even though sidestream smoke condensate contains only about one tenth the amount of free radicals found in the mainstream smoke condensate, the tumor response of both sidestream and mainstream “tar” on mouse skin is not different statistically … Since both types of radicals are present mainly in the particulate matter, it remains questionable whether in freshly generated tobacco smoke organic radicals participate in the carcinogenic effect.

During 1968, Stedman wrote his review on the chemical composition of tobacco and smoke (3797). In his review he summarized much of the prior work on free radicals in MSS. At that time, no free radicals in tobacco or tobacco smoke had been identified. As free radicals were considered to be playing some role in the induction of cancer, efforts were concentrated on determining the quantity of free radicals in smoke and their stability.

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In 1961, Larson et al. (2264) published their book on experimental and clinical studies on tobacco. Free radicals in smoke were not mentioned. However, in Supplements I, II, and III, issued successively in 1968, 1971, and 1975, respectively, Larson and Silvette (2266) summarized reported research on free radicals in tobacco smoke. In the nearly 800-page 1968 Supplement I, they reviewed the free-radical findings of Lyons and Spence (2432), Ingram (1861), Ingram and Allen (1862), and Westermark (4220a) in a few paragraphs. In the over 500-page 1971 Supplement II, Larson and Silvette summarized the findings on free radicals in tobacco smoke by Boenig (370, 371), Peacock and Spence (27A82b), and Cooper et al. (814) in less than a page. In the nearly 800page 1975 Supplement III, their only reference to radicals in tobacco smoke was in two separate paragraphs on a study by Dontenwill et al. (1046a) in which the specific tumorigenicities of the CSCs from control and tobacco treated with n-propyl gallate were compared. The n-propyl gallate was a known scavenger of free radicals. No tumorigenic difference was observed. During 1969, Rathkamp and Hoffmann (3086) reported on the inhibition of the pyrosynthesis of several selective smoke components. They suggested from the results of their pyrolysis studies on tobacco containing KNO3 or I2 that PAHs are at least partially formed via C and H free radicals. In 1969, Tully et al. (27A115) were the first authors to publish a study of the free radicals in the vapor phase of MSS cigarette smoke that was condensed at liquid oxygen temperature. The condensed vapor phase of MSS produced no ESR signal until the temperature of the ESR cavity holding the sample was raised to -100°C. At this temperature, a threeline ESR spectrum was obtained that had nitrogen splitting [a(N)] of 1.26 mT. For cigarettes made with tobacco that contained 3.4% copper nitrate by weight, a complex ESR spectrum consisting of at least seventeen lines was observed. The three-line spectrum from the untreated tobacco increased to a maximum intensity after 1.5 hr at -100°C. When warmed to room temperature, the ESR signals observed at -100°C vanished irreversibly. These authors concluded that the observed free radicals may have formed as a result of some unspecified participation by nitrogen oxides (NOx) in free radical reactions within the smoke. Interestingly, nitrogen dioxide (NO2), itself a free radical, adds to olefinic double bonds to produce carbon-centered free radicals [Estefan et al. (27A35)]. ESR spectra taken on solutions of NO2 mixed with different olefins show three-line spectra that are very much like those observed by Tully et al. (27A115). In each case, a three-line spectrum with a(N) = 1.22 to 1.33 mT is obtained [Estefan et al. (27A35), Bielski and Gebicki (27A09), Pryor et al. (27A91)]. Short-lived particulate- and vapor-phase free radicals that cannot be measured directly by ESR can be measured with the aid of spin traps. The first application of spin trapping to the study of free radicals in tobacco smoke was reported in 1971 by Bluhm et a1. (349). MSS from commercial cigarettes, pipes, and cigars was bubbled through solutions of α-phenylN-tert-butylnitrone (PBN) in benzene (a spin trap). In each case, a doublet of triplets with a(N) = 1.376 and a(H) = 0.199

The Chemical Components of Tobacco and Tobacco Smoke

mT was obtained along with a triplet with a(N) = 0.801 mT. The former splittings were assigned to an alkoxyl free radical adduct of PBN, while the latter signal was assigned to benzoyl tert-butylnitroxide (PBNOx). The intensity of the spinadduct signal from cigarette smoke was the weakest, while that from cigars was the strongest. The identity of the specific alkoxyl radical was not determined. Bilimoria et al. investigated the inhibition of radical initiated polymerization of vinyl acetate by tobacco smoke and some PAHs in 1973 (329). Their results indicated that vapor phase of smoke is an efficient inhibitor of vinyl acetate polymerization and that conjugated dienes like isoprene are responsible for the inhibition. There were no free radicals from tobacco smoke specifically identified in this research. Nisbet and Schmeller presented the results of this research at the 27th Tobacco Chemists’ Research Conference (TCRC) in 1973 (2789a). At that same TCRC in 1973, Johnson (1956) presented a paper on the antioxidant activity of tobacco smoke. The investigation was undertaken to determine whether or not smoke initiates or promotes the formation of radical peroxides which would in turn lead to lipid peroxidation. He found that both the vapor phase and particulate phase of smoke behaved as an antioxidant. Fractionation of the total smoke condensate showed antioxidant activity in the neutral and water-insoluble acidic fractions, with virtually no activity in the basic fractions. The mode of antioxidant action of tobacco smoke was discussed in terms of free radical mechanisms involving atom transfer, addition, substitution, and coupling. De Hys et al. in 1973 (27A25) studied the spin trapping of free radicals in the filtered MSS of 1R1 research cigarettes. They obtained spin-adduct spectra that did not exhibit hydrogen splitting, although the three-line spectra were very broad (the hydrogen splitting was not resolved). They reported that smoke held in the syringe for 15 sec before being bubbled through the PBN solution showed no change in spectral features, while smoke held in the syringe for 30 sec resulted in a 50% decrease in the spin-adduct spectral intensity. These authors also found that spin trapping unfiltered smoke resulted in no spin-adduct spectra. Experiments were also performed using 2-nitrosotoluene and 5-nitroso-8-quinolinol as spin traps. In the first case, a three-line spectrum was obtained with a(N) = 1.56 mT, while the second spin trap gave no spin adduct. No attempt was made to identify the free radical trapped with 2-nitrosotoluene. These results indicate that time and smoke filtration impact free radical collection and measurement. NO2 was bubbled through a solution of PBN in benzene and the resulting solution studied by ESR. A strong three-line ESR spectrum with a(N) = 1.0 mT was observed. Smoke bubbled through cyclohexene produced no ESR signal, although NO2 can react with olefins to give the three-line spectrum described above (27A35, 27A09, 27A91). These authors concluded that the free radicals in the vapor phase of cigarette MSS have half-lives of about 30 sec and that NO2 is not the dominant free radical species responsible for production of spin-adducts from cigarette smoke.

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In 1974, Morie evaluated the effectiveness of free radical traps in cellulose acetate filters for the removal of nitrogen oxides from cigarette smoke (2625). Four free radical spin traps were tested as cigarette filter additives for the removal of nitrogen oxides from tobacco smoke. A filter consisting of cellulose acetate fibers containing 20 mg of 4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-tert-butylamine N-oxide removed 42% of the nitrogen oxides from cigarette smoke. Three other free radical traps when placed on cellulose acetate fibers or activated carbon within cigarette filters reduced the concentration of nitrogen oxides in the smoke to a lesser extent. The mechanism proposed by Morie for the removal of nitrogen oxides was that the free radical spin trap reacted with a free radical in the tobacco smoke to yield a long-lived nitroxide radical, which in turn reacts with nitrogen oxides in the smoke. A spin-trapping study of the free radicals in the MSS from 1R1 research cigarettes was performed by Menzel et al. in 1976 (27A72). These authors used spin-adduct spectral line broadening to determine that the MSS vapor phase results in 1 × 1018 spin-trapped free radicals per cigarette puff (about 1019 spins/g of tar produced). Using spin-trap solutions in series, they estimated the efficiency of spin trapping of the tobacco smoke free radicals with PBN to be about 47%. They obtained extremely broad spectral lines (by ESR) showing no hydrogen splitting. Their results were somewhat suspect as the spin-adduct concentration that they obtained (2 × 1019 spins/g) was much larger than any other free radical concentration reported before or since (2429, 2435, 27A95). During 1976, Pryor edited and contributed to a book on free radicals in biology (2998a). In that book, he discussed free radicals in cigarette smoke and the possible action of free radicals in smokers. A comprehensive study of free radicals in the vapor phase of MSS produced by 1R1 research cigarettes was reported in 1976 by Pryor et al. (27A95). Using three different spin traps, PBN, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), and 3,5-(di-tert-butyl-4-hydroxyphenyl)-N-tertbutylnitrone (OHPBN), they found that MSS produces three types of spin adducts: an alkoxyl or aroyloxyl spin-adduct, PBNOx, and an unknown adduct with a(N) = 1.00 mT. They reported that the intensity of the alkoxyl adduct increases with the distance that the smoke must travel from the cigarette to the spin-trap solution and then decreased thereafter. They called this phenomenon the path length effect. The concentration of spin-trapped free radicals was found to be about 1 × 1015 spins/g of tar. In addition, the effect of aging on the absolute and relative concentrations of the spin adducts was studied. The conditions of collection also had an impact on free radical measurement. Their data did not allow them to specify the identity of either the aromatic group in the aroyloxy (ArCO2˙) radical or the alkyl group in the alkoxy (RO˙) radicals. Ishiguro and Sugawara published their review on chemistry of tobacco smoke in 1980 (1884). This was the last major review of compounds identified in tobacco smoke. In their massive report they reviewed the literature on free radicals in

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tobacco smoke. There were no identified free radicals specifically mentioned in their review. They stated that: The study of radicals in smoke has not advanced very far because of the difficulty of identifying the radicals. It is hoped that further progress will be made in this field so that the formation routes of many components can be understood and the composition of smoke components can be better controlled.

In a paper written in 1982 entitled “Free Radical Biology: Xenobiotics, Cancer, and Aging,” Pryor suggested that free radicals in cigarette MSS could pose a significant health risk to smokers (2998b). In that paper he proposed several complicated interactions between MSS components, for example, NO, dienes, phenols, and free radicals that he believed were operative means leading to carcinogenesis. In 1983, Slaga et al. suggested that free radicals may be involved not only in initiation but also in the promotion of carcinogenesis (3687). In 1983, using ESR spin-trapping techniques with PBN as the spin trap, Pryor et al. (2999a) observed free radicals in the vapor phase of both cigarette MSS and SSS. The principal vapor-phase free radicals appeared to be alkoxyl radicals (RO˙). Pryor et al. determined that each of the vapor phases of cigarette MSS and SSS has about the same concentration of radicals, about 1 × 1016 radicals per cigarette (or 5 × 1014 per puff) (2999a). In that same year, Pryor et al. (2999) examined and found that the particulate matter from both MSS and SSS contained persistent free radicals. The ESR signal was obtained when the particulate matter collected on Cambridge pads was measured directly and when the particulate matter was extracted from the Cambridge pad with various solvents. Pryor et al. listed the occurrence of four paramagnetic radical species in CSC. Three of these radicals, an inorganic phosphorus radical, a graphitic carbon associated radical, and a radical that appeared associated with an odd electron delocalized over an aromatic ring system, appeared to have relatively short half-lives. However, the fourth type of free radical had an unusually long half-life of several days. It was speculated that the dominant ESR signal from this fourth type was from free radicals generated from catechol and hydroquinone. Neither of these free radicals was identified unequivocally (2999). Treatment of alcoholic solutions of particulate matter with base generated a new group of radicals that appeared to be semiquinone radicals derived from the oxidation of phenolic and polyphenolic species in the particulate matter. Pryor et al. suggested this latter radical was associated with a quinone/hydroquinone acceptor/ donor chain (2999). Again, the identification of the specific free radicals was not obtained. In these two papers and again in 1984 (3001), Pryor et al. suggested the possible involvement of particulate-phase MSS free radicals in smoking-related diseases (2999, 2999a). In vitro assays were performed that suggested that cigarette smoke may cause oxidative stress or oxidative damage to essential biological molecules (3000, 27A120). Specifically in 1984,

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ESR evidence of the binding of the particulate-phase MSS free radicals to DNA and polynucleotides was shown (3001). In the 1984 American Chemical Society monograph on chemical carcinogenesis, edited by Searle (3568) and with contributions from experts in carcinogenesis, there was no mention of the carcinogenicity of free radicals, nor any tumorigenic PAH or aza-arene in tobacco smoke, despite the reports by Snook et al. (3756–3759, 3750, 3752, 1544, 3664, 3665, 3908). In 1985, Nakayama et al. published a report that described the generation and identification of H2O2 and superoxide anion radical from cigarette smoke (2677). H2O2 and superoxide anion radical were generated in a neutral buffer solution through which cigarette smoke was bubbled. They speculated that the H2O2 may have been formed by the autooxidation of polyphenols such as catechol and hydroquinone in the cigarette smoke. During 1985, Halpern and Knieper isolated and tentatively identified the tert-butoxy radical by the spin trapping of radicals in the vapor phase of cigarette smoke (27A44). Cosgrove et al. in 1985 (828a) showed that it was possible to detect hydroxyl radicals in an aqueous extract of the particulate phase of cigarette MSS under metal-mediated conditions. An unidentified alkyl radical and the carbon dioxide anion radical were also observed under their experimental conditions. They concluded that the results of their experiment indicated that the major particulate-phase free radical was a quinone/hydroquinone redox system in a polymeric matrix and that the radical signal could become associated with DNA. Unequivocal proof was not provided for these claims. Church and Pryor in a 1985 publication (746) summarized their work (to that point) on the free radical chemistry of cigarette smoke and its toxicological implications. They stated that cigarette smoke contains two very different populations of free radicals, one in the particulate phase and one in the vapor phase. The particulate phase contains several relatively stable free radicals. Church and Pryor stated that they had “identified” the principal radical as a quinone/hydroquinone complex (QH/QH 2) held in the tarry matrix. However, no unequivocal identification was ever made. They suggested that this QH/QH 2 complex was an active redox system that is capable of reducing molecular oxygen to produce superoxide, eventually leading to H2O2 and hydroxyl radicals. In that same publication, Church and Pryor (746) stated that the vapor phase of cigarette smoke contains small oxygenand carbon-centered radicals that are much more reactive than the particulate-phase radicals. Although no vapor-phase radicals were specifically identified, they stated that the vapor-phase radicals do not arise from the initial combustion of the tobacco, but are rather produced in a steady state by the oxidation of NO to NO2, which then reacts with reactive species already present in smoke, such as isoprene. They suggested that these reactive vapor-phase free radicals and the metastable products derived from the radical reactions may be responsible for the inactivation of α1-proteinase inhibitor by fresh smoke.

The Chemical Components of Tobacco and Tobacco Smoke

Church and Pryor (746) proposed that the excess superoxide that is expected to form in lung tissue exposed to cigarette smoke is one possible means of inactivating α1-protease inhibitor, a protein associated with the onset of emphysema in deficient individuals. In the same report, the authors noted that after particulate-phase MSS was incubated with deoxyribonucleic acid (DNA), an ESR signal was observed in the recovered DNA. Later, it was suggested that hydroxyl free radicals generated from the particulate-phase MSS free radicals may cause DNA damage [Kiyosawa et al. (27A60), Pryor (27A85), Pryor et al. (27A93)]. Later in 1992, Pryor (27A85) noted that such molecular damage is not unique to tobacco smoke, but also occurs with smoke from other sources, such as Diesel fuel and wood. In 1986, Pryor wrote a paper on the formation, lifetimes, and reactions of oxy-radicals and related species (2998c). In his overview, he discussed some of the ways in which free radicals and other highly reactive species are produced in biological systems. He discussed the reactivity and lifetimes of these species and listed some pathological conditions and chronic diseases in which these species may be involved. He discussed that cigarette smoking is a rich source of free radicals and that much of the toxicity associated with cigarette smoking may be due to the presence of free radicals in MSS. In 1986, the International Agency for Research on Cancer (IARC) issued its monograph on tobacco smoking (1870). Free radicals in tobacco smoke were discussed: Smoke can be a major indirect or direct source of chemical oxidants and radicals, and also causes a rapid influx of pulmonary alveolar macrophages and polymorphonuclear neutraphils in the lung. These actively phagocytic cells release a variety of oxidative intermediates when exposed to particulates such as those in cigarette smoke. The intermediates found in cigarette smoke and/or released by activated macrophages include superoxide anion, hydrogen peroxide and hydroxyl radical.

Other than referring to the article on free radicals in cigarette smoke by Church and Pryor (746), IARC cited none of the many other pre-1986 references to free radicals in tobacco, for example, Bilimoria et al. (329), Bluhm et al. (349), Boenig (370–372), Browning and Patton (448), Cooper et al. (814), Cosgrove et al. (828a), Forbes (1210), Forbes et al. (1211), Ingram (1861), Ingram and Allen (1862), Lyons et al. (2429), Lyons and Spence (2432, 2435), Marsden and Collins (2466), Morie (2625), Nakayama et al. (2677), Nisbet and Schmeller (2789a), Pryor (2998a, 2998b), Pryor et al. (2999, 2999a, 3001), Slaga et al. (3687), and Takeshita and Ohe (3864). During the 1980s, R.J. Reynolds Tobacco Company (RJRT) developed a new cigarette product called Premier that heated rather than burned tobacco. A tremendous amount of research was conducted on that product prior to introduction. The research on Premier was summarized in a monograph by RJRT (3190). Free radical analyses comparing the Premier product and University of Kentucky 1R4F reference cigarette were conducted by Rice and Hayes in 1989 (1555c, 3129). In two studies, they reported that Premier had

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a 99% reduction in vapor- and particulate-phase free radicals compared to the 1R4F reference cigarette. Similar ESR spectra were obtained but the yields of radicals in both phases were decreased. In the 1R4F cigarette, the particulate-matter free radicals appeared to be from species with an odd electron delocalized over an aromatic ring system, for example, a PAH. The second source of particulate-matter free radicals appeared to come from what Church and Pryor (746) suggested was a donor/acceptor chain involving hydroquinone as the donor and quinone as the acceptor. ESR analysis of 1R4F vapor phase indicated the presence of radical species similar to those previously reported for tobacco-burning cigarettes. No identification of specific free radicals was conducted in these studies. In 1988, O’Brien (27A82a) discussed the fate of free radicals and their effect on chemical carcinogenesis. Only one comment was included on cigarette smoke and it involved the PAH B[a]P in MSS and the assertion of its involvement in lung cancer induction. O’Brien stated that PAHs like B[a]P donate a single electron to an enzyme which may be involved in the generation of tumorigenic diol-epoxides of the PAH. In 1989, Nakayama et al. (27A79) reported on a reliable method for the detection and quantitation of H2O2 generated in aqueous extracts of cigarette smoke tar. Aqueous tar extracts (ACT) were passed through a short reverse-phase column and the H2O2 concentration was determined by differential pulse polarography using an automatic reference subtraction system. The H2O2 concentration in the ACT increased with aging, pH, and temperature; the presence of superoxide dismutase led to lower H2O2 concentrations. Their method was applied to several types of research and commercial cigarettes. They reported that, with few exceptions, the amount of H2O2 formed after a fixed time from each cigarette smoke was proportional to its tar yield. Brunmark and Cadenas (27A15) reviewed the major mechanisms that are involved in quinone-induced cytotoxicity in 1989. The redox chemistry of quinoid compounds was surveyed in terms of (1) reactions involving only electron transfers, such as those accomplished during the enzymatic reduction of quinones and nonenzymatic interaction with redox couples generating semiquinones, and (2) nucleophilic addition reactions. In their explanation of the mechanisms involved, quinone is reduced to the hydroquinone or semiquinone radical by cellular reductase. The semiquinone radical then undergoes rapid autooxidation with the generation of the parent quinone and concomitant formation of superoxide. The hydroquinone reacts rapidly with superoxide to form H2O2 and the semiquinone. In 1992, Pryor (27A85) reviewed, compared, and contrasted the chemistry of cigarette smoke, wood smoke, and the smoke from plastics and building materials that was inhaled by persons trapped in fires. He contended that cigarette smoke produced cancer, emphysema, and other diseases after a delay of years. He discussed that acute exposure to smoke from a fire could produce a loss of lung function and lead to death after a delay of days or weeks. Tobacco smoke and the smoke inhaled in a burning building have

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some similarities from a chemical viewpoint, for example, both contain high concentrations of CO and other combustion products. In addition, both contain varied concentrations of free radicals, which if inhaled could lead to biological harm (27A65). At this time, personnel in Pryor’s laboratory had studied these free radicals, largely by ESR methods, for about 15 years. The article reviewed what was known about the radicals present in these different types of smokes, soots, and tars. His article summarized the evidence that suggested that free radicals could be involved in cigarette-induced pathology and smoke-inhalation deaths. In 1993, Diana and Pryor edited a book entitled Tobacco Smoking and Nutrition: Influence of Nutrition on TobaccoAssociated Health Risks (960c). In that book, Pryor and Stone wrote a chapter on oxidants (free radicals, H2O2, peroxynitrate, and peroxynitrite) in cigarette smoke (3000). They reported that methyl nitrite (CH3ONO), NO, and NO2 were primary oxidants in the vapor phase of MSS and that the proposed quinone/semiquinone/hydroquinone equilibrium complex was the primary oxidant in particulate-phase MSS. They postulated that peroxynitrite (HOO-N=O) and/ or peroxynitrate (HOO-NO2) or their esters (RO-ONO and RO-ONO2) were present in the vapor phase of MSS. They argued that hydroxyl radicals were generated from H2O2 via the Fenton reaction (27A36), that carbon-centered radicals were generated from dienes in MSS, and that peroxyl radicals (ROO˙), alkoxyl radicals (RO˙), and superoxide radicals (O˙-) were present in the vapor phase of MSS. In that same book, Niki et al. reviewed information on membrane damage from lipid oxidation by free radicals in cigarette smoke (2786a). Cigarette smoke contains metals and metal ions (see Chapter 20). Certain metal ions are important in free radical reactions, for example, Fenton-type metal catalyzed free radical reactions. In 1993, Li and Trush (27A67) reported on the oxidation of hydroquinone by copper and provided chemical mechanisms for the generation of quinone species and their biological effects. Since the interaction of several xenobiotics with copper had been shown to result in their metabolism, Li and Trush investigated the role of copper in the oxidation of hydroquinone (HQ) and HQ-induced toxicity to mice bone marrow stromal cells, target cells of HQ in the bone marrow. In phosphate-buffered saline, HQ underwent autooxidation slowly to benzoquinone (BQ), while the presence of Cu2+ ions (1 to 50 µM) strongly accelerated the oxidation of HQ to BQ in a concentration-dependent manner. Reaction of HQ with Cu2+ was also accompanied by the reduction of Cu2+ to Cu1+, the utilization of O2, and the concomitant generation of H2O2. Their results indicate that Cu2+ strongly induced the oxidation of HQ and as such may be a factor involved in the oxidative activation and toxicity of HQ in target cells. As copper, HQ and BQ are known components of MSS, the relevance of the work of Li and Trush became important in light of the postulated mechanism of Pryor and Stone (3000). Cueto and Pryor in 1994 (27A21), following up on the report by Pryor and Stone in 1993 (3000), reported their work on the conversion of NO to NO2 by Fourier Transform IR. They also reported their results on the reactions of olefins

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with nitrogen oxides. In order to explain the apparent longevity of the presumably short-lived free radicals in aging filtered smoke, a steady-state production mechanism was proposed involving oxygen, nitrogen oxides, and vapor-phase olefins. No specific reaction products were discussed. Tanigawa et al. (27A112) published a paper on the spin trapping of superoxide in aqueous solutions of fresh and aged cigarette smoke in 1994. Superoxide generation was determined as a function of the age of the smoke using spin trapping. 5,5-Dimethylpyrroline-N-oxide (DMPO) was used as the spin trap. The superoxide adduct of DMPO was detected in a solution of fresh MSS for over 1 hr. The superoxidegenerating potential of smoke was rapidly lost as the smoke was kept in a plastic syringe. Smoke aged for 3 min did not generate superoxide. Additional evidence of superoxide generation in aqueous solutions of cigarette smoke was obtained by the chemiluminescence method. Church in 1994 (27A19) published an article on the spin trapping of organic radicals. In that article, he postulated a steady-state mechanism that he believed explained the formation of longer-lived vapor-phase free radicals in cigarette MSS. The proposed mechanism was based on the observation that NO2 concentration in MSS followed the concentration of the free radicals in the vapor phase of MSS. In 1995, Stone et al. (27A111) reviewed the previous work conducted in the laboratories of Pryor, which showed that extracts from MSS or SSS nicked DNA. These solutions were believed to contain the semiquinone free radical. Aged solutions of catechol containing a semiquinone species that had ESR properties similar to those of the radical in cigarette tar extracts were used as a model for the MSS particulatephase radical. Both the radical in aged catechol solutions and the cigarette tar radical become associated with the DNA in mammalian cells and nicked DNA. The nicking of DNA caused by both the MSS particulate-phase radical and aged catechol solutions followed saturation kinetics. The authors believed that aged catechol solutions could be used as a model for the MSS particulate-phase radical. Unfortunately, their model did not take into account the fact that MSS is a complex mixture and that other constituents in MSS could have altered their finding. In 1995 Stohs and Bagchi (27A109) reviewed the role of reactive oxygen species, with the subsequent oxidative deterioration of biological macromolecules in the toxicities associated with transition metal ions. Studies have shown that metals, including iron, copper, chromium, and vanadium undergo redox cycling, and that this cycling can result in the production of reactive oxygen species such as superoxide ion, H2O2, and hydroxyl radical. As a consequence, lipid peroxidation can be enhanced, DNA can be damaged, and calcium and sulfhydryl homeostasis can be altered. Various studies have suggested that the ability to generate reactive oxygen species by redox cycling quinones and related compounds may require metal ions. Cigarette MSS contains metal ions. Some mechanisms associated with the toxicities of metal ions are very similar to the effects produced by many organic xenobiotics. Specific differences in the toxicities of metal ions may be

The Chemical Components of Tobacco and Tobacco Smoke

related to differences in solubility, the complex mixture containing the metal, absorbability, transport, chemical reactivity, and the complexes that are formed within the body. Their review summarized studies (through 1995) that had been conducted with transition metal ions, regarding the production of reactive oxygen species and oxidative tissue damage. In 1995, Li et al. (27A66) reported on ESR evidence for the generation of reactive oxygen species from the coppermediated oxidation of the benzene metabolite hydroquinone and its possible role in DNA damage. Prior to this study, Li and Trush (27A67) had observed that Cu2+ strongly induces the oxidation of hydroquinone (HQ), producing benzoquinone and H2O2 through a Cu2+/Cu1+ redox cycle mechanism. The oxidation of HQ by Cu2+ also resulted in plasmid DNA cleavage. In this study, using ESR spectroscopy, they investigated whether this chemical-metal redox system could generate reactive oxygen species that induce DNA damage. Studies were not performed with cigarette MSS but were conducted on solutions of HQ. Results indicated that both H2O2 and Cu1+ are critical for the formation of reactive oxygen from the HQ/Cu2+ systems. Aerobic conditions were necessary for the redox system to function. Reactive oxygen scavengers significantly inhibited the redox mechanism. Overall, the results indicated that it is possible through a copper-redox cycling mechanism, to generate a reactive oxygen species of HQ that may participate in DNA damage. The conditions of the experiments were not those that a smoker would experience. Zang et al. investigated the presence of free radicals in aqueous extracts of cigarette tar by ESR (27A122) in 1995. They demonstrated that aqueous extracts of cigarette tar (ACT) autooxidized to produce semiquinone, hydroxyl, and superoxide radicals in air-saturated, buffered aqueous solutions. Semiquinone species were detected by direct ESR measurements and were tentatively identified as o- and p-benzosemiquinone radicals by comparison with the ESR signals of catechol and hydroquinone radicals under similar conditions. The rate of formation of these radicals was dependent on pH. Hydroxyl and superoxide radicals were detected as 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) spin adducts by ESR spin trapping. Superoxide dismutase (SOD) (20 units/mL) inhibited the formation of the superoxide spin adduct of DMPO completely. Addition of Fe2+ to this system increased the ESR signal intensity of hydroxyl radical spin adduct of DMPO. Their results indicated that superoxide and hydroxyl radicals are produced during the autooxidation of hydroquinone- and catechol-related species in ACT under the specific conditions of their experiments. Borgerding et al. (27A13) presented a paper at the 1995 TCRC on a method for the quantitative determination of free radicals in the vapor phase of cigarette MSS. The method was based on trapping free radicals in a α-phenyl-N-tertbutylnitrone (PBN)/benzene solution to form a stable radical species, that is, spin trapping, followed by detection with an ESR spectrometer. Two smoke collection techniques were discussed which differed in the extent of smoke aging prior to spin trapping. Both techniques were found to be acceptable for the comparison of cigarette smoke yields. Free

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radical analysis of the vapor phase of MSS from cigarettes that contained a novel carbon filter and experimental low N-containing tobacco blend demonstrated that vapor-phase free radical reductions on the order of 80% were possible when compared to other equivalent “tar” cigarettes. At the same conference in 1995, Blakley et al. (27A10) reported the results of their studies on MSS vapor-phase radical formation and possible formation mechanisms. Church and Pryor (746) had previously suggested a mechanism for formation of mainstream vapor-phase radicals that involved a reaction between NO2 and reactive dienes, such as isoprene. Experiments were conducted to systematically explore the proposed mechanism. Included in the experiments were cigarettes from different “tar” categories, cigarettes comprising a new type of carbon filter [Blakley et al. (27A12)] and blends, and cigarettes that primarily heated, rather than burned, tobacco. Some results indicated that the suggested NO2/diene mechanism was viable, while other results did not support the Church-Pryor mechanism. For many of the cigarettes studied, vapor-phase radical yields increased as either isoprene or NOx smoke yields increased. [It should be noted that in 1978, Cooper and Hege (816) reported that there is very little NO2 in cigarette smoke, most of the NOx is NO.] However, in a series of experimental cigarettes where isoprene yield was held constant and NOx levels substantially increased, vapor-phase free radicals were dramatically reduced. In addition, preliminary research suggested that some processed tobaccos yielded diminished radicals as compared to unprocessed tobaccos, while NOx smoke concentrations remained constant. Data were also presented on a cigarette constructed from wood shavings that produced a substantial free-radical response with virtually no isoprene or NOx present in the smoke. In 1996 Rahman and MacNee (27A96, 27A97) reviewed the literature on the imbalance between oxidants and antioxidants concerning the pathogenesis of smoking-induced lung diseases, such as chronic obstructive pulmonary disease (COPD), particularly emphysema. There was evidence that indicated that increased neutrophil sequestration and activation occurred in the pulmonary microvasculature in smokers and in patients with COPD, with the potential to release reactive oxygen species. Reactive oxygen species generated by airspace phagocytes or inhaled directly from the environment can increase the oxidant burden and may contribute to the epithelial damage. Although much research has focused on the protease/antiprotease theory of the pathogenesis of emphysema, less attention had been paid to the role of reactive oxygen species in this condition. The possible effects of the increased oxidant burden in smokers and in patients with COPD are opposed by the lung antioxidant defenses. In their article, they reviewed the evidence for the presence of an oxidant/antioxidant imbalance in smoking-induced lung disease and its relevance to therapy in these conditions. They noted that the involvement of MSS vapor-phase free radicals in oxidative damage was unclear because generally the reactive vapor-phase free radicals in MSS are quenched immediately on contact with the moist surfaces of the respiratory tract.

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In 1997, Kodama et al. (27A62) analyzed multiple components in cigarette smoke for their ability to form active oxygen species using a spin-trapping agent, 5, 5-dimethyl-1pyrroline-N-oxide (DMPO). The main source of O2 and H2O2 was ascribed to polyphenols in a particulate phase of MSS. Hydroxyl free radicals (OH˙) were identified in the vapor phase of MSS. Carbonyl sulfide in the vapor phase was shown to be a source of DMPO-OH adduct. NO in the vapor phase of MSS did not show appreciable reactivity. They added that the quantification and identification of active oxygen species in cigarette smoke could provide important information for elucidating the mechanism of tobacco carcinogenesis, as certain types and concentrations of free radicals have shown genotoxic effects to induce DNA strand breaks, as well as epigenetic effects, to act as cell proliferation signals. In 1997, Pryor summarized the free radical mechanisms developed in his laboratory over the previous twenty-one years (27A86). He stated: Cigarette smoke is a rich source of free radicals, as well as other oxidants and puts an oxidative burden on the entire organism. Smoke contains two phases, operationally defined as gas-phase smoke, which passes through a glassfiber Cambridge filter and particulate matter, or tar, which is retained on the filter. Gas-phase smoke contains reactive, short-lived radicals that can be detected and quantified using electron spin resonance (ESR) spin trap methods. The radicals in gas-phase smoke do not result from the flame directly, but rather are continuously generated by the oxidation of NO to NOx, which then adds to reactive species in the smoke (primarily isoprene) to give R˙ radicals, which react with O2, to give RO- and ROO˙ radicals. Gas-phase smoke, with up to 500 ppm NO as well as oxy-radicals, also produces a variety of reactive nitrogen species (RNS), including HOONO, NOONO˙, ROONO˙, and ROONO˙. Gas-phase smoke oxidizes α-I-antiproteinase by a process involving H2O2 and RNS. Cigarette tar contains a stable semiquinone radical Q -˙, that can be observed by direct ESR; the tar radical reduces O, and thus aqueous cigarette tar (ACT) extracts contain O2-˙, H2O2 and ˙OH. The tar radical binds to and associates with DNA (both by ESR and by 14C). ACT extracts nick DNA, and ˙OH or a species like it are responsible for the damage. Fractionation of ACT shows that the fractions that contain the tar radical O2-˙ are responsible for >85% of the nicks.

In 1997, Stohs et al. (27A110) reviewed the potential of metal ions reacting in conjunction with other constituents of tobacco smoke to cause cellular damage by free radical reactions. Various studies had demonstrated the role of reactive oxygen species in the toxicity of transition metals. They concluded that the presence of several reactive metal ions in tobacco smoke indicates that there may be a role for metal ions in the subsequent toxicity and carcinogenicity of tobacco smoke. They described the metal-catalyzed mechanisms that might be involved. By the early 1990s, free radicals generated from MSS were considered a significant health risk because of their potential involvement in oxidative stress. Müller et al. (27A77) reported that NO in cigarette smoke could react with

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superoxide derived from the reducing constituents in the particulate phase of cigarette smoke to form peroxynitrite (ONOO-). NO may also be converted to a number of more reactive nitrogen derivatives, such as NO2, dinitrogen trioxide (N2O3), and dinitrogen tetraoxide (N2O4). Their results were consistent with a rapid NO-consuming reaction coupled with superoxide-generating properties of the particulate phase of MSS. The roles of superoxide (O2˙-), peroxynitrite, and carbon dioxide (CO2) in the oxidative chemistry of NO was reviewed by Squadrito and Pryor (27A106) in 1998. Each of these reactive oxygen species can cause biological damage at high concentrations. They contended that NO and superoxide are produced by several cell types and can rapidly combine to form peroxynitrite. Peroxynitrite is a potent and versatile oxidant that can attack a wide range of biological targets, if not held in check. In previous publications, Pryor implied that NO and superoxide (both known MSS components) could be linked to numerous diseases associated with smoking. Of course, CO2 is also present in MSS. Peroxynitrite is normally scavenged by antioxidants, but CO2 can also compete with certain antioxidants. Squadrito and Pryor proposed a mechanism for the reaction of CO2 with OONO˙ that produced metastable nitrating, nitrosating, and oxidizing species as intermediates. An analysis of the lifetimes of the possible intermediates and of the catalysis of peroxynitrite decomposition suggested that the reactive intermediates responsible for reactions with a variety of substrates may be the free radicals NO2 and CO3˙-. In closing, Squadrito and Pryor noted that increased formation of peroxynitrite has been linked to Alzheimer disease, rheumatoid arthritis, atherosclerosis, lung injury, amyotrophic lateral sclerosis, and other diseases. Flicker and Green (27A38) developed a new HPLC method for the detection of free radicals in cigarette smoke and diesel exhaust in 1998. Carbon-centered radicals were trapped from the vapor phase of cigarette smoke and diesel engine exhaust by reaction with a nitroxide, 3-amino-2,2,5,5tetramethyl-1-pyrrolidinyloxy (3AP). The resulting mixture of stable, diamagnetic adducts was derivatized with naphthalenedicarboxaldehyde (NDA) to produce highly fluorescent products. Derivatives were separated by HPLC, which revealed distinctly different sets of radicals present in the two systems. Integration of HPLC peaks gave approximately 22 ± 7 nmol of radicals per cigarette and 3 ± 1 nmol of radicals per liter of diesel engine exhaust. An estimated eight to ten different carbon-centered radical species are present in each system. No identification of the free radicals was made. In 1999, Halliwell and Gutteridge (27A41) published a second edition of their book Free Radicals in Biology and Medicine. It has become a classic text in the field of free radical and antioxidant research. In their book, they reviewed the role of free radicals in the life and biomedical sciences and provided methods available to measure reactive species and oxidative damage (and their potential pitfalls), as well as the importance of antioxidants in the human diet. It is important to note that free radicals in cigarettes were not discussed, although, their text has often been cited concerning oxidizing

The Chemical Components of Tobacco and Tobacco Smoke

species/free radicals found in MSS that are known to cause oxidative damage in essential biomolecules. In 1999, a World Patent was granted to Emami on a cigarette filter additive to capture and remove free radicals from cigarette MSS (27A34). The filter additives described in the patent were based on natural polyphenols which efficiently scavenge free radicals in cigarette smoke. Among the various polyphenols tested, oils of rosemary extracts from Rosemarinus officinialis L. proved to be the most active in reducing the yields of both vapor- and particulate-phase free radicals. The additive-containing filters were stable at high temperature, had a twelve-month shelf-life, were not air sensitive, and had normal pressure drop characteristics. Emami et al. reported on the free radical scavenging efficiency of the cigarette filters containing rosemary extract in 2000 (1143). Employing ESR, Emami et al. were only able to tentatively identify the presence of hydroxyl, methoxyl, and cyano free radicals in MSS. Unfortunately, ESR techniques alone give poor structural information on the nature of free radicals. In 2000, Liu et al. (2380a) presented their research on the design of a unique low-“tar” cigarette designed to yield approximately 40% less particulate-phase free radicals. The cigarette employed a special filter, casing additives to reduce free radicals (vitamin E, vitamin A, cysteine, and selenic compounds of mannitol), a specially formulated casing with burn control agents, expanded tobacco, and tobacco filler rich in selenium. Although it was not possible to determine the interactive effects of all the changes in the uniquely designed cigarette, ESR results confirmed a reduction in particulatephase free radicals. Blakley et al. (27A11) published a paper in 2001 that questioned published reports postulating that the particulatephase free radicals of cigarette MSS consisted of a hydroquinone/semiquinone/quinone shuttle. Their results showed that there was no positive correlation between the smoke yield of hydroquinone and the presence of particulate-phase free radicals. When a tenfold reduction in MSS hydroquinone yield was obtained when KNO3 was applied to the surface of tobacco of an American blended cigarette, there was no significant corresponding change in the yield of particulate-phase free radicals. In experiments testing MSS from low- and high-hydroquinone-yielding tobaccos there was no consistent corresponding relationship between hydroquinone and particulate-phase radical yields. In one series of blends there was at best an inverse relationship between hydroquinone and particulate-phase radical yields. In contrast with the published literature, Blakley et al. concluded that the particular compound or compounds driving particulate-phase free radical formation are currently unknown. Flicker and Green (27A37) published an improved method for trapping carbon-centered free radicals (R˙) from the vapor phase of the MSSs from cigarettes and cigars in 2001. They compared free radical concentrations trapped from various cigarettes and model smoke systems. Using a nitroxide trap, 3-amino-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (3AP), on solid support, they trapped radicals directly from the vapor phase, washed them off the support, and analyzed them with HPLC.

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Separation of the trapped radicals showed that the vapor phase of smoke from each cigarette type produced a unique set of free radicals (four to ten distinct peaks). Vapor mixtures used to model tobacco smoke consisted of NO, air, isoprene, and methanol. The model systems produced a set of free radicals that consisted of four major and several minor peaks, two of which matched peaks in tobacco smoke chromatograms. Quantities of free radicals trapped from cigarettes tested varied from 54 ± 2 nmol to 66 ± 9 nmol. The cigar tested produced 185 ± 9 nmol of free radicals. In their experiments, oxygen competed with the nitroxide trap for MSS vapor-phase radicals. A kinetic analysis of the O2 competition shows that actual radical concentrations in the smoke were approximately 100-fold higher than measured. Valavanidis and Haralambous reported in 2001 (27A118) on the free radical populations in the MSS and SSS of cigarettes with conventional acetate filters compared to biofilters (BF) that claimed reductions in yields of certain toxic substances and oxidants in the vapor phase of the MSS (Deliconstantinos et al. 27A26) They found that BF cigarette smoke had similar tar radical species with the same intensity ESR signals to those of the other cigarettes containing cellulose acetate filters. The ability of the aqueous cigarette tar extracts to produce hydroxyl radicals in the cigarettes with the BF filter was very similar to, or even higher than, the other three brands tested. The vapor phase of the MSS of the BF cigarette showed a 30% to 35% reduction in the production of oxygen-centered radicals. In the case of the SSS, BF cigarettes produced substantially higher concentrations of vapor-phase free radicals, compared to the other brands. Their results suggested that cigarettes with the BF were partially effective at removing some of the vapor-phase oxidants but not effective in the reduction of tar and its radical species in the MSS and SSS. In their paper at the 55th Tobacco Science Research Conference (TSRC) in 2001, Wooten et al. reviewed free radicals and proposed mechanisms for their generation in tobacco smoke (4277). Their review was mainly a synopsis of work published by Pryor and his colleagues over the previous twenty years. No specifically identified free radicals were presented. The free radical NO is both found in all living organisms and is required for many physiological functions. NO is also an important regulatory molecule for immune response and cytotoxicity. It is naturally produced from l-arginine by NO synthases (NOS). As a free radical, it produces many reactive intermediates that account for its bioactivity. NO is also a component of MSS. One mechanism for NO-induced cytotoxicity was through its interaction with superoxide to produce peroxynitrite, which can cause DNA damage. Müller et al. (27A76) and Squadrito and Pryor (27A106) previously suggested that this same mechanism may be operative for free radicals in MSS. In 2001, Lala and Chakraborty published a paper on the role of NO in carcinogenesis and tumor progression (27A64). However, they also suggested that selective inhibitors of NOS may have a therapeutic role in certain cancers associated with free radicals.

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In 2002, Takanami et al. reviewed their research on the detection of free radicals in vapor phase of cigarette smoke by ESR at the 56th TSRC (3862). Usually, highly reactive free radicals are detected by ESR techniques once stable spin adducts are formed but this may lead to many pitfalls. In 2002, Masselot et al. (27A68) reported a new methodology to study free radicals based on electrospray ionization (ESI) and MS. The concentration of free radicals in MSS smoke is too low, compared to the total concentration of MSS, to allow for their identification by molecular ion identification alone. Stable spin adducts of free radicals from samples of MSS were analyzed by ESI-MS/MS and the resulting fragmentation spectra were used to determine the nature of the free radicals trapped in MSS. With this methodology, Masselot et al. successfully identified two free radicals in the cigarette smoke, the OH˙ and the CH3˙ radicals, and were able to tentatively identify the O2˙- radical. When coupled to LC techniques, the ESI-MS/MS analyses allowed not only for radical identification, but also for their quantification. Masselot et al. applied their new method to characterize and optimize a new filter, based on rosemary extracts, which efficiently scavenged free radicals in cigarette smoke and had been patented by Emami in 1999. The relative efficiency in the removal of the various free radicals present in cigarette smoke (C-centered, O-centered) were discussed. In 2002, Anderson et al. presented a review on the importance of previous work conducted on free radicals in cigarette smoke at the 56th TSRC (74). Ingebrethsen and Lyman (27A48) examined the mechanism proposed by Cueto and Pryor (27A21) and Pryor and Stone (27A93a) for the formation of reactive free-radical species from NO and NO2 in the vapor phase of cigarette MSS in 2002. Inspection of the generic reaction scheme proposed by Cueto and Pryor (27A21) and Pryor and Stone (27A93a) suggested that some condensable materials were likely to result. The possibility of particle formation and growth due to this condensable material suggested only one route for phase transformation in filtered smoke. From a practical perspective, those working with cigarette smoke have long been aware that totally filtered smoke can yield condensable deposits in smoking machine plumbing even in the absence of temperature gradients. Ingebrethsen and Lyman reported that aerosol particle formation and growth were observed in aging, initially particle-free vapors obtained from filtered cigarette MSS. The time scale of particle formation and growth was on the order of minutes and was highly dependent on cigarette tobacco type. Measurements by both ensemble and single particle light-scattering methods were consistent with scattering from an aerosol with a fixed number of particles that grew into the tenth micron range. The rate of particle size increase agreed best with that predicted for growth controlled by condensable species formation by vapor-phase reaction slower than the diffusion rate of the reaction products. A simple reaction scheme involving NO oxidation and reaction with isoprene reproduced the observed form of the particle growth curves but did not yield a consistent reaction rate constant for the various cigarette tobacco types. Their

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results were inconsistent with the proposed mechanisms of Cueto and Pryor (27A21) and Pryor and Stone (3000) and suggested that additional reactants are involved in the particle formation. Müeller and Intorp reported on the longer-lived particulate-phase free radicals (quinone, hydroquinone, and semiquinone species) they detected in MSS by ESR directly after extraction of Cambridge filter pads in 2003 (27A76). They also reported on their study of short-lived vapor-phase free radicals (alkoxy and alkyl species) in MSS. These radicals were spin trapped with α-phenyl-N-tert-butylnitrone (PBN) and detected by ESR. No specific identification of the free radicals was reported. In 2003, Baum et al. (27A08) reported on a rigorous set of experimental protocols they believed were necessary to conduct ESR experiments on particulate- and vapor-phase free radicals in MSS. In their paper, they discuss experiments that were conducted in order to determine the optimal conditions for maximum signal intensities and reproducibility of results. Their results showed that radical concentrations in smoke vary among cigarettes in both the vapor phase and particulate phase of MSS. By use of a series of commercial cigarettes, where many parameters change from cigarette to cigarette, no statistically significant correlations were found between radical levels and total particulate matter in smoke. However, a weak correlation was found between the vaporphase free radical levels and total particulate matter levels in smoke. They also reported that there may also be a complex effect of tobacco type on radical levels in smoke. Emami et al. presented a paper at the 2003 CORESTA meeting in Freiburg, Germany, on an improved method for the detection, quantification, and identification of vaporphase free radicals in MSS (27A32). They commented that the detection and quantification of vapor-phase free radicals by ESR has two main limitations: (1) free radical/spin-trap adducts are readily oxidized to give nonradical species, which cannot be detected by ESR; and (2) ESR techniques have a low capability to give structural information in the case of mixtures. Consequently, the unequivocal identification of many free radicals in cigarette smoke is still to be determined and in addition, quantitative results for comparison studies are difficult to obtain (27A08). Masselot et al. (27A68, 27A69) had previously reported on use of 4,5,5trimethylpyrroline-N-oxide for characterizing O-centered radicals and of 3-amino-2,2,5,5 tetramethyl-1-pyrrolidinyloxy for C-centered radicals. These two free radical trapping agents were used to identify the hydroxyl (OH˙) and methoxyl (CH3O˙) radicals and cyano (CN˙) radical, respectively. In this report, they described the quantitation of these radicals employing a hyphenated LC-MS/MS technique with a C18 reverse-phase column fitted to a triple quadrupole MS instrument. The addition of a stable free radical as internal standard (TEMPO, 2,2,6,6-tetramethyl-1-piperinodyloxy) allowed them to cleanly quantify the detected free radicals by the socalled MRM (multi-reaction monitoring) mode. The absolute quantification they obtained (ca. 1016 radicals per cigarette) was in good agreement with previous experiments based on

The Chemical Components of Tobacco and Tobacco Smoke

ESR techniques. They applied their improved free-radical method to characterize a new filter, patented by Emami in 1999, containing rosemary extracts, which scavenge free radicals in cigarette smoke (27A34). The relative efficiency in the removal of the various free radicals present in cigarette smoke (C-centered, O-centered) was 50% for filters containing 50 mg of formulated rosemary extract. Numerous presentations on free radicals were made in 2004 at the 58th TSRC and at the CORESTA Congress in Kyoto, Japan. In 2004, Zhou et al. (27A123) presented a systematic approach to the study of these free radicals in the particulate phase of MSS at both the CORESTA Congress and at the 58th TSRC (4415). They reviewed much of the prior research on detection methods for free radicals, discussed means to reduce free radical in MSS, and the need for more biomedical evaluation. In 2004, Rolando et al. (27A100) reported on the identification and quantitation of the hydroxyl (OH˙), methoxyl (CH3O˙), cyano (CN˙), formyl (HC(O)O˙), peroxyl (˙OOH), and nitrite (NO2˙) free radicals employing their previously reported hyphenated LC-MS/MS technique that used a C18 reverse-phase column fitted to a triple quadrupole instrument at the CORESTA Congress in Kyoto. Little et al. presented results of their investigation of phenolic particulate-phase free radicals (e.g., benzoquinonehydroquinone radical) in MSS measured by direct ESR measurements at low temperatures (2379) at the 58th TSRC. Variable temperature ESR studies were performed on the particulate-phase free radicals in MSS. Different particulatephase free radicals showed temperature dependence. Isolated particulate-phase free radicals began to form at about 450°C. It should be noted that stable benzoquinone-hydroquinone complexes (CAS No. 106-34-3) had been identified in tobacco smoke and Cytrel® smoke in 1969 by Green et al. (1378) and by Newell et al. (2767) in 1974. In neither study was any special procedure used to deal with free radicals. At the 58th TSRC, Rickert et al. reported on an ESR method used at LabStat for the determination of the yields of vaporphase and particulate-phase free radicals generated in MSS (3134). No specific identified free radicals were discussed. In 2004 at the 58th TSRC, Johnson and Chapman presented a general review on the identification of free radicals in whole smoke (1957). Again, no specifically identified free radicals were discussed. Johnson reported at the 59th TSRC, in 2005, on the results of the identification of spin-trapped vapor-phase free radicals in MSS via an ESI-triple quadrupole tandem mass spectrometry analysis method. Four alkoxyl free radicals were unequivocally identified (˙OC2H5, ˙OC3H7, ˙OC4H9, and ˙OC5H11). The superoxide free radical was also tentatively identified (27A56). Employing an Amplex Red assay, Yan et al. (27A121) were able to detect, quantify, and positively identify H2O2 in whole cigarette smoke. Although not a free radical, H2O2 has been proposed as an intermediate in certain free radical reactions. Church and Pryor (746) proposed that

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Free Radicals

hydroquinones present in the particulate phase of MSS can reduce dioxygen (O2) to produce superoxide (O2 –˙) and semiquinone (Q –˙) radical anions. The superoxide radical anion was thought to be the immediate precursor to H2O2, which could then be reduced to the hydroxyl radical by metals such as iron. Church and Pryor (746) suggested that the resulting HO˙ radical can then damage DNA. Yan et al. found that there was a time dependency of H2O2 production in whole cigarette smoke in their experiments. The Amplex Red assay showed an increase in the production of H2O2 of up to 120 min and then reached a plateau thereafter; suggesting H2O2 was formed over this time period by some reaction(s) involving the highly complex mixture of chemical constituents present in whole cigarette smoke. In the work of Yan et al., concentrations of 3 to 8 µM H2O2 were found in aqueous solutions of whole-smoke bubbled samples, while there was negligible H2O2 formation from vapor-phase bubbled samples. The data in this work suggest that the major constituents responsible for H2O2 formation are in the particulate phase. Aqueous solutions of hydroquinone and catechol, both of which are particulate-phase constituents of cigarette smoke, generated no H2O2 even though they are free radical precursors involved in the production of reactive oxygen species in the smoke matrix. In 2005, Chouchane et al. (27A18) studied cigarettes that had varied levels of polyphenols in the tobacco filler (flue-cured, burley, Oriental tobacco, and blends of these tobaccos). They found that the yield of particulate-phase free radicals generated in the MSS from these cigarettes was not directly related to the total amount of polyphenolic compounds in the tobacco leaf filler. For example, cigarettes prepared from flue-cured tobacco, which contains a significantly higher amount of polyphenols in comparison to burley tobacco, did not generate a higher yield of particulate-phase free radicals in MSS compared to cigarettes prepared with burley tobacco. Halliwell and Poulson recently published a book on cigarette smoke and oxidative stress (27A42). The currently proposed mechanisms for free radical production in cigarette smoke were discussed. They concluded that the proposed mechanisms by which cigarette smoke causes or contributes to inflammatory diseases like COPD, cardiovascular disease, and cancer remain unclear. In several chapters in their book, they discussed recent developments in cellular signaling and suggested that cigarette smoke may cause oxidative stress in cellular systems. The assessment, consequences, and possible modulation of biological effects from oxidative stress were discussed. Analytical methods for the determination of isolated free radicals and biological assays for free radicals were also discussed. In 2006, Rolando et al. (27A99) developed a new methodology based on liquid chromatography (LC), mass spectrometry (LC-MS and LC-MS/MS) for the identification and quantification of free-radical–spin-trap adducts. The improved method involved the use of a nano-LC fitted with a 75-µmcolumn for separation that allowed for shorter analysis time and higher sensitivity. The main advantage of

1249

their improved method was its ability to detect and identify certain free radical adducts (so-called ESR silent adducts) which had been oxidized or reduced after the trapping. By using spin traps that were specific for the trapping of C- or O-centered free radicals, they unambiguously identified the OH˙ and CH3˙ radicals. Using this new methodology, they were able to ascertain the presence and identification of the cyanide radical (CN˙) and nitrite (ONO˙) radical. They stated that they were continuing their work on the structure of more complex free radicals at higher molecular mass by comparing spectra from chemically generated free radicals to those present in MSS. Free radicals in cigarette smoke have attracted a great deal of attention because they are hypothesized to be responsible in part for several of the pathologies related to smoking. Hydroquinone, catechol, and their methyl-substituted derivatives are abundant in the particulate phase of cigarette smoke, and they are known precursors of semiquinone radicals. In the study by Chouchane et al. (27A17) in 2006, the in vitro cytotoxicity of these dihydroxybenzenes was determined with the neutral red uptake (NRU) assay, and their radicalforming capacity was determined by ESR. All of the dihydroxybenzenes studied were found to generate appreciable amounts of semiquinone radicals when dissolved in the cell culture medium employed in the NRU assay. Hydroquinone exhibited by far the highest capacity to form semiquinone radicals at physiological pH, even though it was not the most cytotoxic dihydroxybenzene. Methyl-substituted dihydroxybenzenes were found to be more cytotoxic than either hydroquinone or catechol. The formation of semiquinone radicals via autooxidation of the dihydroxybenzenes was found to be dependent on the reduction potential of the corresponding quinone/semiquinone radical redox couple. The capacity to generate semiquinone radicals was found to be insufficient to explain the variance in the cytotoxicity among the dihydroxybenzenes in their study; consequently, other possible mechanisms of toxicity must also be involved. The observed interactions between 2,6-dimethylhydroquinone and hydroquinone in the cytotoxicity assay and ESR analysis suggested that care needs to be taken when studying the bioactivity of cigarette smoke constituents, that is, the effect of the whole cigarette smoke complex matrix on the activity of the single constituent studied must be taken into consideration. Biological studies of the separated particulate and vapor phases of MSS may provide results that are different from those of studies of whole MSS. In 2006, Culcasi et al. (27A22) also reported on the free radical-related cytotoxicity of the vapor phase of MSS and the paradoxical temporary inhibition of cytotoxicity of vapor-phase free radicals by the MSS particulate phase. In their ESR studies, the spin trap 5-(diethoxyphosphoryl)-5methyl-1-pyrroline-N-oxide (DEPMPO) was employed. They experimented with cigarettes made with cellulose acetate filters, empty cavity filters, and cavity filters containing carbon (charcoal). In their study, filters containing carbon were effective in reducing vapor-phase free radical formation, cytotoxicity, and lipid peroxidation in three cell lines. The

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results of their experiments also showed that NO and NO2 are more important than hydroxide free radicals in generating the cytotoxicity of vapor-phase MSS free radicals generated from MSS constituents. Culcasi et al. also suggested that something in the MSS TPM reduced the cytotoxicity of vapor-phase free radicals in MSS as there was an unexpected protective effect of TPM on the cytotoxicity of whole smoke compared to that of vapor phase of MSS alone. They concluded that the conventional smoke collection method (separation of the smoke into vapor and particulate phases) distorts the true picture of free radical activity. In other words, free radical activity in cigarette smoke should only be evaluated on a “whole smoke” basis. In 2007, Dellinger et al. (27A27) conducted and reported on the formation and stability of resonance stabilized free radicals of the type hypothesized by Pryor and his associates in the particulate phase of MSS. They concluded that the commonly observed free radicals in the particulate phase of MSS were not a surface associated semiquinone and were more likely an intrinsic, polymeric radical with a delocalized electron. The EPR signal observed by Pryor in the alcohol extract of the particulate phase of MSS may be from an extracted and autooxidized hydroquinone, not a particulatephase-associated semiquinone radical. The semiquinone radical was observed in the particulate-phase MSS collected below 400°C and has a five-line spectrum with g ~ 2.006. Semiquinone radicals were formed in the particulate phase of MSS only after aging. Ghosh et al. in 2007 (27A39) presented their research results on the ESR study of free radicals in the vapor phase of the MSS from 2R4F reference cigarettes. The vapor phase of MSS trapped with DMPO contained a mixture of three free radical species that correspond to two oxygen-centered radicals (90%), and an unidentified radical (10%) resulting from the decomposition of the spin adducts. They were able to identify the methoxy free radical in the vapor phase of MSS via computer simulation. The oxygen-centered free radical concentration in the vapor phase of MSS was in the range of 1014 to 1015 spins per cigarette smoked under ISO standard smoking conditions. In 2007, Bartalis et al. (27A05) identified seven acyl and eleven alkylaminocarbonyl radicals in whole MSS employing HPLC and high-resolution mass spectrometry analysis of stable radical adducts. The combined abundance of these free radicals measured in fresh whole smoke from a single 2R4F cigarette was approximately 225 nmol (1.4 × 1017 radicals). The fiberglass Cambridge filter pad conventionally employed to separate the vapor phase from the particulate phase of MSS was found to reduce the apparent yield of these radicals, introducing artifacts of measurement. They stated that the long-accepted steady-state mechanism for the formation of C-centered radicals in cigarette smoke involving NO2 chemistry cannot account for these newly identified radicals, and does not in general appear to be a major source of C-centered radicals in fresh cigarette MSS. Consequently, they suggested that the precise nature of radicals in cigarette smoke warrants reexamination.

The Chemical Components of Tobacco and Tobacco Smoke

XXVII.E Proposed Mechanisms for the Generation of Free Radicals in MSS Smoking has been implicated in numerous diseases (4012, 27A50, 27A51, 27A83, 27A87). Over the last fifty to sixty years, extensive research has been conducted to understand relationships between individual smoke constituents and smoking-related diseases. Because cigarette smoke is a complex mixture and a great number of complex biological processes are involved in each disease, no simple correlations have been found between smoking and disease. This is not to say that we have not progressed in our understanding of the biological effects of smoking and disease but causal relationships are still largely unknown (27A17). Numerous constituents of cigarette smoke have been identified as potential agents of biological damage, including tobacco-specific N-nitrosamines, PAHs, phenolic compounds, and free radicals (746, 1727, 2999, 3712). Free radicals in tobacco smoke have attracted much attention during the last thirty years. Free radicals in biological systems can cause DNA damage, lipid peroxidation, and protein oxidation [Baskin and Salem (27A07), Halliwell and Gutteridge (27A41)] if not moderated by the body’s oxidative stress defenses. Cigarette smoke and other environmental pollutants contain free radicals (2999, 2999a). Although free radicals in tobacco smoke have been implicated in human disease, no unequivocal proof of their harm has been established. Tobacco smoke is a complex mixture containing thousands of chemical constituents that can readily produce free radicals in aqueous media (828a, 2999). Tobacco smoke also contains an even greater concentration of antioxidants, antimutagens, and anticancer agents that have been shown to effectively inhibit several biological processes that could lead to disease. In Chapter 26 on carcinogens, cocarcinogens, anticarcinogens, and antimutagens, this subject is reviewed. Nevertheless, there are still many unanswered questions concerning the involvement of free radicals in the toxicology of tobacco smoke. In-depth studies are needed to delineate their precise effects (27A17). In 1958, Lyons et al. (2429) first observed free radicals by electron spin resonance (ESR) in whole cigarette smoke that was condensed at liquid oxygen temperature. These workers reported that whole cigarette smoke contains two populations of free radicals, an unstable population that can only be observed at -183°C and that vanishes when the condensate is warmed to 60°C, and a persistent, stable population that exists for “several days” at room temperature. The unstable population of free radicals included those in the vapor phase of whole cigarette smoke and the more stable population of free radicals included those found in the particulate phase of whole smoke. As a result, the early examination of the chemical and physical characteristics of free radicals in tobacco smoke was conducted mainly on free radicals in the particulate phase. In 1969, Tully et al. (27A115) were the first to publish a study of the free radicals in the vapor phase of cigarette MSS that was condensed at liquid oxygen temperature.

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Free Radicals

By passing whole cigarette smoke through a fiberglass filter, called a Cambridge pad, the particulate phase of cigarette smoke can be efficiently separated from the vapor-phase constituents (172, 1067). The use of Cambridge pads allowed investigators to separate and independently investigate the free radicals in both phases of whole smoke. The chemical behaviors of the vapor- and particulate-phase free radicals of MSS smoke were found to be quite distinct. The vapor-phase radicals have been shown to be unstable and very reactive, whereas the radicals in the particulate phase are much longer lived (2999, 2999a, 27A95). Derivative methods or spin-trapping techniques were developed to stabilize the vapor-phase free radicals for quantitation. From about the mid-1960s, chemical and biological research on free radicals in tobacco smoke involved separation of the smoke stream into vapor and particulate phases. From 1976 through 2006, Pryor and his associates studied both vapor- and particulate-phase free radicals in tobacco smoke (746, 828a, 2999, 2999a, 3000, 3001, 27A19, 27A21, 27A24, 27A84-27A95, 27A106, 27A111, 27A122). They generated experimental evidence that suggested possible mechanisms for the initiation, propagation, and termination of free radicals in tobacco smoke. They also alleged that free radicals in MSS were important to numerous smoking-related diseases. They hypothesized that vapor-phase free radicals in tobacco smoke were formed by a continuous mechanism, whereby NO reacted with molecular oxygen in air to form NO2, and subsequent reactions between NO2 and unsaturated molecules in cigarette smoke, for example, isoprene and butadiene, yielded alkyl, peroxyl, and alkoxy radicals. They contended that the reaction of peroxyl radicals with NO generated additional NO2, creating a steady-state cycle (2999a, 27A94). Pryor and his associates also postulated a mechanism for the generation and reaction of free radicals in the particulate phase of tobacco smoke. In that mechanism, particulate-phase free radicals in MSS were postulated to be semiquinone radicals in a polymeric matrix (2999). They stated that the particulate phase of MSS contained numerous dihydroxybenzenes, which could generate semiquinone radicals (27A122). They supported their hypothesis by showing that hydroquinone and catechol can undergo oxidation in air to form semiquinone radicals and ultimately quinones. They further showed under laboratory conditions that reactions between the semiquinone free radicals and molecular oxygen, either in aqueous extracts of cigarette tar (ACT) or in living cells, could lead to the creation of reactive oxygen species (ROS) such as superoxide radical, H2O2, and hydroxyl radical (27A122). It is important to note that the measurements of Pryor et al. (27A93) and others performing research on free radicals in tobacco smoke are not representative of free radical formation under physiological conditions or in biological systems (27A17). The free radical mechanisms proposed by Pryor and his associates were very convincing but, like all mechanisms, as scientific curiosity is piqued, they were vigorously tested by others. In 2001, Blakley et al. (27A11) showed that the yield of particulate-phase free radicals was not correlated with the yield

1251

of hydroquinone in MSS. For a series of cigarettes containing different tobacco blends with variable yields of MSS hydroquinone, the amount of free radicals in the particulate phase of MSS remained unchanged. In their experiments, methylene chloride was used to extract the particulate matter from Cambridge pads, the solvent evaporated, and the residue redissolved in benzene for EPR measurements. Under these experimental conditions, hydroquinone would be less likely to undergo autooxidation, which is less favorable in organic solvents. Nevertheless, significant levels of particulate-phase free radicals were observed, which calls into question the exact nature of the radicals that could be involved in biological damage. Ingebrethsen and Lyman in 2002 conducted experiments on particle formation and growth in vapors from totally filtered cigarette MSS (27A48). In their experiments, they tested a simple reaction scheme involving nitrogen oxide oxidation and its reaction with isoprene. Their experiments reproduced the expected and observed form of the particle growth curves and did not yield a consistent reaction rate constant for the various cigarette tobacco types. Their results were inconsistent with the proposed vapor-phase free radical mechanisms of Cueto and Pryor (27A21) and Pryor and Stone (3000) and suggested that additional reactants are involved in the particle formation. Cytotoxicity is regarded as a potential step in several chronic disease processes, including carcinogenesis and emphysema [Butterworth et al. (27A16)]. The cytotoxic constituents of cigarette smoke and their mechanisms of action are poorly understood [Chouchane et al. (27A17)]. Thus far, most research has focused either on the chemistry of cigarette smoke or on the in vitro and in vivo effects of cigarette smoke on biological systems. The lack of a bridge between these two approaches has made it difficult to assess the relationship between cigarette smoke constituents and their effects in biological systems. It is known, for example, that cigarette smoke contains a substantial amount of dihydroxybenzenes in the particulate phase of MSS (2681, 3175, 3743). In vitro assays have demonstrated that ACT, which contains significant amounts of hydroquinone, catechol, and other mono- and dihydroxybenzenes, can damage DNA [Pryor et al. (27A93)]. However, there is no direct evidence to suggest that pure hydroquinone or catechol can induce the same level of free-radical formation and DNA damage as any isolated fraction of ACT [Chouchane et al. (27A17)]. Again, it must be repeated that the experimental conditions employed by Pryor and others for measurement of free radical activity in tobacco smoke are not representative of free radical formation under physiological conditions or in biological systems (27A17). In 2006, Culcasi et al. (27A22) suggested that something in the MSS particulate phase reduced the cytotoxicity of MSS vapor-phase free radicals as there was an unexpected protective effect of particulate phase on the cytotoxicity of whole smoke compared to that of vapor phase of MSS alone. They concluded that the conventional smoke collection method, that is, separation of the smoke into vapor and particulate phases, distorted the true picture of free radical activity. In other words, free radical activity in cigarette smoke should

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only be evaluated on a “whole smoke” basis, unlike much of the research that had been conducted previously. Therefore, a reexamination of some of the toxicological data on free radicals would be prudent. Chouchane et al. (27A17) recently studied the involvement of semiquinone radicals in the in vitro cytotoxicity of cigarette MSS. Prior to their study it was known that dihydroxybenzenes can generate semiquinone radicals, quinones, and reactive oxygen species (ROS) in oxygenated physiological media in vitro, for example, in the growth media used in cytotoxicity assays. It was believed that certain dihydroxybenzenes could possibly generate similar semiquinone radicals, quinones, and ROS in vivo in the epithelial lining fluid of the lungs of smokers. Brunmark and Cadenas (27A15) suggested that the cytotoxicity of quinols and quinones may be due to the concerted action of several processes that include redox cycling, alteration of thiols balance through oxidation or arylation, inhibition of cellular functions, alteration of Ca2+ homeostasis, and covalent binding to nucleic acids, proteins, and lipids. It is difficult to extrapolate in vitro data analysis to an in vivo system, especially if the in vitro experiments were not conducted under conditions close to physiological conditions. Moreover, few data are available on the cytotoxicity of pure dihydroxybenzenes to compare with the toxicity of a complex mixture containing dihydroxybenzenes, such as cigarette smoke. The dihydroxybenzenes in their study were constituents of the particulate phase of MSS and were found to exhibit significant cytotoxicity. The methyl-substituted dihydroxybenzenes were shown to have higher cytotoxicity than the unsubstituted compounds. The dihydroxybenzenes were shown to generate semiquinone radicals in the medium used in the NRU cytotoxicity assay. Nevertheless, a correlation between the abundance of semiquinone radicals formed and their cytotoxicity was not found. The observed interaction between 2,6-dimethylhydroquinone and hydroquinone in the cytotoxicity assay and EPR analysis demonstrates that the EC50 values in binary mixtures of the dihydroxybenzenes cannot, in general, be assumed to be additive. Consequently, the interpretation of the bioactivity of cigarette smoke evaluated by similar methods should consider the possible effects of the complex mixture of MSS on the activities of the individual constituents. The most recent study of free radicals in tobacco smoke, published by Bartalis et al. (27A05), indicated that the analysis of whole smoke vs. vapor-phase and/or particulate-phase samples is not only important but absolutely necessary in evaluating the true chemistry of free radicals in tobacco smoke. Bartalis et al. measured and identified seven acyl and eleven alkylaminocarbonyl radicals in fresh whole smoke from a single 2R4F cigarette. These eighteen free radicals had a spin concentration of 1.4 × 1017 radicals/cigarette and accounted for nearly the entire ESR signal. They showed that the longaccepted steady-state mechanism for the formation of carboncentered radicals in cigarette smoke involving NO2 chemistry cannot account for these newly identified radicals, and that it does not in general appear to be a major source of carboncentered radicals in fresh cigarette MSS. The fiberglass

The Chemical Components of Tobacco and Tobacco Smoke

Cambridge filter pad conventionally employed to separate the vapor phase from MSS was found to reduce the yield of these radicals, introduced artifacts of measurement. The introduction of a Cambridge pad reduced the yield of the eighteen free radicals measured and identified by 96%. In their experimental procedure that did not use Cambridge pads or any spin traps, no NO2 was detected in the smoke. [This finding parallels that of Cooper and Hege (816), who reported that, even under unfavorable conditions, the nitrogen oxides in cigarette MSS are predominantly NO]. NO2 formation was shown to be an artifact of the smoke separation procedure. Bartalis et al. found no evidence of any type of free radicals containing a NO2 group as previously proposed by Pryor and his associates (746, 2999, 27A88, 27A89) and Flicker and Green (27A37, 27A38). The proposed mechanism of the addition of NO2 to dienes in cigarette smoke, cigarette pyrolysates, or model gas mixtures of NO, air, and isoprene was found to have no merit. The long-accepted steady-state mechanism for the formation of carbon-centered radicals in cigarette smoke involving NO2 chemistry cannot account for these newly identified radicals; consequently, they suggested that the precise nature of radicals in cigarette smoke warrants a total reexamination. Bartalis et al. stated: The widely accepted mechanism for the formation of both alkyl and alkoxyl radicals in cigarette was proposed by Pryor and co-workers and supported by persuasive, but primarily indirect, evidence was based on comparisons of gas-phase cigarette smoke and model gas mixtures.

Based on the work of Blakley et al. (27A11), Ingebrethsen and Lyman (27A48), Chouchane et al. (27A17, 27A18), Culcasi et al. (27A22), and Bartalis et al. (27A05), the proposed mechanisms of Pryor and his associates certainly need to be reexamined. Additionally, the previously made biological assertions need to be reevaluated since the free radicals presumably present in MSS may not actually exist. The clear evidence of artifacts formed by the separation of whole smoke into particulate and vapor phases supports the total reexamination of the chemistry and biology of free radicals in tobacco smoke proposed by Bartalis et al. (27A05). In summary, it would appear that we have come full circle over the last fifty years. Lyons et al. (2429) initially examined free radicals in whole smoke without the use of Cambridge pads and today this appears to be the collection method of choice. Tremendous analytical advancements have occurred over the last fifty years and now the identification and quantification of free radicals in whole tobacco smoke are finally possible. Artifact formation is always possible in research and is not a weakness of the experimenter. As additional research continues on free radicals in tobacco smoke, we express the same concerns and hopes of Ishiguru and Sugawara (1884) in 1980: It is hoped that further progress will be made in this field so that the formation routes of many smoke components can be understood and the composition of smoke components can be better controlled. Table XXVII-1 is a catalog of free radicals identified to date in tobacco and tobacco smoke. The catalog contains

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Free Radicals

 Table XXVII-1  Free Radicals in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke 7DEOH;;9,,)UHHUDGLFDOVLQWREDFFRWREDFFRVPRNHDQGWREDFFRVXEVWLWXWHVPRNH   &$61R



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1254

The Chemical Components of Tobacco and Tobacco Smoke

Table XXVII-1 (continued) Free Radicals in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke   &$61R

 

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Free Radicals

only thirty-five entries, including a general entry labeled Radicals, free. The vast majority of the entries in the table are tobacco smoke components, except for NO and oxygen that are also found in tobacco. Hydrogen peroxide was added for completeness since it was discussed several times in the chapter. It is anticipated that with the new analytical methods

1255

recently demonstrated by Bartalis et al. (27A05), Masselot et al. (27A68), and Rolando et al. (27A99, 27A100) that many additional free radicals in tobacco smoke will soon be identified. It should be kept in mind that, in light of the recent discovery by Bartalis et al. (27A05), some of the previously identified free radicals in tobacco smoke may be artifacts.

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28

Summary

The following initial comments were presented in greater detail in the Foreword. Since the mid-1950s, the combined referenced cataloging of the chemical components of tobacco and tobacco smoke may have been conducted in-house at various U.S. and foreign tobacco companies, as well as by various governmental agencies, but none has been published since the 1968 review by R.L. Stedman of the U.S. Department of Agriculture (3797). Prior to that, there were only a few such publications, one in 1959 [Johnstone and Plimmer (1971)] and one in 1963 [Philip Morris, Inc. (2939)]. In subsequent years, several tobacco and tobacco smoke publications dealt with specific types of components, for example, the 1977 review by Schmeltz and Hoffmann on the nitrogen-containing components in tobacco and tobacco smoke (3491). Several catalogs of the chemical components of only tobacco smoke have been published, but the most recent one was that of Ishiguro and Sugawara (1884) in 1980. Since the 1968 article by Stedman, the number of identified tobacco and tobacco smoke components has increased sevenfold to almost 8600. No other commercial product has been so completely defined. This catalog is our attempt to categorize with references the identified and reported components in tobacco and tobacco smoke as of 2007. Hundreds of scientific articles (many of them referenced in this text) have stated that tobacco and tobacco smoke are complex mixtures. This is an accurate statement. But some have alluded to or emphasized that they are primarily complex, that is, these mixtures of chemicals are just too multifarious, too difficult to completely understand, or so complicated and/or convoluted that the normal individual could not possible comprehend the totality of the concept or composition of the mixture. This was never the intent of the definition of a complex mixture, but nevertheless, some have implied that this multifaceted conglomeration of chemical components in tobacco and tobacco smoke is too difficult to explain and understand. The tobacco industry has often stated that tobacco and tobacco smoke are complex mixtures, without providing a basis for the statement. This text illustrates the complexity of tobacco and tobacco smoke. It provides the reader with an historical perspective on the identification of thousands of chemical components in tobacco and tobacco smoke, it contains reviews of all known and identified classes of chemical components in tobacco and tobacco smoke, and it provides thousands of accessible references on identified chemical components in tobacco and tobacco smoke. Also provided in the preceding pages are references and discussions of one of the major problems with a complex mixture, that is, the extrapolation of a biological property found in experimental studies with an individual compound in the mixture to the property of that component in a mixture which may contain

components that either enhance or offset the experimentally observed biological property of the component. Even though tobacco and tobacco smoke are complex mixtures, they are not incomprehensible. Tobacco and tobacco smoke are among the most extensively studied complex mixtures. There are literally millions of protein fragments being cataloged as part of the tobacco genome projects. Over 30,000 enzymes are known to participate in plant growth and regulation. Oxidation, reduction, additions, hydrogenation, pyrolysis, decarboxylation, and dehydration are but a few of the many chemical reactions known to be involved in tobacco pyrolysis and combustion. These reactions are capable of producing hundreds of thousands of reaction products. The limiting factor in the discovery and identification of additional chemical components in tobacco and tobacco smoke was the early analytical technology but this was changed significantly over the years by the development of new and ever-improved analytical technologies. Since the 1954 listing of fewer than a hundred tobacco smoke components by Kosak (2170), various investigators have estimated from gas chromatographic scans that for each component identified in tobacco smoke there are five to twenty components present at extremely low per cigarette yields that have not yet been identified. Thus, as noted by Wakeham (4103) in 1971 when the identified tobacco smoke components numbered about 1350: Gas chromatographic scans indicate there are many more, probably over ten thousand, possibly even a hundred thousand [tobacco smoke components].

Grob (1422), one of the pioneers of the use of glass capillary gas chromatography in tobacco smoke composition studies, as well as other tobacco smoke investigators, also noted that the number of peaks, each of which represented at least one component, in the chromatographic scans far exceeded the number of identified components. If it were not for scientists’ curiosity and the tremendous advances in analytical chemistry over the last fifty to sixty years, the need for this up-to-date catalog of compounds in tobacco and tobacco smoke would not be critical. As analytical technology advances, surely thousands of new chemical components in tobacco and tobacco smoke will be added to the listings found in this text. In each chapter of this text, one or more tabulations were made that contained the distribution of the components (by chemical class) that were identified in tobacco, tobacco smoke, or in both tobacco and tobacco smoke. Table XXVIII-1 illustrates the total distribution of chemical components distributed between tobacco and tobacco smoke. 1257

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The Chemical Components of Tobacco and Tobacco Smoke

Table XXVIII-1 Distribution of Chemical Components between Tobacco and Tobacco Smoke Component

Table

Totala

Smoke

Tobacco

Smoke and Tobacco

Hydrocarbons Alkanes Alkenes and alkynes Alicyclics Monocyclic aromatic Polycyclic aromatic

Table I.A-10 Table I.B-1 Table I.C-1 Table I.D-1 Table I.E-6

132 363 142 98 586a

111 347 95 89 575a

96 42 61 39 86

75 25 16 30 74

1321

1217

324

220

1462 111 263 1090 745 103 1030 304 20 279 558 48 992

531 44 143 656 354 30 617 162 13 35 444 33 506

1152 102 199 647 614 102 924 201 13 271 244 21 659

221 35 79 213 223 29 511 59 6 27 130 6 173

7005

3568

5149

1712

141 469 212 79 67 73

131 259 118 59 53 55

23 316 127 39 51 19

13 106 33 19 37 1

1041

675

575

209

Table XVII.A-1

5

1

5

1

Table XVII.A-3

321

256

117

52

Table XVII.A-5

14

1

14

1

Table XVII.B-1

538

440

221

123

Table XVII.B-3

95

54

62

21

Table XVII.B-5

76

64

31

19

Table XVII.C-1 Table XVII.D-1 Table XVII.E-6 Table XVII.E-8 Table XVII.F-8

118 56 294 76 9

97 14 286 24 9

35 44 23 55 0

14 2 15 3 0

1602

1246

607

251

260 242 35 146 125

119 169 33 116 22

178 131 22 142 112

37 58 20 112 9

Sub-Totals Oxygen-Containing Components Alcohols Phytosterols and derivatives Aldehydes Ketones Carboxylic acids Amino acids Esters Lactones Anhydrides Carbohydrates Phenols Quinones Ethers

b

Table II.A-5 Table II.B-2 Table III-12 Table III-13 Table IV.A-3 Table IV.B-7 Table V-3 Table VI-2 Table VII-1 Table VIII-3 Table IX.A-22 Table IX.B-2 Table X-2

Sub-Totals Nitrogen-Containing Components Nitriles Amines Amides Imides N-Nitrosamines Nitroalkanes, nitroarenes, and nitrophenols b

Table XI-2 Table XII-2 Table XIII-1 Table XIV-1 Table XV-8 Table XVI-1

Sub-Totals Nitrogen Heterocyclic Components Monocyclic 4-membered N-containing ring compounds Monocyclic 5-membered N-containing ring compounds Compounds with multiple monocyclic 5-membered N-containing ring Monocyclic 6-membered N-containing ring compounds Compounds with a 6-membered N-containing ring and a second 5-membered N-containing ring Compounds with two or more 6-membered N-containing rings Lactams Oxazoles Aza-arenes Aza-arene derivatives c N-Heterocyclic amines Sub-Totals Miscellaneous Components Sulfur-containing Halogen-containing Fixed gases Metal, nonmetals Ions, etc.

Table XVIII.A-1 Table XVIII.B-3 Table XIX-5 Table XX-5 Table XX-6

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Summary

Table XXVIII-1 (Continued) Distribution of Chemical Components between Tobacco and Tobacco Smoke Component Pesticides Enzymes Anticarcinogens Free radicals

Table Table XXI-3 Table XXII-2 Table XXVI-7C Table XXVII-1

Total a

Smoke

Tobacco

303 499 56 34

102 1 55 34

299 499 49 2

Smoke and Tobacco 98 1 48 2

Sub-Totals

1700

651

1434

385

Grand Total

12669

7357

8089

2777

a b

c

This number includes the various isomers of alkyl-PAHs reported in which the position of the alkyl group or groups has not been precisely defined. Polyfunctional O-containing compounds are counted in each functional group, e.g., propanoic acid, 2-hydroxy- {lactic acid} appears in the alcohol catalog and the acid catalog; benzoic acid, 4-hydroxy-3-methoxy- {vanillic acid} appears in the acid catalog, the phenol catalog, and the ether catalog. The number of aza-arene derivatives does not include the nine N-heterocyclic amines.

There are twenty-seven chapters in the book (excluding this Summary). Table XXVIII-1 contains summary data on the distribution of chemicals discussed in all but three chapters (Chapter 23, on “Hoffmann Analytes,” Chapter 24, on Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients, and Chapter 25, on Pyrolysis). The tobacco and tobacco smoke components discussed in Chapters 23, 24, and 25 are all previously covered in the remaining chapters of the book. Table XXVIII-1 is divided into five sections: Hydrocarbons (Tables in Chapter 1), Oxygen-containing components (Tables in Chapters 2 to 10), Nitrogen-containing components (Tables in Chapters 11 to 16), Nitrogen Heterocyclic components (Tables in Chapter 17), and Miscellaneous components (Tables in Chapters 18, 19 to 22, 26, and 27). Below each section in Table XXVIII-1 is a subtotal of the total of identified chemical components found in tobacco, tobacco smoke, or both tobacco and tobacco smoke. As previously mentioned throughout the text, a great number of the individual identified components found in tobacco and/or tobacco smoke are multifunctional. Many contain two or more functionalities and for that reason they are located in multiple chapters. The Alphabetical Index to Components Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke that follows the Reference section contains 8590 components. The Index contains 8398 individually identified components and several isomers. Each component is tabulated to indicate its identification in smoke, tobacco, or both. The total number of isomers noted in the Index is 292, but 100 of them are accounted for in the 8398 listed components. Thus, the number of identified or partially identified components in tobacco and tobacco

smoke listed in the Index totals 8590 (8398 + 292 - 100). The total number of chemical components listed in Table XXVIII-1 is 12669. There are 8089 found in tobacco, 7357 found in tobacco smoke, and 2777 found in both tobacco and smoke. The difference between 12669 and 8590 indicates that indeed many of the chemical components of tobacco and smoke are multifunctional and as such are listed in several chapters. The oxygen-containing components (Tables in Chapters 2 to 10) account for the largest number of compounds found in tobacco and tobacco smoke, that is, 7005. These components are distributed: 5149 in tobacco and 3568 in tobacco smoke, with 1712 found in both tobacco and tobacco smoke. The compounds in Chapters 18 to 22, 26, and 27, listed under miscellaneous components, number 1700. There are 1434 components identified in tobacco, 651 components identified in tobacco smoke, and 385 found in both tobacco and tobacco smoke. The nitrogen heterocyclic components (Tables in Chapter 17) represent the next largest class of compounds, with 1602 components identified in tobacco and tobacco smoke. In this section there are 607 components identified in tobacco, 1246 components identified in tobacco smoke, and 251 found in both tobacco and tobacco smoke. The hydrocarbons (Tables in Chapter 1) represent the next class of compounds identified in tobacco and tobacco smoke. This section of Table XXVIII-1 contains 1321 compounds. There are 324 hydrocarbons identified in tobacco, 1217 hydrocarbons identified in tobacco smoke, and 220 found in both tobacco and tobacco smoke. The nitrogen-containing components (Tables in Chapters 11 to 16) are the smallest and last group of compounds identified in tobacco and tobacco smoke. This group of compounds numbers 1041. There are 575 nitrogen-containing

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1260

components identified in tobacco, 675 identified in tobacco smoke, and 209 found in both tobacco and tobacco smoke. In closing, the authors hope that this text will serve a useful purpose. The content of the book represents over fifty years of effort by the researchers attempting to build a framework about our understanding of the complex mixtures of tobacco and tobacco smoke. Much progress has been made during the last fifty years in terms of understanding of tobacco and tobacco smoke. During that time, the number of identified components in tobacco and tobacco smoke has increased nearly sevenfold. This progress has been due, in large part, to the great strides that have been made in analytical technology, but more than that, these scientists have shown great

The Chemical Components of Tobacco and Tobacco Smoke

perseverance in the face of uncertainty and controversy surrounding the roles of tobacco and tobacco smoke and health. Great works are performed, not by strength, but by perseverance. (Samuel Johnson, ca. 1740)

We hope that present and future scientists will persevere and use the information contained herein to answer new questions by looking back to history. If you want to understand today, you have to search yesterday. (Pearl Buck, 1892–1973)

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914. Davis, R.E.: A combined automated procedure for the determination of reducing sugars and nicotine alkaloids in tobacco product using a new reducing sugar method; Tob. Sci. 20 (1976) 139–144. 915. Davis, R.W. and B.H. Sneade: Determination of total aldehydes and acrolein in mainstream vapor phase cigarette smoke; 24th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 24, Paper No. 12, 1970, p. 8. 915a. Dawson, R.F.: Tobacco alkaloids; 1st Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 1, Paper No. 6, 1947. 915b. Dawson, R.F.: Method for the quantitative determination of nicotine and nornicotine. A progress report; 2nd Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 2, Paper No. 1, 1948. 916. Dawson, R.F.: The cigarette and its smoke; Columbia Eng. Quart. 8(2) (1955) 10–13, 30, 32. 916a. Dawson, R.F., R.D. Carpenter, F.L. Gager Jr, R. W. Jenkins Jr, and R.H. Newman: The utility of carbon-14 for ascertaining precursor-product relationships in cigarette smoke; Proc. World Tob. Sci. Conf. 5 (1970) 105–110. 917. Dawson, R.F. and E. Wada: Flavonoids and depsides of the green tobacco leaf: I. Rutin and chlorogenic acid; Tob. Sci. 1 (1957) 47–50. 918. Day, J.M., R.D. Bateman, and E.C. Cogbill: Determination of trace amounts of nickel in tobacco by neutron activation analysis; 145th Ann. Mtg., Am. Chem. Soc., New York, NY (1963) p. 23A. 918a. DeBardeleben, M.Z., W.E. Claflin, and W.F. Gannon: Role of cigarette physical characteristics on smoke composition; Recent Adv. Tob. Sci. 4 (1978) 85–111. 919. DeBardeleben, M.Z., J.E. Wickham, and W.F. Kuhn: The determination of tar and nicotine in cigarette smoke from an historical perspective; Recent Adv. Tob. Sci. 17 (1991) 115–148. 920. de Campos, M.D.: Tobacco and cigar smoke; Anais Faculdade Farm. Odontol. Unic. (Sao Paulo) 1 (1939/1940) 15–24, see Chem. Abstr. 39 (1945) 5395. 920a. Decarboxylase: By a search (Google) on the Internet, inserting the term decarboxylase glycine tobacco provides numerous references to it, including the following: Peterson, R.B. Regulation of glycine decarboxylase and L-serine hydroxymethyltransferase activities by glyoxylate in tobacco leaf mitochondrial preparations; Plant Physiol. 70 (1982) 61–66. Search for other decarboxylases provides similar references. 921. Decker, C., A. Girardet, P. Golaz, and R. Regamey: A multiple automatic apparatus for the estimation of nicotine and tar in cigarette smoke; Mitt. Gebiete Lebensm. Hyg. 46 (1955) 178–192. 922. de Clercque, M. and R. Truhaut: Nicotyrine and its determination by the Koenig reaction; Ann. Pharm. Franc. 15 (1957) 529–533. 922a. Dehydrogenase: By a search (Google) on the Internet, inserting the term dehydrogenase proline tobacco provides numerous references to it, e.g., Kochetov, A.V., S.E. Titov, et al.: Increase in the level of proline and osmotic pressure of cytoplasm in transformed tobacco bearing an antisense suppressor of the proline dehydrogenaase gene; Genetika 40 (2004) 282–285. A similar search for dehydrogenase xanthine tobacco provides many references, including the following: Nguyen, J. and A. Nato: In vitro study of the

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933. DeMarini, D.M.: Genotoxicity of tobacco smoke and tobacco smoke condensate; Mutation Res. 114 (1983) 59–89. 934. Demetriou, D. and G. Schepers: Determination of benzo[a]pyrene in complex matrix by multidimensional high-performance liquid chromatography; 53rd Tobacco Science Research Conference, Program Booklet and Abstracts, Vol. 53, Paper No. 10, 1999, p. 24. 935. Demian, B.A.: Trace analysis of vanillin in tobacco; 46th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 46, Paper No. 45, 1992, p. 50. 936. Demole, E. and D. Berthet: Identification de la damascenone et de la B-damascone dans le tabac burley [Identification of damascenone and B-damascone in burley tobacco]; Helv. Chim. Acta 54 (1971) 681–682. 937. Demole, E. and D. Berthet: A chemical study of burley tobacco flavour (Nicotiana tabacum L.). I. Volatile to medium-volatile constituents (b.p. a 84–114°C/0.001 Torr); Helv. Chim. Acta 55 (1972) 1866–1882. 938. Demole, E. and D. Berthet: A chemical study of burley tobacco flavour (Nicotiana tabacum L.). II. Mediumvolatile, free acidic constituents (~b.p. 84–114°C/0.001 Torr); Helv. Chim. Acta 55 (1972) 1898–1901. 939. Demole, E. and C. Demole: A chemical study of burley tobacco flavour (Nicotiana tabacum L.). V. Identification and synthesis of the novel terpenoid alkaloids 1,3,6,6tetramethyl-5,6,7,8-tetrahydroisoquinolin-8-one and 3,6, 6-trimethyl-5,6-dihydropyridin-2-one; Helv. Chim. Acta 58 (1975) 523–531. 940. Demole, E. and C. Demole: A chemical study of burley tobacco flavour (Nicotiana tabacum L.). VII. Identification and synthesis of twelve irregular terpenoid alkaloids related to solanone including 7,8-oxabicyclo[3,2,1]octane and 4,5-dioxabicyclo[3,3,1]nonane; Helv. Chim. Acta 58 (1975) 1867–1880. 941. Demole, E., C. Demole, and D. Berthet: A chemical study of burley tobacco flavour (Nicotiana tabacum L.). III. Structure determination and synthesis of 5-(4-methyl-2-furyl)-6-methylheptan-2-one (“solanofuran”) and of 3.4.7-trimethyl-1,6-dioxaspiro[4,5]dec-3-en-2-one (“spiroxabovolide”). Two new flavor components of burley tobacco; Helv. Chim. Acta 56 (1973) 265–271. 942. Demole, E., C. Demole, and D. Berthet: A chemical study of burley tobacco flavour (Nicotiana tabacum L.). IV. Identification of seven new solanone metabolites including 7,8-dioxabicyclo[3,2,1]octane and 4,9dioxabicyclo[3,3,1]nonane derivatives; Helv. Chim. Acta 57 (1964) 192–194. 943. Demole, E. and P. Dietrich: A chemical study of burley tobacco flavour (Nicotiana tabacum L.); in: Recent advances in the chemical composition of tobacco and tobacco smoke, edited by J.L. McKenzie, R.M. Ikeda, T.R. Terrill, D.G. Vickroy, and D.B. Walters, Proc. Am. Chem. Soc. Symp., New Orleans, LA (1977) 1–36. 943a. Demole, E. and P. Enggist: Novel synthesis of 3,5,5-trimethyl-4-(2-butenylidene)-cyclohex-2-en-1-one, a major constituent of burley tobacco flavor; Helv. Chim. Acta 57 (1974) 2087–2091. 944. Demole, E. and P. Enggist: A chemical study of burley tobacco flavour (Nicotiana tabacum L.). VI. Identification and synthesis of four irregular terpenoids related to solanone, including “prenylsolanone”; Helv. Chim. Acta 58 (1975) 1602–1607.

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967. Diekmann, J., C. Biefel, R. Stabbert, and K. Rustemeier: Analysis of unsymdimethylhydrazine in cigarette smoke; 55th Tobacco Science Research Conference, Program Booklet and Abstracts, Vol. 55, Paper No. 12, 2001, p. 27. 968. Diekmann, J. and K. Rustemeier: A new method for the analysis of propylene glycol in cigarette smoke; 56th Tobacco Science Research Conference, Program Booklet and Abstracts, Vol. 56, Paper No. 18, 2002, p. 29. 969. Dieterman, L.J., C.H. Yang, Y. Nakagawa, and S.H. Wender: Identification of esculetin in tobacco and in cigarette smoke; J. Org. Chem. 24 (1959) 1134–1136. 970. Diffee, J.T.: The spectrophotometric determination of total ortho-dihydroxyphenolic compounds in tobacco; RDM, 1973, No. 32, December 11, see www.rjrtdocs. com 500606307 -6317. 971. Diffee, J.T.: The spectrophotometric determination of total carotenoids in cured and green tobacco; RDM, 1974, No. 5, February 27, see www.rjrtdocs.com 503179271 -9287; 500606395 -6407. 972. Diffee, J.T.: Spectrophotometric determination of total carotenoids in cured and green tobacco leaves; 28th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 28, Paper No. 37, 1974, p. 26. 973. Diffee, J.T.: Automated determination of nicotine alkaloids in cigarette smoke total particulate matter; RDM, 1975, No. 20, May 19, see www.rjrtdocs.com 500616251 -6262. 974. Diffee, J.T.: Determination of triethylene glycol, glycerol, and propylene glycol on Winston Lights CPB by near-infrared (NIR) reflectance spectroscopy: A feasibility study; R&DM, 1986, No. 110, July 25, see www.rjrtdocs.com 505448344 -8381. 975. Diffee, J.T. and M. E. Sheppard: An automated method for the determination of nicotine alkaloids in cigarette smoke using cyanogen bromide; 25th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 25, Paper No. 26, 1971, p. 15. 976. DiGiovanni, J., T.J. Slaga, D.L. Berry, and M.R. Juchau: Inhibitory effects of environmental chemicals on polycyclic aromatic hydrocarbon carcinogenesis; in: Carcinogenesis. A comprehensive survey. Vol. 5, edited by T.J. Slaga, Raven Press, New York, NY (1980) 145–168. 976a. Dijkema, C., H.C.M. Kester, and J. Visser: 13C NMR studies of carbon metabolism in the hyphal fungus Aspergillus nidulans; Proc. Nat. Acad. Sci. U.S.A. 82 (1985) 14–18. 977. Dikun, P.P.: Use of the fine structure of the fluorescence spectrum of 3:4-benzpyrene to increase the certainty of its detection; Voprosy Onkol. 5 (12) (1959) 672–677. 978. Dikun, P.P. and S.G. Chushkin: Fluorescence spectral analysis of the products of tobacco smoke; Voprosy Onkol. 5(7) (1959) 34–37. 979. Dikun, P.P., S.G. Chushkin, A.L. Gritsiute, and A.L. Mironova: The results of studies on the possible carcinogenic effect of tobacco products; Voprosy Onkol. 6 (1960) 603–604. 980. Dikun, P.P., I.A. Kalinina, N.D. Krasnitskaya, and V.A. Tokovoi: Absorption of 3,4-benzpyrene from tobacco smoke by various filtering materials; Voprosy Onkol. 11 (1965) 86–89. 981. Dikun, P.P., N.D. Krasnitskaya, and S.G. Chushkin: Some data on the content of 3,4-benzpyrene in tobacco smoke; Voprosy Onkol. 8 (1962) 31–35.

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1247. Fujimori, T.: Chemical studies on the aroma constituents in burley tobacco; Sci. Papers, Cent. Res. Inst., Japan Monopoly Corp. 118 (1976) 85–118. 1248. Fujimori, T. and H. Kaneko: Studies on tobacco aroma; Nippon Nogeikagaku Kaishi 53 (1979) 95–121. 1249. Fujimori, T., R. Kasuga, H. Kaneko, and M. Noguchi: Isolation of R(-)-3-hydroxy-B-ionone from burley tobacco; Agr. Biol. Chem. Japan 38 (1974) 891–892. 1250. Fujimori, T., R. Kasuga, H. Kaneko, and M. Noguchi: Isolation of 3-(4,8,12-trimethyltridecyl)furan (phytofuran) from burley tobacco; Agr. Biol. Chem. Japan 38 (1974) 2293–2294. 1251. Fujimori, T., R. Kasuga, H. Kaneko, and M. Noguchi: Isolation of 3-hydroxy-B-ionol from burley tobacco; Agr. Biol. Chem. Japan 39 (1975) 913–914. 1252. Fujimori, T., R. Kasuga, H. Kaneko, and M. Noguchi: A new acetylenic diol, 3-hydroxy-7,8-dehydro-B-ionol, from burley Nicotiana tabacum; Phytochemistry 14 (1975) 2095. 1253. Fujimori, T., R. Kasuga, H. Kaneko, and M. Noguchi: Isolation of solavetivone from Nicotiana tabacum; Phytochemistry 16 (1977) 392. 1254. Fujimori, T., R. Kasuga, H. Kaneko, and M. Noguchi: Neutral volatile components of burley tobacco; Beitr. Tabakforsch. Int. 9 (1978) 317–325. 1255. Fujimori, T., R. Kasuga, H. Kaneko, S. Sakamura, M. Noguchi, A. Furusaki, N. Hashika, and T. Matsumoto: Solanascone: A novel sesquiterpene ketone from Nicotiana tabacum. X-ray structure determination of its corresponding oxime; J. Chem. Soc. Chem. Comm. (1978) 563–564. 1256. Fujimori, T., R. Kasuga, H. Matsushita, and M. Noguchi: Neutral aroma constituents in burley tobacco; Agr. Biol. Chem. Japan 40 (1976) 303–315. 1256a. Fujioka, K. and T. Shibamoto: Determination of toxic carbonyl compounds in cigarette smoke; Environmental Toxicol. 21 (2006) 47–54. 1256b. Fukuda, Y., M. Ohme, and H. Shinshi: Gene structure and expression of a tobacco endochitinase gene in suspension-cultured tobacco cells; Plant Mol. Biol. Int. J. Fund. Res. Genet. Eng. 16 (1991) 1–10. 1257. Fukuzumi, T., H. Kaneko, and H. Takahara: Isolation of a (-)-2-isopropyl-5-oxohexanoic acid from Turkish tobacco leaves and absolute configuration of solanone; Agr. Biol. Chem. 31 (1967) 607. 1258. Fukuzumi, T., H. Takahara, H. Kaneko, and I. Onishi: Studies of the chemical constituents of tobacco leaves. I. Organic acids in Turkish tobacco; J. Agr. Chem. Soc. Japan 39 (1965) 199–203. 1259. Fukuzumi, T., H. Takahara, H. Kaneko, and I. Onishi: Studies of the chemical constituents of tobacco leaves. II. Isolation of 2-isopropylmalic acid from Turkish tobacco; J. Agr. Chem. Soc. Japan 39 (1965) 204–207. 1260. Fukuzumi, T., H. Takahara, H. Kaneko, and I. Onishi: Isolation of hydroxy acids from Turkish tobacco leaves; Agr. Biol. Chem. Japan 39 (1965) 967–969. 1261. Furukawa, Y. and C. Tokura: Analytical methods for chemical components in tobacco smoke. II. Absorption spectrum and spectrophotometric determination of tobacco smoke tar; Sci. Papers, Cent. Res. Inst., Japan Monopoly Corp. 107 (1965) 315–317. 1262. Furth, A. and W.R. Gustavson: The study of nickel in relation to smoking and lung cancer; Proc. Am. Assoc. Cancer Res. 7 (1966) 86.

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1299. Giles, J.A. III and J.N. Schumacher: Turkish tobacco. I. The isolation and characterization of A- and B-levantenolide; Tetrahedron 14 (1961) 246–251. 1300. Giles, J.A. III, J.N. Schumacher, and G.W. Young: Turkish tobacco. II. The isolation and characterization of A2-levantenolide; Tetrahedron 19 (1963) 107–110. 1301. Giles, J.A. III and B.N. Sullivan: Modified determination of nicotine and water in total particulate matter of cigarette smoke; RDM, 1969, No. 36, May 22, see www. rjrtdocs.com 500604830 -4833. 1302. Gilleland, H.L. and L.A. Lyerly: Triacetin content of cigarette smoke as a function of the age of the filter; RDR, 1966, No. 25. June 30, see www.rjrtdocs.com 500967284 -7291. 1303. Gilleland, H.L. and L.A. Lyerly: Gas chromatographic determination of phenol in cigarette smoke; RDR, 1967, No. 24, August 17, see www.rjrtdocs.com 500968072 -8084. 1304. Gillman, I.G. Jr, J.E. Fossett, N. Finkel, and R.D. Bereman: Investigations into a rapid method for determining tobacco-specific N-nitrosamines and volatile nitrosamines in sidestream tobacco smoke using LC/ MS/MS with positive ion electrospray; 56th Tobacco Science Research Conference, Program Booklet and Abstracts, Vol. 56, Paper No. 36, 2002, p. 41. 1305. Gillman, I.G. Jr, and K.A. Wagner: The rapid and quantitative analysis of tobacco specific N-nitrosamines in mainstream tobacco smoke using LC/MS/MS with positive ion electrospray; 55th Tobacco Science Research Conference, Program Booklet and Abstracts, Vol. 55, Paper No. 56, 2001, p. 53. 1305a. Giovannozzi-Sermanni, G.: Analytical research on Nicotiana tabacum by paper chromatography. III. Organic acids in three varieties of subtropical tobacco during curing and fermentation; Il Tabacco 59 (1955) 329–335; IV. Amino acids in three varieties of subtropical tobacco during curing and fermentation; Il Tabacco 59 (1955) 335–343; V. Variation of some chemical components of Maryland tobacco due to topping and curing methods; Il Tabacco 60 (1956) 400–412. 1305b. Giovannozzi-Sermanni, G.: Analytical research on Nicotiana tabacum by paper chromatography. Il Tabacco 61 (1957) 349–357. 1306. Giovannozzi-Sermanni, G. and N. Carugno: Analytical investigations on tobacco by means of vapour phase chromatography. 2. Effect of fermentation on the gaseous components of smoke. Studies on Kentucky tobacco; Il Tabacco 62 (1958) 265–268; Analytical research on tobacco by means of gas chromatography. II. Effect of fermentation on the gas substances in smoke. Studies on “Kentucky” tobacco; Proc. 2nd Internat. Tob. Sci. Cong., Brussels, Belgium, 1958 (1959) 550–552. 1307. Gladding, R.N., W.B. Wartman, and H.E. Wright: The isolation of a phytadiene from aged burley tobacco; 11th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 11, Paper No. 12, 1957; Identification of neophytadiene in burley tobacco and in cigarette smoke; J. Org. Chem. 24 (1959) 1358–1359. 1308. Gladding, R.N. and H.E. Wright: Paraffin waxes of burley tobacco and their isolation; Tob. Sci. 3 (1959) 81–82. 1309. Glennie, C.W. and J.C. Nel: The polyphenols of fluecured tobacco; Agrochemophysica (1973) 75–76. 1310. Glock, E.: The determination of keto-, mono- and dicarboxylic acids in tobacco and cigarette smoke; 11th Tobacco

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3209. Roberts, D.L.: Burley tobacco components. XIII. Attempted synthesis of SM40C; RDR, 1965, No. 9, February 9, see www.rjrtdocs.com 500965629 -5638. 3210. Roberts, D.L.: Burley tobacco components. XIV. Attempted synthesis of isophorone-related compounds; RDR, 1965, No. 12, February 26, see www.rjrtdocs.com 500965690 -5701. 3211. Roberts, D.L.: The structure of a new sesquiterpene—1keto-A-cyperone - isolated from tobacco; 25th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 25, Paper No. 17, 1971, p. 11. 3212. Roberts, D.L.: The structure of a new sesquiterpene isolated from tobacco; Phytochem, 11 (1972) 2077–2080. 3213. Roberts, D.L.: Chemical and physical modification of tobacco. Literature survey; RDM, 1972, No. 49, October 31, see www.rjrtdocs.com 500615796 -5833. 3214. Roberts, D.L.: Ammonia and nicotine migration in tobacco; RDM, 1974, No. 11, April 8, see www.rjrtdocs. com 514901109 -1114. 3215. Roberts, D.L.: Natural tobacco flavor; Recent Adv. Tob. Sci. 14 (1988) 49–81. 3216. Roberts, D.L., R.A. Heckman, B.P. Hege, and S.A. Bellin: Synthesis of (RS)-abscisic acid; J. Org. Chem. 33 (1968) 3566–3569. 3217. Roberts, D.L. and C.E. Lewis: Tobacco and stem essential oils; RDR, 1974, No. 2, January 8, see www.rjrtdocs.com 510646975 -6985. 3218. Roberts, D.L., C.W. Miller, and R.A. Lloyd Jr: Tobacco carotenoids; 27th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 27, Paper No. 43, 1973, p. 29. 3219. Roberts, D.L. and W.A. Rohde: Isolation and identification of flavor components of burley tobacco; Tob. Sci. 16 (1972) 107–112. 3220. Roberts, D.L. and R.L. Rowland: Characterization of M-II-f as A-3,8,14-duvatriene-1,5-diol; RDR, 1962, No. 29, August 1, see www.rjrtdocs.com 500939496 -9504. 3221. Roberts, D.L. and R.L. Rowland: Macrocyclic diterpenes. A- and B-4,8,13-duvatriene-1,3-diols from tobacco; J. Org. Chem. 27 (1962) 3989–3995. 3222. Roberts, D.L. and J.N. Schumacher: Isolation and characterization of compound XI. A macrocyclic diterpene isolated from tobacco; RDR, 1963, No. 26, April 4, see www.rjrtdocs.com 500961494 -1500. 3223. Roberts, D.L. and J.N. Schumacher: Isolation, characterization and synthesis of compound XXVI; RDR, 1963, No. 36, May 13, see www.rjrtdocs.com 500961631 -1648. 3224. Roberts, D.L., J.N. Schumacher, R.A. Lloyd Jr, R.A. Heckman, and A. Rodgman: List of tobacco and smoke constituents; RDM, 1975, No. 15, April 16, see www. rjrtdocs.com 514901435 -1636. 3225. Roberts, D.L., J.N. Schumacher, R.A. Lloyd Jr, and R.A. Heckman: Carbohydrate pyrolysis products: A review of the literature; RDM, 1976, No. 7, February 4, see www. rjrtdocs.com 500616624 -6642. 3226. Roberts, D.L., J.N. Schumacher, R.A. Lloyd Jr, and R.A. Heckman: Literature study of pyrolysis of amino acids and proteins; RDM, 1976, No. 9, February 11, see www. rjrtdocs.com 500616651 -6671. 3227. Roberts, D.L., J.N. Schumacher, R.A. Lloyd Jr, and R.A. Heckman: Nicotine pyrolysis products: A review of the literature; RDM, 1977, No. 5, January 25, see www.rjrtdocs.com 501009926 -9932, 504019634 -9640.

The Chemical Components of Tobacco and Tobacco Smoke

3228. Roberts, K.C. and P. Watts: The automatic gas chromatograph analysis of water, menthol, phenol, nicotine and triacetin in the ethanol extract of tobacco smoke condensate; 29th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 29, Paper No. 40, 1975, p. 28. 3229. Robertson, L.S.: Carcinogens in cigarette smoke; South Afr. Tydsk. Geneeskunde (1964) 617. 3230. Robinson, D.P., M.A.J. Bevan, and C.F. Hewett: An assessment of solanesol as a marker for environmental tobacco smoke; 46th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 46, Paper No. 7, 1992, p. 23. 3231. Robinson, M.F.: Determination of selected carbonyl components in sidestream smoke; R&DM, 1986, No. 83, May 22, see www.rjrtdocs.com 50493 8679–8690. 3232. Rocchietta, S.: Recent research on the identification of 3,4-benzpyrene in the components of tobacco smoke; Minerva Med. (Torino) 47 (1956) 1831. 3233. Rodgman, A.: Carcinogens and carcinogen precursors present in tobacco substances: A survey; Memorandum, 15 October 1954, pp. 1–59. 3234. Rodgman, A.: The carcinogenicity of arsenic compounds; Memorandum, 18 October, 1954, pp. 1–16. 3235. Rodgman, A.: The carcinogenicity of 3,4-benzpyrene; Memorandum, 18 October 1954, pp. 1–13. 3235a. Rodgman, A.: The synthesis of various substituted phenols for use as flavorants in tobacco products; RDM, 1954, No. 31, December 17, see www.rjrtdocs.com 500610091 -0108. 3236. Rodgman, A.: The fractionation of cigarette smoke and tars; RDM, 1955, No. 13, April 29, see www.rjrtdocs. com 501009739 -9746. 3237. Rodgman, A.: Chemical and biological investigations of tobacco tar and smoke; Memorandum, August 1955, pp. 1–26, see http://tobaccodocuments.org/bliley_rjr/list 500185802 -5849, 502815162 -5189. 3237a. Rodgman, A.: Chemical carcinogenesis; Memorandum, September 1955, pp. 1–69, see http://tobaccodocuments. org/bliley_rjr/list 500508429 -8497, 502815208 -5279. 3238. Rodgman, A.: Arsenic or arsenic compounds: Carcinogenesis studies; Memorandum, October 1955, pp. 1–10, see http://tobaccodocuments.org/bliley_rjr/list 502815457 -5460, 502815461 -5471. 3239. Rodgman, A.: Data discussed by Dr. Ernst L. Wynder in speech “Human and experimental relationship of cancer and tobacco” presented at the symposium on “Tobacco” before the Metropolitan Long Island Subsection of the American Chemical Society, February 24, 1956; RDM, 1956, No. 9, March 16, see www.rjrtdocs.com 501009747 -9754. 3240. Rodgman, A.: The analysis of cigarette smoke condensate. I. The isolation and/or identification of polycyclic aromatic hydrocarbons in Camel cigarette smoke; RDR, 1956, No. 9, September 28, see www.rjrtdocs.com 501008241 -8293. 3240a. Rodgman, A.: The preparation of some phenolic flavorants; RDR, 1956, No. 10, October 1, see www.rjrtdocs.com 500930142 -0155. 3241. Rodgman, A.: The analysis of cigarette smoke condensate. II. The pretreatment of Camel blend tobacco; RDR, 1956, No. 12, November 1, see www.rjrtdocs.com 501008294 -8336, 504912107 -2148, 515839741 -9783.

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3242. Rodgman, A.: The analysis of cigarette smoke condensate. III. Flue-cured tobacco; RDR, 1957, No. 4, March 14, see www.rjrtdocs.com 501008337 -8377. 3243 Rodgman, A.: Tobacco tar fractionation and the pretreatment of tobacco: A conversation with Dr. George F Wright of the University of Toronto, Toronto, Ontario, Canada; RDM, 1957, No. 25, July 22, see www.rjrtdocs. com 500610651 -0656. 3244. Rodgman, A.: The analysis of cigarette smoke condensate. IV. 3,4,8,9-Dibenzpyrene in Camel cigarette smoke condensate; RDR, 1957, No. 13, October 7, see www. rjrtdocs.com 501008378 -8386. 3245. Rodgman, A.: Components reported in tobacco smoke; RDM, 1958, No. 32, April 17, see www.rjrtdocs.com 500610933 -0997. 3246. Rodgman, A.: The analysis of cigarette smoke condensate. VI. The influence of solvent pretreatment of tobacco and other factors on the polycyclic hydrocarbon content of smoke condensate; RDR, 1959, No. 1, January 29, see www.rjrtdocs.com 501008529 -8591. 3247. Rodgman, A.: The analysis of cigarette smoke condensate. IX. Phytadienes; RDR, 1959, No. 11, May 18, see www.rjrtdocs.com 500933338 -3372; The composition of cigarette smoke. III. Phytadienes; J. Org. Chem. 24 (1959) 1916–1924. 3248. Rodgman, A.: The analysis of cigarette smoke condensate. X. The effect of porous paper and/or filter tip materials or aluminized paper and/or alumina additive (Reynolds Metals Company) on total polycyclic hydrocarbons; RDM, 1959, No. 80, July 16, see www.rjrtdocs. com 501009793 -9797. 3249. Rodgman, A.: The analysis of cigarette smoke condensate. XIX. The determination of polycyclic aromatic hydrocarbons; RDR, 1961, No. 1, January 6, see www. rjrtdocs.com 500935976 -5996. 3250. Rodgman, A.: The analysis of cigarette smoke condensate. XXXIII. Polycyclic hydrocarbons in Lark cigarette smoke; RDM, 1963, No. 37, May 13, see www.rjrtdocs. com 500612598 -2601. 3251. Rodgman, A.: The analysis of cigarette smoke condensate. XXXV. A summary of an eight-year study; RDR, 1964, No. 10, February 12, see www.rjrtdocs.com 501008855 -8928. 3252. Rodgman, A.: Components reported in tobacco smoke: An addendum; RDM, 1965, No. 59, August 6, see www. rjrtdocs.com 504381941 -1944. 3253. Rodgman, A.: Components reported in tobacco smoke: An addendum; RDM, 1967, No. 58, September 26, see www.rjrtdocs.com 500613525 -3528. 3253a. Rodgman, A.: Chemical composition and biological properties of tobacco smoke; Presentation to R. J. Reynolds Tobacco Company R&D Personnel (April, 1985). 3254. Rodgman, A.: G13-expanded tobacco and Freon 11®; R&DM, 1984, No. 6, February 13; G13-expanded tobacco and Freon 11®; December, 1972, pp. 1–66, see www.rjrtdocs.com 521189661 -9727; G13-expanded tobacco and Freon 11®, 1st Revision; February, 1974, pp. 1–77, see www.rjrtdocs.com 521189578 -9660; G13-Expanded tobacco and Freon 11®, 2nd Revision; October, 1977, pp. 1–152, see www.rjrtdocs.com 515991960 -2115; G13-expanded tobacco and Freon 11®, 3rd Revision; December, 1979, pp. 1–104, see www.rjrtdocs.com 515979463 -9566.

1391

3255. Rodgman, A.: A comparison of the chemical, physical, and biological properties of cigarette mainstream smoke (MS), cigarette sidestream smoke (SS), and environmental tobacco smoke (ETS); Report submitted to the U. S. Environmental Protection Agency (December 1991; revised July 1992), pp. i-vii + 1–117, see www.rjrtdocs. com 512527469 -7599, 521184527 -4657, 521187004 -7125. 3255a. Rodgman, A.: Environmental tobacco smoke; Regul. Toxicol. Pharmacol. 16 (1992) 223–244. 3256. Rodgman, A.: The N-nitrosamines in tobacco and tobacco smoke; October, 1993: pp. i-xv, 1–259, see www.rjrtdocs.com 509752851 -3134, 522101837 -2121. 3257. Rodgman, A.: The chemical composition of environmental tobacco smoke: Some comments on the Occupational Safety and Health Administration’s notice on “Indoor Air Quality”; Document submitted to the Occupational Safety and Health Administration, 5 August, 1994, pp. i-xiii + 1–172, see www.rjrtdocs.com. 515923456 -3645, 515926646 -6833, 517582702 -2904, 521186677 -6881, 521187802 -7991. 3258. Rodgman, A.: FTC “tar” and nicotine in cigarette mainstream smoke: A retrospective; Recent Adv. Tob. Sci. 23 (1997) 5–74, see pp. 49–52. 3259. Rodgman, A.: Comments on BPDE experiments of Denissenko et al.; Memorandum (November 26, 1996), pp. 1–10. 3260. Rodgman, A.: Tobacco smoke components. Letter to the Editor; Beitr. Tabakforsch. Int. 18 (1998) 127–129. 3261. Rodgman, A.: “Smoke pH”: A review; Beitr. Tabakforsch. Int. 19 (2000) 117–139; Erratum notice; Beitr. Tabakforsch. Int. 19 (2001) 229–235. 3262. Rodgman, A.: Studies of polycyclic aromatic hydrocarbons in cigarette mainstream smoke: Identification, tobacco precursors, control of levels: A review; Beitr. Tabakforsch. Int. 19 (2001) 361–379. 3263. Rodgman, A.: Some studies of the effects of additives on cigarette mainstream smoke properties. I. Flavorants; Beitr. Tabakforsch. Int. 20 (2002) 83–103. 3264. Rodgman, A.: Some studies of the effects of additives on cigarette mainstream smoke properties. II. Casing materials and humectants; Beitr. Tabakforsch. Int. 20 (2002) 279–299. 3265. Rodgman, A.: The composition of cigarette smoke: Problems with lists of tumorigens; Beitr. Tabakforsch. Int. 20 (2003) 402–437. 3266. Rodgman, A.: Some studies of the effects of additives on cigarette mainstream smoke properties. III. Ingredients reportedly used in various commercial cigarette products in the USA and elsewhere; Beitr. Tabakforsch. Int. 21 (2004) 47–104. 3267. VOID 3268. Rodgman, A. and C.K. Chappell: Stigmasterol and B-sitosterol from Camel cigarette smoke; RJRT Notebook 56151–56156 (April, 1957). 3269. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. V. The polycyclic hydrocarbon precursors in tobacco; RDR, 1958, No. 18, December 1, see www.rjrtdocs.com 501008387 -8441, 504912197 -2250. 3270. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. VII. Solanesol and solanesyl acetate; RDR, 1958, No. 22, December 31, see www.rjrtdocs. com 500932470 -2484; The composition of cigarette smoke. I. Solanesyl acetate; Tob. Sci. 3 (1959) 86–88.

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3271. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XI. A-Tocopherol; RDR, 1959, No. 23, September 29, see www.rjrtdocs.com 500933614 -3620; The composition of cigarette smoke. IV. A-Tocopherol; Tob. Sci. 4 (1960) 7–8. 3272. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XIII. Sclareolide from Turkish tobacco smoke; RDR, 1960, No. 8, April 1, see www. rjrtdocs.com 500934533 -4541. 3273. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XIV. Polycyclic aromatic hydrocarbons; RDR, 1960, No. 20, May 26, see www.rjrtdocs. com 501008592 -8660. 3274. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XVII. The effect of aluminasupported catalysts on total polycyclic hydrocarbons; RDR, 1960, No. 36, December 2, see www.rjrtdocs.com 501008682 -8694. 3275. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XVIII. Chloranil and 2,4,7-trinitrofluorenone as filter tip additives; RDR, 1960, No. 38, December 7, see www.rjrtdocs.com 501008695 -8704. 3276. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XX. A note on the normal longchained primary alcohols: An addendum to RDR, 1960, No. 22; RDR, 1961, No. 5, January 26, see www.rjrtdocs.com 500936097 -6106. 3277. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XXI. Phenols; RDR, 1961, No. 10, February 23, see www.rjrtdocs.com 501008731 -8772. 3278. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XXIV. 6-Acetyl-2,3,4-tris-dB-methylvaleryl-B-D-glucopyranoside from Turkish tobacco smoke; RDR, 1961, No. 42, August 18, see www.rjrtdocs.com 500937292 -7299. 3279. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XXVI. Heterocyclic nitrogen compounds from Turkish tobacco smoke; RDR, 1962, No. 14, June 21, see www.rjrtdocs.com 500938892 -8910; The composition of cigarette smoke. XI. Heterocyclic nitrogen compounds from Turkish tobacco smoke; 16th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 16, Paper No. 23, 1962, p. 14, for presentation text, see www.rjrtdocs.com 521189920 -9945; Tob. Sci. 6 (1962) 176–179. 3280. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XXVII. Phenols from Turkish tobacco smoke: Eugenol and isoeugenol; RDR, 1962, No. 15, June 21, see www.rjrtdocs.com 501008799 -8811; Eugenol and isoeugenol from Turkish tobacco smoke; 18th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 18, Paper No. 22, 1964, pp. 33–35, for presentation text, see www.rjrtdocs.com 521188506 -8516; The composition of cigarette smoke. XIII. Eugenol and isoeugenol from Turkish tobacco smoke; Tob. Sci. 8 (1964) 161–162. 3281. Rodgman, A. and L.C. Cook: The composition of cigarette smoke. X. 12A-Hydroxy-13-epimanoyl oxide from Turkish tobacco smoke; Tob. Sci. 6 (1962) 125–126. 3282. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XXIX. Phytol (3,7,11,15-tetramethyl-2-hexadecen-1-ol); RDR, 1963, No. 9, February 6, see www.rjrtdocs.com 500961174 -1190.

The Chemical Components of Tobacco and Tobacco Smoke

3283. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XXXI. A-1,5-Dimethyl-12-isopropyl9-methylene-5,8-oxido-3,13-cyclotetradecadien-1-ol and A-12-isopropyl-5,9-oxido-1,5,9-trimethyl-3,9,13cyclotetradecatrien-1-ol from Turkish tobacco smoke; RDR, 1963, No. 24, March 25, see www.rjrtdocs.com 500961449 -1470. 3284. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XXXII. Isoprenoid alcohols; RDR, 1963, No. 35, May 8, see www.rjrtdocs.com 500961612 -1629. 3285. Rodgman, A. and L.C. Cook: Unsaturated alcohols from Turkish tobacco smoke; 17th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 17, Paper No. 17, 1963, p. 14, see www.rjrtdocs. com 521340001 -0012; The composition of cigarette smoke. XII. Unsaturated alcohols from Turkish tobacco smoke; Tob. Sci. 7 (1963) 151–157. 3286. Rodgman, A. and L.C. Cook: The composition of cigarette smoke; Presented at Sigma Xi Meeting, Wake Forest University, Winston-Salem, NC, 17 March, 1965, see www.rjrtdocs.com 501521599 -1606; the American Chemical Society Section Meeting, Columbus, GA, 2 May 1968, and the Chemistry Club, Chemistry Department, Columbus College, Columbus, GA, 2 May 1968, see www.rjrtdocs.com 501521608 -1615; and the Central North Carolina Section Meeting, American Chemical Society, Greensboro, NC, 14 October 1969, for presentation text and slides, see www.rjrtdocs.com 501521658 -1700. 3287. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XXXVII. A phytyl ester fraction from Turkish tobacco smoke; RDR, 1965, No. 37, August 18, see www.rjrtdocs.com 521188824 -8843; Some ketones and phytyl esters from Turkish tobacco smoke; 19th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 19, Paper No. 30, 1965, p. 45, for presentation text, see www.rjrtdocs.com 521188860 -8878; The composition of cigarette smoke. XV. Phytyl esters from Turkish tobacco smoke; Tob. Sci. 9 (1965) 158–165. 3288. Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XXXIV. 4-(2-Butenylidene)-isophorones from Turkish tobacco smoke; RDR, 1966, No. 3, February 7, see www.rjrtdocs.com 500966768 -6776. 3289. Rodgman, A. and L.C. Cook: Some factors influencing the filtration of the vapor phase of cigarette smoke; RDR, 1966, No. 12, April 13 [Paper XXXVIII in the series The analysis of cigarette smoke condensate], see www.rjrtdocs.com 521188922 -8970. 3290. Rodgman, A. and L.C. Cook: Treatment of 44X fluecured tobacco with hydrogen cyanide: Its effect on hydrogen cyanide in cigarette smoke; RDM, 1967, No. 52, September 14 [Paper XLI in the series The analysis of cigarette smoke condensate], see www.rjrtdocs.com 521188989 -8994. 3291. Rodgman, A. and L.C. Cook: The composition of cigarette smoke. Precursor studies; Unpublished manuscript, see www.rjrtdocs.com 501525257 -5284, 521184403 -4430. 3292. Rodgman, A. and L.C. Cook: The composition of cigarette smoke. Some minor components of the neutralacidic fraction; Unpublished manuscript, see www. rjrtdocs.com 501525285 -5340, 521184431 -4483.

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3293. Rodgman, A. and L.C. Cook: Branch-chained acids in Turkish tobacco smoke; 22nd Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 22, Paper No. 19, 1968, p. 11. 3294. Rodgman, A., L.C. Cook, S.A. Bellin, S.S. Mims, and G.W. Young: The analysis of cigarette smoke condensate. XXII. The composition of an aliphatic ester fraction from tobacco and tobacco smoke; RDR, 1961, No. 15, March 27, see www.rjrtdocs.com 521188124 -8152; The composition of cigarette smoke. IX. The composition of an aliphatic ester fraction from tobacco and tobacco smoke; 15th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 15, Paper No. 9, 1961, p. 5; Tob. Sci. 6 (1962) 42–49. 3295. Rodgman, A., L.C. Cook, and C.K. Chappell: The analysis of cigarette smoke condensate. XV. Comparison of different tobacco types; RDR, 1960, No. 21, June 30, see www.rjrtdocs.com 504912459 -2475; The composition of cigarette smoke. VI. Comparison of different tobacco types; 14th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 14, Paper No. 29, 1960, p. 15; Tob. Sci. 5 (1961) 1–5. 3296. Rodgman, A., L.C. Cook, and P.H. Latimer: The analysis of cigarette smoke condensate. VIII. Solanesyl esters and phytosteryl esters; RDR, 1959, No. 2, February 10, see www.rjrtdocs.com 500933072 -3093; The composition of cigarette smoke. II. Solanesyl and phytosteryl esters; Tob. Sci. 3 (1959) 125–128. 3297. Rodgman, A., L.C. Cook, and S.S. Mims: The analysis of cigarette smoke condensate. XII. Squalenes and solanesenes; RDR, 1960, No. 3, February 10, see www. rjrtdocs.com 500934455 -4473; The composition of cigarette smoke. V. Solanesenes; 14th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 14, Paper No. 23, 1960, pp. 12–13; J. Org. Chem. 26 (1961) 497–501. 3298. Rodgman, A., L.C. Cook, and M.A. Wagoner: The effect of Lexan® on cigarette smoke; RDM, 1967, No. 74, November 21 [Paper XLVIII in the series The analysis of cigarette smoke condensate], see www.rjrtdocs.com 500613647 -3650. 3299. Rodgman, A., L.C. Cook, and G.W. Young: The analysis of cigarette smoke condensate. XVI. Normal longchained primary alcohols; RDR, 1960, No. 22, July 1, see www.rjrtdocs.com 500934833 -4847. 3299a. Rodgman, A., J.D. Fredrickson, E.S. Hickman, M.P. Newell, J.N. Schumacher, C.R. Green, F.W. Best, G.W. Spence, R.E. Shackelford, E.D. Harper, and L.L. Vestal: The Sutton Research Corporation smoking material; RDR, 1970, No. 48, December 4, see www.rjrtdocs.com 501001173 -1175, 501001176 -1189, 501001190 -1289, 501001290 -1406, 501001407 -1438, 501001439 -1463, 501001464 -1468, 501001469 -1475, 501001526 -1539, 501001540 -1591, 501001592 -1772, 501001773 -1783, 501001784 -1788. 3300. Rodgman, A. and C.R. Green: Toxic chemicals in cigarette mainstream smoke- hazard and hoopla; in: Cigarette risk and the potential for risk reduction; Proceedings of the 2002 CORESTA Congress, New Orleans, LA, pp. 2–52, see www.rjrtdocs.com 526909637 -9687; Beitr. Tabakforsch. Int. 20 (2003) 481–545. 3300a. Rodgman, A., P. Martin, T.A. Perfetti, C.J. Smith, G.A. Long, and C. Hansch: Molecular parameters reported for a series of polycyclic aromatic hydrocarbons (PAHs). II;

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3773. Spiegelhalder, B., S. Fischer, and R. Preussmann: Tobacco-specific nitrosamines in mainstream smoke of West German cigarettes: Influence of tar and tobacco type; in: Tobacco and cancer. Perspectives in preventive research, edited by A.P. Maskens, R. Molimard, R. Preussmann, and J.W. Wilmer, Excerpta Medica (1989) 23–34. 3774. Spiegelhalder, B., S.J. Kubacki, and S. Fischer: A method for the determination of tobacco-specific nitrosamines (TSNA), nitrate and nitrite in tobacco leaves and processed tobacco; Beitr. Tabakforsch. Int. 14 (1989) 135–144. 3775. Spincer, D.: The estimation of some metals in tobacco and cigarette smoke; 30th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 30, Paper No. 32, 1976, p. 25. 3776. Spincer, D. and B.C. Chard: The determination of formaldehyde in cigarette smoke; Beitr. Tabakforsch. 6 (1971) 74–78. 3777. Spincer, D. and D.T. Westcott: Formation of nitrosodimethylamine in smoke from cigarettes manufactured from different tobacco types; in: Environmental N-nitroso compounds: Analysis and formation, edited by E.A. Walker, P. Bogovski, and L. Griciute, IARC, Lyon, France, IARC Sci. Publ. No. 14 (1976) 133–139. 3778. Springer, J.P., J. Clardy, R.H. Cox, H.G. Cutler, and R.J. Cole: The structure of a new type of plant growth inhibitor extracted from immature tobacco leaves; Tetrahedron Lett. (1975) 2737–2740. 3779 Spurr, H.W. Jr, J.F. Chaplin, N. Einolf, E. Trusdell, and H.R. Randolph: Determination of neophytadiene by gas chromatography of an isopropyl extract of TPM; 29th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 29, Paper No. 35, 1975, p. 26. 3779a. Squire, K.R. and B.E. Waymack: Thermal decomposition of pectin; 35th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 35, Paper No. 47, 1981, p. 25. 3779b. Srikrishna, A. and S.S.V. Ramsastry: Enantiospecific total synthesis of (+)-2B-hydroxysolanascone, the aglycone of the photoalexin isolated from flue-cured tobacco leaves; Tetrahedron Lett. 47 (2006) 335–339. 3780. Srivastava, R.P. and K. Jha: Changes in free amino acids during air-curing of Dixie shade wrapper tobacco; 43rd Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 43, Paper No. 11, 1989, p. 19; Tob. Sci. 35 (1991) 20–21. 3781. Stabbert R, K.-H. Schaefer, C. Biefel, and K. Rustemeier: Analysis of aromatic amines in cigarette [smoke]; 55th Tobacco Science Research Conference, Program Booklet and Abstracts, Vol. 55, Paper No. 84, 2001, p. 69. 3782. Staberg, E.: Tar and nicotine content of cigarette smoke; Nord. Hyg. Tidskr. 40 (1959) 71–88. 3783. Staberg, E.: Content of tar and nicotine in cigarette smoke. Comparison between different cigarette brands and studies of the effect of duration and mode of smoking; Nord. Hyg. Tidskr. 41 (1960) 199–216. 3784. Stähli, M.: Research on tobacco smoke; Thesis, Eidgenossichen Technischen Hochschule, Zurich, Switzerland, Publ. No. 757 (1933) pp. 1–53. 3785. Stahly, E.E.: Some considerations of metal carbonyls in tobacco smoke; Chem. Ind. (London) (1973) 620–623.

The Chemical Components of Tobacco and Tobacco Smoke

3786. Stahly, E.E. and E.W. Lard: Further considerations of metal carbonyls in tobacco smoke; Chem. Ind. (London) (1977) 85–86. 3787. Stamey, T.W. Jr and J.T. Dobbins Jr: Fluorometric determination of polynuclear hydrocarbons; RDR, 1965, No. 45, October 11, see www.rjrtdocs.com 500966272 -6303. 3788. Stamey, T.W. Jr, R.B. Hege Jr, F.A. Thacker Jr, and J.T. Dobbins Jr: Fluorometric method for determination of polynuclear hydrocarbons in cigarette smoke; RDR, 1971, No. 12, May 18, see www.rjrtdocs.com 501002076 -2104. 3789. Stamey, T.W. Jr, R.B. Hege Jr, F.A. Thacker Jr, and J.T. Dobbins Jr: A rapid thin-layer method for fluorometric determination of benzo[a]pyrene in cigarette smoke; RDR, 1971, No. 20, September 16, see www.rjrtdocs. com 501002299 -2331. 3789a. Stanfill, S.B. and D.L. Ashley: Quantitation of flavorrelated alkenylbenzenes in tobacco smoke particulate by selected ion monitoring gas chromatography-mass spectrometry; J Agr. Food Chem. 48 (2000) 1298–1306. 3789b. Starr, T.B. and J.E. Gibson: The mechanistic toxicology of formaldehyde and its implications for quantitative risk estimation; Ann. Rev. Pharmacol. Toxicol. 25 (1985) 745–767. 3790. Staub, M. and H. Furrer: The determination of nicotine and tar in tobacco smoke; Mitt. Gebiete Lebensm. Hyg. 44 (1953) 371–377; The testing of nicotine filters; Mitt. Gebiete Lebensm. Hyg. 44 912953) 472–474. 3791. Stauffer, H.P. and J. Bourquin: The determination of formaldehyde in whole cigarette smoke; CORESTA Bull. (1971) 73–74; Eine spektralphotometrische Methode zur Bestimmung von Formaldehyd im Vollrauch von Cigaretten [A spectrophotometric method for the determination of formaldehyde in whole cigarette smoke]; Beitr. Tabakforsch. 6 (1971) 21–26. 3792. Steck, W. and S.H. Wender: Chlorogenic and neochlorogenic acids in cigarette smoke; Tob. Sci. 9 (1965) 54–55. 3793. Steck, W., C.H. Yang, and S.H. Wender: Identification of salicylic and isovanillic acids in cigarette smoke; Chem. Ind. (1965) 560–561. 3794. Stedman, R.L.: Polyphenolic constituents of tobacco; Tob. Sci. 1 (1957) 155–160. 3795. Stedman, R.L.: Aroma, flavor and chemical composition of cigarette tobacco and smoke; CORESTA Inf. Bull. 1963(4) 11–23. 3796. Stedman, R.L: Nicotine reduction in tobacco smoke; in: Toward a less harmful cigarette, edited by E.L. Wynder and D. Hoffmann, Natl. Cancer Inst. Monograph 28 (1968) 113–119. 3797. Stedman, R.L: The chemical composition of tobacco and tobacco smoke; Chem. Rev. 68 (1968) 153–207. 3798. Stedman, R.L., R.C. Benedict, M. Dymicky, and D.G. Bailey: Composition studies on tobacco. XXXVIII. Evidence for the origin of the high molecular weight, acidic pigment in cigarette smoke condensate; Beitr. Tabakforsch. 5 (1969) 97–103. 3799. Stedman, R.L., D. Burdick, W.J. Chamberlain, and I. Schmeltz: Composition studies on tobacco. XVIII. Steam-volatile acids in smoke of cigarettes having different organoleptic properties; Tob. Sci. 8 (1964) 79–81. 3800. Stedman, R.L., D. Burdick, and I. Schmeltz: Composition studies on tobacco. XVII. Steam-volatile acidic fraction of cigarette smoke; Tob. Sci. 7 (1963) 166–169.

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3828b. Sugimura, T.: Mutagenic factors in cooked food; Crit. Rev. Toxicol. 6 (1979) 182–209. 3828c. Sugimura, T.: Past, present, and future of mutagens in cooked foods; Environmental Hlth. Perspect. 67 (1986) 5–10. 3828d. Sugimura T: Naturally occurring genotoxic carcinogens; in: Naturally occurring carcinogens-mutagens and modulators of carcinogenesis, edited by E.C. Miller, J.A. Miller, I. Hirono, T. Sugimura, and S. Takayama, Japan Scientific Societies Press, Tokyo, Japan (1979) 241–262, see 256. 3828e. Sugimura, T: Mutagens, carcinogens, and tumor promoters in our daily food; Cancer 49 (1982) 1970–1984. 3828f. Sugimura, T.: Carcinogenicity of mutagenic heterocyclic amines formed during cooking process; Mutation Res. 150 (1985) 33–41. 3829. Sugimura, T., T. Kawachi, M. Nagao, T. Yohagi, Y. Seino, T. Okamoto, K. Shudo, T. Kosuge, K. Tsuji, K. Watabayashi, Y. Iitaka, and A. Ita: Mutagenic principle(s) in tryptophan and phenylalanine pyrolysis products; Proc. Japan Acad. 53B (1977) 58–61. 3829a. Sugimura, T., M. Nagao, T. Kawachi, M. Honda, T. Yohagi, Y. Seino, S. Sato, N. Matsukura, T. Matsushima, A. Shitai, M. Sawamura, and H. Matsumoto: Mutagencarcinogens in food, with special reference to highly mutagenic pyrolytic products in broiled foods; in: Origins of human cancer, edited by H.H. Hiatt, J.D. Watson, and J.A. Winsten, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (1977) 1561–1577. 3829b. Sugimura, T. and M. Nagao: Mutagenic factors in cooked foods; Crit. Rev. Toxicol. 6 (1979) 189–209. 3830. Sula, J.P.: Exogenous carcinogens in the human organism; Acta Unio Internat. Contra Cancrum 15 (1959) 688–691. 3831. Sula, J.P.: The carcinogen 3,4-benzpyrene in the living environment and human organism; Neoplasma 10 (1963) 571–579. 3832. Sullivan, B.N. Jr: Total bases in the smoke of competitive brand cigarettes: Summary for 1964; RDM, 1965, No. 30, April 28, see www.rjrtdocs.com 500602647 -2649. 3833. Sullivan, B.N. Jr and T.G. Harrell: Determination of total bases in cigarette smoke; RDR, 1956, No. 2, February 15, see www.rjrtdocs.com 500930012 -0036. 3834. Sullivan, B.N. Jr and T.G. Harrell: Arsenic content of tobacco; RDM, 1956, No. 25, September 14, see www. rjrtdocs.com 500610468 -0468; RDM, 1957, No. 10, May 3, see www.rjrtdocs.com 500610608 -0608. 3835. Summers, V.W.: Rapid gas chromatographic determination of glycerin, propylene glycol, triethylene glycol, and triacetin in cigarette smoke; R&DM, 1986, No. 172, November 18, see www.rjrtdocs.com 508615295 -5310, 505456272 -6286. 3836. Sunderman, F.W. Jr.: Cancer-causing chemical changes acid; J. Am. Med. Assoc. 181(13) (1962) 33. 3836a. Sunderman, F.W., K.S. McCully, S.B. Taubman, P.R. Allpass, M.C. Reid, and L.A. Rinehimer: Manganese inhibition of sarcoma induction by benzo[a]pyrene in rats; Carcinogenesis 1 (1980) 613–620. 3837. Sunderman, F.W. and F.W. Sunderman Jr: Implication of nickel as a possible carcinogen in cigarettes; Joint Ann. Mtg. Am. Soc. Clin. Path. & College Am. Path., Chicago, IL (1960); Nickel poisoning. XI. Implication of nickel as a pulmonary carcinogen in tobacco smoke; Am. J. Clin. Path. 35 (1961) 203–209.

The Chemical Components of Tobacco and Tobacco Smoke

3838. Sunderman, F.W. Jr and F.W. Sunderman: Studies of nickel carcinogenesis: Subcellular partition of nickel in lungs and liver following inhalation of nickel carbonyl; Am. J. Clin. Path. 40 (1963) 563–575. 3839. Swain, A.P., J.E. Cooper, and R.L. Stedman: Largescale fractionation of cigarette smoke condensate for chemical and biological investigations; 22nd Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 22, Paper No. 16, 1968, p. 10; Cancer Res. 29 (1969) 579–583. 3840. Swain, A.P., J.E. Cooper, R.L. Stedman, and F.G. Bock: Composition studies on tobacco. XL. Large scale fractionation of the neutrals of cigarette smoke condensate using adsorption chromatography and solvent partitioning; 23rd Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 23, Paper No. 14, 1969, p. 9; Beitr. Tabakforsch. 5 (1969) 109–114. 3841. Swain, A.P., R.F. Peterson Jr, and R.L. Stedman: Composition studies on tobacco. XXI. The head-space vapors of leaf; J. Agr. Food Chem. 17 (1966) 349–353. 3842. Swain, A.P. and R.L. Stedman: Higher fatty acids of various tobacco types and grades; 15th Tobacco Chemists’ Research Conference, Program Booklet and Abstracts, Vol. 15, Paper No. 2, 1961, p. 3. 3843. Swartz, H.: Tobacco smoke: A noxious air pollutant. A review and comment. Part II; Rev. Allergy 25 (1971) 490–505. 3844. Swauger, J.E., M.J. Morton, C.A. Rahn, B.B. Collie, E.A. Bombick, J.T. Avalos, M.F. Borgerding, and D.C. Rees: A comparison of the mainstream cigarette smoke chemistry and mutagenicity of a representative sample of the US cigarette market with Kentucky Reference Cigarettes K1R4F and K1R5F; The Toxicologist 36(1) Part 2 (1997) 152 Abstract 774. Presented at the Society of Toxicology Annual Meeting (March 1997); Food Chem. Toxicol. 38 (2000) 949–962. 3844a. Synthase: By a search (Google) on the Internet, inserting the term synthase anthranilate tobacco, synthase malate tobacco, etc. provides a comprehensive list of references to the specified enzyme in tobacco. 3844b. Synthetase: by a search (Google) on the Internet, inserting the term synthetase indoleacetate tobacco, synthetase adenosine triphosphate tobacco, etc. provides a comprehensive list of references to the specified enzyme in tobacco. 3845. Szadkowski, D., H.P. Harke, and T. Anderer: Kohlenmonoxidbelastung durch Passivrauchen in BüroRaumen [Carbon monoxide burden from passive smoking in offices]; Innere Med. 3 (1976) 310–313. 3846. Szadkowski, D., H. Schultze, K.H. Schaller, and G. Lehnert: Zur ökologischen Bedeuting der Schwermetallgehaltes von Zigaretten. Blei-, Cadmium-, und Nickelanalysen des Tabaks sowie der Gas- und Partikelphase [The oncological significance of the heavy metal content of cigarettes. Lead, cadmium, and nickel analysis of tobacco as well as of its vapor and particulate phases]; Arch. Hyg. 153 (1969) 1–8. 3847. Szent-Gyorgyi, A.: Removal of polycyclic aromatic hydrocarbons from cigarette mainstream smoke by chloranil; Personal communication in 1960 to R.J. Reynolds Tobacco Company, see Rodgman, A. and L.C. Cook: The analysis of cigarette smoke condensate. XVII. Chloranil and 2,4,7-trintrofluorenone as filter-tip additives; RDR, 1960, No. 38, December 7, see www. rjrtdocs.com 501008695 -8704.

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The Chemical Components of Tobacco and Tobacco Smoke

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The Chemical Components of Tobacco and Tobacco Smoke

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The Alphabetical Index to Components Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke The Index was created for two purposes. The first was to capture in one site all the basic information on the identified tobacco and tobacco smoke components discussed in the chapters of the book. The components in the Index are listed alphabetically. Secondly, the Index may permit the reader to easily retrieve or search for information on a specific tobacco and/or smoke component or class of components so that further study will be facilitated. To achieve these goals, the Index was constructed to include the following: 1) The CAS No. for many of the components, 2) an indication of the component identification in tobacco, tobacco smoke, or both, 3) the structure of many of the components, 4) the table number and chapter in which the component is not only referenced but its properties are described, particularly if they are considered adverse, 5) for multifunctional components, several chapters and table numbers are cited. Additionally, the publishers of the book, Taylor and Francis Books/CRC Press of Boca Raton, FL, have provided a Compact Disk (readonly memory) (CD-ROM) format of the Index. Hopefully, the searchable format of the CD-ROM will aid the reader in retrieving any desired information. The Index comprises almost 8700 components completely or partially identified in tobacco, tobacco smoke, and tobacco substitute smoke. It includes not only over 8400 identified components but also several hundred compounds not identified in tobacco or tobacco smoke but reported by Doull et al. (1053) as tobacco ingredients used in the U.S.A. and by Baker et al. (172a, 174b) as tobacco ingredients used outside the U.S.A. and in a summary by Rodgman (3266) and in our Chapter 24. Because the transfer from a tobacco product to smoke of very few of the added ingredients has been examined, they primarily are listed as tobacco components. Exceptions include several humectants used in tobacco products for many years. However, it should be noted that the detailed pyrolysis study by Baker and Bishop (172a) indicated that many such added ingredients would transfer in part to MSS during the tobacco smoking process. In some instances, the reader may wonder about the peculiar nature of the component listing. For example, a tobacco smoke component initially reported as 2-butene was later shown to be present in the smoke as cis-and trans-2butene. Thus, three items are listed in the Index for 2-butene, namely, 2-butene (CAS No. 107-10-7), 2-butene, (Z)-(CAS No. 590-18-1), and 2-butene, (E)-(CAS No. 624-64-6). In the

appropriate chapter and table, Chapter 1, Table I.B-1, references to the identification of each are provided. 2-Butenedioic acid is similarly listed in Chapter 4, Table IV.A-3 as 2-butenedioic acid (CAS No. 6915-18-0), 2-butenedioic acid, (Z)-(maleic acid) (CAS No. 110-16-7), 2-butenedioic acid, (E)-(fumaric acid) (CAS No. 110-17-8). The reader will also find in the Index certain broad classifications of components, like oxidases and free radicals. These and similar examples in the Index are not there to confuse the reader, as many of the individual components in the broad classifications have specific CAS numbers1. Generally, the references associated with these classes of components (found within the chapters noted in the Index) will provide the reader with information of a common nature. In nearly all cases, individual components such as ascorbate oxidase, choline oxidase, cytochrome oxidase, and glycolate oxidase follow after the broadly classified component, oxidase. Likewise, specific free radicals such as methyl-acyl radical, ethyl-acyl radical, and propyl-acyl radical {2 isomers} may be found in the Index. For some components in the Index, several partially identified isomers exist, their number noted, and included in the total number of components identified in tobacco and/or smoke. While the number of enzymes, genes, and nucleotides listed in the Index is fewer than 500, their known number, as noted in Chapter 21, exceeds many thousands. The paltry number of enzymes, genes, and nucleotides listed in Chapter 21, Table XXI-2 was never intended to represent the total biological agents operating in the plant. Those selected for inclusion were from texts, research manuscripts, and patents where active research was conducted in the past in attempts to better understand the physiology and biochemistry of tobacco. As future genetic research develops, it is envisioned that the identity and function of hundreds of thousands of additional chemicals will be published. The authors hope that the format of the Index and accompanying CD-ROM will help the reader to reach a better understanding of the components of tobacco and tobacco smoke.

1

Each CAS Registry Number used throughout the Alphabetical Components Index and the various preceding chapters is a Registered Trademark of the American Chemical Society.

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The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke Note: S = tobacco smoke component, T = tobacco component, ST = component of both S and T Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

202-03-9

1

0

0

Aceanthrylene

I.E

340-99-8

1

0

0

Acenaphth[1,2-a]acenaphthylene

I.E

71265-26-4

1

0

0

Acenaphth[1,2-a]acenaphthylene, methyl-

206-49-5

1

0

0

Acenaphtho[1,2-b]pyridine

Name (per CA Collective Index)

Selected structures

Chapter Table

I.E

{7-azafluoranthene}

XVII.E

N

208-96-8

1

0

0

Acenaphthylene

1

I.E

2

3

8

4

7 6

{acenaphthene}

5

83-32-9

1

0

0

Acenaphthylene, 1,2-dihydro-

60684-29-9

1

0

0

Acenaphthylene, 1,2-dihydrodimethyl-

I.E

36541-21-6

1

0

0

Acenaphthylene, 1,2-dihydromethyl-

I.E

I.E

60826-72-4

1

0

0

Acenaphthylene, 1,2-dihydrotetramethyl-

I.E

60826-69-9

1

0

0

Acenaphthylene, 1,2-dihydrotrimethyl-

I.E

60826-68-8

1

0

0

Acenaphthylene, dimethyl-

I.E

19346-00-0

1

0

0

Acenaphthylene, 1,3-dimethyl-

I.E

58548-40-6

1

0

0

Acenaphthylene, diphenyl-

I.E

58548-38-2

1

0

0

Acenaphthylene, methyl-

I.E

19345-99-4

1

0

0

Acenaphthylene, 1-methyl-

I.E

19345-94-9

1

0

0

Acenaphthylene, 3-methyl-

I.E

19345-97-2

1

0

0

Acenaphthylene, 4-methyl-

I.E

19345-91-6

1

0

0

Acenaphthylene, 5-methyl-

I.E

60826-73-5

1

0

0

Acenaphthylene, tetramethyl-

I.E

60826-70-2

1

0

0

Acenaphthylene, trimethyl-

I.E

201-06-9

1

0

0

Acephenanthrylene

I.E

6232-48-0

1

0

0

Acephenanthrylene, 4,5-dihydro-

I.E

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Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Chapter Table

Selected structures

75-07-0

1

0

0

Acetaldehyde

H3C-CH=O

III-12

5371-49-3

1

0

0

Acetaldehyde, (acetyloxy)-

H3C-COO-CH2-CH=O

III-12

6542-88-7

1

0

0

Acetaldehyde, amino-

141-46-8

1

0

0

Acetaldehyde, hydroxy-

1

0

0

Acetaldehyde, methoxy-

0

1

0

Acetaldehyde, (2,6,6-trimethyl-4-oxo-2-cyclohexen1-ylidene)-

16825-04-0

{glycolaldehyde}

H2N-CH2-CH=O

III-12, XII-2

HO-CH2-CH=O

III-12, II.A-6

CH3O-CH2-CH=O H3C

CH2-CH=O

O

60-35-5

1

0

0

Acetamide

1113-68-4

1

1

1

Acetamide, N-acetyl-N-methyl-

1119-49-9

1

0

0

Acetamide, N-butyl-

15972-60-8

0

1

0

Acetamide, 2-chloro-N-(2,6-diethylphenyl)-N(methoxymethyl){Alachlor®}

III-12, X-2 III-12, III-13

CH3

CH3

H3C-CO-NH2

XIII-1

CH H3C-CO-N< 3 CO-CH3

XIII-1

H3C-CO-NH-C4H9

XIII-1 XIII-1, XVIII.B-3, XXI-3

CH3 CO-CH2-Cl N CH2-OCH3 C2H5

51218-45-2

0

1

0

Acetamide, 2-chloro-N-(2-ethyl-6-methylphenyl)-N(2-methoxy-1-methylethyl){Metolachlor®}

X-2, XIII-1, XVIII.B-3, XXI-3

CH3 CO-CH2-Cl N CH-CH2-OCH3 C2H5

107-91-5

1

0

0

Acetamide, 2-cyano-

57966-95-7

0

1

0

Acetamide, 2-cyano-2-methoxyimino-N(ethylcarbamoyl){Cymoxanil®}

CH3

NC-CH2-CO-NH2 CN H N

N O

O

H N

XI-2, XIII-1 XI-2, XIII-1, XXI-3

O

685-91-6

1

0

0

Acetamide, N,N-diethyl-

H3C-CO-N=(C2H5)2

XIII-1

127-19-5

1

1

1

Acetamide, N,N-dimethyl

H3C-CO-N=(CH3)2

XIII-1

H3C-CO-NH-C2H5

XIII-1

625-50-3

1

0

0

Acetamide, N-ethyl-

38806-26-7

1

0

0

Acetamide, N-ethyl-N-methyl-

5663-62-7

1

0

0

Acetamide, N-(2-furanylmethyl)-

621-42-1

0

1

0

Acetamide, 3-hydroxyphenyl-

CH3 H3C-CO-N< C2H5

XIII-1 X-2, XIII-1 IX-22, XIII-1

79-16-3

1

0

0

Acetamide, N-methyl-

H3C-CO-NH-CH3

XIII-1

54824-90-7

1

0

0

Acetamide, N-(2-methylbutyl)-

H3C-CO-NH-CH2-CH(CH3)-C2H5

XIII-1

13434-12-3

0

1

0

Acetamide, N-(3-methylbutyl)

H3C-CO-NH-(CH2)2-CH=(CH3)2

XIII-1

1189-05-5

1

0

0

Acetamide, N-(1-methylpropyl)-

H3C-CO-NH-CH(CH3)-C2H5

XIII-1

1540-94-9

1

1

1

Acetamide, N-(2-methylpropyl)-

H3C-CO-NH-CH2-CH=(CH3)2

XIII-1

7737-16-8

1

0

0

Acetamide, N-(2-oxopropyl)-

H3C-CO-NH-CH2-CO-CH3

103-84-4

1

0

0

Acetamide, N-phenyl-

H3C-CO-NH-C6H5

XIII-1

877-95-2

1

0

0

Acetamide, N-(2-phenylethyl)-

H3C-CO-NH-CH2-CH2-C6H5

XIII-1

692-33-1

1

0

0

Acetamide, N-2-propenyl-

H3C-CO-NH-CH2-CH=CH2

XIII-1

5331-48-6

1

0

0

Acetamide, N-propyl-

H3C-CO-NH-C3H7

354-38-1

1

0

0

Acetamide, 2,2,2-trifluoro-

F3C-CO-NH2

III-13, XIII-1

XIII-1 XIII-1, XVIII.B-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1485

11/24/08 1:55:33 PM

1486

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

16752-77-5

0

1

0

Name (per CA Collective Index) Acetamidic acid, thio-, N-[(methylcarbamoyl)oxy]-, methyl ester {Methomyl®}

XIII-1, XXI-3

O S

N

O

N H

-

1

0

0

Acetate

H3C-COO

64-19-7

1

1

1

Acetic acid

H3C-COOH

13831-30-6

1

1

1

Acetic acid, (acetyloxy)-

H3C-COO-CH2-COOH (H3C-CO)2O

108-24-7

1

0

0

Acetic acid, anhydride

162188-92-3

0

1

0

Acetic acid, bromo-, 7,9,9-trimethyl-8-oxo-1,4dioxaspiro[4.5]dec-7-yl ester, (r)-

123-86-4

1

1

1

Acetic acid, butyl ester

79-43-6

0

1

0

Acetic acid, dichloro-

94-75-7

0

1

0

Acetic acid, 2,4-dichlorophenoxy-

162188-93-4

0

1

0

Acetic acid, (diethoxyphosphinyl)-, 7,9,9-trimethyl-8oxo-1,4-dioxaspiro[4.5]dec-7-yl ester, (r)-

{butyl acetate}

XX-6 IV.A-3 VII-1

H3C-COO-C4H9

V-3

Cl2CH-COOH

IV.A-3

{2,4-D}

IV.A-3, X-2, XXI-3 V-3, X-2

0

1

0

Acetic acid, (dimethylamino)oxo-

108-05-4

1

0

0

Acetic acid, ethenyl ester

{vinyl acetate}

H3C-COO-CH=CH2

{ethyl acetate}

H3C-COO-C2H5

141-78-6

1

1

1

Acetic acid, ethyl ester

1

0

0

Acetic acid, 2-furanyl-

(H3C)2=N-CO-COOH

0

1

0

Acetic acid, heptyl ester

629-70-9

0

1

0

Acetic acid, 1-hexadecyl ester

142-92-7

0

1

0

Acetic acid, hexyl ester

79-14-1

1

1

1

Acetic acid, hydroxy-

IV.A-3, V-3 V-3 V-3 IV.A-3, X-2

O

112-06-1

IV.A-3, V-3 V-3, XVIII.B-3

32833-96-8

123617-80-1

Chapter Table

Selected structures

{hexyl acetate} {glycolic acid}

CH2-COOH

H3C-COO-(CH2)6-CH3

V-3

H3C-COO-(CH2)15-CH3

V-3

H3C-COO-(CH2)5-CH3

V-3

HOCH2-COOH

II.A-5, IV.A-3

623-50-7

1

0

0

Acetic acid, hydroxy-, ethyl ester

HOCH2-COO-C2H5

II.A-5, V-3

61892-60-2

1

1

1

Acetic acid, hydroxy-, 2-hydroxypropyl ester

HOCH 2-COO-CH2-CHOH-CH3

II.A-5, V-3

96-35-5

1

0

0

Acetic acid, hydroxy-, methyl ester

HOCH2-COO-CH3

II.A-5, V-3

90357-58-7

1

1

1

Acetic acid, hydroxy-, propyl ester

HOCH2-COO-C3H7

II.A-5, V-3

1

0

0

Acetic acid, hydroxymethyl ester

H3C-COO-CH2OH

II.A-5, V-3

1

0

0

Acetic acid, 2-hydroxypropyl ester

H3C-COO-CH2-CHOH-CH3

II.A-5, V-3 IV.A-3, X-2

627-69-0 625-45-6

0

1

0

Acetic acid, methoxy-

H3C-O-CH2-COOH

79-20-9

1

1

1

Acetic acid, methyl ester

H3C-COO-CH3

V-3

0

1

0

Acetic acid, 2-methylbutyl ester

H3C-COO-CH2-CH(CH3)-CH2-CH3

V-3

123-92-2

0

1

0

Acetic acid, 3-methylbutyl ester

H3C-COO-(CH2)2-CH=(CH3)2

V-3

1191-16-8

0

1

0

Acetic acid, 3-methyl-2-butenyl ester

H3C-COO-CH2-CH=C=(CH3)2

V-3

H3C-COO-CH=(CH3)2

108-21-4

1

1

1

Acetic acid, 1-methylethyl ester

72360-04-4

1

0

0

Acetic acid, 2-(5-methylfuranyl)H3C

35897-16-6

0

1

0

V-3 IV.A-3, X-2

Acetic acid, 2-methyl-3-pentyl ester

O

CH2-COOH

H3C-COO-CH(C2H5)-CH=(CH3)2

110-19-0

0

1

0

Acetic acid, 2-methylpropyl ester {isobutyl acetate}

H3C-COO-CH2-CH=(CH3)2

298-12-4

1

1

1

Acetic acid, oxo-

O=CH-COOH

{glyoxylic acid}

V-3 V-3 IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1486

11/24/08 1:55:33 PM

1487

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

1

0

0

Acetic acid, 2-oxopropyl ester

H3C-COO-CH2-CO-CH3

628-63-7

0

1

0

Acetic acid, pentyl ester

H3C-COO-(CH2)4-CH3

24851-98-7

0

1

0

Acetic acid, 2-pentyl-3-oxo-1-cyclopentyl-, methyl ester {methyl dihydrojasmonate}

103-45-7

1

1

1

Acetic acid, 2-phenylethyl ester {2-phenethyl acetate}

140-11-4

1

1

1

122-72-5

0

1

0

13147-57-4

0

1

0

Acetic acid, (phosphonoxy)-

Chapter Table III-13, V-3 V-3 V-3

H3C-COO-(CH2)2-C6H5

V-3

Acetic acid, phenylmethyl ester {benzyl acetate}

H3C-COO-CH2-C6H5

V-3

Acetic acid, phenylpropyl ester

H3C-COO-(CH2)3-C6H5

V-3

127-08-2

0

1

0

Acetic acid, potassium salt

109-60-4

0

1

0

Acetic acid, propyl ester

IV.A-3 H3C-COO-K {propyl acetate}

127-09-3

0

1

0

Acetic acid, sodium salt

93-76-5

0

1

0

Acetic acid, 2,4,5-trichlorophenoxy-

XX-6

H3C-COO-(CH2)2-CH3 H3C-COO-Na

{2,4,5-T®}

XX-6 IV.A-3, X-2, XXI-3

Cl Cl

V-3

O-CH2COOH Cl

76-49-3

0

1

0

Acetic acid, endo-1,7,7trimethylbicyclo[2,2,1]heptan-2-yl ester {bornyl acetate}

75-05-8

1

0

0

Acetonitrile

H3C-CN

926-64-7

1

0

0

Acetonitrile, (dimethylamino)-

(H3C)2=N-CH2-CN

107-16-4

1

0

0

Acetonitrile, hydroxy-

HOCH2-CN

II.A-5, XI-2

O=CH-CN

III-12. XI-2

4471-47-0

V-3

XI-2 XI-2

1

0

0

Acetonitrile, oxo-

0

1

0

Acetylserine sulfhydrylase

XXII-2

9040-07-7

0

1

0

Acetyltransferase, chloramphenicol

XXII-2

260-94-6

1

0

0

Acridine

{benzo[b]quinoline}

XVII.E-6 N

92-81-9

1

0

0

Acridine, 9,10-dihydro-

XVII.E-6

{acridan} N H

6267-02-3

1

0

0

Acridine, 9,10-dihydro-9,9-dimethyl{9,9-dimethylacridan}

XVII.E-6

26914-16-9

1

0

0

Acridine, 9,10-dihydro-9,9-dimethyl-(1-methylethyl)-

XVII.E-6

63451-42-3

1

0

0

Acridine, 9,10-dihydro-9,9-dimethyl-2-(1methylethyl)-

XVII.E-6

64828-44-0

1

0

0

Acridine, ethyl-

XVII.E-6

54116-90-4

1

0

0

Acridine, methyl-

XVII.E-6

64828-45-1

1

0

0

Acridine, propyl-

XVII.E-6

7440-34-8

1

1

1

Actinium

Ac

XX-5 XX-5 XX-5

20379-10-6,

0

1

0

Actinium, isotope of mass 226

226

14331-83-0

0

1

0

Actinium, isotope of mass 228

228

50-76-0

0

1

0

Actinomycin D

1

0

0

Acyl radical, methyl-

COCH3

XXVII-1

1

0

0

Acyl radical, ethyl-

COCH2CH3

XXVII-1

Ac Ac

XXI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1487

11/24/08 1:55:33 PM

1488

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

Acyl radical, propyl-

{2 isomers}

COCH2CH2CH3

XXVII-1

1

0

0

Acyl radical, butyl-

{3 isomers}

COCH 2CH2CH2CH3

XXVII-1

141733-40-6

0

1

0

Acyltransferase, glycerol phosphate (Arabidopsis thaliana clone BX3.6/BB2.6 reduced)

58-61-7

0

1

0

Adenosine

XXII-2 NH2 N N O

N

II.A-5, VIII-3, XVII.E-6

N OH

HOCH2 OH

60-92-4

0

1

0

Adenosine, cyclic 3',5'-(hydrogen phosphate)

II.A-5

139636-55-8

0

1

0

Adenosine, 2'-deoxyadenylyl-(3'o5')-thymidylyl(3'o5')-2'-deoxyguanylyl-(3'o5')-2'-deoxyguanylyl(3'o5')-thymidylyl-(3'o5')-2'-deoxyguanylyl(3'o5')-thymidylyl-(3'o5')-thymidylyl-(3'o5')thymidylyl-(3'o5')-thymidylyl-(3'o5')-thymidylyl(3'o5')-2'-deoxyguanylyl-(3'o5')-2'-deoxyadenylyl(3'o5')-thymidylyl-(3'o5')-2'-deoxycytidylyl(3'o5')-thymidylyl-(3'o5')-2'-deoxyguanylyl(3'o5')-2'-deoxy-

XXII-2

146689-29-4

0

1

0

Adenosine, 2'-deoxycytidylyl-(5'o3')-2'deoxycytidylyl-(5'o3')-2'-deoxyguanylyl-(5'o3')-2'deoxycytidylyl-(5'o3')-2'-deoxycytidylyl-(5'o3')-2'deoxyguanylyl-(5'o3')-2'-deoxy-

XXII-2

28542-78-1

0

1

0

Adenosine, N-(4-hydroxy-3-methyl-2-butenyl)-

II.A-5, VIII-3, XVII.E-6

6025-53-2

0

1

0

Adenosine, N-(4-hydroxy-3-methyl-2-butenyl)-, (E)-

II.A-5, VIII-3, XVII.E-6

15896-46-5

0

1

0

Adenosine, N-(4-hydroxy-3-methyl-2-butenyl)-, (Z)-

II.A-5, VIII-3, XVII.E-6

26190-61-4

0

1

0

Adenosine, N-(4-hydroxy-3-methyl-2-butenyl)-2(methylthio)-

II.A-5, VIII-3, XVII.E-6

53274-45-6

0

1

0

Adenosine, N-(4-hydroxy-3-methyl-2-butenyl)-2(methylthio)-, (E)-

II.A-5, VIII-3, XVII.E-6

52049-48-6

0

1

0

Adenosine, N-(4-hydroxy-3-methyl-2-butenyl)-2(methylthio)-, (Z)-

II.A-5, VIII-3, XVII.E-6

22663-55-4

0

1

0

Adenosine, N-(4-hydroxy-3-methylbutyl)-

II.A-5, VIII-3, XVII.E-6

7724-76-7

0

1

0

Adenosine, N-(3-methyl-2-butenyl)-

II.A-5, VIII-3, XVII.E-6

75081-82-2

0

1

0

Adenosine, N-[3-methyl-4-[(O-phosphono-E-Dglucopyranosyl)oxy]-2-butenyl]-, (E)-

II.A-5, VIII-3, XVII.E-6

4294-16-0

0

1

0

Adenosine, N-(phenylmethyl)-

II.A-5, VIII-3, XVII.E-6

56-65-5

0

1

0

Adenosine 5'-(tetrahydrogen triphosphate)

II.A-5, VIII-3, XVII.E-6

40922-97-2

0

1

0

Adenosine 5'-(tetrahydrogen triphosphate), N(phenylmethyl)-

58-64-0

0

1

0

Adenosine 5'-(trihydrogen diphosphate)

53-57-6

0

1

0

Adenosine 5'-(trihydrogen diphosphate), 2'(dihydrogen phosphate), P'o5'-ester with 1,4dihydro-1-E-D-ribofuranosyl-3pyridinecarboxamide

II.A-5 II.A-5 II.A-5, VIII-3, XVII.E-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1488

11/24/08 1:55:34 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1489

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

53-59-8

0

1

0

Adenosine 5'-(trihydrogen diphosphate), 2'(dihydrogen phosphate), P'o5'-ester with 3(aminocarbonyl)-1-E-D-ribofuranosylpyridinium hydroxide, inner salt

II.A-5, X-2, XII-2, XVII.B-2

7298-93-3

0

1

0

Adenosine 5'-(trihydrogen diphosphate), 5'o5'-ester with 3-(aminocarbonyl)-1-D-Dribofuranosylpyridinium hydroxide, inner salt

II.A-5, X-2, XII-2, XVII.B-2

55030-93-8

0

1

0

Adenosine 5'-(trihydrogen diphosphate), N-(3methyl-2-butenyl)-

22732-83-8

0

1

0

Adenosine 5'-(trihydrogen pyrophosphate), mono-Dglucopyranosyl ester

II.A-5, VIII-3, XVII.E-6

40811-89-0

0

1

0

Adenosine 5'-(trihydrogen diphosphate), N(phenylmethyl)-

II.A-5, VIII-3, XVII.E-6

58-68-4

0

1

0

Adenosine 5'-(trihydrogen diphosphate), P'o5'ester with 1,4-dihydro-1-E-D-ribofuranosyl-3pyridinecarboxamide

II.A-5, VIII-3, XVII.E-6

53-84-9

0

1

0

Adenosine 5'-(trihydrogen diphosphate), P'o5'ester with 3-(aminocarbonyl)-1-E-Dribofuranosylpyridinium hydroxide, inner salt

II.A-5, VIII-3, XVII.E-6

9012-52-6

0

1

0

Adenosyltransferase, methionine

Name (per CA Collective Index)

84-21-9

0

1

0

3'-Adenylic acid

61-19-8

0

1

0

5'-Adenylic acid

Chapter Table

Selected structures

II.A-5, V-3

XXII-2 II.A-5, X-2, XII-2 II.A-5, X-2, XII-2

N H2N

N

N

OH

N

OH O

O

CH2O--P

OH

OH

20268-93-3

0

1

0

5'-Adenylic acid, N-(3-methyl-2-butenyl)-

II.A-5, X-2, XII-2

13484-66-7

0

1

0

5'-Adenylic acid, N-(phenylmethyl)-

II.A-5, X-2, XII-2

9012-39-9

0

1

0

Adenylyltransferase, sulfate

XXII-2

6898-94-8

1

1

1

Alanine

62-57-7

0

1

0

Alanine, 2-methyl-

(CH3)2=C(NH2) COOH

IV.A-3, IV.B-7

13100-82-8

0

1

0

Alanine, 3-sulfo-

HO-SO2-CH2-C(NH2) COOH IV.A-3, IV.B-7

107-95-9

0

1

0

E-Alanine

H2N-(CH2)2-COOH

79-83-4

0

1

0

E-Alanine, N-(2,4-dihydroxy-3,3-dimethyl-1oxobutyl)-, (R)-

10478-42-9

1

1

1

E-Alanine, N-methyl-N-nitroso- = Propanoic acid, 3(methylnitrosamino){NMPA}

133201-38-4

1

0

0

E-Alanine, N-(nitrosomethyl)-

1

0

0

E-Alanine, N-methyl-N-nitroso-, methyl ester

H3C-N(NO)-(CH2)2-COOCH3 IV.A-3, IV.B-7, XV-8

923-16-0

0

1

0

D-Alanine, N-D-alanyl-

H2N-(CH2)2-CO-NH-(CH2)2-COOH IV.A-3, IV.B-7

56-41-7

1

1

1

L-Į-Alanine

H3C-CH(NH2)-COOH

IV.A-3, IV.B-7 IV.A-3, IV.B-7 IV.A-3, IV.B-7

H3C-N(NO)-(CH2)2-COOH IV.A-3, IV.B-7, XV-8 IV.A-3, IV.B-7, XV-8

IV.A-3, IV.B-7

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1489

11/24/08 1:55:34 PM

1490

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

52756-25-9

0

1

0

Name (per CA Collective Index)

Selected structures Cl

DL-Alanine, N-benzoyl-N-(3-chloro-4-fluorophenyl)-, methyl ester {Flamprop-methyl®}

XXI-3

O C6H5

N

F

Chapter Table

CH-CH3 H3C-OOC

16124-24-6

0

1

0

L-Alanine, N-(1-deoxy-D-fructos-1-yl)-

82560-54-1

0

1

0

ȕ-Alanine, N-(((((2,3-dihydro-2,2-dimethyl-7benzofuranyl)oxy)carbonyl)methylamino)thio)-N(1-methylethyl)-, ethyl ester {Benfuracarb®}

II.A-5, IV.A-3 OOC-R O

X-2, XVIII.B-3, XXI-3 R = -NH-S-N[CH(CH3)2]-(CH2)2-COOC2H5 57646-30-7

0

1

0

X-2, XXI-3

O

DL-Alanine, N-(2,6-dimethylphenyl)-N-(2furanylcarbonyl-, methyl ester {Furalaxyl®}

O O

N

O

57837-19-1

0

1

0

X-2, XXI-3

O

DL-Alanine, N-(2,6-dimethylphenyl)-N(methoxyacetyl)-, methyl ester {Ridomil®}

H3 C CH3

CH3

O N

O

CH3

71626-11-4

0

1

0

CH3

O

XXI-3

DL-Alanine, N-(2,6-dimethylphenyl)-N(phenylacetyl)-, methyl ester {Benalaxyl®}

O

N

O O

9006-50-2

0

1

0

Albumin

XXII-2

9048-46-8

0

1

0

Albumins, blood serum

XXII-2

9024-52-6

0

1

0

Aldolase, fructose diphosphate

XXII-2

9026-94-2

0

1

0

Aldolase, phospho-2-keto-3-deoxyheptonate

XXII-2

145137-43-5

0

1

0

Aldolase, phospho-2-keto-3-deoxyheptonate (tobacco clone NtDAHPS-1 precursor reduced)

XXII-2

1

0

0

Alkylaminocarbonyl radical, methyl-

CONHCH3

XXVII-1

1

0

0

Alkylaminocarbonyl radical, ethyl-

CONHCH2CH3

XXVII-1

1

0

0

Alkylaminocarbonyl radical, propyl- {2 isomers}

CONHCH2CH2CH3

XXVII-1

1

0

0

Alkylaminocarbonyl radical, butyl-

CONHCH2CH2CH2CH3

XXVII-1

1

0

0

Alkylaminocarbonyl radical, pentyl- {3 isomers}

CONHCH2CH2CH2CH2CH3

XXVII-1

1

0

0

Alkylaminocarbonyl radical (unsaturated)

C5H8NO

XXVII-1

1

0

0

Alkylaminocarbonyl radical (unsaturated)

C7H12NO

0

1

0

D-Allose

2595-97-3

{2 isomers}

HO

XXVII-1

O OH

II.A-5, VIII-3

HO OH

OH

7429-90-5

1

1

1

Aluminum

Al

XX-5

1344-28-1

0

1

0

Aluminum oxide

Al2O3

9031-85-0

0

1

0

Aminoacyltransferase

XXII-2

9031-94-1

0

1

0

Aminopeptidase

XXII-2

XX-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1490

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1491

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 9001-61-0

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

0

1

0

Aminopeptidase, cytosol

XXII-2

0

1

0

Aminopeptidase, leucine

XXII-2

37277-82-0

0

1

0

Aminopropyltransferase, putrescine

XXII-2

9031-66-7

0

1

0

Aminotransferase

XXII-2

9000-86-6

0

1

0

Aminotransferase, alanine

XXII-2

9000-97-9

0

1

0

Aminotransferase, aspartate

XXII-2

50812-10-7

0

1

0

Aminotransferase, glutamate-glyoxylate

XXII-2

9030-42-6

0

1

0

Aminotransferase, ornithine-keto acid

XXII-2

37259-57-7

0

1

0

Aminotransferase, serine-glyoxylate

7664-41-7

1

1

1

Ammonia

9024-28-6

0

1

0

Ammonia-lyase, phenylalanine

XXII-2 NH3

XII-2 XXII-2

NH4

+1

14798-03-9

1

1

1

Ammonium

53516-76-0

0

1

0

Ammonium chloride, alkyldimethylbenzyl{Benazlkonium chloride®}

XX-6

1336-21-6

0

1

0

Ammonium hydroxide

NH4OH

XX-6

12135-76-1

0

1

0

Ammonium sulfide

(NH4)2S

XVIII.A-1, XX-6

9000-92-4

0

1

0

Amylase

9000-90-2

0

1

0

Amylase, D-

XXII-2

9000-91-3

0

1

0

Amylase, E-

XXII-2

9067-73-6

0

1

0

Amylase, iso-

XXII-2

XVIII.B-3, XX1-3

XXII-2

9005-84-9

0

1

0

Amylodextrin

VIII-3

9037-22-3

0

1

0

Amylopectin

VIII-3

9005-82-7

0

1

0

Amylose

VIII-3

32222-21-2

0

1

0

Androsta-3,5-dien-7-one

III-13

0

1

0

Anhydrase, carbonate

189-58-2

1

0

0

Anthra[9,1,2-cde]benzo[h]cinnoline

610-49-1

1

0

0

1-Anthracenamine

O

XXII-2

XVII.E-6

9 1

7

5

1

0

0

9-Anthracenamine

120-12-7

1

1

1

Anthracene

2 3

6

779-03-3

XII-2

NH2 8

10

4

XII-2 8

9

1

7

2

6

3 5

10

I.E-6

4

1

0

0

Anthracene, alkyl-

I.E-6

613-31-0

1

0

0

Anthracene, 9,10-dihydro-

I.E-6

29063-00-1

1

0

0

Anthracene, dimethyl-

I.E-6

© 2009 by Taylor & Francis Group, LLC

78836_C030.indd 1491

11/24/08 1:55:35 PM

1492

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

781-43-1

1

0

0

Anthracene, 9,10-dimethyl-

I.E-6

41637-86-9

1

0

0

Anthracene, ethyl-

I.E-6

Name (per CA Collective Index)

Chapter Table

Selected structures

605-83-4

1

0

0

Anthracene, 9-ethyl-

I.E-6

71265-29-7

1

0

0

Anthracene, ethylmethyl-

I.E-6

26914-18-1

1

0

0

Anthracene, methyl-

I.E-6

610-48-0

1

0

0

Anthracene, 1-methyl-

I.E-6

613-12-7

1

0

0

Anthracene, 2-methyl-

I.E-6

779-02-2

1

0

0

Anthracene, 9-methyl-

I.E-6

71265-30-0

1

0

0

Anthracene, propyl-

I.E-6

27358-28-7

1

0

0

Anthracene, trimethyl-

I.E-6

0

1

0

1,4-Anthracenedione, 2,3-dimethyl-

IX.B-2

0 CH3

CH3 0

84-65-1

1

1

1

9,10-Anthracenedione

{9,10-anthraquinone}

IX.B-2, XXI-3

O 1 2 2 4 O

20724-30-5

1

0

0

9,10-Anthracenedione, 1,2-diethyl-

IX.B-2

71265-31-1

1

0

0

9,10-Anthracenedione, dimethyl-

IX.B-2

1

0

0

9,10-Anthracenedione, 2,3-dimethyl-

IX.B-2

27936-34-1

1

0

0

9,10-Anthracenedione, methyl-

IX.B-2

84-54-8

1

1

1

9,10-Anthracenedione, 2-methyl-

IX.B-2

1

0

0

9,10-Anthracenedione, trimethyl-

IX.B-2

1

0

0

9(10H)-Anthracenone

90-44-8

{anthrone}

1 9

7

2 3

6 5

7440-36-0

1

1

1

III-13

O 8

10

4

Antimony

Sb

XX-5 XX-5 XX-5

14683-10-4

1

1

1

Antimony, isotope of mass 124

124

14331-88-5

0

1

0

Antimony, isotope of mass 129

129

Sb Sb

9000-95-7

0

1

0

Apyrase

11078-27-6

0

1

0

Arabinan

XXII-2

20261-96-5

1

1

1

Arabinohexonic acid, 3-deoxy-, J-lactone

II.A-5, VI-3, VIII-3

42400-32-8

0

1

0

D-Arabinohexonic acid, 2-deoxy-, J-lactone

II.A-5, VI-3, VIII-3

23675-06-1

0

1

0

D-D-Arabinohexopyranoside, 2-deoxy-D-D-arabinohexopyranosyl 2-deoxy-

154-17-6

0

1

0

D-Arabinohexose, 2-deoxy-

16449-30-2

0

1

0

D-Arabinohexose, 2-deoxy-4-O-E-D-glucopyranosyl-

13752-83-5

0

1

0

Arabinonic acid

II.A-5, VIII-3

II.A-5, VIII-3 II.A-5, VIII-3, X-2 II.A-5, VIII-3 HO-CH2-(CHOH)3-COOH

II.A-5, IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1492

11/24/08 1:55:35 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1493

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

13280-76-7

1

0

0

Name (per CA Collective Index)

Selected structures

Arabinonic acid, J-lactone

HO

147-81-9

II.A-5, VI-3

OH

HOCH2

Chapter Table

O

O

1

1

1

Arabinose

HO-CH2-(CHOH)3-CH=O

0

1

0

Arabitinol , 2,3-di-O-methyl-

HO-CH2-CHOH-(CHOCH3)2-CH=O II.A-5, III-12, X-2

II.A-5, III-12

0

1

0

Arabitinol , 2,5-di-O-methyl-

H3CO-CH2-(CHOH)2-(CHOCH3)-CH=O II.A-5, III-12, X-2

0

1

0

Arabitinol , 3,5-di-O-methyl-

H3CO-CH2-CHOH-(CHOCH3)-CHOH-CH=O II.A-5, III-12, X-2

0

1

0

Arabitinol , 2,3,4-tri-O-methyl-

HO-CH2-(CHOCH3)3-CH=O II.A-5, III-12, X-2

0

1

0

Arabitinol , 2,3,5-tri-O-methyl-

H3CO-CH2-CHOH-(CHOCH3)2-CH=O II.A-5, III-12, X-2

9040-27-1

0

1

0

Arabinoxylan

7004-12-8

0

1

0

Arginine

1069-09-6 34522-32-2

0

1

0

Arginine, N2-(1-carboxyethyl)-

74-79-3

0

1

0

L-Arginine

7440-37-1

1

0

0

Argon

A

7440-38-2

1

1

1

Arsenic

As

15575-20-9

0

1

0

Arsenic, isotope of mass 76

76

7778-44-1

0

1

0

Arsenic acid, calcium salt

Ca3(AsO4)2

7645-25-2

0

1

0

Arsenic acid (H3AsO4), lead salt

Pb3(AsO4)2

XX-6, XXI-3

7784-40-9

0

1

0

Arsenic acid, lead salt (PbHAsO4)

PbHAsO4

XX-6, XXI-3

1327-53-3

0

1

0

Arsenic oxide

As2O3

XX-6

7784-42-1

1

0

0

Arsine

H3As

XX-6

603-32-7

1

0

0

Arsine, triphenyl-

As(C6H5)3

XX-6

50-81-7

1

1

1

L-Ascorbic acid

VIII-3 H2N-C(=NH)-NH-(CH2)3-CH(NH2)-COOH IV.A-3, IV.B-7 IV.A-3, IV.B-7 H2N-C(=NH)-NH-(CH2)3-CH(NH2)-COOH IV.A-3, IV.B-7 XX-5 XX-5, XXI-3

As

{arsenious oxide}

{L-gulofuranolactone, 3-oxo-}

XX-5 XX-6, XXI-3

II.A-5, VI-3

CH2OH O

HO

O

OH

7006-34-0

1

1

1

Asparagine

70-47-3

0

1

0

L-Asparagine

IV.A-3, IV.B-7

5794-13-8

0

1

0

L-Asparagine monohydrate

IV.A-3, IV.B-7

6899-03-2

1

1

1

Aspartic acid

56-84-8

1

1

1

L-Aspartic acid

2456-73-7

0

1

0

L-Aspartic acid, N-(1H-indol-3-ylacetyl)-

H2N-CO-CH2-CH(NH2)-COOH IV.A-3, IV.B-7

IV.A-3, IV.B-7 HOOC-CH2-CH(NH2)-COOH IV.A-3, IV.B-7 IV.A-3, IV.B-7

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1493

11/24/08 1:55:35 PM

1494

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

271-63-6

S

T

S T

1

0

0

Azaindene

1

0

0

7-Azaindole

Name (per CA Collective Index)

Selected structures

XVII.E-6

N

7

1

5

0

0

7-Azaindole, N-methyl-

0

1

0

Azathymine

XVII.E-6 N

O

503-29-7

1

1

1

Azetidine

34441-14-0

0

1

0

1-Azetidinebutanoic acid, D-[(3-amino-3carboxypropyl)amino]-2-carboxy-, [2S[1[DR*(R*)],2R*]]{nicotianamine}

XIV-1, XVII.B-2

NH O

N H

XVII.A-1

NH

2517-04-6

0

1

0

2-Azetidinecarboxylic acid

55556-98-4

0

1

0

2-Azetidinecarboxylic acid, 1-nitroso-

275-51-4

2

3

4

1

XVII.E-6

H N

N

6

Chapter Table

IV.A-3

IV.A-3

1

0

0

Azulene

1

0

0

Azulene, 1,4-dimethyl-7-ethyl-

68038-71-1

0

1

0

Bacillus thuringiensis

7440-39-3

1

1

1

Barium

203-33-8

1

0

0

Benz[a]aceanthrylene

202-33-5

1

0

0

Benz[j]aceanthrylene

COOH

ON

IV.A-3, XV-8

N

{cyclopentacycloheptene}

I.E-6

I.E-6 {Dipel®}

XXI-3 Ba

XX-5 I.E-6

{benzo[a]fluoranthene}

{cholanthrylene}

I.E-6 e

f

g

j

i

h

d c b

a 2

479-23-2

1

0

0

1

I.E-6

Benz[j]aceanthrylene, 1,2-dihydro- {cholanthrene} e

f

g

j

i

h

d c b

a 2

56-49-5

1

0

0

Benz[j]aceanthrylene, 1,2-dihydro-3-methyl{3-methylcholanthrene}

1

I.E-6 e

f

g

h

i

j

d H3C

c b

a 2

1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1494

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1495

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

76774-50-0

1

0

0

Benz[fg]acenaphthylene

I.E-6

205-99-2

1

1

1

Benz[e]acephenanthrylene {benzo[b]fluoranthene}

I.E-6

41637-94-9

1

0

0

Benz[e]acephenanthrylene, methyl-

I.E-6

149021-93-2

1

0

0

Benz[e]acephenanthrylene, 10-methyl-

225-11-6

1

0

0

Benz[a]acridine

1

0

0

Benz[a]acridine, 8,10-dimethyl-

1

0

0

Benz[c]acridine

225-51-4

Name (per CA Collective Index)

Selected structures

Chapter Table

I.E-6 XVII.E-6

XVII.E-6 7

8

XVII.E-6

6

9

5

10 N

11

4 1

3 2

10567-95-0

1

0

0

Benz[c]acridine, 5,7-dimethyl-

XVII.E-6

71265-19-5

1

0

0

Benz[c]acridine, 6,9-dimethyl-

XVII.E-6

963-89-3

1

0

0

Benz[c]acridine, 7,9-dimethyl-

XVII.E-6

2381-40-0

1

0

0

Benz[c]acridine, 7,10-dimethyl-

XVII.E-6

32740-01-5

1

0

0

Benz[c]acridine, 7,11-dimethyl-

XVII.E-6

3340-94-1

1

0

0

Benz[c]acridine, 7-methyl-

XVII.E-6

14319-90-5

1

0

0

Benz[c]acridine, 8-methyl-

XVII.E-6

33942-93-7

1

0

0

Benz[c]acridine, 9-methyl-

XVII.E-6

7230-71-9

1

0

0

Benz[c]acridine, 10-methyl-

XVII.E-6

67028-20-0

1

0

0

Benz[c]acridine, 11-methyl-

XVII.E-6

58430-01-6

1

0

0

Benz[c]acridine, 7,9,10-trimethyl-

XVII.E-6

51787-42-9

1

0

0

Benz[c]acridine, 7,9,11-trimethyl-

100-52-7

1

1

1

Benzaldehyde

XVII.E-6 6

CH=O

5 4

III-12

2 3

1620-98-0

0

1

0

Benzaldehyde, 3,5-di(1,1-dimethylethyl)-4-hydroxy-

33774-71-9

1

1

1

Benzaldehyde, dihydroxy-

III-12 III-12, IX-22

24677-78-9

1

1

1

Benzaldehyde, 2,3-dihydroxy-

III-12, IX-22

95-01-2

1

0

0

Benzaldehyde, 2,4-dihydroxy-

III-12, IX-22

1194-98-5

1

0

0

Benzaldehyde, 2,5-dihydroxy-

III-12, IX-22

139-85-5

1

1

1

Benzaldehyde, 3,4-dihydroxy{protocatechualdehyde}

III-12, IX-22

613-45-6

0

1

0

Benzaldehyde, 2,4-dimethoxy-

III-12, X-2

4925-88-6

1

0

0

Benzaldehyde, 2,5-dimethoxy-4-methyl-

III-12, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1495

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1496

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

3392-97-0

1

1

1

Benzaldehyde, 2,6-dimethoxy-

120-14-9

1

1

1

Benzaldehyde, 3,4-dimethoxy-

{veratraldehyde}

III-12, X-2

134-96-3

1

1

1

Benzaldehyde, 3,5-dimethoxy-4-hydroxy{syringaldehyde}

III-12, IX-22, X-2

15764-16-6

1

0

0

Benzaldehyde, 2,4-dimethyl-

III-12

5779-94-2

1

0

0

Benzaldehyde, 2,5-dimethyl-

III-12

100-10-7

1

0

0

Benzaldehyde, 4-(dimethylamino)-

121-32-4

1

1

1

Benzaldehyde, 3-ethoxy-4-hydroxy- {ethylvanillin}

53951-50-1

0

1

0

Benzaldehyde, ethyl-

III-12

4748-78-1

0

1

0

Benzaldehyde, 4-ethyl-

III-12

Name (per CA Collective Index)

Selected structures

Chapter Table III-12, X-2

III-12, XII-2 III-12, IX-22, X-2

90-02-8

1

1

1

Benzaldehyde, 2-hydroxy-

148-53-8

0

1

0

Benzaldehyde, 2-hydroxy-3-methoxy-

III-12, IX-22

100-83-4

0

1

0

Benzaldehyde, 3-hydroxy-

III-12, IX-22

123-08-0

1

1

1

Benzaldehyde, 4-hydroxy-

III-12, IX-22

106799-60-4

0

1

0

Benzaldehyde, hydroxymethoxy-

121-33-5

{salicylaldehyde}

III-12, IX-22

III-12, IX-22, X-2

1

1

1

Benzaldehyde, 4-hydroxy-3-methoxy-

1

1

1

Benzaldehyde, 4-hydroxy-3-methoxy-, labeled with 14 14 C {vanillin- C}

{vanillin}

III-12, IX-22, X-2 XXV-29

1

0

0

Benzaldehyde, hydroxy-methyl-

III-12, IX-22

97122-27-5

1

0

0

Benzaldehyde, hydroxy-3-methyl-

III-12, IX-22

57295-30-4

1

0

0

Benzaldehyde, 3-hydroxy-4-methyl-

III-12, IX-22 III-12, IX-22

15174-69-3

1

0

0

Benzaldehyde, 4-hydroxy-3-methyl-

1

0

0

Benzaldehyde, methoxy-

III-12

123-11-5

1

1

1

Benzaldehyde, 4-methoxy-

1334-78-7

1

0

0

Benzaldehyde, methyl-

{p-anisaldehyde}

III-12, X-2

529-20-4

1

1

1

Benzaldehyde, 2-methyl-

{o-tolualdehyde}

III-12

620-23-5

1

1

1

Benzaldehyde, 3-methyl-

{m-tolualdehyde}

III-12

III-12

104-87-0

1

1

1

Benzaldehyde, 4-methyl-

{p-tolualdehyde}

III-12

122-03-2

1

1

1

Benzaldehyde, 4-(1-methylethyl)- {cuminaldehyde}

III-12

29344-95-4

0

1

0

Benzaldehyde, 2,3,4,5-tetramethyl-

III-12

55-21-0

1

1

1

Benzamide

15310-01-7

0

1

0

Benzamide, 2-iodo-N-phenyl-

C6H5-CO-NH2 {Benodanil®}

XIII-1 XIII-1, XXI-3

I CO-NH-C6H5

1

0

0

Benzanthracene

I.E-6

63194-18-3

1

0

0

Benzanthracene, methyl-

I.E-6

56-55-3

1

1

1

Benz[a]anthracene

{BaA or B[a]A}

1 11

12

8

7

2 3 4

10 9

43178-07-0

I.E-6

5 6

1

0

0

Benz[a]anthracene, alkyl-

I.E-6

1

0

0

Benz[a]anthracene, dimethyl-

I.E-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1496

11/24/08 1:55:36 PM

1497

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

57-97-6

1

0

0

Benz[a]anthracene, 7,12-dimethyl-

0

0

0

Benz[a]anthracene, 9,10-dimethylThere can be no such compound as 7,12dimethyl-1,2-benzanthracene because, according to the now obsolete nomenclature shown, there was never a 12 position in the 1,2-benzanthracene molecule. Also shown is 7,12dimethylbenz[a]anthracene named according to the current nomenclature.

31632-62-9

1

0

0

Name (per CA Collective Index)

Chapter Table

Selected structures {DMBA}

I.E-6 CH3 8 9

6

10

4'

2 3

4

5

CH3

3' 1

7

2

2'

1'

11 10

3 a

12

4 b

7

9 8

CH3

1

5

6

c

CH3

I.E-6

Benz[a]anthracene, ethyl-

I.E-6

71265-32-2

1

0

0

Benz[a]anthracene, ethylmethyl-

I.E-6

43178-22-9

1

0

0

Benz[a]anthracene, methyl-

I.E-6

2498-77-3

1

0

0

Benz[a]anthracene, 1-methyl-

I.E-6

2498-76-2

1

0

0

Benz[a]anthracene, 2-methyl-

I.E-6

2498-75-1

1

0

0

Benz[a]anthracene, 3-methyl-

I.E-6

316-49-4

1

0

0

Benz[a]anthracene, 4-methyl-

I.E-6

2319-96-2

1

0

0

Benz[a]anthracene, 5-methyl-

I.E-6

316-14-3

1

0

0

Benz[a]anthracene, 6-methyl-

I.E-6

2381-31-9

1

0

0

Benz[a]anthracene, 8-methyl-

I.E-6

2381-16-0

1

0

0

Benz[a]anthracene, 9-methyl-

I.E-6

2381-15-9

1

0

0

Benz[a]anthracene, 10-methyl-

I.E-6

2422-79-9 71265-33-3

1

0

0

Benz[a]anthracene, 12-methyl-

I.E-6

1

0

0

Benz[a]anthracene, methylene-

I.E-6

1

0

0

Benz[a]anthracene, propyl-

I.E-6

1

0

0

Benz[a]anthracene, tetramethyl-

I.E-6

60826-78-0

1

0

0

Benz[a]anthracene, trimethyl-

I.E-6

199-94-0

1

0

0

7H-Benz[de]anthracene

2

e

I.E-6

3

1 d

c

4 b

a

7

62-53-3

1

0

0

Benz[a]anthrone

1

1

1

Benzenamine

5

6

III-13

O

{aniline}

XII-2

NH2 6

2 3

5 4

106-40-1

1

0

0

Benzenamine, 4-bromo-

XII-2, XVIII.B-3

1861-40-1

0

1

0

Benzenamine, N-butyl-2,6-dinitro-N-ethyl-4(trifluoromethyl){Benefin®; Benfluralin®}

NO2 (CH2)3-CH3 F3C

XII-2, XXI-3

N CH2-CH3 NO2

95-51-2

1

0

0

Benzenamine, 2-chloro-

{2-chloroaniline}

XII-2, XVIII.B-3, XXI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1497

11/24/08 1:55:37 PM

1498

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Chapter Table

Selected structures

106-47-8

1

0

0

Benzenamine, 4-chloro-

46175-80-8

0

1

0

Benzenamine, 2-(cyclohexen-1-yl)-

XII-2, XVIII.B-3

95-76-1

0

1

0

Benzenamine, 3,4-dichloro-

99-30-9

0

1

0

Benzenamine, 2,6-dichloro-4-nitro- {Dicloran®)

87-59-2

1

1

1

Benzenamine, 2,3-dimethyl-

{2,3-xylidine}

XII-2

95-68-1

1

1

1

Benzenamine, 2,4-dimethyl-

{2,4-xylidine}

XII-2

95-78-3

1

1

1

Benzenamine, 2,5-dimethyl-

{2,5-xylidine}

XII-2

87-62-7

1

1

1

Benzenamine, 2,6-dimethyl-

{2,6-xylidine}

XII-2

95-64-7

1

1

1

Benzenamine, 3,4-dimethyl-

{3,4-xylidine}

40487-42-1

0

1

0

Benzenamine, 3,4-dimethyl-2,6-dinitro-N-(1ethylpropyl){Pendimethalin®}

XII-2 XII-2, XVIII.B-3 XII-2, XVIII.B-3, XXI-3

XII-2 XII-2, XXI-3

HN-CH(C2H5)2 O2N

NO2

108-69-0

1

1

1

Benzenamine, 3,5-dimethyl-

{3,5-xylidine}

XII-2

611-21-2

1

0

0

Benzenamine, N,2-dimethyl-

XII-2

623-08-5

1

0

0

Benzenamine, N,4-dimethyl-

XII-2

121-69-7

1

0

0

Benzenamine, N,N-dimethyl-

33629-47-9

0

1

0

Benzenamine, 4-(1,1-dimethylethyl)-2,6-dinitro-N(1-methylpropyl){Butralin®}

XII-2 NO2 (H3C)3C

NH-CH(CH 3)-CH2CH3 NO2

XII-2, XXI-3 33820-53-0

0

1

0

Benzenamine, 2,6-dinitro-N,N-dipropyl-4-(1methylethyl){Isopropalin®}

XII-2, XXI-3

NO2 H3C

(CH2)2CH3 N (CH2)2CH3

H3C NO2

1582-09-8

0

1

0

Benzenamine, 2,6-dinitro-N,N-dipropyl-4(trifluoromethyl){Trifluralin®}

NO2 (CH2)2-CH3 F3C

XII-2, XXI-3

N (CH2)2-CH3 NO2

0

1

0

Benzenamine, 4-ethenyl-

XII-2

578-54-1

1

1

1

Benzenamine, 2-ethyl-

XII-2

587-02-0

1

0

0

Benzenamine, 3-ethyl-

XII-2

589-16-2

1

0

0

Benzenamine, 4-ethyl-

XII-2

103-69-5

1

0

0

Benzenamine, N-ethyl-

1821-38-1

1

1

1

Benzenamine, 2-ethyl-N-methyl-

{N-ethylaniline}

C6H5-NH-CH2-CH3

XII-2

XII-2

71265-20-8

1

0

0

Benzenamine, 3-ethyl-N-methyl-

XII-2

37846-06-3

1

0

0

Benzenamine, 4-ethyl-N-methyl-

XII-2

94-68-8

1

0

0

Benzenamine, N-ethyl-2-methyl-

XII-2

102-27-2

0

1

0

Benzenamine, N-ethyl-3-methyl-

XII-2

71265-27-5

1

0

0

Benzenamine, ar-ethyl-ar-methyl-

XII-2

90-04-0

1

1

1

Benzenamine, 2-methoxy-

{o-anisidine}

X-2, XII-2

536-90-3

1

1

1

Benzenamine, 3-methoxy-

{m-anisidine}

X-2, XII-2

104-94-9

1

0

0

Benzenamine, 4-methoxy-

{p-anisidine}

X-2, XII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1498

11/24/08 1:55:37 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1499

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Chapter Table

Selected structures

26915-12-8

1

0

0

Benzenamine, ar-methyl-

XII-2

95-53-4

1

1

1

Benzenamine, 2-methyl- {o-toluidine; 2-toluidine}

XII-2

108-44-1

1

0

0

Benzenamine, 3-methyl- {m-toluidine 3-toluidine}

XII-2

106-49-0

1

0

0

Benzenamine, 4-methyl- {p-toluidine; 4-toluidine}

XII-2

100-61-8

1

0

0

Benzenamine, N-methyl-

5266-85-3

0

1

0

Benzenamine, 2-methyl-6-(1-methylethyl)-

1

1

1

Benzenamine, N-methyl-N-nitroso-

1

0

0

Benzenamine, (1-methylethyl)-N-(1methylethylphenyl)-

XII-2

1

0

0

Benzenamine, 4-(1-methylethyl)-N-phenyl-

XII-2

5650-10-2 552-82-9

{N-methylaniline}

C6H5-NH-CH3

XII-2 XII-2 XII-2, XV-8

1

0

0

Benzenamine, N-methyl-N-phenyl-

XII-2

1

0

0

Benzenamine, N-nitroso-N-phenyl-

XII-2, XV-8

122-39-4

1

0

0

Benzenamine, N-phenyl-

13066-19-8

1

0

0

Benzenamine, 2-(2-phenylethenyl){2-aminostilbene}

14064-37-0

1

0

0

Benzenamine, 3-(2-phenylethenyl)-, (Z)-

XII-2

834-24-2

1

0

0

Benzenamine, 4-(2-phenylethenyl)-

XII-2

71265-28-6

1

0

0

Benzenamine, ar,ar,ar,ar-tetramethyl-

XII-2 XII-2

31093-11-5

1

0

0

Benzenamine, ar,ar,ar-trimethyl-

88-05-1

1

0

0

Benzenamine, 2,4,6-trimethyl-

71-43-2

1

1

1

Benzene

{diphenylamine}

C6H5-NH-C6H5

XII-2 XII-2

{mesitylamine}

XII-2 I.D-1

1 2

6

3

5 4

1

0

0

Benzene, C3-alkyl-

I.D-1

1

0

0

Benzene, C4-alkyl-

I.D-1

1

0

0

Benzene, C5-alkyl-

I.D-1

103-33-3

0

1

0

Benzene, azobis-

C6H5-N=N-C6H5

XVI-1

886-66-8

1

0

0

Benzene, 1,1'-(1,3-butadiyne-1,4-diyl)bis-

C6H5-CŁC-CŁC-C6H5

I.D-1

824-90-8

1

0

0

Benzene, 1-butenyl-

C6H5-CH=CH-(CH2) 2-CH3

I.D-1

104-51-8

1

0

0

Benzene, butyl-

C6H5-(CH2)3-CH3

108-90-7

1

0

0

Benzene, chloro-

C6H5-Cl

22349-74-2

1

0

0

Benzene, 1-chloro-4-(2-chloro-1-phenylethenyl)-

103-17-3

0

1

0

Benzene, 1-chloro-4-((4-chlorophenyl)methyl)thio){Chlorobenside®}

{azobenzene}

XVIII.B-3 S Cl

3424-82-6

1

0

0

Benzene, 1-chloro-2-[2,2-dichloro-1-(4chlorophenyl)ethenyl]-

53-19-0

1

1

1

Benzene, 1-chloro-2-[2,2-dichloro-1-(4chlorophenyl)ethyl]{o,p’-DDD; o.p’-TDE}

I.D-1 XVIII.B-3, XXI-3

Cl

XVIII.B-3 XXI-3

XVIII.B-3 XVIII.B-3, XXI-3

CHCl 2 Cl

Cl

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1499

11/24/08 1:55:37 PM

1500

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

4329-12-8

1

1

1

Benzene, 1-chloro-3-[2,2-dichloro-1-(4chlorophenyl)ethyl]{m,p’-DDD}

789-02-6

1

1

1

Benzene, 1-chloro-2-[2,2,2-trichloro-1-(4chlorophenyl)ethyl]{o,p’-DDT}

Name (per CA Collective Index)

Selected structures

XVIII.B-3, XXI-3

1

0

0

Benzene, 1,1'-(chloroethenylidene)bis-

1022-22-6

1

1

1

Benzene, 1,1'-(chloroethenylidene)bis[4-chloro{DDM}

CCl3

XVIII.B-3 XVIII.B-3, XXI-3

Cl

Cl

2642-80-0

1

1

1

XVIII.B-3, XXI-3

Cl

Cl

4541-89-3

Benzene, 1,1'-(2-chloroethylidene)bis[4-chloro{DDMS}

Cl

XVIII.B-3, XXI-3

Cl

Cl

Cl

622-24-2

0

1

0

Benzene, 2-chloroethyl-

Chapter Table

C6H5-(CH2)2-Cl

XVIII.B-3

0

1

0

Benzene, chloromethoxy-

25167-67-3

1

0

0

Benzene, chloromethyl-

{chloroanisole}

X-2, XVIII.B-3

95-50-1

1

1

1

Benzene, 1,2-dichloro-

XVIII.B-3

541-73-1

1

0

0

Benzene, 1,3-dichloro-

XVIII.B-3

C6H5-CH2-Cl

106-46-7

1

0

0

Benzene, 1,4-dichloro-

72-55-9

1

1

1

Benzene, 1,1'-(dichloroethenylidene)bis[4-chloro{p,p’-DDE}

XVIII.B-3

XVIII.B-3 Cl

Cl

XVIII.B-3, XXI-3

CCl2

27013-25-8

1

0

0

Benzene, 1,1'-(2,2-dichloroethylidene)bis[chloro-

72-54-8

1

1

1

Benzene, 1,1'-(2,2-dichloroethylidene)bis[4-chloro{p,p’-DDD, p,p’-TDE}

XVIII.B-3, XXI-3 Cl

Cl

XVIII.B-3

CHCl2

25340-17-4

1

1

1

Benzene, diethyl-

I.D-1

105-05-5

1

0

0

Benzene, 1,4-diethyl-

I.D-1

25550-13-4

1

0

0

Benzene, diethylmethyl-

I.D-1

27598-81-8

1

0

0

Benzene, dimethoxy-

X-2

91-16-7

1

1

1

Benzene, 1,2-dimethoxy-

{veratrole}

X-2

1

0

0

Benzene, 1,2-dimethoxy-4-ethenyl-

X-2

494-99-5

1

0

0

Benzene, 1,2-dimethoxy-4-methyl-

X-2

151-10-0

0

1

0

Benzene, 1,3-dimethoxy-

X-2

150-78-7

1

1

1

Benzene, 1,4-dimethoxy-

X-2

14753-08-3

0

1

0

Benzene, 1,4-dimethoxy-2-methyl-5-(1-methylethyl)-

X-2

1330-20-7

1

1

1

Benzene, dimethyl-

{xylene}

I.D-1

95-47-6

1

1

1

Benzene, 1,2-dimethyl-

{o-xylene}

I.D-1

108-38-3

1

1

1

Benzene, 1,3-dimethyl-

{m-xylene}

I.D-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1500

11/24/08 1:55:38 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1501

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Chapter Table

Selected structures

106-42-3

1

1

1

Benzene, 1,4-dimethyl-

2039-89-6

1

0

0

Benzene, 1,4-dimethyl-2-ethenyl-

I.D-1

934-80-5

{p-xylene}

I.D-1

1

0

0

Benzene, 1,2-dimethyl-4-ethyl-

I.D-1

1

0

0

Benzene, 1,3-dimethyl-4-ethyl-

I.D-1

1758-88-9

1

0

0

Benzene, 1,4-dimethyl-2-ethyl-

I.D-1

3459-80-1

0

1

0

Benzene, [(1,1-dimethylethoxy)methyl]-

X-2

98-06-6

1

1

1

Benzene, (1,1-dimethylethyl)-

1

0

0

Benzene, 3,5-bis(1,1-dimethylethyl)-1-methyl-

I.D-1

C6H5-C(CH3)3

I.D-1

644-30-4

0

1

0

Benzene, 1-(1,5-dimethyl-4-hexenyl)-4-methyl-

I.D-1

4176-17-4

0

1

0

Benzene, 1-(1,5-dimethyl-4-hexenyl)-4-methyl-, (R)-

I.D-1

99-51-4

1

0

0

Benzene, 1,2-dimethyl-4-nitro-

XVI-1

89-58-7

1

0

0

Benzene, 1,4-dimethyl-2-nitro{2,5-dimethyl-1-nitrobenzene}

XVI-1

89-87-2

1

0

0

Benzene, 2,4-dimethyl-1-nitro-

XVI-1

1007-26-7

0

1

0

Benzene, (2,2-dimethylpropyl)-

103-29-7

1

0

0

Benzene, 1,1'-(1,2-ethanediyl)bis-

588-59-0

1

1

1

Benzene, 1,1'-(1,2-ethenediyl)bis-

645-49-8

1

0

0

Benzene, 1,1'-(1,2-ethenediyl)bis-, (Z)-

I.D-1

103-30-0

1

0

0

Benzene, 1,1'-(1,2-ethenediyl)bis-, (E)-

I.D-1

5121-74-4

1

1

1

Benzene, 1,1'-(1,2-ethenediyl)bis[4-chloro{DCS = dichlorostilbene}

1657-56-3

1

1

1

Benzene, 1,1'-(1,2-ethenediyl)bis[4-chloro-, (E){trans-DCS}

2510-74-9

1

0

0

C6H5-CH2-C(CH3)3

I.D-1

{bibenzyl}

C6H5-CH2-CH2-C6H5

I.D-1

{stilbene}

C6H5-CH=CH-C6H5

I.D-1

XVIII.B-3 XVIII.B-3

Cl Cl

XVIII.B-3, XXI-3

Benzene, 1,1'-(1,2-ethenediyl)bis[4-chloro-, (Z){cis-DCS} Cl

{styrene}

C6H5-CH=CH2

Cl

100-42-5

1

1

1

Benzene, ethenyl-

6380-23-0

1

1

1

Benzene, 4-ethenyl-1,2-dimethoxy-

I.D-1

27576-03-0

1

0

0

Benzene, ethenyl-, dimethyl-

I.D-1

28106-30-1

1

0

0

Benzene, ethenylethyl-

I.D-1

71607-81-3

1

0

0

Benzene, ethenylethyldimethyl-

I.D-1

27138-10-9

1

0

0

Benzene, ethenylethylmethyl-

I.D-1

637-69-4

1

0

0

Benzene, 1-ethenyl-4-methoxy-

X-2

1

0

0

Benzene, ethenylmethyl-

I.D-1

611-15-4

1

0

0

Benzene, 1-ethenyl-2-methyl-

I.D-1

100-80-1

1

0

0

Benzene, 1-ethenyl-3-methyl-

I.D-1

X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1501

11/24/08 1:55:38 PM

1502

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Chapter Table

Selected structures

622-97-9

1

0

0

Benzene, 1-ethenyl-4-methyl-

I.D-1

71607-82-4

1

0

0

Benzene, ethenyltetramethyl-

I.D-1

50976-21-1

1

0

0

Benzene, ethenyltrimethyl-

103-73-1

1

0

0

Benzene, ethoxy-

5076-72-2

1

0

0

Benzene, 1-ethoxy-4-methoxy

100-41-4

1

1

1

Benzene, ethyl-

I.D-1 C6H5-O-CH2-CH3

X-2

C6H5-CH2-CH3

I.D-1

X-2

874-41-9

1

0

0

Benzene, 1-ethyl-2,4-dimethyl-

I.D-1

25550-14-5

1

0

0

Benzene, ethylmethyl-

I.D-1

611-14-3

1

1

1

Benzene, 1-ethyl-2-methyl-

I.D-1

620-14-4

1

1

1

Benzene, 1-ethyl-3-methyl-

I.D-1

622-96-8

1

1

1

Benzene, 1-ethyl-4-methyl-

I.D-1

18908-70-8

0

1

0

Benzene, 1-ethyl-2-(1-phenylethyl)-

I.D-1

18640-62-5

1

0

0

Benzene, 1-ethyl-4-(2-propenyl)-

I.D-1 I.D-1

536-74-3

1

0

0

Benzene, ethynyl-

1

0

0

Benzene, 1-(2-hepten-6-yl)-4-methyl-

118-74-1

0

1

0

Benzene, hexachloro-

1077-16-3

1

0

0

Benzene, hexyl-

{phenylacetylene}

I.D-1 XVIII.B-3, XXI-3 C6H5-(CH2)5-CH3

I.D-1

622-78-6

0

1

0

Benzene, (isothiocyanatomethyl)-

XVIII.A-1

2257-09-2

0

1

0

Benzene, (2-isothiocyanatoethyl)-

XVIII.A-1

100-66-3

1

1

1

Benzene, methoxy-

{anisole} 14

C6H5-O-CH3

X-2

14

21730-66-5

1

1

1

Benzene, methoxy-, 1- C, labeled with C 14 {anisole-1- C}

X-2

26897-24-5

0

1

0

Benzene, methoxy-methyl- {2 isomers detected}

X-2

538-86-3

0

1

0

Benzene, (methoxymethyl)- {benzyl methyl ether}

X-2

578-58-5

1

0

0

Benzene, 1-methoxy-2-methyl- {o-methylanisole}

X-2

100-84-5

1

0

0

Benzene, 1-methoxy-3-methyl- {m-methylanisole}

X-2

104-93-8

1

1

1

Benzene, 1-methoxy-4-methyl- {p-methylanisole}

X-2

3794-96-5

0

1

0

Benzene, 2-methoxy-1-methyl-4-(1-methylethenyl)-

X-2

6379-73-3

0

1

0

Benzene, 2-methoxy-1-methyl-4-(1-methylethyl)-

X-2

1076-56-8

0

1

0

Benzene, 2-methoxy-4-methyl-1-(1-methylethyl)-

X-2

104-46-1

1

1

1

Benzene, 1-methoxy-4-(1-propenyl)-

{anethole}

X-2

140-67-0

1

0

0

Benzene, 1-methoxy-4-(2-propenyl)- {estragole}

X-2

104-45-0

0

1

0

Benzene, 1-methoxy-4-propyl- {dihydroanethole}

X-2

16277-67-1

0

1

0

Benzene, (3-methoxy-1-propenyl)-

X-2

108-88-3

1

1

1

Benzene, methyl-

101-81-5

1

0

0

Benzene, 1,1'-methylenebis- {diphenylmethane}

101-76-8

1

0

0

Benzene, 1,1'-methylenebis[4-chloro-

{toluene}

C6H5-CH3

I.D-1

C6H5-CH2-C6H5

I.D-1 XVIII.B-3

Cl

Cl

98-83-9

1

0

0

Benzene, (1-methylethenyl)- {D-methylstyrene}

C6H5-C(CH3)=CH2

I.D-1

98-82-8

1

1

1

Benzene, (1-methylethyl)-

C6H5-CH=(CH3)2

I.D-1

{cumene}

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1502

11/24/08 1:55:38 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1503

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

1817-47-6

1

0

0

Benzene, 1-(1-methylethyl)-4-nitro- {4-nitrocumen}

1124-20-5

1

0

0

Benzene, 1-methyl-3-(1-methylethenyl)-

I.D-1

1195-32-0

1

0

0

Benzene, 1-methyl-4-(1-methylethenyl){p,Į-dimethylstyrene}

I.D-1

535-77-3

1

1

1

Benzene, 1-methyl-3-(1-methylethyl)- {m-cymene}

I.D-1

99-87-6

1

1

1

Benzene, 1-methyl-4-(1-methylethyl)- {p-cymene}

I.D-1

88-72-2

1

0

0

Benzene, 1-methyl-2-nitro-

XVI-1

99-08-1

1

0

0

Benzene, 1-methyl-3-nitro-

XVI-1

99-99-0

1

0

0

Benzene, 1-methyl-4-nitro-

XVI-1

17271-70-4

1

0

0

Benzene, 1-methyl-3-(1-propenyl)-

I.D-1

1074-43-7

1

0

0

Benzene, 1-methyl-3-propyl-

I.D-1

1074-55-1

1

0

0

Benzene, 1-methyl-4-propyl-

I.D-1

538-93-2

1

0

0

Benzene, (2-methylpropyl)-

1139-49-7

1

0

0

Benzene, 1-methyl-3-(2,2,6-trimethylcyclohexyl){toluene, m-(2,2,6-trimethylcyclohexyl}

Selected structures

Chapter Table XVI-1

C6H5-CH2-CH(CH3)2 CH3

I.D-1 I.D-1

CH3

H3C CH3

16982-00-6

0

1

0

Benzene, 1-methyl-4-(1,2,2-trimethylcyclopentyl)-, (R)-

98-95-3

1

0

0

Benzene, nitro-

15457-05-3

0

1

0

Benzene, 2-nitro-1-(4-nitrophenoxy)-4(trifluoromethyl){Fluorodifen®}

82-68-8

0

1

0

Benzene, nitropentachloro-

CH3

CH3

H3C

C6H5-NO2

1

0

0

Benzene, octyl-

0

1

0

Benzene, 1,1'-oxybis-

103-50-4

1

0

0

Benzene, 1,1'-[oxybis(methylene)]bis{dibenzyl ether}

55044-97-8

1

0

0

Benzene, 1,1'-[oxybis(methylene)]bis[4-ethyl-

538-68-1

1

1

1

Benzene, pentyl-

637-50-3

1

0

0

Benzene, 1-propenyl-

300-57-2

1

0

0

Benzene, 2-propenyl-

103-65-1

1

1

1

673-32-5

1

0

0

{diphenyl ether}

XVI-1 XVI-1, XXI-3

{Quintocen®}

101-84-8

I.D-1

CH3

XVI-1 C6H5-(CH2)7-CH3

I.D-1

C6H5-O-C6H5

X-2

C6H5-CH2-O-CH2-C6H5

X-2 X-2

C6H5-(CH2)4-CH3

I.D-1

C6H5-CH=CH-CH3

I.D-1

C6H5-CH2-CH=CH2

I.D-1

Benzene, propyl-

C6H5-(CH2)2-CH3

I.D-1

Benzene, 1-propynyl-

C6H5-CŁC-CH3

I.D-1

{allyl benzene}

938-22-7

0

1

0

Benzene, 1,2,3,5-tetrachloro-4-methoxy-

25619-60-7

1

1

1

Benzene, tetramethyl-

I.D-1

488-23-3

1

0

0

Benzene, 1,2,3,4-tetramethyl-

I.D-1

527-53-7

1

0

0

Benzene, 1,2,3,5-tetramethyl-

I.D-1

95-93-2

1

0

0

Benzene, 1,2,4,5-tetramethyl-

I.D-1

116-29-0

0

1

0

Benzene, 1,2,4-trichloro-5-((4chlorophenyl)sulfonyl)-

{Tetradifon®}

X-2, XVIII.B-3

XVIII.B-3, XXI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1503

11/24/08 1:55:39 PM

1504

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

50-29-3

1

1

1

Name (per CA Collective Index) Benzene, 1,1'-(2,2,2-trichloroethylidene)bis[4chloro{p,p’-DDT}

XVIII.B-3, XXI-3

CCl3

Cl

Cl

87-40-1 634-36-6

0

1

0

Chapter Table

Selected structures

Benzene, 1,3,5-trichloro-2-methoxy-

X-2, XVIII.B-3

1

1

1

Benzene, 1,2,3-trimethoxy-

X-2

1

0

0

Benzene, 1,2,4-trimethoxy-

X-2

1

0

0

Benzene, 1,3,5-trimethoxy-

X-2

487-11-6

0

1

0

Benzene, 1,2,3-trimethoxy-5-(2-propenyl)-

X-2

2883-98-9

0

1

0

Benzene, 1,2,4-trimethoxy-5-(2-propenyl)-, (Z)-

X-2

5273-86-9

0

1

0

Benzene, 1,2,4-trimethoxy-5-(2-propenyl)-, (E)-

X-2

25551-13-7

1

1

1

Benzene, trimethyl-

I.D-1

526-73-8

1

1

1

Benzene, 1,2,3-trimethyl-

95-63-6

1

1

1

Benzene, 1,2,4-trimethyl-

I.D-1

108-67-8

1

1

1

Benzene, 1,3,5-trimethyl-

122-78-1

1

1

1

Benzeneacetaldehyde

4411-89-6

1

1

1

Benzeneacetaldehyde, D-ethylidene{2-phenyl-2-butenal}

57568-60-2

0

1

0

Benzeneacetaldehyde, D-(2-furanylmethylene)-

III-12, X-2

5031-83-4

0

1

0

Benzeneacetaldehyde, D-(2-phenylethylidene)-

III-12

0

1

0

Benzeneacetaldehyde, 4-methyl-

III-12

{pseudocumene}

I.D-1

{mesitylene}

I.D-1

{phenylacetaldehyde}

103-81-1

1

1

1

Benzeneacetamide

4695-13-0

0

1

0

Benzeneacetamide, D-phenyl-

{phenylacetamide}

957-51-7

1

1

1

Benzeneacetamide, N,N-dimethyl-D-phenyl{diphenamid; Enide®}

III-12

CH2-CH=O

III-12

C6H5-CH2-CO-NH2

XIII-1

(C6H5)2=CH-CO-NH2

XIII-1 XIII-1, XXI-3

CH3 N

CH3

O

954-21-2

1

1

1

XIII-1, XXI-3

Benzeneacetamide, N-methyl-D-phenyl{desmethyl diphenamid}

CH3 N-H O

103-82-2

1

1

1

Benzeneacetic acid

{phenylacetic acid}

1

1

1

Benzeneacetic acid, labeled with C 14 {phenylacetic acid- C}

122-43-0

0

1

0

Benzeneacetic acid, butyl ester

17119-15-2

1

0

0

Benzeneacetic acid, D,3-dihydroxy-

1198-84-1

1

0

0

Benzeneacetic acid, D,4-dihydroxy-

IV.A-3, XXI-3

CH2-COOH

14

IV.A-3, XXV-29 C6H5-CH2-COO-(CH2)3-CH3 HO

CH2OH-COOH

V-3 II.A-5, IV.A-3, IX.A-22

II.A-5, IV.A-3, IX.A-22

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1504

11/24/08 1:55:39 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1505

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

1

0

0

Benzeneacetic acid, D,?-dihydroxy-ethyl-

20432-26-2

0

1

0

Benzeneacetic acid, D-ethylidene-, (E)-

90-64-2

0

1

0

Benzeneacetic acid, D-hydroxy-

{mandelic acid} {hydratropic acid}

Chapter Table

Selected structures

II.A-5, IV.A-3, IX.A-22 IV.A-3 II.A-5, IV.A-3

492-37-5

1

0

0

Benzeneacetic acid, D-methyl-

19988-45-5

1

0

0

Benzeneacetic acid, 2,3-dihydroxy-

IV.A-3, IX.A-22

IV.A-3

451-13-8

1

0

0

Benzeneacetic acid, 2,5-dihydroxy-

IV.A-3, IX.A-22

102-32-9

1

1

1

Benzeneacetic acid, 3,4-dihydroxy-

IV.A-3, IX.A-22

4670-09-1

1

0

0

Benzeneacetic acid, 3,5-dihydroxy-

IV.A-3, IX.A-22

96937-42-7

1

0

0

Benzeneacetic acid, ar,ar-dihydroxy-ar,ar-dimethyl-

IV.A-3, IX.A-22

96937-37-0

1

0

0

Benzeneacetic acid, ar,D-dihydroxy-ar-ethyl-

IV.A-3, IX.A-22

96937-48-3

1

0

0

Benzeneacetic acid, ar,ar-dihydroxy-ar-methyl-

IV.A-3, IX.A-22

96937-41-6

1

0

0

Benzeneacetic acid, 3,4-dihydroxy-ar-methyl-

IV.A-3, IX.A-22

614-75-5

1

1

1

Benzeneacetic acid, 2-hydroxy-

IV.A-3, IX.A-22

621-37-4

1

1

1

Benzeneacetic acid, 3-hydroxy-

IV.A-3, IX.A-22

51630-58-1

0

1

0

Benzeneacetic acid, 4-chloro- Į-(1-methylethyl)-, cyano(3-phenoxyphenyl)methyl ester {Fenvalerate®}

O

COO-CH(CN)Cl

V-3, X-2, XI-2, XVIII.B-3, XXI-3 70124-77-5

0

1

0

F

Benzeneacetic acid, 4-(difluoromethoxy)-Į-(1methylethyl)-, cyano(3-phenoxyphenyl)methyl ester

O

F

{Flucythrinate®} CH3

O

O CN

O

CH3

V-3, X-2, XI-2, XVIII.B-3, XXI-3 IV.A-3, IX.A-22

156-38-7

1

1

1

Benzeneacetic acid, 4-hydroxy-

306-08-1

1

0

0

Benzeneacetic acid, 4-hydroxy-3-methoxy{homovanillic acid}

IV.A-3, IX.A-22, X-2

102-22-7

0

1

0

Benzeneacetic acid, 3,7-dimethyl-2,6-octadien-1-yl ester {geranyl phenylacetate}

V-3

101-97-3

1

1

1

Benzeneacetic acid, ethyl ester {ethyl phenylacetate}

C6H5-CH2-COO-CH2-CH3

V-3

5421-17-0

0

1

0

Benzeneacetic acid, hexyl ester

C6H5-CH2-COO-(CH2)5-CH3

V-3

101-41-7

1

1

1

Benzeneacetic acid, methyl ester {methyl phenylacetate}

C6H5-CH2-COO-CH3

V-3

102-19-2

1

1

1

Benzeneacetic acid, 3-methylbutyl ester

V-3

101-94-0

0

1

0

Benzeneacetic acid, 4-methylphenyl ester {p-tolyl phenylacetate}

V-3

102-13-6

0

1

0

Benzeneacetic acid, 2-methylpropyl ester

V-3

102-20-5

0

1

0

Benzeneacetic acid, 2-phenylethyl ester

C6H5-CH2-COO-(CH2)2-C6H5

V-3

102-16-9

0

1

0

Benzeneacetic acid, phenylmethyl ester {benzyl phenylacetate}

C6H5-CH2-COO-CH2-C6H5

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1505

11/24/08 1:55:39 PM

1506

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

140-29-4

1

1

1

Benzeneacetonitrile

14191-95-8

1

0

0

Benzeneacetonitrile, 4-hydroxy-

IX.A-22, XI-2

21850-61-3

1

0

0

Benzeneacetonitrile, 4-hydroxy-D-methyl-

IX.A-22, XI-2

1

0

0

Benzeneacetonitrile, methyl-

XI-2

1

0

0

Benzeneacetonitrile, 2-methyl-

XI-2

1

0

0

Benzeneacetonitrile, 4-methyl-

0

1

0

Benzenebutanoic acid, D,2-diamino-J-oxo{kynurenine}

22364-68-7 343-65-7

Name (per CA Collective Index)

Selected structures

{benzyl cyanide}

CH2-CN

Chapter Table XI-2

XI-2 O

III-13, IV.A-3, XII-2

NH2 COOH

NH2

53392-07-7

1

0

0

Benzenebutanol, 4-methyl-

II.A-5

71607-71-1

1

0

0

Benzenediamine, N-methyl-

95-54-5

1

0

0

1,2-Benzenediamine

3171-45-7

1

0

0

1,2-Benzenediamine, 4,5-dimethyl-

XII-2

25376-45-8

XII-2 {o-phenylenediamine}

XII-2

1

0

0

1,3-Benzenediamine, ar-methyl-

XII-2

1

0

0

1,4-Benzenediamine, N-methyl-

XII-2

101-54-2

1

0

0

1,4-Benzenediamine, N-phenyl-

140-56-7

0

1

0

Benzenediazosulfonate, dimethylamino-, sodium salt {Fenaminosulf®}

91-15-6

1

0

0

1,2-Benzenedicarbonitrile

XII-2 XX-6, XXI-3 XI-2

626-17-5

1

0

0

1,3-Benzenedicarbonitrile

1897-45-6

0

1

0

1,3-Benzenedicarbonitrile, 2,4,5,6-tetrachloro {Chlorothalonil®}

XI-2 CN Cl

Cl

Cl

XI-2, XVIII.B-3, XXI-3

CN Cl

623-26-7

1

0

0

1,4-Benzenedicarbonitrile

88-99-3

1

1

0

1,2-Benzenedicarboxylic acid

XI-2

121-91-5

1

0

0

100-21-0

1

1

1

7299-89-0

1

0

0

1,2-Benzenedicarboxylic acid, bis(2-ethylbutyl) ester

V-3

117-81-7

1

1

1

1,2-Benzenedicarboxylic acid, bis(2-ethylhexyl) ester

V-3

131-20-4 27554-26-3

1

1

1

1,2-Benzenedicarboxylic acid, bis(6-methylheptyl) ester {diisooctyl phthalate}

V-3

84-69-5

0

1

0

1,2-Benzenedicarboxylic acid, bis(2-methylpropyl) ester

V-3

85-69-8

1

1

1

1,2-Benzenedicarboxylic acid, butyl, 2-ethylhexyl ester

V-3

0

1

0

1,2-Benzenedicarboxylic acid, butyl, 2-methylbutyl ester

V-3

0

1

0

1,2-Benzenedicarboxylic acid, butyl, 3-methylbutyl ester

V-3

{phthalic acid}

IV.A-3

1,3-Benzenedicarboxylic acid

{isophthalic acid}

IV.A-3

1,4-Benzenedicarboxylic acid

{terephthalic acid}

IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1506

11/24/08 1:55:40 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1507

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke S

T

S T

0

1

0

1,2-Benzenedicarboxylic acid, butyl, phenylmethyl ester

V-3

1

0

0

1,2-Benzenedicarboxylic acid, dialkyl ester {four isomers detected}

V-3

84-74-2

1

1

1

1,2-Benzenedicarboxylic acid, dibutyl ester {dibutyl phthalate}

V-3

84-66-2

1

1

1

1,2-Benzenedicarboxylic acid, diethyl ester {diethyl phthalate}

V-3

CAS No.

Name (per CA Collective Index)

Selected structures

Chapter Table

84-75-3

0

1

0

1,2-Benzenedicarboxylic acid, dihexyl ester

V-3

131-11-3

1

1

1

1,2-Benzenedicarboxylic acid, dimethyl ester {dimethyl phthalate}

V-3

117-84-0

1

1

1

1,2-Benzenedicarboxylic acid, dioctyl ester

V-3

131-16-8

1

1

1

1,2-Benzenedicarboxylic acid, dipropyl ester

1861-32-1

0

1

0

1,4-Benzenedicarboxylic acid, 2,3,5,6-tetrachloro-, dimethyl ester {DCPA®}

1

0

0

Benzenediol, C2-alkyl-

71630-70-1 80934-44-7

1

0

0

Benzenediol, C3-alkyl-

1

0

0

Benzenediol, ethyl-nitro-

V-3 V-3, XXI-3 IX.A-22 IX.A-22 IX.A-22, XVI-1

1

0

0

Benzenediol, methyl-

1

0

0

Benzenediol, methyl-nitro-

IX.A-22, XVI-1

IX.A-22

62726-14-1

1

0

0

Benzenediol, nitro{at least 4 isomers were detected}

IX.A-22, XVI-1

120-80-9

1

1

1

1,2-Benzenediol

{catechol; pyrocatechol}

IX.A-22

OH OH

6 5

3 4

69845-49-4

1

0

0

1,2-Benzenediol, dimethyl-

IX.A-22

2785-75-3

1

0

0

1,2-Benzenediol, 3,5-dimethyl-

IX.A-22

2785-78-6

1

0

0

1,2-Benzenediol, 3,6-dimethyl-

IX.A-22

98-29-3

1

0

0

1,2-Benzenediol, 4-(1,1-dimethylethyl)-

IX.A-22

1

0

0

1,2-Benzenediol, 3-ethenyl-

IX.A-22

6053-02-7

1

0

0

1,2-Benzenediol, 4-ethenyl-

IX.A-22

28930-20-3

1

0

0

1,2-Benzenediol, ethyl-

IX.A-22

933-99-3

1

0

0

1,2-Benzenediol, 3-ethyl-

IX.A-22

1124-39-6

1

0

0

1,2-Benzenediol, 4-ethyl-

IX.A-22

71608-02-1

1

0

0

1,2-Benzenediol, 5-ethyl-3-nitro-

934-00-9

1

0

0

1,2-Benzenediol, 3-methoxy-

28930-19-0

1

0

0

1,2-Benzenediol, methyl-

IX.A-22

488-17-5

1

0

0

1,2-Benzenediol, 3-methyl-

IX.A-22

IX.A-22, XVI-1 IX-22, X-2

452-86-8

1

0

0

1,2-Benzenediol, 4-methyl-

IX.A-22

2138-48-9

1

0

0

1,2-Benzenediol, 3-(1-methylethyl)-

IX.A-22

2138-43-4

1

0

0

1,2-Benzenediol, 4-(1-methylethyl)-

102-29-4

1

0

0

1,2-Benzenediol, monoacetate

6665-98-1

1

0

0

1,2-Benzenediol, 3-nitro-

IX.A-22 V-3, IX.A-22 IX.A-22, XVI-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1507

11/24/08 1:55:40 PM

1508

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

3316-09-4

1

0

0

1,2-Benzenediol, 4-nitro-

1126-61-0

1

1

1

1,2-Benzenediol, 4-(2-propenyl)-

29031-84-3

1

0

0

1,2-Benzenediol, propyl-

IX.A-22

2896-63-1

1

0

0

1,2-Benzenediol, 3-propyl-

IX.A-22

Name (per CA Collective Index)

2525-02-2

1

0

0

1,2-Benzenediol, 4-propyl-

108-46-3

1

1

1

1,3-Benzenediol

Selected structures

IX.A-22, XVI-1 IX.A-22

IX.A-22 {resorcinol}

IX.A-22

OH 2

6 5

OH

4

25377-27-9 67965-47-3 2896-60-8 608-25-3 504-15-4 71608-03-2

Chapter Table

1

0

0

1,3-Benzenediol, dimethyl-

IX.A-22

1

0

0

1,3-Benzenediol, 2,5-dimethyl-

IX.A-22

1

0

0

1,3-Benzenediol, ethenyl-

IX.A-22

1

0

0

1,3-Benzenediol, ethyl-

IX.A-22

1

0

0

1,3-Benzenediol, 4-ethyl-

IX.A-22

1

0

0

1,3-Benzenediol, methyl-

IX.A-22

1

0

0

1,3-Benzenediol, 2-methyl-

IX.A-22

1

0

0

1,3-Benzenediol, 5-methyl-

1

0

0

1,3-Benzenediol, (1-methylethyl)-

1

0

0

1,3-Benzenediol, 4-methyl-6-nitro-

1

0

0

1,3-Benzenediol, monoacetate

{orcinol}

IX.A-22 IX.A-22 IX.A-22, XVI-1 V-3, IX.A-22

3163-07-3

1

0

0

1,3-Benzenediol, 4-nitro-

IX.A-22, XVI-1

68146-94-1

1

0

0

1,3-Benzenediol, propyl-

IX.A-22

123-31-9

1

1

1

1,4-Benzenediol

{hydroquinone}

IX.A-22

OH 6

2

5

3

OH

1 3233-32-7

0

0

1,4-Benzenediol, dimethyl-

IX.A-22

1

0

0

1,4-Benzenediol, monoacetate

V-3, IX-22

1

0

0

1,4-Benzenediol, monopropanoate

V-3, IX-22

608-43-5

1

0

0

1,4-Benzenediol, 2,3-dimethyl-

IX.A-22

615-90-7

1

0

0

1,4-Benzenediol, 2,5-dimethyl-

IX.A-22

2349-70-4

1

0

0

1,4-Benzenediol, 2-ethyl- = 1,4-Benzenediol, ethyl-

IX.A-22

72693-14-2

1

0

0

1,4-Benzenediol, 2-ethyl-6-methyl-

IX.A-22

3233-32-7

1

0

0

1,4-Benzenediol, monoacetate

V-3, IX-22

824-46-4

1

1

1

1,4-Benzenediol, 2-methoxy-

IX-22, X-2

95-71-6

1

1

1

1,4-Benzenediol, 2-methyl- = 1,4-Benzenediol, methyl-

IX.A-22

2349-71-5

0

1

0

1,4-Benzenediol, 2-(1-methylethyl)-

IX.A-22

4693-31-6

1

0

0

1,4-Benzenediol, 2-propyl-

IX.A-22

700-13-0

1

0

0

1,4-Benzenediol, 2,3,5-trimethyl-

IX.A-22

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1508

11/24/08 1:55:40 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1509

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

64-04-0

1

1

1

Benzeneethanamine

C6H5-CH2-CH2-NH2

XII-2

582-22-9

1

0

0

Benzeneethanamine, E-methyl-

C6H5-CH(CH3)-CH2-NH2

XII-2

Name (per CA Collective Index)

Selected structures

589-08-2

1

1

1

Benzeneethanamine, N-methyl-

C6H5-CH2-CH2-NH-CH3

60-12-8

1

1

1

Benzeneethanol {phenethyl alcohol} Occasionally listed as 1321-27-3 Ethanol, phenyl-

C6H5-CH2CH2-OH

5040-23-3

1

0

0

Benzeneethanol, D,4-dimethyl-

Chapter Table

XII-2 II.A-5 II.A-5

7779-78-4

0

1

0

Benzeneethanol, D-(2-methylpropyl)-

13398-94-2

1

1

1

Benzeneethanol, 3-hydroxy-

II.A-5 II.A-5, IX.A-22

501-94-0

1

1

1

Benzeneethanol, 4-hydroxy-

2380-78-1

1

0

0

Benzeneethanol, 4-hydroxy-3-methoxy-

II.A-5, IX.A-22

699-02-5

0

1

0

Benzeneethanol, 4-methyl-

100-46-9

1

1

1

Benzenemethanamine

62924-70-3

0

1

0

Benzenemethanamine, 2-chloro-N-(2,6-dinitro-4(trifluoromethyl)phenyl)-N-ethyl-6-fluoro{Flumetralin®}

100-51-6

1

1

1

Benzenemethanol

1197-01-9

1

1

1

Benzenemethanol, D,D,4-trimethyl-

II.A-5, IX.A-22, X-2 II.A-5

{benzylamine}

{benzyl alcohol}

C6H5-CH2-NH2

XII-2

XII-2, XVI-1, XVIII.B-3, XXI-3

C6H5-CH2OH

II.A-5 II.A-5

{p,D,D-trimethylbenzyl alcohol} 617-94-7

1

1

1

Benzenemethanol, D,D-dimethyl-

C6H5-C(CH3)2OH

II.A-5

536-50-5

0

1

0

Benzenemethanol, D,4-dimethyl-

4393-06-0

0

1

0

Benzenemethanol, D-ethenyl-

C6H5-CH(CH=CH2)OH

II.A-5

93-54-9

0

1

0

Benzenemethanol, D-ethyl- {1-phenyl-1-propanol}

C6H5-CH(C2H5)OH

II.A-5

98-85-1

1

1

1

Benzenemethanol, D-methyl-

C6H5-CH(CH3)OH

II.A-5

93-92-5

0

1

0

Benzenemethanol, D-methyl-, acetate

13651-14-4

1

0

0

Benzenemethanol, 2,3-dimethyl-

II.A-5

89-95-2

1

1

1

Benzenemethanol, 2-methyl-

II.A-5

II.A-5

V-3

620-24-6

1

1

1

Benzenemethanol, 3-hydroxy-

105-13-5

0

1

0

Benzenemethanol, 4-methoxy-

{anisyl alcohol}

II.A-5, IX.A-22 II.A-5, X-2

104-21-2

1

1

1

Benzenemethanol, 4-methoxy-, acetate {anisyl acetate}

V-3, X-2

122-91-8

0

1

0

Benzenemethanol, 4-methoxy-, formate

V-3, X-2

102-17-0

0

1

0

Benzenemethanol, 4-methoxy-, phenylacetate

V-3, X-2

7549-33-9

0

1

0

Benzenemethanol, 4-methoxy-, propanoate

V-3, X-2

589-18-4

0

1

0

Benzenemethanol, 4-methyl-

II.A-5

6282-37-7

1

0

0

Benzenemethanol, 4-methyl-D-propyl-

II.A-5

1331-81-3

0

1

0

Benzenemethanol, ar-methoxy-

27043-34-1

1

0

0

Benzenemethanol, methyl-

104-53-0

0

1

0

Benzenepropanal

80638-48-8

1

0

0

Benzenepropanal, 4-hydroxy-3-methoxy-

103-95-3

0

1

0

Benzenepropanal, Į-methyl-4-(1-methylethyl){cyclamen aldehyde}

102-93-2

1

1

1

Benzenepropanamide

II.A-5, X-2 II.A-5 C6H5-CH2CH2-CH=O

III-12 III-12, IX.A-22, X-2 III-12

C6H5-CH2CH2-CONH2

XIII-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1509

11/24/08 1:55:41 PM

1510

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

121850-61-1

0

1

0

Benzenepropanamide, N-[3-[[4-[[3-(3,4dihydroxyphenyl)-1-oxo-2propenyl]amino]butyl]amino ]propyl]-3,4-dihydroxy-

645-59-0

1

0

0

Benzenepropanenitrile

C6H5-CH2CH2-CN

501-52-0

1

1

1

Benzenepropanoic acid {3-phenylpropionic acid or hydrocinnamic acid}

C6H5-CH2CH2-COOH

156-06-8

0

1

0

Benzenepropanoic acid, D-hydroxy{phenyllactic acid}

C6H5-CH2-CH2OH-COOH

7326-19-4

0

1

0

Benzenepropanoic acid, D-hydroxy-, (R)-

4593-90-2

1

0

0

Benzenepropanoic acid, E-methyl-

156-06-9

0

1

0

Benzenepropanoic acid, D-oxo{phenylpyruvic acid}

24696-05-7

0

1

0

Benzenepropanoic acid, 2-(E-D-glucopyranosyloxy)-

1

0

0

Benzenepropanoic acid, dihydroxy-methoxy-

1

1

1

Benzenepropanoic acid, 2-(methylnitrosamino)-

3714-73-6

1

0

0

Benzenepropanoic acid, 2,3-dihydroxy-

IV.A-3, IX.A-22

96937-38-1

1

0

0

Benzenepropanoic acid, 2,3-dihydroxy-ar-methyl-

IV.A-3, IX.A-22

10538-47-3

1

0

0

Benzenepropanoic acid, 2,5-dihydroxy-

IV.A-3, IX.A-22

96937-34-7

1

0

0

Benzenepropanoic acid, 2,5-dihydroxy-ar-methyl-

IV.A-3, IX.A-22

Name (per CA Collective Index)

Chapter Table

Selected structures

IX.A-22, XIII-1

XI-2 IV.A-3 II.A-5, IV.A-3 II.A-5, IV.A-3 IV.A-3

C6H5-CH2-CO-COOH

IV.A-3 II.A-5, IV.A-3, X-2

IV.A-3, X-2, IX.A-22 IV.A-3, XV-8

495-78-3

1

1

1

Benzenepropanoic acid, 2-hydroxy-

IV.A-3, IX.A-22

1078-61-1

1

1

1

Benzenepropanoic acid, 3,4-dihydroxy{dihydrocaffeic acid}

IV.A-3, IX.A-22

96961-47-6

1

0

0

Benzenepropanoic acid, 3,4-dihydroxy-2,5,6trimethyl-

IV.A-3, IX.A-22

96937-33-6

1

0

0

Benzenepropanoic acid, 3,4-dihydroxy-ar-methyl-

IV.A-3, IX.A-22

621-54-5

1

1

1

Benzenepropanoic acid, 3-hydroxy-

IV.A-3, IX.A-22

501-97-3

1

1

1

Benzenepropanoic acid, 4-hydroxy-

IV.A-3, IX.A-22

156-39-8

1

0

0

Benzenepropanoic acid, 4-hydroxy-D-oxo-

IV.A-3, IX.A-22

5597-50-2

1

0

0

Benzenepropanoic acid, 4-hydroxy-, methyl ester

V-3, IX.A-22

1135-23-5

1

0

0

Benzenepropanoic acid, 4-hydroxy-3-methoxy{hydroferulic acid}

IV.A-3, IX.A-22, X-2

96937-36-9

1

0

0

Benzenepropanoic acid, ar,ar-dihydroxy-armethoxy-

IV.A-3, IX.A-22, X-2

96937-35-8

1

0

0

Benzenepropanoic acid, ar,ar-dihydroxy-ar-methyl-

IV.A-3, IX.A-22, X-2

122-97-4

1

1

1

Benzenepropanol

C6H5-CH2-CH2-CH2OH

II.A-5

1992-50-3

1

0

0

Benzenepropanol, D-ethyl-

{3-phenyl-1-propanol}

C6H5-CH2-CH2-CH(C2H5)OH

II.A-5

2845-25-2

1

0

0

Benzenepropanol, J-ethyl-, (S)-

C6H5-CH(C2H5)-CH2-CH2OH

II.A-5

10210-17-0

1

0

0

Benzenepropanol, 4-hydroxy-

19044-88-3

0

1

0

Benzenesulfonamide, 4-(dipropylamino)-3,5-dinitro{Oryzalin®}

II.A-5, IX.A-22

108-98-5

1

0

0

Benzenethiol

87-66-1

1

1

1

1,2,3-Benzenetriol

{phenyl mercaptan} {pyrogallol}

XVI-1, XVIII.A-1, XXI-3 C6H5-SH

XVIII.A-1 IX.A-22

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1510

11/24/08 1:55:41 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1511

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 533-73-3 51-17-2

S

T

S T

Name (per CA Collective Index)

1

0

0

1,2,4-Benzenetriol

1

0

0

1,2,4-Benzenetriol, methyl-

1

0

0

1H-Benzimidazole

Selected structures

{hydroxyhydroquinone}

Chapter Table IX.A-22 IX.A-22 XVII.E-6

N N H

1

0

0

1H-Benzimidazole, C2-alkyl-

XVII.E-6

5851-44-5

1

0

0

1H-Benzimidazole, 2-butyl-

XVII.E-6

72692-74-1

1

0

0

1H-Benzimidazole, dimethyl-

XVII.E-6

2876-08-6

1

0

0

1H-Benzimidazole, 1,2-dimethyl-

XVII.E-6

72692-75-2

1

0

0

1H-Benzimidazole, ethyl-

XVII.E-6

30304-58-6

1

0

0

1H-Benzimidazole, methyl-

XVII.E-6

1632-83-3

1

0

0

1H-Benzimidazole, 1-methyl-

XVII.E-6

615-15-6

1

0

0

1H-Benzimidazole, 2-methyl-

XVII.E-6

946-18-9

1

0

0

1H-Benzimidazole, 2-(3-methylbutyl)-

XVII.E-6

82326-40-7

1

0

0

1H-Benzimidazole, 2-(2-naphthalenylmethyl)-

XVII.E-6

148-79-8

1

1

1

1H-Benzimidazole, 2-(4-thiazolyl){Thiabendazole®}

3363-56-2

0

1

0

1H-Benzimidazole, 2,5,6-trimethyl-

10605-21-7

0

1

0

1H-Benzimidazole-2-carbamic acid, methyl ester {Carbendazim®}

XVIII.A-1

N

N S

N H

XVII.E-6 V-3, XXI-3

H N NH-COO-CH3 N

17804-35-2

0

1

0

1H-Benzimidazole-2-carbamic acid, 1(butylcarbamomyl)-, methyl ester {Benomyl®}

CO-NH-C4H9 N

V-3, XXI-3

NH-COO-CH3 N

232-54-2

1

0

0

1H-Benz[e]indene

I.E-6

1

0

0

1H-Benz[e]indene, dimethyl-

I.E-6

1

0

0

1H-Benz[e]indene, ethylmethyl-

I.E-6

64031-90-9

1

0

0

1H-Benz[e]indene, methyl-

I.E-6

268-40-6

1

0

0

1H-Benz[f]indene

I.E-6

60826-71-3

1

0

0

1H-Benz[f]indene, dimethyl-

I.E-6

71265-34-4

1

0

0

1H-Benz[f]indene, ethylmethyl-

I.E-6

60826-63-3

1

0

0

1H-Benz[f]indene, methyl-

I.E-6

1

0

0

Benzocarbazole

XVII.E-6

1

0

0

Benzocarbazole, dimethyl-

XVII.E-6

1

0

0

Benzocarbazole, methyl-

XVII.E-6

1

0

0

11H-Benzo[a]carbazole

XVII.E-6

239-01-0

N H

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1511

11/24/08 1:55:42 PM

1512

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

243-28-7

1

0

0

Name (per CA Collective Index)

Chapter Table

Selected structures

XVII.E-6

5H-Benzo[b]carbazole

N H

205-25-4

1

0

0

XVII.E-6

7H-Benzo[c]carbazole

N H

214-17-5

1

0

0

Benzo[b]chrysene

{dibenzo[b,h]phenanthrene}

146506-80-1

1

0

0

Benzo[g]chrysene, methyl-

I.E-6

7099-43-6

1

0

0

1H-Benzo[a]cyclopent[h]anthracene, 2,3-dihydro{5,6-cyclopentano-1,2-benzanthracene, 2,3dihydro-}

I.E-6

7099-42-5

1

0

0

9H-Benzo[a]cyclopent[i]anthracene, 10,11-dihydro{6,7-cyclopentano-1,2-benzanthracene, 9,10dihydro-}

I.E-6

3811-49-2

0

1

0

4H-1,3,2-Benzodioxaphosphorin-2-sulfide, 2methoxy{Salithion®}

I.E-6

P

OCH3

O

51-03-6

0

1

0

X-2, XVIII.A-1, XXI-3

S O

1,3-Benzodioxole, 5-[[2-(2butoxyethoxy)ethoxy]methyl]-6-propyl{piperonyl butoxide}

O

O

O

O

[

]

(CH2)3-CH3

2

(CH2)2-CH3

X-2, XXI-3 607-91-0

1

1

1

1,3-Benzodioxole, 4-methoxy-6-(2-propenyl){myristicin}

4

94-59-7

0

1

0

1,3-Benzodioxole, 5-(2-propenyl)-

1

1

1

1,3-Benzodioxole-5-carboxaldehyde {piperonal; heliotropin}

O 3

5

H2C=CH=CH2

120-57-0

X-2

OCH3

6

1

CH2

O

7

{safrole}

X-2 4

3

O

III-12, X-2

CH=O

5

2

O 1

56832-73-6

16135-81-2 42126-84-1

1

0

0

Benzofluoranthene

I.E-6

1

0

0

Benzofluoranthene, dimethyl-

I.E-6

1

0

0

Benzofluoranthene, ethyl-

I.E-6

1

0

0

Benzofluoranthene, methyl-

I.E-6

1

0

0

11H-Benzo[cd]fluoranthene

10

I.E-6

11

9

1

6

3

8 2

7

5

4

© 2009 by Taylor & Francis Group, LLC

78836_C030.indd 1512

11/24/08 1:55:42 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1513

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

203-12-3

1

0

0

Name (per CA Collective Index)

Selected structures

Benzo[ghi]fluoranthene

e

Chapter Table I.E-6

f g

d c b a

i

h

64760-14-1

1

0

0

Benzo[ghi]fluoranthene, dimethyl-

71265-35-5

1

0

0

Benzo[ghi]fluoranthene, ethyl-

I.E-6

51001-44-6

1

0

0

Benzo[ghi]fluoranthene, methyl-

I.E-6

71265-21-9

1

0

0

Benzo[ghi]fluoranthene, 1-methyl-

I.E-6

71265-22-0

1

0

0

Benzo[ghi]fluoranthene, 2-methyl-

I.E-6

71265-23-1

1

0

0

Benzo[ghi]fluoranthene, 3-methyl-

I.E-6

71265-24-2

1

0

0

Benzo[ghi]fluoranthene, 4-methyl{also known as 7-methylbenzo[ghi]fluoranthene}

I.E-6

205-82-3

1

0

0

Benzo[j]fluoranthene

I.E-6

60826-67-7

1

0

0

Benzo[j]fluoranthene, methyl-

I.E-6

207-08-9

1

0

0

Benzo[k]fluoranthene

I.E-6

41637-93-8

1

0

0

Benzo[k]fluoranthene, methyl-

I.E-6

1

0

0

Benzofluorene

I.E-6

1

0

0

Benzofluorene, alkyl-

I.E-6

77271-50-2

1

0

0

Benzofluorene, dimethyl{at least three isomers in MSS}

I.E-6

60918-47-0

1

0

0

Benzofluorene, methyl{at least four isomers in MSS}

I.E-6

77271-51-3

1

0

0

Benzofluorene, tetramethyl{at least two isomers in MSS}

I.E-6 I.E-6

1

0

0

Benzofluorene, trimethyl-

30777-18-5

1

0

0

Benzo[a]fluorene

238-79-9

1

0

0

5H-Benzo[a]fluorene

I.E-6

I.E-6 1 11

10

3 a

9

4

b 8

238-84-6

1

0

0

5

6

7

11H-Benzo[a]fluorene

I.E-6

2

I.E-6

2

1 11

10

3

9

4 8

7

6

5

1

0

0

11H-Benzo[a]fluorene, dimethyl-

I.E-6

60826-64-4

1

0

0

11H-Benzo[a]fluorene, methyl-

I.E-6

71265-25-3

1

0

0

11H-Benzo[a]fluorene, 11-methyl-

I.E-6

71607-85-7

1

0

0

11H-Benzo[a]fluorene, trimethyl{at least three isomers in MSS}

I.E-6

30777-19-6

1

0

0

5H-Benzo[b]fluorene

I.E-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1513

11/24/08 1:55:42 PM

1514

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

243-17-4

1

0

0

Name (per CA Collective Index)

Selected structures

11H-Benzo[b]fluorene

11

10

I.E-6

1 2

a

9

b 8

3

6

7

4

5

60826-65-5

205-12-9

1

0

0

11H-Benzo[b]fluorene, methyl-

I.E-6

1

0

0

11H-Benzo[b]fluorene, 9-methyl-

I.E-6

1

0

0

Benzo[c]fluorene, methyl-

1

0

0

7H-Benzo[c]fluorene

I.E-6 7

8

I.E-6

6 a

9 c

10

b

5

11

4

1 3

2

60826-66-6

Chapter Table

1

0

0

7H-Benzo[c]fluorene, methyl-

1

0

0

11H-Benzo[c]fluorene

I.E-6 7

8

I.E-6

6 a

9 c

10

b

5

11

4

1 2

1

0

0

11H-Benzo[c]fluoren-11-one

3

III-13

O

271-89-6

1

0

0

Benzofuran

{benzo[b]furan; coumarone}

7

2

5

3

4

25586-39-4

1

0

0

Benzofuran, dimethyl-

X-2

O

6

X-2

{3 isomers detected}

58924-34-8

1

0

0

Benzofuran, ethyl-

X-2

71265-37-7

1

0

0

Benzofuran, ethyldimethyl-

X-2

25586-38-3

1

0

0

Benzofuran, methyl-

13054-97-2

1

0

0

Benzofuran, octahydro-

X-2

71265-38-8

1

0

0

Benzofuran, pentamethyl-

X-2

36618-49-2

1

0

0

Benzofuran, tetramethyl-

X-2

36541-17-0

1

0

0

Benzofuran, trimethyl-

X-2

X-2

{3 isomers detected}

496-16-2

1

1

1

Benzofuran, 2,3-dihydro-

71265-36-6

1

0

0

Benzofuran, 2,3-dihydromethyl-

{coumaran}

X-2

1746-11-6

0

1

0

Benzofuran, 2,3-dihydro-2-methyl-

X-2

3782-00-1

1

0

0

Benzofuran, 2,3-dimethyl-

X-2

28715-26-6

1

0

0

Benzofuran, 2,3-dimethyl-

1

0

0

Benzofuran, 2,3,3a,4,5,7a-hexahydro-4,4,7atrimethyl-

X-2

X-2 4 3a

5

7a

6 7

4265-25-2 17059-52-8

X-2

3 2

O

1

0

0

Benzofuran, 2-methyl-

X-2

1

0

0

Benzofuran, 3-ethyl-

X-2

1

0

0

Benzofuran, 5-methyl-

X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1514

11/24/08 1:55:43 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1515

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 494-90-6

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

Benzofuran, 4,5,6,7-tetrahydro-3,6-dimethyl-

1

0

0

Benzofuran, 4-hydroxy-5,6-dimethyl-

X-2

60026-12-2

1

1

1

Benzofuran, 5-hydroxy-6,7-dimethyl-

IX.A-22, X-2

35355-35-2

0

1

0

Benzofuran, 5-methoxy-6,7-dimethyl-

IX.A-22, X-2

16655-82-6

1

1

1

3,7-Benzofurandiol, 2,3-dihydro-2,2-dimethyl-, 7(methylcarbamate) {3-Hydroxycarbofuran®}

IX.A-22, X-2

II.A-5, V-3, X-2, XXI-3

OOC-NH-CH3 O

CH3 CH3 OH

1

0

0

1,3-Benzofurandione, 5-(1,1-dimethylheptyl)-

III-13, VII-1

31297-30-0

1

0

0

2,3-Benzofurandione, 2,3-dihydro-4,7-dimethyl-

III-13, VI-3

19355-58-9

0

1

0

2,6-Benzofurandione, 4,5,7,7a-tetrahydro-4,4,7atrimethyl-

73051-72-6

0

1

0

2-Benzofuranmethanol, 2,4,5,6,7,7a-hexahydro-6hydroxy-D,4,4,7a-tetramethyl-

0

1

0

6-Benzofuranol, 4,5,7,7a-tetrahydro-2-(1hydroxyethyl)-4,4,7a- trimethyl-

3

7a

6

O

III-13, VI-3

3a

4

5

2

1

O

O

7

II.A-5 H3C

II.A-5, X-2

CH3 OH CH3

O

HO

CH3

39815-67-3

0

1

0

6-Benzofuranol, octahydro-4,4,7a-trimethyl-

7a

6

HO

1563-66-2

26225-79-6

1

0

1

1

1

0

7-Benzofuranol, 2,3-dihydro-2,2-dimethyl-, methylcarbamate = Methylcarbamic acid, 2,3dihydro-2,2-dimethyl-7-benzofuranyl ester {Furadan®; Carbofuran®}

3a

4

5

II.A-5, X-2 3 2

1

O

7

X-2, XXI-3

OOC-NH-CH3 O

CH3 CH3

7-Benzofuranol, 2,3-dihydro-3,3-dimethyl-2-ethoxy-, methanesulfonate {Ethofumesate®}

O O-C2H5 H3C-SO2-O

13341-72-5

X-2, XVIII.A-1, XXI-3

0

1

0

Benzofuranone, dimethyltetrahydro-

VI-3

1

0

0

2(3H)-Benzofuranone

VI-3

61892-48-6

1

0

0

2(3H)-Benzofuranone, hexahydro-3a-hydroxy-

16778-27-1

1

1

1

2(3H)-Benzofuranone, hexahydro-4,4,7a-trimethyl{mariolide; dihydroactinidiolide}

II.A-5, VI-3 5

7a

6 7

VI-3

3

4

2 1

O

O

37531-06-9

0

1

0

2(3H)-Benzofuranone, hexahydro-4,4,7a-trimethyl-, (Z)-

VI-3

37531-07-0

0

1

0

2(3H)-Benzofuranone, hexahydro-4,4,7a-trimethyl-, (E)-

VI-3

0

1

0

2(3H)-Benzofuranone, octahydro-4,4,7a-trimethyl{tetrahydroactinidiolide}

VI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1515

11/24/08 1:55:43 PM

1516

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

19432-09-8

1

1

1

Name (per CA Collective Index)

Selected structures

2(3H)-Benzofuranone, 3a,4,5,7a-tetrahydro-4,4,7atrimethyl-, cis-

Chapter Table VI-3

O O

75840-26-5

0

1

0

2(4H)-Benzofuranone, 5,6-dihydro-3,6-dimethyl-

VI-3

17063-17-1

0

1

0

2(4H)-Benzofuranone, 5,7a-dihydro-4,4,7atrimethyl-, (R)-

VI-3

82395-89-9

0

1

0

2(4H)-Benzofuranone, 6-(E-D-glucopyranosyloxy)5,6,7,7a-tetrahydro-4,4,7a-trimethyl-, (6S-Z)-

VI-3

10481-90-0

0

1

0

2(4H)-Benzofuranone, 6-hydroxy-5,6,7,7atetrahydro-4,4,7a-trimethyl-, Z-(r){loliolide}

VI-3

5989-02-6

1

1

1

2(4H)-Benzofuranone, 6-hydroxy-5,6,7,7atetrahydro-4,4,7a-trimethyl-, (6S-Z)-

VI-3

38725-47-2

0

1

0

2(4H)-Benzofuranone, tetrahydro-4,4,7a-trimethyl-

VI-3

15356-74-8

1

1

1

2(4H)-Benzofuranone, 5,6,7,7a-tetrahydro-4,4,7atrimethyl-

VI-3

17092-92-1

1

1

1

2(4H)-Benzofuranone, 5,6,7,7a-tetrahydro-4,4,7atrimethyl-, (R)-

VI-3

124052-02-4

0

1

0

3(2H)-Benzofuranone, 2-(3,4-dihydroxyphenyl)2,4,6-trihydroxy-

117769-21-8

0

1

0

5(4H)-Benzofuranone, 2,7a-dihydro-2-(1hydroxyethyl)-4,4-dimethyl-

39815-70-8

0

1

0

6(2H)-Benzofuranone, hexahydro-4,4,7a-trimethyl-

III-13, IX.A-22 III-13, VI-3, X-2

6

0

1

0

6(2H)-Benzofuranone, 4,5,7,7a-tetrahydro-2-(1hydroxyethyl)-4,4,7a-trimethyl-

3 2

7

O

70875-03-5

III-13, X-2

4

5

O

2

6

O

39815-73-1

0

1

0

65-85-0

1

1

1

6(2H)-Benzofuranone, 4,5,7,7a-tetrahydro-4,4,7atrimethylBenzoic acid {benzenecarboxylic acid}

II.A-5, III-13, X-2

3

4

5

O

7

OH

III-13, X-2 6

COOH

5 4

IV.A-3

2 3

136-60-7

1

0

0

Benzoic acid, butyl ester

96937-46-1

1

0

0

Benzoic acid, dihydroxy-dimethyl-

IV.A-3, IX.A-22

96937-47-2

1

0

0

Benzoic acid, dihydroxy-ethyl-

IV.A-3, IX.A-22

96937-44-9

1

0

0

Benzoic acid, dimethyl-hydroxy-

IV.A-3, IX.A-22

93-89-0

1

0

0

Benzoic acid, ethyl ester

96937-43-8

1

0

0

Benzoic acid, ethyl-hydroxy-

C6H5-COO-(CH2)3-CH3

{ethyl benzoate}

C6H5-COO-CH2-CH3

V-3

V-3 IV.A-3, IX.A-22

6789-88-4

0

1

0

Benzoic acid, hexyl ester

87323-67-9

1

0

0

Benzoic acid, hydroxy-methoxy-

IV.A-3, IX.A-22

28965-86-8

1

0

0

Benzoic acid, hydroxy-methyl-

IV.A-3, IX.A-22

1

0

0

Benzoic acid, methyl-

1

1

1

Benzoic acid, methyl ester

{methyl benzoate} {amyl benzoate}

93-58-3 2049-96-9

1

0

0

Benzoic acid, pentyl ester

93-99-2

0

1

0

Benzoic acid, phenyl ester

C6H5-COO-(CH2)5-CH3

{toluic acid}

V-3

IV.A-3 C6H5-COO-CH3

V-3

C6H5-COO-(CH2)4-CH3

V-3

C6H5-COO-C6H5

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1516

11/24/08 1:55:43 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1517

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

120-51-4

1

1

1

Benzoic acid, phenylmethyl ester {benzyl benzoate}

C6H5-COO-CH2-C6H5

V-3

2315-68-6

1

1

1

Benzoic acid, propyl ester

C6H5-COO-(CH2)2-CH3

V-3

Name (per CA Collective Index)

Selected structures

Chapter Table

532-32-1

0

1

0

Benzoic acid, sodium salt

118-92-3

0

1

0

Benzoic acid, 2-amino-

XX-6

134-20-3

0

1

0

Benzoic acid, 2-amino-, methyl ester {methyl anthranilate}

612-19-1

1

0

0

Benzoic acid, 2-ethyl-

10366-91-3

0

1

0

Benzoic acid, 2-(E-D-glucopyranosyloxy)-

II.A-5, IV.A-3

612-20-4

1

0

0

Benzoic acid, 2-(hydroxymethyl)-

II.A-5, IV.A-3

85-91-6

0

1

0

Benzoic acid, 2-(methylamino)-, methyl ester

69-72-7

1

1

1

Benzoic acid, 2-hydroxy-

{salicylic acid}

IV.A-3, IX.A-22

118-61-6

0

1

0

Benzoic acid, 2-hydroxy-, ethyl ester {ethyl salicylate}

V-3, IX.A-22

6259-76-3

0

1

0

Benzoic acid, 2-hydroxy-, hexyl ester

V-3, IX.A-22

119-36-8

1

1

1

Benzoic acid, 2-hydroxy-, methyl ester {methyl salicylate}

V-3, IX.A-22

87-20-7

0

1

0

Benzoic acid, 2-hydroxy-, 3-methylbutyl ester {isoamyl salicylate}

V-3, IX.A-22

87-19-4

0

1

0

Benzoic acid, 2-hydroxy-, 2-methylpropyl ester {isobutyl salicylate}

V-3, IX.A-22

118-55-8

0

1

0

Benzoic acid, 2-hydroxy-, 2-phenylethyl ester {phenethyl salicylate}

V-3, IX.A-22

118-58-1

0

1

0

Benzoic acid, 2-hydroxy-, phenylmethyl ester {benzyl salicylate}

V-3, IX.A-22

50-85-1

1

0

0

Benzoic acid, 2-hydroxy-4-methyl-

IV.A-3, XII-2 V-3 IV.A-3

V-3

IV.A-3, IX.A-22

579-75-9

0

1

0

Benzoic acid, 2-methoxy-

{o-anisic acid}

IV.A-3, X-2

118-90-1

1

1

1

Benzoic acid, 2-methyl-

{o-toluic acid}

IV.A-3

94-47-3

0

1

0

Benzoic acid, 2-phenylethyl ester {2-phenylethyl benzoate}

V-3

583-04-0

0

1

0

Benzoic acid, 2-propenyl ester

303-38-8

1

1

1

Benzoic acid, 2,3-dihydroxy-

3934-81-4

1

0

0

Benzoic acid, 2,3-dihydroxy-4-methoxy-

3929-89-3

1

0

0

Benzoic acid, 2,3-dihydroxy-4-methyl-

V-3 IV.A-3, IX.A-22 IV.A-3, IX.A-22, X-2 IV.A-3, IX.A-22

603-79-2

1

0

0

Benzoic acid, 2,3-dimethyl-

610-02-6

1

0

0

Benzoic acid, 2,3,4-trihydroxy-

IV.A-3

89-86-1

1

0

0

Benzoic acid, 2,4-dihydroxy-

{E-resorcylic acid}

IV.A-3, IX.A-22

{gentisic acid}

IV.A-3, IX.A-22, XXI-3

IV.A-3, IX.A-22

490-79-9

1

1

1

Benzoic acid, 2,5-dihydroxy-

96937-49-4

1

0

0

Benzoic acid, 2,5-dihydroxy-methyl-

610-72-0

1

0

0

Benzoic acid, 2,5-dimethyl-

303-07-1

1

1

1

Benzoic acid, 2,6-dihydroxy-

619-20-5

1

0

0

Benzoic acid, 3-ethyl-

99-06-9

1

1

1

Benzoic acid, 3-hydroxy-

IV.A-3, IX.A-22 IV.A-3 IV.A-3, IX.A-22 IV.A-3 IV.A-3, IX.A-22

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1517

11/24/08 1:55:44 PM

1518

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

19438-10-9

1

0

0

Benzoic acid, 3-hydroxy-, methyl ester

645-08-9

1

0

0

Benzoic acid, 3-hydroxy-4-methoxy{isovanillic acid}

87513-63-1

0

1

0

Benzoic acid, 3-hydroxy-6-methoxy-, methyl ester

586-30-1

1

1

1

Benzoic acid, 3-hydroxy-4-methyl-

586-38-9

1

1

1

Benzoic acid, 3-methoxy-

99-04-7

Name (per CA Collective Index)

Chapter Table V-3, IX.A-22

IV.A-3, IX.A-22, X-2 V-3, IX.A-22, X-2 IV.A-3, IX.A-22 IV.A-3, X-2

1

1

1

Benzoic acid, 3-methyl-

0

1

0

Benzoic acid, 3-methylbutyl ester

99-50-3

1

1

1

Benzoic acid, 3,4-dihydroxy- {protocatechuic acid}

96937-39-2

1

0

0

Benzoic acid, 3,4-dihydroxy-dimethyl-

96937-40-5

Selected structures

{m-toluic acid}

IV.A-3 V-3 IV.A-3 IV.A-3, IX.A-22

1

0

0

Benzoic acid, 3,4-dihydroxy-methyl-

IV.A-3, IX.A-22

1

0

0

Benzoic acid, 3,4-dihydroxy-C4-alkyl-methyl-

IV.A-3, IX.A-22

93-07-2

0

1

0

Benzoic acid, 3,4-dimethoxy-

619-04-5

1

0

0

Benzoic acid, 3,4-dimethyl-

IV.A-3, X-2

149-91-7

1

0

0

Benzoic acid, 3,4,5-trihydroxy-

{gallic acid}

IV.A-3, IX.A-22

121-79-9

1

0

0

Benzoic acid, 3,4,5-trihydroxy-, propyl ester {propyl gallate}

V-3, IX.A-22

99-10-5

1

0

0

Benzoic acid, 3,5-dihydroxy-

IV.A-3

IV.A-3, IX.A-22

499-06-9

0

1

0

Benzoic acid, 3,5-dimethyl-

1918-00-9

0

1

0

Benzoic acid, 3,6-dichloro-2-methoxy-

IV.A-3 IV.A-3, X-2, XVIII.B-3, XXI-3 {Dicamba®}

126-64-7

0

1

0

Benzoic acid, 3,7-dimethyl-1,6-octadien-6-yl ester {linalyl benzoate}

619-64-7

1

0

0

Benzoic acid, 4-ethyl-

32142-31-7

0

1

0

Benzoic acid, 4-(E-D-glucopyranosyloxy)-3methoxy-

99-96-7

1

1

1

Benzoic acid, 4-hydroxy-

35285-68-9

0

1

0

Benzoic acid, 4-hydroxy-, ethyl ester, sodium salt

V-3 IV.A-3 II.A-5, IV.A-3, VIII-3, X-2

{p-salicylic acid}

IV.A-3, IX.A-22 NaO

V-3, XX-6 COO-C2H5

99-76-3

1

0

0

Benzoic acid, 4-hydroxy-, methyl ester

530-57-4

1

1

1

Benzoic acid, 4-hydroxy-3,5-dimethoxy{syringic acid}

IV.A-3, IX.A-22, X-2

V-3, IX.A-22

IV.A-3, IX.A-22, X-2, XXI-3

121-34-6

1

1

1

Benzoic acid, 4-hydroxy-3-methoxy- {vanillic acid}

617-05-0

0

1

0

Benzoic acid, 4-hydroxy-3-methoxy-, ethyl ester

V-3, IX.A-22, X-2 V-3, IX.A-22, X-2

3943-74-6

1

0

0

Benzoic acid, 4-hydroxy-3-methoxy-, methyl ester

96937-45-0

1

0

0

Benzoic acid, 4-hydroxy-methyl-

121-98-2

0

1

0

Benzoic acid, 4-methoxy-, methyl ester {methyl anisate}

99-94-5

0

1

0

Benzoic acid, 4-methyl-

3619-22-5

1

0

0

Benzoic acid, 4-methyl-, hydrazide

1

0

0

Benzoisoquinoline

XVII.E-6

1

0

0

Benzoisoquinoline, dimethyl-

XVII.E-6

IV.A-3, IX.A-22

{p-toluic acid}

V-3, X-2 IV.A-3 XIII-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1518

11/24/08 1:55:44 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1519

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

1

0

0

Benzoisoquinoline, methyl-

XVII.E-6

1

0

0

Benzoisoquinoline, tetramethyl-

XVII.E-6 XVII.E-6

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

Benzoisoquinoline, trimethyl-

226-88-0

1

0

0

Benzo[a]naphthacene

I.E-6

239-30-5

1

0

0

Benzo[b]naphtho[2,1-d]furan

X-2

1

0

0

Benzo[b]naphtho[2,3-d]furan

1

0

0

Benzo[b]naphtho[2,1-d]thiophene

243-42-5 100-47-0

X-2

1

1

1

Benzonitrile

1

0

0

Benzonitrile, C2-alkyl-

{2 isomers detected}

{phenyl cyanide} {5 isomers detected}

XVIII.A-1 C6H5-CN

XI-2 XI-2

1

0

0

Benzonitrile, C3-alkyl-

6136-68-1

1

0

0

Benzonitrile, 3-acetyl-

XI-2

1885-29-6

1

0

0

Benzonitrile, 2-amino-

36541-24-9

1

0

0

Benzonitrile, dimethyl-

XI-2

5724-56-1

1

0

0

Benzonitrile, 2,3-dimethyl-

XI-2

21789-36-6

1

0

0

Benzonitrile, 2,4-dimethyl-

XI-2

13730-09-1

1

0

0

Benzonitrile, 2,5-dimethyl-

XI-2

XI-2 {anthranilonitrile}

XI-2, XII-2

6575-13-9

1

0

0

Benzonitrile, 2,6-dimethyl-

XI-2

22884-95-3

1

0

0

Benzonitrile, 3,4-dimethyl-

XI-2

34136-59-9

1

0

0

Benzonitrile, 2-ethyl-

XI-2

25550-22-5

1

0

0

Benzonitrile, methyl-

XI-2

529-19-1

1

0

0

Benzonitrile, 2-methyl-

XI-2

34136-57-7

1

0

0

Benzonitrile, 3-ethyl-

873-62-1

1

0

0

Benzonitrile, 3-hydroxy-

XI-2 XI-2, IX.A-22

620-22-4

1

0

0

Benzonitrile, 3-methyl-

XI-2

3435-51-6

1

0

0

Benzonitrile, 4-ethenyl-

XI-2

25309-65-3

1

0

0

Benzonitrile, 4-ethyl-

XI-2

767-00-0

1

0

0

Benzonitrile, 4-hydroxy-

XI-2

104-85-8

1

0

0

Benzonitrile, 4-methyl-

XI-2

60484-66-4

1

0

0

Benzonitrile, 4-propyl-

XI-2

1

0

0

Benzonitrile, trimethyl-

189-55-9

1

0

0

Benzo[rst]pentaphene

XI-2

11057-45-7

1

0

0

Benzoperylene

I.E-6

197-70-6

1

0

0

Benzo[b]perylene

I.E-6

{dibenzo[a,i]pyrene}

I.E-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1519

11/24/08 1:55:44 PM

1520

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

191-24-2

1

0

0

Benzo[ghi]perylene

I.E-6

64760-22-1

1

0

0

Benzo[ghi]perylene, dimethyl{at least 3 isomers in MSS}

I.E-6

41699-09-6

1

0

0

Benzo[ghi]perylene, methyl{at least 2 isomers in MSS}

I.E-6

64760-23-2

1

0

0

Benzo[ghi]perylene, trimethyl{at least 2 isomers in MSS}

I.E-6

195-19-7

1

0

0

Benzo[c]phenanthrene

I.E-6

1

0

0

Benzo[c]phenanthrene, methyl-

I.E-6

1

0

0

Benzo[lmn]phenanthridine

194-03-6

Name (per CA Collective Index)

Chapter Table

Selected structures

{thebenidine} N

4250-90-2

0

1

0

Benzo[g]pteridine-10(2H)-acetaldehyde, 3,4dihydro-7,8-dimethyl-2,4-dioxo-

1086-80-2

0

1

0

Benzo[g]pteridine-2,4(1H,3H)-dione, 7,8-dimethyl-

III-12, XVII.E-8 H3C

N

H3 C

N

H N

O

XIV-1, XVII.E-8

NH O

1088-56-8

0

1

0

Benzo[g]pteridine-2,4(3H,10H)-dione, 7,8,10trimethyl-

XIV-1, XVII.E-8

CH3 H3C

N

H3C

N

N

O NH

O

0

1

0

2H-1-Benzopyran-3-carboxylic acid, 6,7-dihydroxy2-oxo-

IV.A-3, VI-3, IX.A-22

19484-74-3

0

1

0

2H-1-Benzopyran-3-carboxylic acid, 7,8-dihydroxy2-oxo-

IV.A-3, VI-3, IX.A-22

124052-01-3

0

1

0

2H-1-Benzopyran-3,4-dione, 2-(3,4dihydroxyphenyl)-2,5,7-trihydroxy-

59-02-9

1

1

1

2H-1-Benzopyran-6-ol, 3,4-dihydro-2,5,7,8tetramethyl-2-(4,8,12-trimethyltridecyl)-, [2R[2R*(4R*,8R*)]]{D-tocopherol}

II.A-5, III-13, IX.A-22, X-2 CH3

IX.A-22, X-2

HO CH3 O

H3C CH3

CH2-[CH2-CH2-CH(CH3)-CH2]3-H

148-03-8

1

0

0

2H-1-Benzopyran-6-ol, 3,4-dihydro-2,5,8-trimethyl2-(4,8,12-trimethyltridecyl)- {ȕ-tocopherol}

IX.A-22, X-2

7616-22-0

0

1

0

2H-1-Benzopyran-6-ol, 3,4-dihydro-2,7,8-trimethyl2-(4,8,12-trimethyltridecyl)-

IX.A-22, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1520

11/24/08 1:55:45 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1521

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

56084-94-7

0

1

0

91-64-5

1

1

1

Name (per CA Collective Index) 2H-1-Benzopyran-6-ol, 3,4-dihydro-2,7,8-trimethyl2-(4,8,12,16,20,24,28,32-octamethyl3,7,11,15,19,23,27,31-tritriacontaoctaenyl[3E,7E,11E,15E,19E,23,E,27E] {solanochromene; solanachromene} 2H-1-Benzopyran-2-one

Chapter Table

Selected structures

IX.A-22, X-2

HO CH3 O

H3C CH3

CH2-[CH2-CH=C(CH3)-CH2]8-H

VI-3

{coumarin} O

O

26093-31-2

0

1

0

2H-Benzopyran-2-one, 7-amino-4-methyl-

74712-71-3

0

1

0

2H-1-Benzopyran-2-one, 7-[[6-O-(6-deoxy-D-Lmannopyranosyl)-E-D-glucopyranosyl]oxy]-6methoxy-

VI-3, XII-2

119-84-6

1

1

1

2H-1-Benzopyran-2-one, 3,4-dihydro{dihydrocoumarin}

VI-3

305-01-1

1

1

1

2H-1-Benzopyran-2-one, 6,7-dihydroxy{esculetin}

VI-3, IX.A-22

60091-00-1

0

1

0

2H-1-Benzopyran-2-one, 7-[(6-O-E-Dglucopyranosyl-E-D-glucopyranosyl)oxy]-6methoxy-

531-75-9

1

1

1

2H-1-Benzopyran-2-one, 6-(E-Dglucopyranosyloxy)-7-hydroxy-

II.A-5, VI-3, VIII-3

II.A-5, VI-3, X-2

II.A-5, VI-3, IX.A-22, X-2

{esculin}

HO

HOCH 2

O

O

O

O OH

OH

HO

531-58-8

0

1

0

2H-1-Benzopyran-2-one, 7-(E-Dglucopyranosyloxy)-6-hydroxy-

HO

{cichoriin HOCH2

O

O

O

O

OH OH

HO

II.A-5, VI-3, IX.A-22, X-2, XXI-3 531-44-2

0

1

0

2H-1-Benzopyran-2-one, 7-(E-Dglucopyranosyloxy)-6-methoxy-

H3CO

{scopolin} HOCH2

O

O

O

O

OH OH

HO

II.A-5, VI-3, X-2 93-35-6

0

1

0

2H-1-Benzopyran-2-one, 7-hydroxy-

VI-3, IX.A-22 HO

148-83-4

0

1

0

2H-1-Benzopyran-2-one, 7-hydroxy-6-(3,7-dimethyl2,6-octadienyl){ostruthin}

HO

1

1

1

2H-1-Benzopyran-2-one, 7-hydroxy-6-methoxy{scopoletin}

0

1

0

2H-1-Benzopyran-2-one, 7-hydroxy-4-methyl-

531-59-9

0

1

0

2H-1-Benzopyran-2-one, 7-methoxy-

O

CH3

VI-3, IX.A-22

H3CO

HO

90-33-5

O

H3C CH3

92-61-5

O

O

O

O

VI-3, IX.A-22, X-2, XXI-3 VI-3, IX.A-22 VI-3, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1521

11/24/08 1:55:45 PM

1522

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

0

1

0

2H-1-Benzopyran-2-one, 8-methoxy-

71050-53-8

0

1

0

2H-1-Benzopyran-2-one, 6-methoxy-7-(E-Dxylofuranosyloxy)-

II.A-5, VI-3, VIII-3, X-2

VI-3, X-2

18309-73-4

0

1

0

2H-1-Benzopyran-2-one, 6-methoxy-7-[(6-O-E-Dxylopyranosyl-E-D-glucopyranosyl)oxy]-

II.A-5, VI-3, VIII-3, X-2

2445-82-1

1

0

0

2H-1-Benzopyran-2-one, 3-methyl-

92-48-8 66-76-2

1

0

0

2H-1-Benzopyran-2-one, 6-methyl2H-1-Benzopyran-2-one, 3,3'-methylenebis[4hydroxy{dicumarol}

4430-31-3

0

1

0

2H-1-Benzopyran-2-one, octahydro-

970-73-0

0

1

0

2H-1-Benzopyran-3,5,7-triol, 3,4-dihydro-2-(3,4,5trihydroxyphenyl)-, (2R-E)-

VI-3 VI-3, IX.A-22 Dicumarol not detected in MSS from coumarin-treated tobacco. VI-3 OH HO 3

HO

2

5

4

HO

4

5

6 7

1

O

OH

8

3

OH

II.A-5, IX.A-22, X-2 970-74-1

0

1

0

2H-1-Benzopyran-3,5,7-triol, 3,4-dihydro-2-(3,4,5trihydroxyphenyl)-, (2R-Z)-

II.A-5, IX.A-22, X-2

124052-00-2

0

1

0

4H-1-Benzopyran-4-one, 2-(3,4-dihydroxyphenyl)2,3-dihydro-2,3,5,7-tetrahydroxy-

II.A-5, IX.A-22, X-2

21637-25-2

0

1

0

4H-1-Benzopyran-4-one, 2-(3,4-dihydroxyphenyl)-3(E-D-glucofuranosyloxy)-5,7-dihydroxy{isoquercitrin}

117-39-5

1

1

1

4H-1-Benzopyran-4-one, 2-(3,4-dihydroxyphenyl)3,5,7-trihydroxy{quercitin}

II.A-5, III-13, IX.A-22, X-2, XXI-3

OH

7

HO

II.A-5, III-13, IX.A-22, X-2

O

5 6

4 1

O

OH 3 2

OH

OH

7215-44-3

0

1

0

4H-1-Benzopyran-4-one, 2-(3,4-dihydroxyphenyl)-3[(2-O-E-D-glucopyranosyl-D-glucopyranosyl)oxy]5,7-dihydroxy-

II.A-5, III-13, IX.A-22, X-2

1486-70-0

0

1

0

4H-1-Benzopyran-4-one, 2-(3,4-dihydroxyphenyl)5,7-dihydroxy-3-methoxy-

III-13, IX.A-22, X-2

2068-02-2

0

1

0

4H-1-Benzopyran-4-one, 2-(3,4-dihydroxyphenyl)-5hydroxy-3,7-dimethoxy-

III-13, IX.A-22, X-2

491-50-9

0

1

0

II.A-5, III-13, IX.A-22, X-2

124051-99-6

0

1

0

4H-1-Benzopyran-4-one, 2-(3,4-dihydroxyphenyl)-7(E-D-glucopyranosyloxy)-3,5-dihydroxy{quercimeritrin} 4H-1-Benzopyran-4-one, 2-(3,4-dihydroxyphenyl)-7[[2-(3,4-dihydroxyphenyl)-2,3-dihydro-2,6dihydroxy-3-oxo-4-benzofuranyl]oxy]-2,3-dihydro3,5-dihydroxy-

480-41-1

0

1

0

4H-1-Benzopyran-4-one, 2,3-dihydro-5,7-dihydroxy2-(4-hydroxyphenyl)-, (S){naringenin}

III-13, IX.A-22, X-2

III-13, IX.A-22, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1522

11/24/08 1:55:45 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1523

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

480-10-4

0

1

0

Name (per CA Collective Index) 4H-1-Benzopyran-4-one, 3-(E-Dglucopyranosyloxy)-5,7-dihydroxy-2-(4hydroxyphenyl){kaempferol glycoside}

HO

O

1

4H-1-Benzopyran-4-one, 3,5,7-trihydroxy-2-(4hydroxyphenyl){kaempferol}

OH

OH

HO

1

II.A-5, III-13, IX.A-22, X-2

O

O OH

1

OH

O

HOCH2

520-18-3

Chapter Table

Selected structures

II.A-5, III-13, IX.A-22, X-2

OH HO

O

OH OH

O

55136-76-0

0

1

0

4H-1-Benzopyran-4-one, 3-[(2-O-E-Dglucopyranosyl-E-D- glucopyranosyl)oxy]-7-(E-Dglucopyranosyloxy)-5-hydroxy-2-(4hydroxyphenyl)-

II.A-5, III-13, IX.A-22, X-2

142235-82-3

0

1

0

4H-1-Benzopyran-4-one, 3-[(2-O-E-Dglucopyranosyl-E-D-galactopyranosyl)oxy]-7-(E-Dglucopyranosyloxy)-5-hydroxy-2-(4hydroxyphenyl)-

II.A-5, III-13, IX.A-22, X-2

19895-95-5

0

1

0

4H-1-Benzopyran-4-one, 3-[(2-O-E-Dglucopyranosyl-E-D-glucopyranosyl)oxy]-5,7dihydroxy-2-(4-hydroxyphenyl)-

II.A-5, III-13, IX.A-22, X-2

522-12-3

0

1

0

4H-1-Benzopyran-4-one, 3-[(6-deoxy-D-Lmannopyranosyl)oxy]-2-(3,4-dihydroxyphenyl)-5,7dihydroxy{quercitrin}

II.A-5, III-13, IX.A-22, X-2

55696-57-6

0

1

0

4H-1-Benzopyran-4-one, 3-[(O-6-deoxy-D-Lmannopyranosyl-(1o2)-O-[6-deoxy-D-Lmannopyranosyl-(1o6)]-E-D-glucopyranosyl)oxy]2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-

II.A-5, III-13, IX.A-22, X-2

55804-74-5

0

1

0

4H-1-Benzopyran-4-one, 3-[(O-6-deoxy-D-Lmannopyranosyl-(1o2)-O-[6-deoxy-D-Lmannopyranosyl-(1o6)]-E-D-glucopyranosyl)oxy]5,7-dihydroxy-2-(4-hydroxyphenyl)-

II.A-5, III-13, IX.A-22, X-2

153-18-4

0

1

0

4H-1-Benzopyran-4-one, 3-[[6-O-(6-deoxy-D-Lmannopyranosyl)-E-D-glucopyranosyl]oxy]-2-(3,4dihydroxyphenyl)-5,7-dihydroxy{rutin}

HO OH

O

HO ruffinose

O O

OH

II.A-5,III-13,IX.A-22, X-2, XXI-3 II.A-5, III-13, IX.A-22, X-2

17650-84-9

0

1

0

4H-1-Benzopyran-4-one, 3-[[6-O-(6-deoxy-D-Lmannopyranosyl)-E-D-glucopyranosyl]oxy]-5,7dihydroxy-2-(4-hydroxyphenyl)-

30311-61-6

0

1

0

4H-1-Benzopyran-4-one, 3-[[6-O-(6-deoxy-D-Lmannopyranosyl)-E-D-glucopyranosyl]oxy]-2-(3,4dihydroxyphenyl)-7-(E-D-glucopyranosyloxy)-5hydroxy-

II.A-5, III-13, IX.A-22, X-2

34336-18-0

0

1

0

4H-1-Benzopyran-4-one, 3-[[6-O-(6-deoxy-D-Lmannopyranosyl)-E-D-glucopyranosyl]oxy]-7-(E-Dglucopyranosyloxy)-5-hydroxy-2-(4hydroxyphenyl)-

II.A-5, III-13, IX.A-22, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1523

11/24/08 1:55:46 PM

1524

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

29859-91-4

0

1

0

4H-1-Benzopyran-4-one, 3-[[O-(6-deoxy-Lmannosyl)-D-galactosyl]oxy]-5,7-dihydroxy-2-(4hydroxyphenyl)-

II.A-5, III-13, IX.A-22, X-2

27554-19-4

0

1

0

4H-1-Benzopyran-4-one, 3-[[O-(6-deoxy-Lmannosyl)-D-glucosyl]oxy]-5,7-dihydroxy-2-(4hydroxy phenyl)-

II.A-5, III-13, IX.A-22, X-2

58934-57-9

0

1

0

4H-1-Benzopyran-4-one, 3-[[O-(6deoxymannosyl)glucosyl]oxy]-7-(E-Dglucopyranosyloxy)-5-hydroxy-2-(4hydroxyphenyl)-

II.A-5, III-13, IX.A-22, X-2

828-82-0

1

0

0

4H-1-Benzopyran-4-one, 3-ethyl-

520-34-3

0

1

0

4H-1-Benzopyran-4-one, 5,7-dihydroxy-2-(3hydroxy-4-methoxyphenyl){diosmetin}

4382-17-6

0

1

0

4H-1-Benzopyran-4-one, 5,7-dihydroxy-2-(4hydroxy-3-methoxyphenyl)-3-methoxy-

III-13, IX.A-22, X-2

1

0

0

4H-1-Benzopyran-4-one, hydroxy-

III-13, IX.A-22, X-2

38445-24-8

1

0

0

4H-1-Benzopyran-4-one, 6-hydroxy-

III-13, IX.A-22, X-2

10236-47-2

0

1

0

4H-1-Benzopyran-4-one, 7-[[2-O-(6-deoxy-D-Lmannopyranosyl)-E-D-glucopyranosyl]oxy]-2,3dihydro-5-hydroxy-2-(4-hydroxyphenyl)-, (S){naringin}

II.A-5, III-13, IX.A-22, X-2

0

1

0

4H-1-Benzopyran-4-one, 2-phenyl-, 3',4',5,5',7pentahydroxy-3-[[O-(6-deoxymannosyl)-Dglucosyl]oxy]-

II.A-5, III-13, IX.A-22, X-2

0

1

0

4H-1-Benzopyran-4-one, 2-phenyl-, 3',4',5,7tetrahydroxy-3-[[O-(6-deoxymannosyl)-Dglucosyl]oxy]-

II.A-5, III-13, IX.A-22, X-2

0

1

0

7H-1-Benzopyran-7-one, 2,4a,5,6,8,8a-hexahydro2,5,5,8a-tetramethyl-

1

1

1

7H-1-Benzopyran-7-one, 2,3,5,6,8,8a-hexahydro2,5,5,8a-tetramethyl{1,5,5,9-tetramethyl-10-oxabicyclo[4.4.0]dec-6-en3-one}

20194-67-6

5835-18-7

83-79-4

1

0

1

1

1

0

Name (per CA Collective Index)

7H-1-Benzopyran-7-one, octahydro-2,5,5,8atetramethyl{7-chromanone, hexahydro-2,5,5,8a-tetramethyl-} Benzopyrano[3,4-b]furo[2,3-h][1]benzopyran6(6aH)-one, 1,2,12,12a-tetrahydro-8,9-dimethoxy2-(1-methylethenyl)-, [2R-(2Į,6aĮ,12aĮ)]{Rotenone®}

Selected structures

Chapter Table

III-13, X-2 III-13, IX.A-22, X-2

III-13, X-2

8a

7

III-13, X-2

4

5

3

4a 8a

O

2

1

O

8

6

3

4a

7

O

III-13, X-2

4

5

6

1

2

O

8

III-13, X-2, XXI-3

CH2 H3C H

O

O

O

H

O

OCH3 OCH3

50-32-8

1

0

0

Benzopyrene

1

1

1

Benzo[a]pyrene

I.E-6 {B[a]P}

11

1

12

2

10

I.E-6

3

9 8

4 7

6

5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1524

11/24/08 1:55:46 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1525

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke S

T

S T

1

0

0

Benzo[a]pyrene, alkyl-

I.E-6

1

0

0

Benzo[a]pyrene, 3,4-dihydro-

I.E-6

17573-23-8

1

0

0

Benzo[a]pyrene, 7,8-dihydro-

I.E-6

25167-90-2

1

0

0

Benzo[a]pyrene, dimethyl{at least 2 isomers in MSS}

I.E-6

CAS No.

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

Benzo[a]pyrene, ethyl-

I.E-6

25167-89-9

1

0

0

Benzo[a]pyrene, methyl{at least 2 isomers in MSS}

I.E-6

69453-35-6

1

0

0

Benzo[a]pyrenediol

63455-19-6

1

0

0

Benzo[a]pyrenol

IX.A-22

20928-82-9

1

0

0

Benzo[a]pyren-6-yloxy

IX.A-22

7130-15-6

1

0

0

3H-Benzo[cd]pyrene, 4,5-dihydro-

192-97-2

1

1

1

Benzo[e]pyrene

41699-06-3

1

0

0

Benzo[e]pyrene, dimethyl{at least 2 isomers in MSS}

I.E-6

41699-04-1

1

0

0

Benzo[e]pyrene, methyl{at least 2 isomers in MSS}

I.E-6

64760-21-0

1

0

0

Benzo[e]pyrene, trimethyl-

I.E-6

30907-88-1

0

1

0

6H-Benzo[c]pyrido[3,2,1-jk]carbazole

IX.A-22

I.E-6

I.E-6

{B[e]P}

XVII.E-6

N

528-58-5

0

1

0

1-Benzopyrylium, 2-(3,4-dihydroxyphenyl)-3,5,7trihydroxy-, chloride

22688-80-8

0

1

0

1-Benzopyrylium, 2-(3,4-dihydroxyphenyl)-3-[(2-OE-D-glucopyranosyl-D-glucopyranosyl)oxy]-5,7dihydroxy-, chloride

528-53-0

0

1

0

1-Benzopyrylium, 3,5,7-trihydroxy-2-(3,4,5trihydroxyphenyl)-, chloride

18719-76-1

0

1

0

1-Benzopyrylium, 3-[6-O-(6-deoxy-D-Lmannopyranosyl)-E-D-glucopyranosyl]oxy]-2-(3,4dihydroxyphenyl)-5,7-dihydroxy-, chloride

II.A-5, IX.A-22, X-2, XVIII.B-3

33978-17-5

0

1

0

1-Benzopyrylium, 3-[6-O-(6-deoxy-D-Lmannopyranosyl)-E-D-glucopyranosyl]oxy]-5,7dihydroxy-2-(4-hydroxyphenyl)-, chloride

II.A-5, IX.A-22, X-2, XVIII.B-3

39327-16-7

1

0

0

Benzoquinoline

{benzo[g]quinoline}

IX.A-22, X-2, XVIII.B-3 II.A-5, IX.A-22, X-2, XVIII.B-3

II.A-5, IX.A-22, XVIII.B-3

f

e

XVII.E-6

c

d

g

a

b

N

1

0

0

Benzoquinoline, dimethyl-

XVII.E-6

© 2009 by Taylor & Francis Group, LLC

78836_C030.indd 1525

11/24/08 1:55:46 PM

1526

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke S

T

S T

1

0

0

Benzoquinoline, methyl-

XVII.E-6

1

0

0

Benzoquinoline, tetramethyl-

XVII.E-6

1

0

0

Benzoquinoline, trimethyl-

XVII.E-6

1

0

0

Benzo[c]quinoline {phenanthridine; 9-azaphenanthrene}

XVII.E-6

85-02-9

1

0

0

Benzo[f]quinoline

{1-azaphenanthrene}

XVII.E-6

230-27-3

1

0

0

Benzo[h]quinoline

{4-azaphenanthrene}

XVII.E-6

1

0

0

o-Benzosemiquinone radical

1

0

0

p-Benzosemiquinone radical

95-16-9

1

1

1

Benzothiazole

120-78-5

0

1

0

Benzothiazole, 2,2’-dithiobis-

CAS No.

Name (per CA Collective Index)

Selected structures

Chapter Table

XXVII-1 XXVII-1 {benzosulfonazole}

XVIII.A-1

S N

{Thiofide®}

_

XVIII.A-1, XXI-3

_

N

S_

615-22-5

0

1

0

Benzothiazole, 2-methylthio-

934-34-9

0

1

0

2(3H)-Benzothiazolone

S

_

2

XVIII.A-1 XVIII.A-1

S O N H

1128-67-2

1

0

0

2(3H)-Benzothiazolone, 3-methyl-, hydrazone

XVIII.A-1

95-15-8

1

0

0

Benzo[b]thiophene

XVIII.A-1 S

1

0

0

Benzo[b]thiophene, C2-alkyl-

1

0

0

Benzo[b]thiophene, C3-alkyl-

1

0

0

Benzo[b]thiophene, methyl-

14315-11-8

1

0

0

Benzo[b]thiophene, 4-methyl-

95-14-7

1

0

0

1H-Benzotriazole

XVIII.A-1 XVIII.A-1 {4 isomers reported}

{1,2,3-triaza-1H-indene}

XVIII.A-1 XVIII.A-1 XVII.E-6

H N N N

215-58-7

1

0

0

Benzo[b]triphenylene

{dibenz[a,c]anthracene}

64760-20-9

1

0

0

Benzo[b]triphenylene, methyl-

I.E-6

I.E-6

© 2009 by Taylor & Francis Group, LLC

78836_C030.indd 1526

11/24/08 1:55:47 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1527

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

17924-92-4

0

1

0

1H-2-Benzoxacyclotetradecin-1,7(8H)-dione, 3,4,5,6,9,10-hexahydro-14,16-dihydroxy-3methyl-, [S-(E)]-

273-53-0

1

0

0

Benzoxazole

Name (per CA Collective Index)

{1-oxa-3-azaindene}

Selected structures

II.A-5

4

XVII.D-2

3

N

5

2

6

O

7

72692-90-1

Chapter Table

1

1

0

0

Benzoxazole, C2-alkyl-

XVII.D-2

1

0

0

Benzoxazole, 2,4-dimethyl-

XVII.D-2

5676-58-4

1

0

0

Benzoxazole, 2,5-dimethyl-

XVII.D-2

72692-91-2

1

0

0

Benzoxazole, 4,6-dimethyl-

XVII.D-2

78210-58-9

1

0

0

Benzoxazole, 5,7-dimethyl-

XVII.D-2

78210-57-8

1

0

0

Benzoxazole, 7-ethyl-

XVII.D-2

95-21-6

1

0

0

Benzoxazole, 2-methyl-

XVII.D-2

27548-56-7

0

1

0

3-Benzoxepin-7-methanol, 5a,6,7,8,9,9ahexahydro-D,D,5,9a-tetramethyl-, (5aD,7D,9aD)-(-)-

7440-41-7

1

1

1

Beryllium

434-85-5

1

0

0

[9,9'-Bianthracene]-10,10'(9H,9'H)-dione {bianthrone; dianthraquinone}

II.A-5, X-2 Be

XX-5 III-13

O 1

8 9

7

2 3

6 4

5

O

121-46-0

0

1

0

Bicyclo[2.2.1]hepta-2,5-diene

I.C-1

79-92-5

1

1

1

Bicyclo[2.2.1]heptane, 2,2-dimethyl-3-methylene{camphene}

I.C-1

8001-35-2

0

1

0

Bicyclo[2.2.1]heptane, 2,2-dimethyl-3-methylene-, polychlorinated {Toxaphene®}

XVIII.B-3, XXI-3

8001-50-1

0

1

0

Bicyclo[2.2.1]heptane, 2,2-dimethyl-3-methylene-, polychlorinated + Bicyclo[3.1.1]hept-2-ene, 2,6,6-trimethyl-, polychlorinated {Strobane®; Dichloricide®}

XVIII.B-3, XXI-3

509-11-5

0

1

0

Bicyclo[2.2.1]heptan-2-ol, 1,7-dimethyl-, (exo,anti)-

507-70-0

1

1

1

Bicyclo[2.2.1]heptan-2-ol, 1,7,7-trimethyl-, endo{borneol}

{norbornadiene}

II.A-5 II.A-5

CH3 OH H3C__ CH3

125-12-2

0

1

0

Bicyclo[2,2,1]heptan-2-ol, 1,7,7-trimethyl-, acetate {isobornyl acetate}

V-3

2756-56-1

0

1

0

Bicyclo[2.2.1]heptan-2-ol, 1,7,7-trimethyl-, propanoate, exo-

V-3

1195-79-5

0

1

0

Bicyclo[2.2.1]heptan-2-one, 1,3,3-trimethyl-

III-13

4695-62-9

0

1

0

Bicyclo[2,2,1]heptan-2-one, 1,3,3-trimethyl{d-fenchone}

III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1527

11/24/08 1:55:47 PM

1528

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

76-22-2

0

1

0

Name (per CA Collective Index)

Selected structures

Bicyclo[2.2.1]heptan-2-one, 1,7,7-trimethyl{camphor}

Chapter Table III-13

CH3 O H3C__ CH3

I.C-1

498-66-8

1

0

0

Bicyclo[2.2.1]hept-2-ene

127-91-3 18172-67-3

1

1

1

Bicyclo[3.1.1]heptane, 6,6-dimethyl-2-methylene{E-pinene}

I.C-1

22422-24-0

0

1

0

Bicyclo[3,1,1]heptane-2,3-diol, 2,6,6-trimethyl{2,3-pinanediol}

II.A-5

{norbornene}

HO

80-56-8 7785-26-4

1

1

1

Bicyclo[3.1.1]hept-2-ene, 2,6,6-trimethyl{D-pinene}

4889-83-2

0

1

0

Bicyclo[3.1.1]hept-2-ene, 3,6,6-trimethyl-

515-00-4

0

1

0

Bicyclo[3.1.1]hept-2-ene-2-methanol, 6,6-dimethyl-

HO

I.C-1

I.C-1 II.A-5

CH3 CH3

CH2OH

3387-41-5

0

1

0

Bicyclo[3.1.0]hexane, 4-methylene-1-(1methylethyl){sabinene}

I.C-1

471-16-9

0

1

0

Bicyclo[3.1.0]hexan-3-ol, 4-methylene-1-(1methylethyl)-, [1S-(1D,3E,5D)]{sabinol}

II.A-5

2867-05-2

0

1

0

Bicyclo[3.1.0]hex-2-ene, 2-methyl-5-(1-methylethyl){3-thujene}

I.C-1

3917-48-4

0

1

0

Bicyclo[3.1.0]hex-2-ene, 2-methyl-5-(1-methylethyl), (1R)-

I.C-1

92-51-3

1

1

1

1,1'-Bicyclohexyl

I.C-1

280-65-9

1

0

0

Bicyclo[3.3.1]nonane

{cyclohexylcyclohexane}

I.C-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1528

11/24/08 1:55:47 PM

1529

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

124749-69-5

1

0

0

Name (per CA Collective Index) Bicyclo[3.3.1]nonan-3-one, 1-hydroxy-6-(1methylethyl)-, endo-

Chapter Table

Selected structures

II.A-5, III-13

CH3 H3C

O

OH

123695-64-7

1

0

0

Bicyclo[3.3.1]nonan-3-one, 1-hydroxy-6-(1methylethyl)-, exo-

61185-25-9

0

1

0

Bicyclo[3.3.1]non-6-en-2-one, 4,4,9-trimethyl-8methylene-, anti-

II.A-5, III-13 III-13

H3C 5

6

H3C

7

3

9

1

8

CH3

4 2

O

H2C

0

1

0

Bicyclo[3.3.1]non-6-en-2-one, 4,9,9-trimethyl-8methylene-

13466-78-9

0

1

0

Bicyclo[4.1.0]hept-3-ene, 3,7,7-trimethyl-

87-44-5

0

1

0

Bicyclo[7.2.0]undec-4-ene, 4,11,11-trimethyl-8methylene-, [1R-(1R*,4E,9S*)]- {E-caryophyllene}

III-13 I.C-1 I.C-1

CH3 10 9

H2C

CH3

11 1

2

8 5

7

3

4

6

CH3

32214-91-8

0

1

0

Bicyclo[7.2.0]undec-4-ene, 4,11,11-trimethyl-8methylene-, acetate {E-caryophyllene acetate}

V-3

53093-94-0

0

1

0

2,2'-Bifuran, 2,3,4,5-tetrahydro-2,5'-dimethyl-5-(1methylethenyl)-, (Z)- (±)-

X-2

53093-95-1

0

1

0

2,2'-Bifuran, 2,3,4,5-tetrahydro-2,5'-dimethyl-5-(1methylethenyl)-, (E)- (±)-

X-2

53093-96-2

0

1

0

2,2'-Bifuran, 2,3,4,5-tetrahydro-2,5'-dimethyl-5-(1methylethyl)-, (Z)- (r)-

X-2

53093-97-3

0

1

0

2,2'-Bifuran, 2,3,4,5-tetrahydro-2,5'-dimethyl-5-(1methylethyl)-, (E)- (±)-

X-2

20298-86-6

0

1

0

21H-Biline-8,12-dipropanoic acid, 18-ethyl-3ethylidene-1,2,3,19,22,24-hexahydro-2,7,13,17tetramethyl-1,19-dioxo-, (2R,3E)-

HOOC

H3C CH CH3

H3C

O

4

1

N H

(CH2)2 (CH2)2 7

3

2

5

C H2

COOH

8

12 9

6

N H

10

C H

11

N H

CH3 13 14

CH3

C2H5

17 18 15

C H2

16

19

N H

O

IV.A-3, XVII.C-1 604-53-5

1

0

0

1,1'-Binaphthalene

I.E-6

71265-39-9

1

0

0

1,1'-Binaphthalene, dimethyl-

I.E-6

71277-81-1

1

0

0

1,1'-Binaphthalene, ethyl-

I.E-6

59615-45-5

1

0

0

1,1’-Binaphthalene, methyl-

I.E-6

1

0

0

1,2’-Binaphthalene

I.E-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1529

11/24/08 1:55:48 PM

1530

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

612-78-2

1

0

0

2,2'-Binaphthalene

I.E-6

71294-43-4

1

0

0

2,2'-Binaphthalene, dimethyl-

I.E-6

Name (per CA Collective Index)

Selected structures

Chapter Table

71277-82-2

1

0

0

2,2'-Binaphthalene, ethyl-

I.E-6

41637-91-6

1

0

0

2,2'-Binaphthalene, methyl-

I.E-6

92-52-4

1

1

1

1,1'-Biphenyl

{diphenyl}

2'

3'

2 1'

4' 5'

6'

I.D-1

3

1

4 6

5

2051-24-3

1

1

1

1,1'-Biphenyl, decachloro-

92-87-5

1

0

0

1,1’-Biphenyl, 4,4’-diamino-

XII-2

61141-66-0

0

1

0

1,1’-Biphenyl, 3,4-diethyl-

I.D-1

1133-63-7

1

0

0

1,1’-Biphenyl, 2,3-dihydroxy-

0

1

0

1,1'-Biphenyl, 3,4'-dimethyl-

XVIII.B-3

IX.A-22 I.D-1

613-33-2

1

0

0

1,1'-Biphenyl, 4,4'-dimethyl-

I.D-1

28013-11-8

1

1

1

1,1'-Biphenyl, ar,ar'-dimethyl-

I.D-1

40529-66-6

1

0

0

1,1'-Biphenyl, ethyl-

I.D-1

1

0

0

1,1'-Biphenyl, 2-ethyl-

I.D-1

71277-83-3

1

0

0

1,1'-Biphenyl, ethylmethyl-

I.D-1

28652-72-4

1

1

1

1,1'-Biphenyl, methyl-

I.D-1

643-58-3

1

0

0

1,1'-Biphenyl, 2-methyl-

I.D-1

643-93-6

1

0

0

1,1'-Biphenyl, 3-methyl-

I.D-1

644-08-6

1

0

0

1,1'-Biphenyl, 4-methyl-

I.D-1

92-93-3

1

0

0

1,1'-Biphenyl, 4-nitro-

XVI-1

71294-42-3

1

0

0

1,1'-Biphenyl, propyl-

I.D-1

30581-97-6

1

0

0

1,1'-Biphenyl, trimethyl-

90-41-5

1

0

0

[1,1'-Biphenyl]-2-amine

{3 isomers detected}

I.D-1 XII-2

2243-47-2

1

0

0

[1,1'-Biphenyl]-3-amine

XII-2

92-67-1

1

0

0

[1,1'-Biphenyl]-4-amine

1

0

0

[1,1'-Biphenyl]-ol

IX.A-22

90-43-7

1

0

0

[1,1'-Biphenyl]-2-ol

IX.A-22

92-69-3

1

0

0

[1,1'-Biphenyl]-4-ol

IX.A-22

259-79-0

1

0

0

Biphenylene

531-67-9

0

1

0

2,2’-Bipiperidine

37275-48-2

1

0

0

Bipyridine

78310-61-9

1

0

0

Bipyridine, dimethyl-

64859-48-9

1

0

0

Bipyridine, ethyl-

64859-47-9

1

0

0

Bipyridine, methyl-

64859-47-8

1

0

0

Bipyridine, methyl-

{4-aminobiphenyl}

XII-2

I.E-6

H N

H N

XVII.B-6

XVII.B-6 {2 isomers detected}

XVII.B-6 XVII.B-6

{4 isomers in all}

XVII.B-6 XVII.B-6

© 2009 by Taylor & Francis Group, LLC

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1531

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

78310-62-0

1

0

0

Bipyridine, phenyl-

366-18-7

1

1

1

2,2'-Bipyridine

1

0

0

2,2’-Bipyridine, amino-

XVII.B-6

1

0

0

2,2'-Bipyridine, 4,5-dimethyl-

XVII.B-6

78210-73-8 56100-19-7

1

0

0

2,2'-Bipyridine, 4-methyl-

581-50-0

1

1

1

2,3'-Bipyridine

XVII.B-6 {nicoteine}

XVII.B-6

XVII.B-6 {isonicoteine}

XVII.B-6

4 5

3 4'

6

5'

N 2'

2743-90-0

581-49-7

N

6'

1

0

0

2,3'-Bipyridine, dimethyl-

XVII.B-6

1

0

0

2,3'-Bipyridine, methyl-

XVII.B-6

0

1

0

2,3'-Bipyridine, 1,2,3,6-tetrahydro-, (r)-

XVII.B-6

1

0

0

2,3'-Bipyridine, 1,2,3,6-tetrahydro-, (R){d-anatabine}

XVII.B-6

1

1

1

2,3'-Bipyridine, 1,2,3,6-tetrahydro-, (S){l-anatabine}

XVII.B-6 N H N

61892-64-6

1

0

0

2,3'-Bipyridine, 1,2,3,6-tetrahydro-ethyl-

XVII.B-6

1

0

0

2,3'-Bipyridine, 1,2,3,6-tetrahydro-methyl-

XVII.B-6

1

1

1

2,3'-Bipyridine, 1-acetyl-1,2,3,6-tetrahydro-, (S){N’-acetylanatabine}

XVII.B-6 N N

CO-CH3

5953-51-5

1

1

1

2,3'-Bipyridine, 1,2,3,6-tetrahydro-1-methyl-, (S)-

XVII.B-6

96552-71-5

1

0

0

2,3'-Bipyridine, 1,2,3,6-tetrahydro-1-(1-oxohexyl)-, (S){N’-hexanoylanatabine}

XVII.B-6

96552-72-6

1

0

0

2,3'-Bipyridine, 1,2,3,6-tetrahydro-1-(1-oxooctyl)-, (S){N’-octanoylanatabine}

XVII.B-6

71267-22-6

1

1

1

2,3'-Bipyridine, 1,2,3,6-tetrahydro-1-nitroso-, (S){NAT}

61892-98-6

1

0

0

2,3'-Bipyridine, 1-ethyl-1,2,3,6-tetrahydro-, (S)-

XVII.B-6

26636-59-9

1

0

0

2,3'-Bipyridine, 2'(or 3)-methyl-

XVII.B-6

78210-76-1

1

0

0

2,3'-Bipyridine, 3-ethyl-

XVII.B-6

XV-8, XVII.B-6

78210-75-0

1

0

0

2,3'-Bipyridine, 4-(2-butenyl)-

XVII.B-6

78210-74-9

1

0

0

2,3'-Bipyridine, 4-(2-propenyl)-

XVII.B-6

38840-05-0

1

1

1

2,3'-Bipyridine, 4-methyl-

XVII.B-6

20410-87-1

0

1

0

2,3'-Bipyridine, 5-(1-methyl-2-piperidinyl)-, (+)-

XVII.B-6

0

1

0

2,3'-Bipyridine, 5-(2-piperidinyl)-

XVII.B-6

78210-79-4

1

0

0

2,3'-Bipyridine, 5-(1-propenyl)-

XVII.B-6

78210-81-8

1

0

0

2,3'-Bipyridine, 5-ethenyl-

XVII.B-6

{anabasamine}

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1531

11/24/08 1:55:48 PM

1532

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

34671-89-1

1

0

0

2,3'-Bipyridine, 5-ethyl-

XVII.B-6

26844-80-4

1

1

1

2,3'-Bipyridine, 5-methyl-

XVII.B-6

78210-80-7

1

0

0

2,3'-Bipyridine, 5-propyl-

XVII.B-6

78210-77-2

1

0

0

2,3'-Bipyridine, 6-ethyl-

XVII.B-6

78210-78-3

1

0

0

2,3'-Bipyridine, 6-methyl-

61892-65-7

1

1

1

[2,3'-Bipyridine]-1(2H)-carboxaldehyde, 3,6-dihydro, (S){N’-formylanatabine}

III-12, XVII.B-6

96552-70-4

1

0

0

[2,3'-Bipyridine]-1(2H)-carboxylic acid, 3,6-dihydro-, methyl ester, (S)-

V-3, XVII.B-6

70898-21-4

1

0

0

[2,3'-Bipyridin]-6'(1'H)-one, 3,4,5,6-tetrahydro-

581-47-5

1

1

1

2,4'-Bipyridine

XVII.B-6

581-46-4

1

1

1

3,3'-Bipyridine

XVII.B-6

38840-06-1

0

1

0

3,3'-Bipyridine, 4-methyl-

XVII.B-6

78210-82-9

1

0

0

3,3'-Bipyridine, 5-methyl-

XVII.B-6

Name (per CA Collective Index)

Chapter Table

Selected structures

XVII.B-6

XVII.B-6, XVII.C-1

78210-83-0

1

0

0

3,3'-Bipyridine, 6-methyl-

XVII.B-6

553-26-4

1

1

1

4,4'-Bipyridine

XVII.B-6

7440-69-9

1

1

1

Bismuth

Bi

14331-79-4

1

1

1

Bismuth, isotope of mass 210

210

XX-5 XX-5 XX-5

7440-42-8

XX-5 Bi

0

1

0

Bismuth, isotope of mass 216

216

1

1

1

Boron

B

Bi

-1

24959-67-9

1

1

1

Bromide

7726-95-6

1

1

1

Bromine

Br2

XVIII.B-3, XX-5

14686-69-2

1

1

1

Bromine, isotope of mass 82

82

XVIII.B-3, XX-5

25339-57-5

Br

Br2

XVIII.B-3, XX-5

1

0

0

Butadiene

1

0

0

Butadiene radical

590-19-2

1

0

0

1,2-Butadiene

H2C=C=CH-CH3

I.B-1

106-99-0

1

0

0

1,3-Butadiene

H2C=CH-CH=CH2

I.B-1

78-79-5

1

0

0

1,3-Butadiene, 2-methyl-

1

0

0

1,3-Butadiene, 2-methyl- radical {isoprene radical}

1

0

0

1,3-Butadiene, 1,2,4-trialkyl1,3-Butadiene, 2-(4’,8’,12’-trimethyltridecyl)-

460-12-8

1

0

0

1,3-Butadiyne

123-72-8

1

1

1

Butanal

0

1

0

Butanal, 4-amino-

H2N-(CH2)3-CH=O

III-12, XII-2

1

0

0

Butanal, 3,4-dihydroxy-

HOCH2-CHOH-CH2-CH=O

II.A-5, III-12

34764-22-2 2109-98-0

1

0

0

Butanal, 2,3-dimethyl-

97-96-1

1

1

1

Butanal, 2-ethyl-

107-89-1

1

0

0

Butanal, 3-hydroxy-

0

1

0

Butanal, 3-hydroxy-2-oxo-

1

0

0

Butanal, 4-hydroxy-

25714-71-0

I.B-1 XXVII-1

{isoprene}

H2C=C(CH3)-CH=CH2

I.B-1 XXVII-1

R-CH=C(R1)-CH=CH-R2 I.B-1 See: 1-Hexadecene, 3-methylene-7,11,15trimethyl-

{butyraldehyde}

HCŁC-CŁCH

I.B-1

H3C-(CH2)2-CH=O

III-12

III-12 {diethylacetaldehyde} {aldol} {methylreductone}

(C 2 H5)2=CH-CH=O H3C-CHOH-CH2-CH=O

III-12 II.A-5, III-12

H3C-CHOH-CO-CH=O II.A-5, III-12, III-13 HO-(CH2)3-CH=O

II.A-5, III-12

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1532

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1533

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke S

T

S T

1

0

0

Butanal, 4-(2-hydroxyethoxy)-

96-17-3

1

1

1

Butanal, 2-methyl-

590-86-3

1

1

1

Butanal, 3-methyl{3-methylbutyraldehyde; isovaleraldehyde}

(H3C)2=CH-CH2-CH=O

III-12

7729-27-3

0

1

0

Butanal, 4-(methylamino)-

H3C-NH-(CH2)3-CH=O

III-12

0

1

0

Butanal, 2-methyl-4-phenyl-

1

0

0

Butanal, 2-oxo-

CAS No.

4417-81-6

Name (per CA Collective Index)

Chapter Table

Selected structures

{2-methylbutyraldehyde}

HO-CH2CH2-O-(CH2)3-CH=O II.A-5, III-12, X-2 III-12 H3C-CH2-CH(CH3)-CH=O

C5H6-(CH2)2-CH(CH3)-CH=O {ethylglyoxal} {erythrose}

III-12

H3C-CH2-CO-CH=O

III-12, III-13

HOCH2-(CHOH)2-CH=O

II.A-5, III-12

1758-51-6

0

1

0

Butanal, 2,3,4-trihydroxy-, (R*,R*)-

541-35-5

1

0

0

Butanamide

H3C-(CH2)2-CO-NH2

XIII-1

66309-91-9

1

0

0

Butanamide, 2,3-dimethyl-

(H3C)2=CH-CH(CH3)-CO-NH2

XIII-1

1113-57-1

1

0

0

Butanamide, 2-methyl-

H3C-CH2-CH(CH3)-CO-NH2

XIII-1

61892-66-8

1

0

0

Butanamide, 3-cyano-3-methyl-

(H3C)2=C(CN)-CH2-CO-NH2

XIII-1

541-46-8

1

0

0

Butanamide, 3-methyl-

(H3C)2=CH-CH2-CO-NH2

53897-27-1

1

0

0

Butanamide, 4-cyano-

NC-(CH2)3-CO-NH2 H3C-(CH2)3-NH2

109-73-9

1

1

1

1-Butanamine

71277-84-4

1

0

0

1-Butanamine, methyl-

XIII-1 XI-2, XIII-1 XII-2 XII-2

96-15-1

1

0

0

1-Butanamine, 2-methyl-

H3C-CH2-CH(CH3)-CH2-NH2

XII-2

107-85-7

1

1

1

1-Butanamine, 3-methyl-

(H3C)2=CH-(CH2)2-NH2

XII-2

78579-58-5

1

1

1

1-Butanamine, 3-methyl-N-propyl-

(H3C)2=CH-(CH2)2-NH-(CH2)2-CH3

XII-2

111-92-2

0

1

0

1-Butanamine, N-butyl-

[H3C-(CH2)3]2=NH

XII-2

924-16-3

1

0

0

1-Butanamine, N-butyl-N-nitroso-

[H3C-(CH2)3]2=N-NO

XII-2, XV-8

110-68-9

1

1

1

1-Butanamine, N-methyl-

H3C-(CH2)3-NH-CH3

XII-2

7068-83-9

1

0

0

1-Butanamine, N-methyl-N-nitroso-

H3C-(CH2)3-N(NO)-CH3

{NDBA}

XII-2, XV-8

1

0

0

1-Butanamine, N-(1-methylethyl)-

H3C-(CH2)3-NH-CH=(CH3)2

56375-33-8

1

0

0

1-Butanamine, N-nitroso-

H3C-(CH2)3-NH-NO

20810-06-4

1

0

0

1-Butanamine, N-(2-methylpropyl)-

H3C-(CH2)3-NH-CH2-CH=(CH3)2

XII-2

4104-44-3

0

1

0

1-Butanamine, N,3-dimethyl-

(H3C)2=CH-(CH2)2-NH-CH3

XII-2

13952-84-6

XII-2 XII-2, XV-8

1

1

1

2-Butanamine

H3C-CH2-CH(NH2)-CH3

XII-2

1

0

0

2-Butanamine, N-methyl-

H3C-CH2-CH(NH-CH3)-CH3

XII-2

626-23-3

0

1

0

2-Butanamine, N-(1-methylpropyl)-

106-97-8

1

0

0

Butane

H3C-(CH2)2-CH3

1.A-10

75-83-2

1

0

0

Butane, 2,2-dimethyl-

(H3C)3ŁC-CH2-CH3

1.A-10

1

0

0

Butane, methyl-

C4H9-CH3

1.A-10

78-78-4

1

1

1

Butane, 2-methyl-

(H3C)2=CH-CH2-CH3

1.A-10

628-29-5

1

0

0

Butane, 1-(methylthio)-

627-05-4

1

0

0

Butane, 1-nitro-

XII-2

{butyl methyl sulfide}

H3C-S-(CH2)3-CH3 H3C-(CH2)2-CH2-NO2

XVIII.A-1 XVI-1

600-24-8

1

0

0

Butane, 2-nitro-

H3C-CH2-CH(NO2)-CH3

1613-46-3

1

0

0

Butane, 1-(propylthio)-

H3C-(CH2)2-S-(CH2)3-CH3

XVIII.A-1

H3C-(CH2)3-S-(CH2)3-CH3

XVIII.A-1

544-40-1

1

0

0

Butane, 1,1'-thiobis-

638-37-9

1

0

0

Butanedial

110-14-5

1

0

0

Butanediamide

{dibutyl sulfide} {succinaldehyde} {succinamide}

O=CH-(CH2)2-CH=O H2N-CO-(CH2)2-CO-NH2

XVI-1

III-12 XIII-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1533

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1534

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Chapter Table

16748-73-5

0

1

0

Butanediamide, 2-amino-, (S)- {asparagine amide}

H2N-CO-CH2-CH(NH2)-CO-NH2 XII-2, XIII-1

110-60-1

0

1

0

1,4-Butanediamine

H2N-(CH2)4-NH2

XII-2

124-20-9

0

1

0

1,4-Butanediamine, N-(3-aminopropyl){spermidine}

H2N-(CH2)4-NH-(CH2)3-NH2

XII-2

71-44-3

0

1

0

1,4-Butanediamine, N,N'-bis(3-aminopropyl){spermine}

H2N-(CH2)3-NH-(CH2)4-NH-(CH2)3-NH2 XII-2

Selected structures

{putrescine}

15657-58-6

0

1

0

1,4-Butanediamine, 2-methyl-

H2N-(CH2)2-CH(CH3)-CH2-NH2

XII-2

14475-60-6

0

1

0

1,4-Butanediamine, N-methyl-

H2N-(CH2)4-NH-CH3

XII-2

0

1

0

1,4-Butanediamine, 3-phenylpropenoyl{cinnamoylputrescine}

110-61-2

1

0

0

Butanedinitrile

16411-13-5

0

1

0

Butanedinitrile, 2,3-dimethyl-

{succinonitrile}

V-3, XII-2 NC-(CH2)2-CN

XI-2

NC-CH(CH3)-CH(CH3)-CN

XI-2

1

1

1

Butanedioate, hydroxy-

110-15-6

1

1

1

Butanedioic acid

121-75-5

1

1

1

Butanedioic acid, [(dimethoxyphosphinothioyl)thio]-, diethyl ester {Malathion®}

(H3CO)2=P=S Ň S Ň HC-COO-C2H5 Ň H2C-COO-C2H5

106-65-0

1

1

1

Butanedioic acid, dimethyl ester {dimethyl succinate}

H3C-OOC-(CH2)2-COO-CH3

HOOC-CHOH-CH2-COOH II.A-5, IV.A-3

6915-15-7

{malate} {succinic acid}

{malic acid}

II.A-5, XX-6 HOOC-(CH2)2-COOH

IV.A-3 V-3, XVIII.A-1, XXI-3

V-3

1

1

1

Butanedioic acid, hydroxy-

1

1

1

Butanedioic acid, hydroxy-, labeled with C 14 {malic acid- C}

XXV-29

1587-15-1

1

0

0

Butanedioic acid, hydroxy-, dimethyl ester {dimethyl malate; malic acid dimethyl ester}

H3C-OOC-CHOH-CH2-COO-CH3 II.A-5, V-3

585-09-1

0

1

0

Butanedioic acid, hydroxy-, dipotassium salt

KOOC-CHOH-CH2-COOK

71608-04-3

1

0

0

Butanedioic acid, (hydroxymethylene)-

498-21-5

1

0

0

Butanedioic acid, methyl-

14

II.A-5, XX-6 II.A-5, IV.A-3

HOOC-CH(CH3)-CH2-COOH

IV.A-3

HOOC-C(=CH2)-CH2-COOH

IV.A-3

636-60-2

1

0

0

Butanedioic acid, methyl-, (±)-

97-65-4

1

1

1

Butanedioic acid, methylene-

IV.A-3

2338-45-6

0

1

0

Butanedioic acid, (1-methylethyl)-

3878-55-5

1

0

0

Butanedioic acid, monomethyl ester

HOOC-(CH2)2-COO-CH3 HOOC-CO-CH 2-COOH

{itaconic acid}

IV.A-3

328-42-7

0

1

0

Butanedioic acid, oxo-

3237-44-3

0

1

0

Butanedioic acid, 2-hydroxy-2-(1-methylethyl)-

18734-79-7

0

1

0

Butanedioic acid, 2-methyl-3-phenyl-

35392-77-9

0

1

0

Butanedioic acid, 2,3-diethyl-, (R*,R*)-(±){succinic acid, 2,3-diethyl-}

HOOC-CH(C2H5)-CH(C2H5)-COOH

Butanedioic acid, 2,3-dihydroxy-

HOOC-CHOH-CHOH-COOH

526-83-0

1

1

1

{oxalacetic acid}

IV.A-3, V-3

{tartaric acid}

IV.A-3 II.A-5, IV.A-3 IV.A-3 IV.A-3 II.A-5, IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1534

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1535

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

147-71-7

0

1

0

Butanedioic acid, 2,3-dihydroxy{d-tartaric acid}

II.A-5, IV.A-3

87-69-4

0

1

0

Butanedioic acid, 2,3-dihydroxy{l-tartaric acid}

II.A-5, IV.A-3

133-37-9

0

1

0

Butanedioic acid, 2,3-dihydroxy-

II.A-5, IV.A-3

147-73-9

0

1

0

Butanedioic acid, 2,3-dihydroxy{meso-tartaric acid}

II.A-5, IV.A-3

921-53-9

0

1

0

Butanedioic acid, 2,3-dihydroxy- [R-(R*,R*)]-, dipotassium salt

II.A-5, XX-6

13545-04-5

0

1

0

Butanedioic acid, 2,3-dimethyl{succinic acid, 2,3-dimethyl-}

52642-07-6

1

0

0

Butanediol, monoacetate

107-88-0

1

1

1

1,3-Butanediol

{1,3-butylene glycol}

110-63-4

0

1

0

1,4-Butanediol

{tetramethylene glycol}

Name (per CA Collective Index)

Chapter Table

Selected structures

{dl-tartaric acid}

HOOC-CH(CH3)-CH(CH3)-COOH IV.A-3 II.A-5, V-3 H3C-CHOH-CH2-CH2OH

II.A-5

HOCH2-(CH2) 2-CH2OH

II.A-5

513-85-9

1

1

1

2,3-Butanediol

5341-95-7

1

0

0

2,3-Butanediol, (R*,S*)-

431-03-8 29350-67-2

1

1

1

2,3-Butanedione

109-74-0

1

0

0

Butanenitrile

H3C-(CH2) 2-CN

13989-82-7

1

0

0

Butanenitrile, 4-(dimethylamino)-

(H3C)2=N-(CH2)3-CN

{diacetyl; biacetyl}

H3C-CHOH-CHOH-CH3

II.A-5

H3C-CO-CO-CH3

II.A-5 III-13 XI-2 XI-2, XII-2

4476-02-2

1

0

0

Butanenitrile, 2-hydroxy-

H3C-CH2-CHOH-CN

II.A-5, XI-2

15344-34-0

1

0

0

Butanenitrile, 2-hydroxy-3-methyl-

(H3C)2=CH-CHOH-CN

II.A-5, XI-2

18937-17-9

1

0

0

Butanenitrile, 2-methyl-

H3C-CH2-CH(CH3)-CN

XI-2

625-28-5

1

1

1

Butanenitrile, 3-methyl-

(H3C)2=CH-CH2-CN

XI-2

HOCH2-(CHOH) 2-CH2OH

149-32-6

1

1

1

1,2,3,4-Butanetetrol, (R*,S*)- {erythritol}

68510-02-1

0

1

0

1,2,3,4-Butanetetrol, 1-[5-(2,3,4trihydroxybutyl)pyrazinyl]{2,5-deoxyfructosazine}

N R

0

1

0

1,2,3,4-Butanetetrol, 1-[6-(2,3,4trihydroxybutyl)pyrazinyl]{2,6-deoxyfructosazine}

R = HOCH2-(CHOH)2-

OH R

N

N

109-79-5

1

0

0

1-Butanethiol

{butyl mercaptan}

II.A-5, XVII.B-2

N OH

68510-03-2

R

II.A-5

R

II.A-5, XVII.B-2

R = HOCH2-(CHOH)2-

H3C-(CH2)3-SH

XVIII.A-1

541-31-1

1

0

0

1-Butanethiol, 3-methyl-

(H3C)2=CH-(CH2)2-SH

XVIII.A-1

513-53-1

1

0

0

2-Butanethiol

H3C-CH2-CH(SH)-CH3

XVIII.A-1

4435-50-1

1

0

0

1,2,3-Butanetriol

3068-00-6

0

1

0

1,2,4-Butanetriol

1

1

1

Butanimine

1

1

1

Butanoic acid

107-92-6

{1-methylglycerol}

{butyric acid}

H 3C-CHOH-CHOH-CH2OH

II.A-5

H2COH-CHOH-CH2-CH2OH

II.A-5

H3C-(CH2)2-CH=NH

XII-2

H3C-(CH2)2-COOH

IV.A-3

109-21-7

0

1

0

Butanoic acid, butyl ester

10094-34-5

0

1

0

Butanoic acid, 1,1-dimethyl-2-phenylethyl ester

H3C-(CH2) 2-COO-(CH2)3-CH3

V-3

V-3

106-29-6

0

1

0

Butanoic acid, 3,7-dimethyl-2,6-octadien-1-yl ester {geranyl butyrate}

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1535

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1536

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index) {ethyl butyrate}

Chapter Table

Selected structures

105-54-4

1

1

1

Butanoic acid, ethyl ester

26912-31-2

0

1

0

Butanoic acid, hexenyl ester

H3C-(CH2)2-COO-(CH2)4-n-CH=CH-(CH2)n-H V-3

H3C-(CH2)2-COO-C2H5

V-3

H3C-(CH2)2-COO-CH3

623-42-7

0

1

0

Butanoic acid, methyl ester

5398-90-2

0

1

0

Butanoic acid, 2-methylpropyl ester

V-3

540-18-1

0

1

0

Butanoic acid, pentyl ester

H3C-(CH2)2-COO-(CH2)4-CH3

V-3

103-37-7

1

1

1

Butanoic acid, phenylmethyl ester {benzyl butyrate}

H3C-(CH2) 2-COO-CH2-C6H5

V-3

80-60-4

1

1

1

Butanoic acid, 2-amino-

H3C-CH2-CH(NH2)-COOH

7004-04-8

1

1

1

Butanoic acid, 2-amino-3-hydroxy-

H3C-CHOH-CH(NH2)-COOH II.A-5, IV.A-3, XII-2

454-41-1

0

1

0

Butanoic acid, 2-amino-4-(methylsulfinyl)-

1118-85-0 3226-65-1

0

1

0

Butanoic acid, 2-amino-4-(methylsulfonyl){methionine sulfone; methionine S-oxide}

2338-03-6

0

1

0

Butanoic acid, 2-amino-4-oxo-, (S)-

14287-61-7

0

1

0

Butanoic acid, 2,3-dimethyl(H3C)2=CH-CH(CH3)-COOH

141-16-2

0

1

0

Butanoic acid, 3,7-dimethyl-6-octenyl ester {citronellyl butyrate}

V-3

IV.A-3, XII-2

IV.A-3, XII-2, XVIII.A-1 H3C-SO-(CH2)2-CH(NH2)-COOH IV.A-3, XII-2, XVIII.A-1 IV.A-3, XII-2 IV.A-3

{diethylacetic acid}

V-3

88-09-5

1

1

1

Butanoic acid, 2-ethyl-

(H 3C-CH2)2=CH-COOH

IV.A-3

565-70-8

1

1

1

Butanoic acid, 2-hydroxy-

H3C-CH2-CHOH-COOH

II.A-5, IV.A-3

3739-30-8

0

1

0

Butanoic acid, 2-hydroxy-2-methyl-

H3C-CH2-C(CH3)(OH)-COOH II.A-5, IV.A-3

4026-18-0

1

1

1

Butanoic acid, 2-hydroxy-3-methyl-

H3C-CH(CH3)-CHOH-COOH II.A-5, IV.A-3

116-53-0

1

1

1

Butanoic acid, 2-methyl-

H 3C-CH2-CH(CH3)-COOH

7452-79-1

0

1

0

Butanoic acid, 2-methyl-, ethyl ester

{2-methylbutyric acid}

IV.A-3

H3C-CH2-CH(CH3)-COO-CH2-CH3

V-3

10032-15-2

0

1

0

Butanoic acid, 2-methyl-, hexyl ester

H3C-CH2-CH(CH3)-COO-(CH2)5-CH3 V-3

868-57-5

0

1

0

Butanoic acid, 2-methyl-, methyl ester

H3C-CH2-CH(CH3)-COO-CH3

0

1

0

Butanoic acid, 2-methyl-, 2-methylbutyl ester

V-3

0

1

0

Butanoic acid, 2-methyl-, 3-methylbutyl ester

V-3

0

1

0

Butanoic acid, 2-methyl-, 2-methylpropyl ester

V-3

0

1

0

Butanoic acid, 2-methyl-, 2-phenylethyl ester

V-3

600-18-0

1

1

1

Butanoic acid, 2-oxo-

78986-08-0

0

1

0

Butanoic acid, 2,4,4-trimethyl-3-(3-oxo-1-butenyl)-2cyclohexen-1-yl ester

0

1

0

Butanoic acid, 3-amino-

H3C-CH(NH2)-CH2-COOH

1070-83-3

0

1

0

Butanoic acid, 3,3-dimethyl-

(H3C)3ŁC-CH2-COOH

300-85-6

1

0

0

Butanoic acid, 3-hydroxy-

H3C-CHOH-CH2-COOH

625-08-1

0

1

0

Butanoic acid, 3-hydroxy-3-methyl-

H3C-C(CH3)(OH)-CH2-COOH II.A-5, IV.A-3 (H3C)2=CH-CH2-COOH

H3C-CH2-CO-COOH

503-74-2

1

1

1

Butanoic acid, 3-methyl-

109-19-3

0

1

0

Butanoic acid, 3-methyl-, butyl ester;

{isovaleric acid}

V-3

III-13, IV.A-3 III-13, V-3 IV.A-3, XII-2 IV.A-3 II.A-5, IV.A-3

IV.A-3 V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1536

11/24/08 1:55:50 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1537

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

1009-20-6

0

1

0

Butanoic acid, 3-methyl-, 3,7-dimethyl-2,6octadieny-1-yl ester

V-3

76-50-6

0

1

0

Butanoic acid, 3-methyl-, 1,7,7trimethylbicyclo[2.2.1]hept-2-yl ester, endo{bornyl isovalerate}

V-3

Name (per CA Collective Index)

Selected structures

Chapter Table

0

1

0

Butanoic acid, 3-methyl-, 2-methylbutyl ester

V-3

78-35-3

0

1

0

Butanoic acid, 3-methyl-, 3,7-dimethyl-1,6-octadien6-yl ester {linalyl isobutyrate}

V-3

16409-46-4

0

1

0

Butanoic acid, 3-methyl-, 5-methyl-2-(1methylethyl)-cyclohexanyl ester {menthyl isovalerate}

V-3

55066-56-3

1

1

1

Butanoic acid, 3-methyl-, 4-methylphenyl ester

V-3

0

1

0

Butanoic acid, 3-methyl-, 2-methylpropyl ester

V-3

140-26-1

1

1

1

Butanoic acid, 3-methyl-, 2-phenylethyl ester {phenethyl isovalerate}

V-3

108-64-5

1

1

1

Butanoic acid, 3-methyl-, ethyl ester {ethyl isovalerate}

(H3C)2=CH-CH2-COO-C2H5

V-3

556-24-1

0

1

0

Butanoic acid, 3-methyl-, methyl ester {methyl isovalerate}

(H3C)2=CH-CH2-COO-CH3

V-3

659-70-1

1

1

1

Butanoic acid, 3-methyl-, 3-methylbutyl ester {isoamyl isovalerate}

V-3

103-38-8

0

1

0

Butanoic acid, 3-methyl-, phenylmethyl ester {benzyl isovalerate}

V-3

140-27-2

1

1

1

Butanoic acid, 3-methyl-, 3-phenyl-2-propenyl ester

V-3

106-27-4

0

1

0

Butanoic acid, 3-methylbutyl ester

V-3

541-50-4

0

1

0

Butanoic acid, 3-oxo-

H3C-CO-CH2-COOH

III-13, IV.A-3

56-12-2

1

1

1

Butanoic acid, 4-amino-

H2N-(CH2)3-COOH

IV.A-3, XII-2

61445-55-4 133201-39-5

1

1

1

Butanoic acid, 4-(methylnitrosoamino)- = Butanoic acid, 4-[(nitrosomethyl)amino]- {NMBA}

H3C-N(NO)-(CH2)3-COOH

IV.A-3, XV-8

1

0

0

Butanoic acid, 4-(methylnitrosoamino)-, methyl ester

H3C-N(NO)-(CH2)3-COOCH3

583-92-6

0

1

0

Butanoic acid, 4-(methylthio)-2-oxo-

H3C-S-(CH2)2-CO-COOH III-13, IV.A-3, XVIII.A-1

54344-76-2

0

1

0

Butanoic acid, 4-(2,6,6-trimethylcyclohexen-1-yl)-

IV.A-3

462-10-2

0

1

0

Butanoic acid, 4,4'-dithiobis[2-amino{homocystine}

[S-(CH2)2-CH(NH2)-COOH]2 IV.A-3, XII-2, XVIII-1

71-36-3

1

1

1

1-Butanol

H3C-(CH2)2-CH2OH

20281-85-0 91599-03-0

{acetoacetic acid}

{n-butyl alcohol}

V-3, XV-8

II.A-5

0

1

0

1-Butanol, 2,3-dimethyl-

0

1

0

1-Butanol, 2-ethoxy-

II.A-5, X-2

II.A-5

0

1

0

1-Butanol, 4-[(7-E-D-glucopyranosyl-7H-purin-6yl)amino]-2-methyl-

II.A-5, X-2

137-32-6

1

1

1

1-Butanol, 2-methyl-

II.A-5

23599-75-9

1

1

1

1-Butanol, 2-methyl-4-(1H-purin-6-ylamino)-

II.A-5

123-51-3

1

1

1

1-Butanol, 3-methyl-

{isoamyl alcohol}

II.A-5

94-46-2

1

1

1

1-Butanol, 3-methyl-, benzoate {isoamyl benzoate}

V-3

0

1

0

1-Butanol, 4-(methylnitrosoamino)-1-(3-pyridinyl){NNAL}

II.A-5, XII-2, XV-8, XVII.B-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1537

11/24/08 1:55:51 PM

1538

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

78-92-2

1

1

1

2-Butanol

6291-17-4

1

0

0

2-Butanol, 3-amino-2-methyl-

155728-85-1

0

1

0

2-Butanol, 1-(4-bromophenoxy)-3[(phenylmethyl)amino]-, (R*,R*)-

75-85-4

1

0

0

2-Butanol, 2-methyl-

II.A-5

0

1

0

2-Butanol, 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-

II.A-5

35734-62-4

1

0

0

1-Butanone, 1-(4-hydroxy-2,6,6-trimethyl-1cyclohexen-1-yl)-

II.A-5, III-13

51769-21-2

0

1

0

1-Butanone, 1-(4-hydroxy-2,6,6-trimethyl-1cyclohexen-1-yl)-, (±)-

II.A-5, III-13

495-40-9

1

0

0

1-Butanone, 1-phenyl-

61892-81-7

1

0

0

1-Butanone, 1-pyrazinyl-

1701-70-8

1

1

1

1-Butanone, 1-(3-pyridinyl)-

28384-26-1

0

1

0

1-Butanone, 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-

1

0

0

1-Butanone, 1-(methyl-2-pyridinyl)-

III-13, XVII.B-2

1

0

0

1-Butanone, 1-(2-pyridinyl)-

III-13, XVII.B-2

1

0

0

1-Butanone, 1-(3-methyl-2-pyridinyl)-

III-13, XVII.B-2

1

0

0

1-Butanone, 1-(4-methyl-2-pyridinyl)-

III-13, XVII.B-2

78210-70-5

1

0

0

1-Butanone, 2-methyl-1-(3-pyridinyl)-

III-13, XVII.B-2

68697-66-5

0

1

0

1-Butanone, 3-(methylthio)-1-(2,6,6-trimethyl-1,3cyclohexadien-1-yl)-

III-13, XVIII.A-1

0

1

0

1-Butanone, 3-(methylthio)-1-(2,6,6trimethylcyclohexenyl)-

III-13, XVIII.A-1

1

1

1

1-Butanone, 4-amino-1-(3-pyridinyl)-

71278-11-0 59578-62-0

{sec-butyl alcohol}

Chapter Table

Selected structures H3C-CH2-CHOH-CH3

II.A-5 II.A-5, XII-2

II.A-5, XII-2, XVIII.B-3

H3C-(CH2)2-CO-C6H5

III-13 III-13, XVII.B-2 III-13, XVII.B-2

{propyl pyridyl ketone}

III-13

{poikiline}

III-13, XVII.B-2

0

1

0

1-Butanone, 4-hydroxy-1-(3-pyridinyl)-

II.A-5, III-13, XVII.B-2

0

1

0

1-Butanone, 4-(methylamino)-1-(2.6-dihydroxy-3pyridinyl)-

II.A-5, III-13, XVII.B-2

0

1

0

1-Butanone, 4-(methylamino)-1-(6-hydroxypyridinyl)-

II.A-5, III-13, XVII.B-2

2055-23-4

0

1

0

1-Butanone, 4-(methylamino)-1-(3-pyridinyl)-

III-13, XII-2, XVII.B-2

64091-91-4, 121268-99-3, 126165-82-0

1

1

1

1-Butanone, 4-(methylnitrosoamino)-1-(3-pyridinyl){NNK} {1-Butanone, 4-[(nitrosomethyl)amino]-1-(3pyridinyl)-}

III-13, XII-2, XV-8, XVII.B-2

76014-82-9

0

1

0

1-Butanone, 4-(methylnitrosoamino)-1-(3-pyridinyl)-, N-oxide

III-13, XII-2, XV-8, XVII.B-2

78-93-3

1

1

1

2-Butanone

1575-57-1

1

1

1

2-Butanone, 1-(acetyloxy)-

{methyl ethyl ketone}

H3C-CO-CH2-CH3 H3C-CH2-CO-CH2-OOC-CH3

III-13 III-13, V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1538

11/24/08 1:55:51 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1539

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

43121-43-3

0

1

0

2-Butanone, 1-(4-chlorophenoxy)-3,3-dimethyl-1(1,2,4-triazol-1-yl) {Triadimefon®}

5077-67-8

1

1

1

2-Butanone, 1-hydroxy-

H3C-CH2-CO-CH2OH

1007-32-5

1

0

0

2-Butanone, 1-phenyl-

C6H5-CH2-CO-CH2-CH3

III-13

H3C-CO-CHOH-CH2OH

II.A-5, III-13

H3C-CO-CHOH-CH3

II.A-5, III-13

H3C-CO-CH=(CH3)2

III-13

Name (per CA Collective Index)

75-97-8

1

0

0

2-Butanone, 3,3-dimethyl-

57011-15-1

1

0

0

2-Butanone, 3,4-dihydroxy-

513-86-0

1

1

1

2-Butanone, 3-hydroxy-

563-80-4

1

1

1

2-Butanone, 3-methyl-

Chapter Table

Selected structures

X-2, XVII.A-4, XXI-3

II.A-5, III-13 III-13

{acetoin}

53872-97-2

1

0

0

2-Butanone, 3-methyl-1-(3-pyridinyl)-

10150-87-5

1

0

0

2-Butanone, 4-(acetyloxy)-

10266-75-8

0

1

0

2-Butanone, 4-(decahydro-5,5,8a-trimethyl-2methylene-1-naphthalenyl)-, [1S-(1D,4aE,8aD)]-

III-13, XVII.B-2 H3C-CO-CH2-CH2-OOC-CH3 H3C

H3C

H3C

III-13, V-3 III-13

O

CH2

CH3

590-90-9

1

1

1

2-Butanone, 4-hydroxy-

H3C-CO-CH2-CH2OH

II.A-5, III-13

1823-90-1

1

0

0

2-Butanone, 4-hydroxy-3,3-dimethyl-

H3C-CO-C(CH3)2-CH2OH

II.A-5, III-13

104-20-1

0

1

0

2-Butanone, 4-(4-methoxyphenyl)-

34047-39-7

1

1

1

2-Butanone, 4-(methylthio)-

2550-26-7

1

0

0

2-Butanone, 4-phenyl-

50767-77-6

0

1

0

2-Butanone, 4-(2-ethenyl-2,6,6-trimethylcyclohexyl)-

60761-23-1

0

1

0

2-Butanone, 4-(2,2,6-trimethylcyclohexyl)-, cis{tetrahydroionone}

III-13, X-2 III-13, XVIII.A-1 H3C-CO-(CH2)2-C6H5

III-13 III-13

H3C

III-13

O

CH3

CH3 CH3

58720-40-4

0

1

0

2-Butanone, 4-(2,3,6-trimethylphenyl)-

III-13

20483-36-7

0

1

0

2-Butanone, 4-(2,6,6-trimethyl-1,3-cyclohexadien-1yl)-

III-13

14506-65-1

0

1

0

2-Butanone, 4-(3,4,4a,5,6,7,8,8a-octahydro2,5,5,8a-tetramethyl-1-naphthalenyl)-, (4aS-trans)-

CH3 H3C

III-13

O CH3 H3C

CH3

158815-72-6

0

1

0

2-Butanone, 4-[3,6-dihydro-6-hydroxy-6-methyl-3(1-methylethyl)-1,2-dioxin-3-yl]-, (E)-

II.A-3, III-13, X-2

158815-73-7

0

1

0

2-Butanone, 4-[3,6-dihydro-6-hydroxy-6-methyl-3(1-methylethyl)-1,2-dioxin-3-yl]-, (Z)-

II.A-3, III-13, X-2

160115-51-5

0

1

0

2-Butanone, 4-[3,6-dihydro-6-hydroxy-6-methyl-3(1-methylethyl)-1,2-dioxin-3-yl]-, (E)- (+)-

II.A-3, III-13, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1539

11/24/08 1:55:52 PM

1540

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

160115-52-6

0

1

0

2-Butanone, 4-[3,6-dihydro-6-hydroxy-6-methyl-3(1-methylethyl)-1,2-dioxin-3-yl]-, (Z)- (-)-

0

1

0

2-Butanone, 4-[5,6-dihydro-3-methyl-6-(1methylethyl)-pyran-2-yl]

5471-51-2

1

1

1

2-Butanone, 4-(4-hydroxyphenyl){4-(p-hydroxyphenyl)-2-butanone}

III-13, X-2

13679-56-6

1

1

1

2-Butanone, 4-(5-methyl-2-furanyl)-

III-13, X-2

0

1

0

2-Butanone, 4-(2-methyl-5-(1-methylethyl)-2furanyl)-

III-13, X-2

0

1

0

2-Butanone, 4-(2-methyl-6-(1-methylethyl)-2tetrahydropyranyl)-

III-13, X-2

0

1

0

2-Butanone, 4-(4,5-dihydro-3-methylene-6dimethylmethylene-2-pyranyl)-

Name (per CA Collective Index)

Selected structures

Chapter Table II.A-3, III-13, X-2 III-13, IX.A-22

III-13, X-2

CH2 H3C

C

O

CH2CH2-CO

CH3

4170-30-3

1

1

1

2-Butenal

1115-11-3

1

1

1

2-Butenal, 2-methyl-

{crotonaldehyde}

107-86-8

1

0

0

2-Butenal, 3-methyl-

83841-47-8

0

1

0

2-Butenal, 4-(decahydro-2-hydroxy-2,5,5,8atetramethyl-1-naphthalenyl)-2-methyl-, [1R[1D(E),2E,4aE,8aD]]-

{senecialdehyde}

H 3C-CH=CH-CH=O

III-12

H3C-CH=C(CH3)-CH=O

III-12

H3C-C(CH3)=CH-CH=O H3C

II.A-5, III-12

CH=O

H3C

CH3 OH

H3C

7319-38-2

1

0

0

3-Butenal

625-37-6 23350-58-5

1

0

0

2-Butenamide, (E)-

{crotonamide}

CH3

H2C=CH-CH2-CH=O

III-12

H3C-CH=CH-CO-NH2

XIII-1

1

0

0

2-Butenamide, (Z)-

XIII-1

72693-06-2

1

0

0

2-Butenamide, N,2-dimethyl-

XIII-1

32793-37-6

1

0

0

2-Butenamide, 2-methyl-

28446-58-4

1

0

0

3-Butenamide

18938-03-9

1

0

0

3-Butenamide, 3-methyl-

XIII-1

692-31-9

1

0

0

2-Buten-1-amine, N,N-dimethyl-

XII-2

2524-49-4

1

0

0

3-Buten-1-amine

20173-36-8

1

0

0

3-Buten-1-amine, N,N-dimethyl-4-(3-pyridinyl)-

538-79-4

1

1

1

3-Buten-1-amine, N-methyl-4-(3-pyridinyl){metanicotine}

XIII-1 H2C=CH-CH2-CO-NH2

H2C=CH-CH2-CH2-NH2

XIII-1

XII-2 XII-2, XVII.B-2

NH-CH 3

XII-2, XVII.B-2

N

1

0

0

Butene

I.B-1

1

0

0

Butene, methyl-

106-98-9

1

0

0

1-Butene

H2C=CH-CH2-CH3

I.B-1

563-78-0

1

1

1

1-Butene, 2,3-dimethyl-

H2C=C(CH3)-CH=(CH3)2

I.B-1

558-37-2

1

0

0

1-Butene, 3,3-dimethyl-

H2C=CH-CŁ(CH3)3

I.B-1

563-46-2

1

0

0

1-Butene, 2-methyl-

H2C=C(CH3)-CH2-CH3

I.B-1

563-45-1

1

0

0

1-Butene, 3-methyl-

H2C=CH-CH=(CH3)2

I.B-1

I.B-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1540

11/24/08 1:55:52 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1541

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

107-01-7

1

0

0

2-Butene

624-64-6

1

0

0

2-Butene, (E)

Name (per CA Collective Index)

Selected structures H3C-CH=CH-CH3 H3C C

H

590-18-1

1

0

0

2-Butene, (Z)-

I.B-1 I.B-1

H C

Chapter Table

CH3

H3C

CH3 C

I.B-1

C

H

H

563-79-1

1

0

0

2-Butene, 2,3-dimethyl-

(H3C)2=C=C=(CH3)2

I.B-1

513-35-9

1

0

0

2-Butene, 2-methyl-

(H3C)2=C=CH-CH3

I.B-1

6915-18-0

0

1

0

2-Butenedioic acid

110-17-8

1

1

1

2-Butenedioic acid (E)-

HOOC-CH=CH-COOH {fumaric acid}

C

C

H

110-16-7

1

1

1

2-Butenedioic acid (Z)-

{maleic acid}

IV.A-3 IV.A-3

H

HOOC

COOH

HOOC

COOH C

IV.A-3

C

H

H

623-91-6

0

1

0

2-Butenedioic acid (E)-, diethyl ester {diethyl fumarate}

V-3

141-05-9

1

0

0

2-Butenedioic acid (Z)-, diethyl ester {diethyl maleate}

V-3

21788-49-8

0

1

0

2-Butenedioic acid, 2,3-dimethyl-, (E)-

HOOC

CH3 C

H3C

488-21-1

0

1

0

2-Butenedioic acid, 2,3-dimethyl-, (Z)-

COOH

HOOC

COOH C

624-48-6

1

0

0

2-Butenedioic acid (Z)-, dimethyl ester

28098-80-8

0

1

0

2-Butenedioic acid, 2-ethyl-3-methyl-, (E)-

H3C

CH3

HOOC

C2H5

V-3 C

0

1

0

2-Butenedioic acid, 2-ethyl-3-methyl-, (Z)-

C

COOH

HOOC

0

0

2-Butenedioic acid, 2-methyl-, (E){mesaconic acid}

C2H5

H

HOOC C

1

1

1

2-Butenedioic acid, 2-methyl-, (Z){citraconic acid}

497-06-3 4786-20-3 109-75-1

1

0

0

3-Butene-1,2-diol

1

0

0

2-Butenenitrile

1

0

0

2-Butenenitrile, 3-methyl-

1

0

0

3-Butenenitrile

COOH COOH

HOOC C H3C

IV.A-3

C H

HOCH2-CHOH-CH=CH2 {crotononitrile}

IV.A-3

C

H3C

498-23-7

IV.A-3

C

H3C

1

IV.A-3

COOH

C

498-24-8

IV.A-3

C

H3C

41654-09-5

IV.A-3

C

H3C-CH=CH-CN

II.A-5 XI-2 XI-2

{allyl cyanide}

H2C=CH-CH2-CN

XI-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1541

11/24/08 1:55:53 PM

1542

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

1

0

0

3-Butenenitrile, 3-methyl-

3724-65-0

1

1

1

2-Butenoic acid

107-93-7

1

1

1

2-Butenoic acid, (E)-

XI-2 {crotonic acid} {trans-crotonic acid}

H 3C-CH=CH-COOH H

0

0

2-Butenoic acid, (Z)-

{cis-crotonic acid}

IV.A-3

C

H3C

1

IV.A-3

COOH C

503-64-0

Chapter Table

Selected structures

H

H3C

IV.A-3

COOH C

C

H

H

10544-63-5

0

1

0

2-Butenoic acid (E)-, ethyl ester

V-3

18707-60-3

0

1

0

2-Butenoic acid, methyl ester

13201-46-2

1

1

1

2-Butenoic acid, 2-methyl-, (Z)-

{angelic acid}

IV.A-3

{tiglic acid}

IV.A-3

{ethyl crotonate} H3C-CH=CH-COO-CH3

V-3

80-59-1

1

1

1

2-Butenoic acid, 2-methyl-, (E)-

37526-88-8

0

1

0

2-Butenoic acid, 2-methyl-, phenylmethyl ester {benzyl tiglate}

V-3

39300-45-3

0

1

0

2-Butenoic acid, 2-(1-methylheptyl)-4,6dinitrophenyl ester {Dinocap®}

V-3, XVI-1, XXI-3

7786-34-7

0

1

0

2-Butenoic acid, 3[(dimethoxyphosphinyl)oxy]-, methyl ester {Mevinphos®; Phosdrin®}

H3CO

O

H3CO

O

V-3, XXI-3

COOCH3

P CH3

541-47-9

1

1

1

2-Butenoic acid, 3-methyl-

IV.A-3

32040-41-8

0

1

0

2-Butenoic acid, 4-(formylamino)-4-oxo-, (Z)-

O=CH-NH-CO-CH=CH-COOH

625-38-7

1

0

0

3-Butenoic acid

H2C=CH-CH2-COOH

1617-31-8

1

1

1

3-Butenoic acid, 3-methyl-

2243-53-0

1

1

1

3-Butenoic acid, 4-phenyl-

43000-45-9

1

1

1

1-Buten-1-ol, 3-methyl-

II.A-5

4675-87-0

0

1

0

2-Buten-1-ol, 2-methyl-

II.A-5

556-82-1

0

1

0

2-Buten-1-ol, 3-methyl-

1637-39-4

0

1

0

2-Buten-1-ol, 2-methyl-4-(1H-purin-6-ylamino)-, (E)-

II.A-5, XII-2

0

1

0

2-Buten-1-ol, 2-methyl-4-(1H-purin-6ylaminoribosyl)-

II.A-5, XII-2

29736-33-2

0

1

0

2-Buten-1-ol, 2-methyl-4-[[2-(methylthio)-1H-purin6-yl]amino]-, (E)-

72074-11-4

0

1

0

2-Buten-1-ol, 3-(dodecahydro-3a,6,6,9atetramethylnaphtho[2,1-b]furan-2-yl)-, [2S[2D(E),3aD,5aE,9aD,9bE]]-

II.A-5, XII-2

87584-34-7

0

1

0

2-Buten-1-ol, 3-(dodecahydro-3a,6,6,9atetramethylnaphtho[2,1-b]furan-2-yl)-, [2R[2D(E),3aE,5aD,9aE,9bD]]-

II.A-5, XII-2

627-27-0

1

0

0

3-Buten-1-ol

H2C=CH-CH2-CH2OH

II.A-5

IV.A-3, XIII-1

115-18-4 13215-89-9

IV.A-3 IV.A-3

{styrylacetic acid}

IV.A-3

II.A-5

II.A-5, XII-2, XVIII.A-1

1

0

0

3-Buten-2-ol, 2-methyl-

H2C=CH-CHOH=(CH3)2

II.A-5

0

1

0

3-Buten-2-ol, 4-phenyl-

C6H5-CH=CH-CHOH-CH3

II.A-5

0

1

0

3-Buten-2-ol, 4-(2,6,6-trimethyl-1,3-cyclohexadien1-yl)-

OH

II.A-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1542

11/24/08 1:55:53 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1543

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke S

T

S T

1

1

1

3-Buten-2-ol, 4-(3-hydroxy-2,6,6-trimethyl-1cyclohexen-1-yl){3-hydroxy-ȕ-ionol}

II.A-5

0

1

0

3-Buten-2-ol, 4-(4-hydroxy-2,6,6-trimethyl-1cyclohexen-1-yl){4-hydroxy-ȕ-ionol}

II.A-5

27008-60-2 22029-76-1

0

1

0

3-Buten-2-ol, 4-(2,6,6-trimethyl-1-cyclohexen-1-yl){ȕ-ionol}

OH

II.A-5

472-78-6

0

1

0

3-Buten-2-ol, 4-(2,6,6-trimethyl-2-cyclohexen-1-yl){Į-ionol}

OH

II.A-5

79925-80-7

0

1

0

3-Buten-2-ol, 4-(6,6-dimethyl-2-methylene-3cyclohexen-1-yl)-

II.A-5

54345-38-9

0

1

0

2-Buten-1-one, 1-(2,3,6-trimethylphenyl)-, (E)-

III-13

23726-93-4 23696-85-7

1

1

1

2-Buten-1-one, 1-(2,6,6-trimethyl-1,3cyclohexadien-1-yl)-, (E){ȕ-damascenone}

0

1

0

2-Buten-1-one, 1-(2,6,6-trimethyl-1,3cyclohexadien-1-yl){ȕ-damascenone isomer}

III-13

80111-68-8 23770-92-3 35044-68-9

1

1

1

2-Buten-1-one, 1-(2,6,6-trimethylcyclohexenyl){damascone}

III-13

23726-91-2

1

1

1

2-Buten-1-one, 1-(2,6,6-trimethyl-1-cyclohexen-1yl)-, (E)-

III-13

23726-92-3 85949-43-5

1

1

1

2-Buten-1-one, 1-(2,6,6-trimethyl-1-cyclohexen-1yl)-, (Z){ȕ-damascone}

102488-09-5

1

1

1

2-Buten-1-one, 1-(3-hydroxy-2,6,6-trimethyl-1cyclohexen-1-yl){3-hydroxy-ȕ-damascone}

80508-24-3

1

0

0

2-Buten-1-one, 1-(3-pyridinyl)-

0

1

0

2-Buten-1-one, 1-(4-hydroxy-2,6,6trimethycyclohexanyl){4-hydroxydihydro-ȕ-damascone}

1

1

1

2-Buten-1-one, 1-(4-hydroxy-2,6,6-trimethyl-1cyclohexen-1-yl){4-hydroxy-ȕ-damascone}

CAS No.

56915-02-7

Name (per CA Collective Index)

Selected structures

Chapter Table

III-13

O

III-13

O

III-13 III-13, XVII.B-2 O

III-13

O

III-13

HO

HO

35734-61-3

1

1

1

2-Buten-1-one, 1-(4-hydroxy-2,6,6-trimethyl-1cyclohexen-1-yl)-, (E)-

II.A-5, III-13

160550-79-8

0

1

0

2-Buten-1-one, 1-(4-hydroxy-2,6,6-trimethyl-1cyclohexen-1-yl)-, [R-(E)]-

II.A-5, III-13

87562-12-7

0

1

0

2-Buten-1-one, 1-[3-(formyloxy)-2,6,6-trimethyl-1cyclohexen-1-yl]-, (E)-

III-13, V-3

62512-25-8

0

1

0

2-Buten-1-one, 1-[4-(E-D-glucopyranosyloxy)-2,6,6trimethyl-1-cyclohexen-1-yl]-

II.A-5, III-13, X-2

160550-77-6

0

1

0

2-Buten-1-one, 1-[4-(E-D-glucopyranosyloxy)-2,6,6trimethyl-1-cyclohexen-1-yl]-, [R-(E)]-

II.A-5, III-13, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1543

11/24/08 1:55:53 PM

1544

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

495-45-4

0

1

0

2-Buten-1-one, 1,3-diphenyl-

78-94-4

1

1

1

3-Buten-2-one

814-78-8

1

0

0

3-Buten-2-one, 3-methyl-

125-51-5

0

1

0

3-Buten-2-one, 3-methyl-4-(2,6,6-trimethyl-2cyclohexen-1-yl){D-isomethylionone}

73892-47-4

0

1

0

3-Buten-2-one, 4-[3-(acetyloxy)-2,6,6-trimethyl-1cyclohexen-1-yl]-,[R-(E)]-

50281-40-8

0

1

0

3-Buten-2-one, 4-[4-(acetyloxy)-2,2,6-trimethyl-7oxabicyclo[4.1.0]hept-1-yl]-, [1R-[1D(E),4E,6D]]-

{methyl vinyl ketone}

Selected structures

III-13 H2C=CH-CO-CH3

III-13

H2C=C(CH3)-CO-CH3

III-13, V-3 H3C

1

0

3-Buten-2-one, 4-[4-(acetyloxy)-2,2,6-trimethyl-7oxabicyclo[4.1.0]hept-1-yl]-, [1S-[1D(E),4D,6D]]-

42569-64-2

0

1

0

3-Buten-2-one, 4-(decahydro-2-hydroxy-2,5,5,8atetramethyl-1-naphthalenyl)-, [1R[1D(E),2E,4aE,8aD]]-

CH3

0

1

0

CH3

III-13, V-3, X-2 CH3 H3C

OH CH3

CH3

II.A-5, III-13

3-Buten-2-one, 4-(decahydro-2-hydroxy-2,5,5,8atetramethyl-1-naphthalenyl)-, [1D(E),2D,4aE,8aD](±)-

623-15-4

1

1

1

3-Buten-2-one, 4-(2-furanyl)-

14398-34-6

0

1

0

3-Buten-2-one, 4-(3-hydroxy-2,6,6-trimethyl-1cyclohexen-1-yl)-, (E)-

61892-82-8

1

0

0

3-Buten-2-one, 4-(4-hydroxy-1-cyclohexen-1-yl)-

50281-42-0

0

1

0

3-Buten-2-one, 4-(4-hydroxy-2,2,6-trimethyl-7oxabicyclo[4.1.0]hept-1-yl)-, [1S-[1D(E),4D,6D]]-

III-13, X-2 II.A-5, III-13 II.A-5, III-13 H3C

CH3

HO

0

1

0

3-Buten-2-one, 4-(4-hydroxy-2,2,6-trimethyl-7oxabicyclo[4.1.0]hept-1-yl)-, [1R-[1D(E),4E,6D]]-

H3C

CH3

CH3

CH3 O

HO

II.A-5, III-13, X-2

O

O

61116-99-2

II.A-5, III-13

O

H3C

54656-80-3

III-13, V-3, X-2

O

CH3 O

0

III-13 III-13

H3C-COO

50281-41-9

Chapter Table

II.A-5, III-13, X-2

O CH3

CH3

72491-46-4

0

1

0

3-Buten-2-one, 4-(4-hydroxy-2,6,6-trimethyl-1cyclohexen-1-yl){4-hydroxy-ȕ-ionone}

II.A-5, III-13

38963-41-6

1

0

0

3-Buten-2-one, 4-(4-hydroxy-2,6,6-trimethyl-2cyclohexen-1-yl){4-hydroxy-D-ionone}

II.A-5, III-13

23120-57-2

1

0

0

3-Buten-2-one, 4-(5-methyl-2-furanyl)-

66434-99-9

0

1

0

3-Buten-2-one, 4-(5-methyl-2-furanyl)-, (E)-

122-57-6

1

1

1

3-Buten-2-one, 4-phenyl-

2433-57-0

1

0

0

3-Buten-2-one, 4-(1H-pyrrol-2-yl)-, (E)-

79-69-6

0

1

0

3-Buten-2-one, 4-(2,5,6,6-tetramethyl-2-cyclohexen1-yl){Į-irone}

III-13, X-2 III-13, X-2 C6H5-CH=CH-CO-CH3

III-13 III-13, XVII.A-4 III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1544

11/24/08 1:55:54 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1545

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

23267-57-4

0

1

0

Name (per CA Collective Index) 3-Buten-2-one, 4-(2,2,6-trimethyl-7oxabicyclo[4.1.0]hept-1-yl)-

Selected structures

H3C

III-13, X-2

O

CH3

Chapter Table

CH3

O CH3

56681-06-2

0

1

0

3-Buten-2-one, 4-(2,3,6-trimethylphenyl)-

III-13

1203-08-3

1

1

1

3-Buten-2-one, 4-(2,6,6-trimethyl-1,3cyclohexadien-1-yl){dehydro-E-ionone}

III-13

14398-35-7

0

1

0

3-Buten-2-one, 4-(2,6,6-trimethyl-1,3cyclohexadien-1-yl)-, (E)-

III-13

14901-07-6

1

1

1

3-Buten-2-one, 4-(2,6,6-trimethyl-1-cyclohexen-1yl){E-ionone}

79-77-6

0

1

0

3-Buten-2-one, 4-(2,6,6-trimethyl-1-cyclohexen-1yl)-, (Z)-

127-41-3 8013-90-9

1

1

1

3-Buten-2-one, 4-(2,6,6-trimethyl-2-cyclohexen-1yl)-, (E){D-ionone}

689-97-4

1119-19-3

III-13

O

III-13 III-13

O

1

0

0

1-Buten-3-yne

H2C=CH-CŁCH

1

0

0

Butoxyl radical

OC4H9

1

0

0

tert-Butoxyl radical

I.B-1 XXVII-1 XXVII-1

1

0

0

2-Butynal

H3C-CŁC-CH=O

III-12

1

0

0

Butyne

H-(CH2)n-CŁC-(CH2)(2-n)-H

I.B-1

107-00-6

1

0

0

1-Butyne

H3C-CH2-C ŁCH

I.B-1

503-17-3

1

1

1

2-Butyne

H3C-CŁC-CH3

I.B-1

7440-43-9

1

1

1

Cadmium

Cd

XX-5

7440-70-2

1

1

1

Calcium

Ca

XX-5

14127-61-8

0

1

0

Calcium, ion

Ca

+2

XX-5

1305-78-8

0

1

0

Calcium oxide

CaO

XX-5, XX-6

15124-81-9

0

1

0

Calcium, isotope of mass 49

9064-51-1 54724-00-4

0

1

0

Callose

{1,3-ȕ-D-glucan}

II.A-5, VIII-3

XX-5

101-21-3

0

1

0

Carbamic acid, 3-chlorophenyl-, (1-methylethyl) ester {Chloropropham®}

XXI-3

23103-98-2

0

1

0

Carbamic acid, dimethyl-, 2-(dimethylamino)-5,6dimethyl-4-pyrimidinyl ester {Pirimicarb®}

XXI-3, XVII.B-2, XXI-3

25606-41-1

0

1

0

Carbamic acid, 3-(dimethylamino)propyl-, propyl ester, hydrochloride {Propamocarb hydrochloride®}

51-79-6

1

1

1

Carbamic acid, ethyl ester

{urethan}

598-55-0

0

1

0

Carbamic acid, methyl ester

137-42-8

0

1

0

Carbamic acid, N-methyldithio-, monosodium salt {Metham-sodium®}

594-07-0

0

1

0

Carbamodithioic acid

COO-(CH2)2-CH3 HCl. HN

V-3, XXI-3

(CH2)3-N(CH3)2

H 2N-COO-C2H5 H2N-COO-CH3

V-3 V-3 XVIII.A-1, XX-6, XXI-3

H2N-CSSH XVIII.A-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1545

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1546

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

9006-42-2

0

1

0

Carbamodithioic acid, 1,2-ethylene(bis-, polymer with ammonia complex of zinc ethylenebisdithiocarbamate {Metiram®}

1114-71-2

0

1

0

Carbamothioic acid, butylethyl-, S-propyl ester {Tillam®; Pebulate®}

Name (per CA Collective Index)

Selected structures

Chapter Table XXI-3

XVIII.A-1, XXI-3

H3C-(CH2)3 H3C-CH2

N-CO-S-(CH2)2-CH3

759-94-4

0

1

0

Carbamothioic acid, dipropyl-, S-ethyl ester {EPTC®}

XVIII.A-1, XXI-3

1929-77-7

0

1

0

Carbamothioic acid, dipropyl-, S-propyl ester {Vernolate®}

XVIII.A-1, XXI-3

2303-17-5

0

1

0

Carbamothioic acid, S-(2,3,3-trichloro-2-propenyl) bis(1-methylethyl) ester {Triallate®}

XVIII.A-1, XXI-3

9012-49-1

0

1

0

Carbamoyltransferase, aspartate

1

0

0

Carbazole

86-74-8

1

0

0

9H-Carbazole

XXII-2 XVII.E-6

{dibenzo[b,d]pyrrole}

8

7 6

2

XVII.E-6

9 5

4539-51-9

1

N H

4

1

0

0

9H-Carbazole, alkyl-

XVII.E-6

1

0

0

9H-Carbazole, 9-alkyl-

XVII.E-6

1

0

0

9H-Carbazole, 2-amino-

XII-2, XVII.E-6

1

0

0

9H-Carbazole, 2-amino-ethyl-

XII-2, XVII.E-6

30642-38-7

1

0

0

9H-Carbazole, dimethyl-

XVII.E-6

14171-85-8

1

0

0

9H-Carbazole, 1,9-dimethyl-

XVII.E-6

24075-47-6

1

0

0

9H-Carbazole, 2,9-dimethyl-

XVII.E-6

24075-48-7

1

0

0

9H-Carbazole, 3,9-dimethyl-

XVII.E-6

24075-49-8

1

0

0

9H-Carbazole, 4,9-dimethyl-

XVII.E-6

71277-85-5

1

0

0

9H-Carbazole, ethyl-

XVII.E-6

86-28-2

1

0

0

9H-Carbazole, 9-ethyl-

XVII.E-6

27323-29-1

1

0

0

9H-Carbazole, methyl-

XVII.E-6

6510-65-2

1

0

0

9H-Carbazole, 1-methyl-

XVII.E-6

3652-91-3

1

0

0

9H-Carbazole, 2-methyl-

XVII.E-6

4630-20-0

1

0

0

9H-Carbazole, 3-methyl-

XVII.E-6

3770-48-7

1

0

0

9H-Carbazole, 4-methyl-

XVII.E-6

1484-12-4

1

0

0

9H-Carbazole, 9-methyl-

XVII.E-6

64844-53-7

1

0

0

9H-Carbazole, tetramethyl-

XVII.E-6

64844-51-5

1

0

0

9H-Carbazole, trimethyl-

XVII.E-6

7440-44-0

1

1

1

Carbon

C

XX-5

14762-75-5

1

0

0

Carbon, isotope of mass 14

14

C

XX-5

124-38-9

1

1

1

Carbon dioxide

CO2

XIX-5 XIX-5

14

51-90-1

1

0

0

Carbon- C dioxide

14

75-15-0

1

0

0

Carbon disulfide

CS2

XIX-5

630-08-0

1

0

0

Carbon monoxide

CO

XIX-5

CO2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1546

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1547

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

7665-54-5

1

0

0

Carbon- C monoxide

463-58-1

1

0

0

Carbon oxide sulfide (COS)

Name (per CA Collective Index) 14

75-44-5

0

1

0

Carbon oxychloride

2944-05-0

1

0

0

Carbon sulfide

{carbonyl sulfide} {phosgene}

Chapter Table

Selected structures 14

CO

XIX-5

COS

XIX-5

COCl2

XIX-5, XVIII.B-3, XXI-3

CS

XIX-5

56-23-5

0

1

0

Carbon tetrachloride

CCl4

10361-29-2

1

0

0

Carbonic acid, ammonium salt

(NH4)2CO3

XVIII.B-3, XXI-3 XX-6

471-34-1

1

0

0

Carbonic acid, calcium salt

CaCO3

XX-6

13717-00-5

0

1

0

Carbonic acid, magnesium salt

MgCO3

XX-6

584-08-7

0

1

0

Carbonic acid, dipotassium salt

K2CO3

XX-6

497-19-8

0

1

0

Carbonic acid, disodium salt

Na2CO3

XX-6

1066-33-7

1

1

1

Carbonic acid, monoammonium salt {ammonium hydrogen carbonate}

(NH4)HCO3

XX-6

298-14-6

0

1

0

Carbonic acid, monopotassium salt

KHCO3

XX-6

144-55-8

0

1

0

Carbonic acid, monosodium salt

NaHCO3

XX-6

{sodium carbonate}

9031-55-4

0

1

0

Carboxylase

XXII-2

9067-77-0

0

1

0

Carboxylase, phosphoenolpyruvate (phosphate)

XXII-2

37341-54-1

0

1

0

Carboxylase, phosphopyruvate

XXII-2

9027-23-0

0

1

0

Carboxylase, ribulose diphosphate

XXII-2

131201-61-1

0

1

0

Carboxylase, ribulose diphosphate (Nicotiana sylvestris clone NySS4 small subunit precursor reduced)

XXII-2

9031-98-5

0

1

0

Carboxypeptidase

7235-40-7

1

1

1

E,E-Carotene

XXII-2 {E-carotene, all-trans}

H3C

CH3

CH3

H3C

CH3

CH3

CH3

H3C

CH3

CH3

I.C-3

6811-73-0

0

1

0

E,E-Carotene, 13-cis-

I.C-3

68295-84-1

0

1

0

E,E-Carotene, neo

I.C-3

14660-91-4

0

1

0

E,E-Carotene, 6,7-didehydro-5',6'-epoxy-5,5',6,6'tetrahydro-3,3',5-trihydroxy-, (3S,3'S,5R,5'R,6R,6'S,9'-cis)- {neoxanthin}

II.A-5

30743-41-0

0

1

0

E,E-Carotene, 6,7-didehydro-5',6'-epoxy-5,5',6,6'tetrahydro-3,3',5-trihydroxy-, (3S,3'S,5R,5'R,6R,6'S)-

II.A-5

29472-68-2

0

1

0

E,E-Carotene-3,3'-diol

{zeaxanthin}

II.A-5

144-68-3

0

1

0

E,E-Carotene-3,3'-diol, (3R,3'R)-

{zeaxanthin}

II.A-5

126-29-4

0

1

0

E,E-Carotene-3,3'-diol, 5,6:5',6'-diepoxy-5,5',6,6'tetrahydro-, (3S,3'S,5R,5'R,6S,6'S)- {violaxanthin}

H3C

CH3

CH 3

H3C

CH3

O HO

CH3

OH

O

CH3

H3C

CH3

CH 3

II.A-5, X-2

26927-07-1

0

1

0

E,E-Carotene-3,3'-diol, 5,6:5',6'-diepoxy-5,5',6,6'tetrahydro-, (3S,3'S,5R,5'R,6S,6'S,9-cis)-

II.A-5, X-2

68831-78-7

0

1

0

E,E-Carotene-3,3'-diol, 5,6-epoxy-5,6-dihydro-, (3S,3'R,5R,6S,9-cis)-

II.A-5, X-2

472-70-8

0

1

0

E,E-Caroten-3-ol, (3R)-

7488-99-5

0

1

0

E,H-Carotene, (6'R)-

{cryptoxanthin}

II.A-5

{D-carotene}

I.C-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1547

11/24/08 1:55:55 PM

1548

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

17539-43-4

0

1

0

E,H-Carotene-3,3'-diol, 5,6-epoxy-5,6-dihydro-

II.A-5, X-2

28368-08-3

0

1

0

E,H-Carotene-3,3'-diol, 5,6-epoxy-5,6-dihydro-, (3S,3'R,5R,6S,6'R)-

II.A-5, X-2

512-29-8

0

1

0

E,H-Carotene-3,3'-diol, 5,8-epoxy-5,8-dihydro-, (3S,3'R,5R,6'R,8R){flavoxanthin}

II.A-5, X-2

127-40-2

0

1

0

E,H-Carotene-3,3'-diol, (3R,3'R,6'R){xanthophyll; lutein}

Name (per CA Collective Index)

Chapter Table

Selected structures

H3C

HO

502-65-8

1

1

1

540-04-5

0

1

0

\,\-Carotene, 7,7',8,8',11,11',12,12'-octahydro{phytoene}

540-05-6

0

1

0

\,\-Carotene, 7,7',8,8',11,12-hexahydro{phytofluene}

CH3

CH3

H3C

CH3

CH3

CH3

CH3

OH

H3C

CH3

II.A-5

{lycopene}

\,\-Carotene

I.C-3 I.C-3

I.C-3 9001-05-2

0

1

0

Catalase

28231-03-0

0

1

0

Cedrenol

XXII-2 OH

H3C

CH3 CH3

CH3

CH3

H3C

OH

II.A-5 528-50-7

0

1

0

Cellobiose

9012-54-8

0

1

0

Cellulase

9004-34-6

II.A-5, VIII-3, X-2 XXII-2

0

1

0

Cellulose

0

1

0

Cellulose, labeled with C

II.A-5, VIII-3

9000-11-7

0

1

0

Cellulose, carboxymethyl ether

II.A-5, VIII-3, X-2

9004-57-3

0

1

0

Cellulose, ethyl ether

II.A-5, VIII-3, X-2

9004-67-5

0

1

0

Cellulose, methyl ether

7440-45-1

1

1

1

Cerium

Ce

XX-5 XX-5

14

14

{cellulose- C}

XXV-29

II.A-5, VIII-3, X-2

14762-78-8

0

1

0

Cerium, isotope of mass 144

144

7440-46-2

1

1

1

Cesium

Cs

XX-5

13967-70-9

1

1

1

Cesium, isotope of mass 134

134

XX-5

137

Ce Cs

10045-97-3

1

1

1

Cesium, isotope of mass 137

9001-06-3

0

1

0

Chitinase

Cs

XXII-2

XX-5

131554-01-3

0

1

0

Chitinase (Nicotiana tabacum samsun isoenzyme reduced)

XXII-2

148348-37-2

0

1

0

Chitinase (Nicotiana tabacum xanthi clone pBSCL226 isoenzyme III precursor reduced)

XXII-2

152619-17-5

0

1

0

Chitinase (tobacco basic isoenzyme III precursor reduced)

XXII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1548

11/24/08 1:55:55 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1549

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

128285-05-2

0

1

0

Chitinase (tobacco clone lambda.CHN17 basic isoenzyme precursor reduced)

XXII-2

128285-06-3

0

1

0

Chitinase (tobacco clone lambda.CHN17 basic isoenzyme reduced)

XXII-2

159520-75-9

0

1

0

Chitinase (tobacco clone 59 gene chi-V precursor reduced)

XXII-2

16887-00-6

1

1

1

Chloride

Cl

7782-50-5

1

1

1

Chlorine

Cl2

XVIII.B-3, XX-5

14158-34-0

0

1

0

Chlorine, isotope of mass 38

38

XVIII.B-3, XX-5

Name (per CA Collective Index)

-1

XVIII.B-3, XX-5

Cl2

9025-96-1

0

1

0

Chlorophyllase

42617-16-3

0

1

0

Chlorophyll a

{also listed under Magnesium} {also listed under Magnesium}

Chapter Table

Selected structures

XXII-2 XX-6, XVII.A-5

519-62-0

0

1

0

Chlorophyll b

1406-65-1

0

1

0

Chlorophylls a + b

XX-6, XVII.A-5

14897-06-4

0

1

0

Chlorophyllide

XX-6, XVII.A-5

11006-34-1

0

1

0

Chlorophyllin

XX-6, XVII.A-5

119973-28-3

1

0

0

Chol-3-ene, 23-methyl-, (5D)-

747-90-0 481-21-0

XX-6, XVII.A-5

I.C-1

1

0

0

Cholesta-3,5-diene

I.C-1

1

0

0

Cholesta-3,5-diene, 24-ethyl-

I.C-1

0

1

0

Cholestane, (5D)-

{coprostane}

H3C CH3 CH3 CH3

CH3

I.C-1 1

0

0

119973-28-3

1

0

0

Chol-3-ene, 23-methyl-, (5D)-

I.C-1

747-90-0

1

0

0

Cholesta-3,5-diene

I.C-1

1

0

0

Cholesta-3,5-diene, 24-ethyl-

0

1

0

Cholestane, (5D)-

481-21-0

Cholesta-3,5,22-triene, 24-methyl-

I.C-1

I.C-1 {coprostane}

H3C CH3 CH3 CH3

CH3

I.C-1 1

0

0

Cholesta-3,5,22-triene, 24-methyl-

I.C-1

96443-01-5

1

0

0

Cholest-4-en-3-ol, 4-methyl- (3D)

II.B-2

57-88-5

1

1

1

Cholest-5-en-3-ol (3E)-

{cholesterol}

CH3 CH3 CH3

CH3 CH3

HO

II.B-2 0

1

0

Cholest-5-en-3-ol (3E)-, 9,12,15-octadecatrienoate, [3E(Z,Z,Z),22E]{cholesteryl linolenate}

II.B-2, V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1549

11/24/08 1:55:56 PM

1550

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

0

1

0

Cholest-5-en-3-ol (3E)-, 9-octadecenoate, [3E(Z),22E]{cholesteryl oleate}

II.B-2, V-3

0

1

0

Cholest-5-en-3-ol (3E)-, octadecanoate, (3E,22E){cholesteryl stearate}

II.B-2, V-3

Name (per CA Collective Index)

Selected structures

Chapter Table

474-77-1

0

1

0

Cholest-5-en-3-ol, (3D)-)

1253-88-9

0

1

0

II.B-2

Cholest-5-en-3-ol, 4,4-dimethyl-, (3E)-

II.B-2

6036-58-4

0

1

0

Cholest-7-en-3-ol, (3E)-

II.B-2

{epicholesterol}

481-25-4

0

1

0

Cholest-7-en-3-ol, 4-methyl-, (3E,4D,5D)-

II.B-2

6062-47-1

0

1

0

Cholest-8-en-3-ol, 14-methyl-, (3E,5D)-

II.B-2

5241-24-7

0

1

0

Cholest-8-en-3-ol, 4,4-dimethyl-, (3E,5D)-

II.B-2

5241-22-5

0

1

0

Cholest-8-en-3-ol, 4-methyl-, (3E,4D,5D)-

II.B-2

100017-41-2

0

1

0

Cholest-9(11)-en-3-ol, 14-methyl-, (3E,5D)-

7440-47-3

1

1

1

Chromium

Cr

XX-5

51

XX-5

14392-02-0

1

1

1

Chromium, isotope of mass 51

218-01-9

1

1

1

Chrysene

1

0

0

Chrysene, alkyl-

1

0

0

Chrysene, 6-amino-

2642-98-0

II.B-2 Cr

{1,2-benzophenanthrene}

I.E-6

I.E-6 I.E-6, XII-2

41637-92-7

1

0

0

Chrysene, dimethyl-

71277-86-6

1

0

0

Chrysene, ethyl-

I.E-6

71277-87-7

1

0

0

Chrysene, ethylmethyl-

I.E-6

41637-90-5

1

0

0

Chrysene, methyl-

I.E-6

3351-28-8

1

0

0

Chrysene, 1-methyl-

I.E-6

3351-32-4

1

0

0

Chrysene, 2-methyl-

I.E-6

3351-31-3

1

0

0

Chrysene, 3-methyl-

I.E-6

3351-30-2

1

0

0

Chrysene, 4-methyl-

I.E-6

3697-24-3

1

0

0

Chrysene, 5-methyl-

I.E-6

1705-85-7

1

0

0

Chrysene, 6-methyl-

I.E-6

7496-02-8

1

0

0

Chrysene, 6-nitro-

71277-88-8

1

0

0

Chrysene, pentamethyl-

I.E-6

71277-89-9

1

0

0

Chrysene, propyl-

I.E-6

71277-90-2

1

0

0

Chrysene, tetramethyl-

I.E-6

60826-77-9

1

0

0

Chrysene, trimethyl-

I.E-6

253-66-7

1

0

0

Cinnoline

63863-33-2

1

0

0

Cinnoline, dihydro-

14722-38-4

1

0

0

Cinnoline, 4-methyl-

7440-48-4

1

1

1

Cobalt

Co

XX-5

60

XX-5

10198-40-0

{at least 3 isomers in MSS}

1

1

1

Cobalt, isotope of mass 60

1

0

0

Cobalt carbonyl

I.E-6

XVI-1

{1,2-diazanaphthalene}

XVII.E-6

XVII.E-6 XVII.E-6 Co

XX-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1550

11/24/08 1:55:56 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1551

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

85-61-0

0

1

0

Coenzyme A

XXII-2

604-98-8

0

1

0

Coenzyme A, S-(hydrogen butanedioate)

XXII-2

7440-50-8

Name (per CA Collective Index)

1

1

1

Copper

0

1

0

Copper, ion

Selected structures

Chapter Table

XX-5 Cu

+2

XX-5

1317-39-1

0

1

0

Copper oxide

1332-40-7 1332-65-6

0

1

0

Copper oxychloride

XX-6

8012-69-9

0

1

0

Copper oxychloride sulfate

7758-98-7

0

1

0

Copper sulfate

191-07-1

1

1

1

Coronene

I.E-6

64760-15-2

1

0

0

Coronene, dimethyl-

I.E-6

{RAME}

XXI-3 Cu2Cl(OH)3 + Cu4(OH)6(SO4)

XXI-3 XXI-3

13119-86-3

1

0

0

Coronene, methyl-

115742-70-6

0

1

0

Cryptogein

156-62-7

0

1

0

Cyanamide, calcium salt

1467-79-4

1

0

0

Cyanamide, dimethyl-

(CH3)2=N-CN

590-28-3

0

1

0

Cyanic acid, potassium salt

K-OCN

57-12-5

1

0

0

Cyanide ion

CN

1

0

0

Cyanide radical

CN

XXVII-1

1

0

0

Cyanide radical {acrylonitrile radical}

C3H2N

XXVII-1

1

0

0

Cyanide radical

C3H4N

XXVII-1

94185-89-4

0

1

0

Cyclase, farnesyl pyrophosphate

XXII-2

60485-38-3

0

1

0

9,19-Cyclocholest-24-en-3-ol, 4,14-dimethyl-, (3E,4D,5D)-

II.B-2

34443-88-4

0

1

0

9,19-Cycloergost-24(28)-en-3-ol, 14-methyl-, (3E,5D)-

II.B-2

469-39-6

0

1

0

9,19-Cycloergost-24(28)-en-3-ol, 4,14-dimethyl-, (3E,4D,5D)-

II.B-2

34347-58-5

0

1

0

9,19-Cycloergostan-3-ol, 14-methyl-, (3E,5D,9E)-

II.B-2

59780-40-4

0

1

0

9,19-Cycloergostan-3-ol, 4,14-dimethyl-, (3E,4D,5D,24[)-

II.B-2

0

1

0

2,4-Cycloheptadien-1-one, 2,6,6-trimethyl{eucarvone}

III-13

1

0

0

Cycloheptanone

502-42-1

I.E-6 XXII-2 Ca=N-CN -

XI-2, XXI-3 XI-2 XX-6, XXI-3

-1

XI-2

{suberone}

III-13 O

544-25-2

1

0

0

1,3,5-Cycloheptatriene

29797-09-9

1

0

0

Cyclohexadiene

592-57-4

1

0

0

1,3-Cyclohexadiene

{tropilidene}

I.C-1

I.C-1 1 2

6

3

I.C-1

5 4

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1551

11/24/08 1:55:56 PM

1552

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

99-86-5

1

1

1

1,3-Cyclohexadiene, 1-methyl-4-(1-methylethyl){D-terpinene}

99-83-2

1

1

1

1,3-Cyclohexadiene, 2-methyl-5-(1-methylethyl){D-phellandrene}

I.C-1

4221-98-1

1

1

1

1,3-Cyclohexadiene, 2-methyl-5-(1-methylethyl)-, (R){D-phellandrene}

I.C-1

116-26-7

0

1

0

1,3-Cyclohexadiene-1-carboxaldehyde, 2,6,6trimethyl{safranal}

III-12

0

1

0

1,3-Cyclohexadiene, 1,2,6,6-tetramethyl-

I.C-1

0

1

0

1,4-Cyclohexadiene

628-41-1

Name (per CA Collective Index)

Chapter Table

Selected structures

I.C-1

I.C-1

1 2

6

3

5 4

99-85-4

0

1

0

1,4-Cyclohexadiene, 1-methyl-4-(1-methylethyl)-

617-12-9

0

1

0

1,5-Cyclohexadiene-1-carboxylic acid, 3-[(1carboxyethenyl)oxy]-4-hydroxy-, (3R-E)-

I.C-1 II.A-5, IV.A-3

1

0

0

Cyclohexadienedione

106-51-4

1

0

0

2,5-Cyclohexadiene-1,4-dione

106-34-3

1

0

0

2,5-Cyclohexadiene-1,4-dione, compd. with 1,4benzenediol (1:1)

1

0

0

2,5-Cyclohexadiene-1,4-dione, 2,3-dihydro-

IX.B-2

1

1

1

2,5-Cyclohexadiene-1,4-dione, 2,3-dihydro-2,2,6trimethyl-

IX.B-2

0

1

0

2,5-Cyclohexadiene-1,4-dione, 2,3-dimethoxy-5(3,7,11,15,19,23,27,31,35,39-decamethyl2,6,10,14,18,22,26,30,34,38-tetracontadecenyl)-6methyl{ubiquinone-10}

303-98-0

{quinone} {p-benzoquinone}

IX.B-2 O

IX.B-2

O

IX.A-22, IX.B-2

(

H3CO

IX.B-2

CH3

O H3CO

)

H

10

CH3 O

137-18-8

1

0

0

2,5-Cyclohexadiene-1,4-dione, 2,5-dimethyl-

IX.B-2

0

1

0

2,5-Cyclohexadiene-1,4-dione, 2,6-bis(1,1dimethylethyl)-

IX.B-2

527-61-7

1

0

0

2,5-Cyclohexadiene-1,4-dione, 2,6-dimethyl-

IX.B-2

4299-57-4

0

1

0

2,5-Cyclohexadiene-1,4-dione, 2,3-dimethyl-5(3,7,11,15,19,23,27,31,35-nonamethyl2,6,10,14,18,22, 26,30,34-hexatriacontanonaenyl), (all-E){plastoquinone}

IX.B-2

606-06-4

0

1

0

2,5-Cyclohexadiene-1,4-dione, 2-(3,7-dimethyl-2,6octadienyl)-5,6-dimethoxy-3-methyl-, (E)-

IX.B-2, X-2

2474-72-8

1

0

0

2,5-Cyclohexadiene-1,4-dione, 2-hydroxy-

II.A-5, IX.B-2

3361-10-2

0

1

0

2,5-Cyclohexadiene-1,4-dione, 2-(3-hydroxy3,7,11,15-tetramethylhexadecyl)-6-methyl-

II.A-5, IX.B-2

7559-04-8

0

1

0

2,5-Cyclohexadiene-1,4-dione, 2-(3-hydroxy3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethyl-, [3R- (3R*,7R*,11R*)]-

II.A-5, IX.B-2

1

0

0

2,5-Cyclohexadiene-1,4-dione, 2-methoxy-

553-97-9

1

0

0

2,5-Cyclohexadiene-1,4-dione, 2-methyl-

IX.B-2

527-17-3

1

0

0

2,5-Cyclohexadiene-1,4-dione, 2,3,5,6-tetramethyl-

IX.B-2

IX.B-2, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1552

11/24/08 1:55:57 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1553

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

935-92-2

1

0

0

2,5-Cyclohexadiene-1,4-dione, 2,3,5-trimethyl-

583-63-1

1

1

1

3,5-Cyclohexadiene-1,2-dione

Name (per CA Collective Index)

{o-benzoquinone}

Selected structures

Chapter Table IX.B-2 IX.B-2

O O

0

1

0

2,4-Cyclohexadien-1-one, 2,6,6-trimethyl-

0

1

0

2,5-Cyclohexadien-1-one, 2,6-bis(1,1dimethylethyl)-4-hydoxy-4-methyl-

110-82-7

1

0

0

Cyclohexane

I.C-1

27195-67-1

1

0

0

Cyclohexane, dimethyl-

I.C-1

1

0

0

Cyclohexane, ethyl-

I.C-1

1

0

0

Cyclohexane, methyl-

I.C-1

108-87-2

III-13 II.A-5, III-13

1

0

0

Cyclohexane, propyl-

I.C-1

27013-35-0

1

0

0

Cyclohexane, methyl-(1-methylethenyl)-

I.C-1

29887-60-3

0

1

0

Cyclohexane, 1,2-dimethoxy-, (E)

X-2

590-66-9

1

0

0

Cyclohexane, 1,1-dimethyl-

I.C-1

591-21-9

1

0

0

Cyclohexane, 1,3-dimethyl-

I.C-1

33880-83-0

0

1

0

Cyclohexane, 1-ethenyl-1-methyl-2,4-bis(1methylethenyl)-, (1D,2E,4E)-

I.C-1

515-13-9

0

1

0

Cyclohexane, 1-ethenyl-1-methyl-2,4-bis(1methylethenyl)-, [1S-(1D,2E,4E)]-

I.C-1

62238-31-7

1

0

0

Cyclohexane, 1-ethyl-1,3-dimethyl-, (Z)-

I.C-1

62238-29-3

1

0

0

Cyclohexane, 1-ethyl-1,3-dimethyl-, (E)-

I.C-1

62238-30-6

1

0

0

Cyclohexane, 1-ethyl-1,4-dimethyl-, (Z)-

I.C-1

62238-32-8

1

0

0

Cyclohexane, 1-ethyl-1,4-dimethyl-, (E)-

I.C-1

1

0

0

Cyclohexane, 1-ethyl-2-propyl-

I.C-1

608-73-1

1

1

1

Cyclohexane, 1,2,3,4,5,6-hexachloro-

XVIII.B-3, XXI-3

319-84-6

1

1

1

Cyclohexane, 1,2,3,4,5,6-hexachloro{Į Lindane®}

XVIII.B-3, XXI-3

319-85-7

1

1

1

Cyclohexane, 1,2,3,4,5,6-hexachloro{ȕ Lindane®}

XVIII.B-3, XXI-3

58-89-9

1

1

1

Cyclohexane, 1,2,3,4,5,6-hexachloro-, (1D,2D,3E,4D,5D,6E){Ȗ-Lindane®}

XVIII.B-3, XXI-3

319-86-8

1

1

1

Cyclohexane, 1,2,3,4,5,6-hexachloro{į Lindane®}

XVIII.B-3, XXI-3

13828-34-7

1

0

0

Cyclohexane, 1-methyl-3-(1-methylethylidene)-

I.C-1

1

0

0

Cyclohexane, 1-methyl-4-(1-methylethyl){p-menthane}

I.C-1

1

0

0

Cyclohexane, 1,2,4,5-tetraethyl-

I.C-1

3073-66-3

1

0

0

Cyclohexane, 1,1,3-trimethyl-

I.C-1

2043-61-0

0

1

0

Cyclohexanecarboxaldehyde

III-12

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1553

11/24/08 1:55:57 PM

1554

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

34214-77-2

0

1

0

Cyclohexanecarboxylic acid, 3-(3,4dihydroxyphenyl)-1-oxo-2-propenyl]oxy]trihydroxy, (1D,3D,4D,5E)-

77-95-2 562-73-2

1

1

1

Cyclohexanecarboxylic acid, 1,3,4,5-tetrahydroxy{quinic acid}

Name (per CA Collective Index)

Chapter Table

Selected structures

II.A-2, IV.A-3, IX.A-22

II.A-2, IV.A-3

HO OH HO COOH HO

36413-60-2

0

1

0

Cyclohexanecarboxylic acid, 1,3,4,5-tetrahydroxy-, (1D,3D,4D,5E)-

27044-07-1

0

1

0

Cyclohexanecarboxylic acid, 1,3,4,5-tetrahydroxy-, monoester with 3-(4-hydroxy-3-methoxyphenyl)-2propenoic acid, (1D,3D,4D,5E)-

1899-29-2

0

1

0

Cyclohexanecarboxylic acid, 1,3,4-trihydroxy-5-[[3(4-hydroxy-3-methoxyphenyl)-1-oxo-2propenyl]oxy]-, (1D,3D,4D,5E){3-O-feruloylquinic acid}

II.A-2, IV.A-3 II.A-2, IV.A-3, V-3, IX.A-22, X-2

O OCH3

O

OH

HO OH

HOOC OH

II.A-2, IV.A-3, V-3, IX.A-22, X-2 1899-30-5

0

1

0

Cyclohexanecarboxylic acid, 1,3,4-trihydroxy-5-[[3(4-hydroxyphenyl)-1-oxo-2-propenyl]oxy]-, [1S(1D,3D,4D,5E)]{p-coumaroylquinic acid}

II.A-2, IV.A-3, V-3, IX.A-22, X-2

2450-53-5

0

1

0

Cyclohexanecarboxylic acid, 3,5-bis[[3-(3,4dihydroxyphenyl)-1-oxo-2-propenyl]oxy]-1,4dihydroxy-, [1R-(1D,3D,4D,5E)]-

II.A-2, IV.A-3, V-3, IX.A-22, X-2

15016-60-1

0

1

0

Cyclohexanecarboxylic acid, 3-[[3-(3,4dihydroxyphenyl)-1-oxo-2-propenyl]oxy]-1,4,5trihydroxy-, [1R- [1D,3E(Z),4D,5D]]-

II.A-2, IV.A-3, V-3, IX.A-22, X-2

15076-00-3

0

1

0

Cyclohexanecarboxylic acid, 3-[[3-(3,4dihydroxyphenyl)-1-oxo-2-propenyl]oxy]-1,4,5trihydroxy-, [1R- [1D,3E(E),4D,5D]]-

II.A-2, IV.A-3, V-3, IX.A-22, X-2

327-97-9 93451-46-8

1

1

1

Cyclohexanecarboxylic acid, 3-[[3-(3,4dihydroxyphenyl)-1-oxo-2-propenyl]oxy]-1,4,5trihydroxy-, [1S-(1D,3E,4D,5D)]{chlorogenic acid; 3-O-caffeoylquinic acid}

O OH

O OH HOOC

OH

OH OH

II.A-2, IV.A-3, V-3, IX.A-22, X-2, XXI-3 906-33-2

0

1

0

Cyclohexanecarboxylic acid, 3-[[3-(3,4dihydroxyphenyl)-1-oxo-2-propenyl]oxy]-1,4,5trihydroxy-, [1R-(1D,3D,4D,5E)]-

II.A-2, IV.A-3, V-3, IX.A-22, X-2

1

1

1

Cyclohexanecarboxylic acid, 5-[[3-(3,4dihydroxyphenyl)-1-oxo-2-propenyl]oxy]-1,4,5trihydroxy{neochlorogenic acid; 5-O-caffeoylquinic acid}

II.A-2, IV.A-3, V-3, IX.A-22, X-2

55635-13-7

0

1

0

Cyclohexanecarboxylic acid, 2,2-dimethyl-2,4-dioxo3-(1-((2-propenyloxy)amino)butylidene)-, methyl ester, sodium salt {Alloxydim-sodium®}

24321-18-4

0

1

0

Cyclohexanecarboxylic acid, 3-[[3-(3,4-dioxo-1,5cyclohexadien-1-yl)-1-oxo-2-propenyl]oxy]-1,4,5trihydroxy-

III-13, XXI-3

II.A-2, IV.A-3, V-3, IX.A-22, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1554

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1555

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

70898-22-5

0

1

0

Cyclohexanecarboxylic acid, 3-[[3-[4-(E-Dglucopyranosyloxy)-3-hydroxyphenyl]-1-oxo-2propenyl]oxy]-1,4,5-trihydroxy-, [1S(1D,3E,4D,5D)]-

II.A-2, IV.A-3, V-3, IX.A-22, X-2

17608-52-5

0

1

0

Cyclohexanecarboxylic acid, 4-[[3-(3,4dihydroxyphenyl)-1-oxo-2-propenyl]oxy]-1,3,5trihydroxy{4-O-caffeoylquinic acid}

II.A-2, IV.A-3, V-3, IX.A-22, X-2

905-99-7

0

1

0

Cyclohexanecarboxylic acid, 4-[[3-(3,4dihydroxyphenyl)-1-oxo-2-propenyl]oxy]-1,3,5trihydroxy-, (1D,3D,4D,5E)-

II.A-2, IV.A-3, V-3, IX.A-22, X-2

82612-14-4

0

1

0

1,2-Cyclohexanediol, 4-[1-(acetyloxy)-1methylethyl]-1-methyl-, (1D,2E,4D)-(±)-

112019-00-8

0

1

0

1,2-Cyclohexanediol, 2-(3-hydroxy-1-butenyl)-1,3,3trimethyl-, [1R-[1D,2D,2(1E,3S*)]]-

38713-11-0

0

1

0

1,2-Cyclohexanediol, 1,3,3-trimethyl-

88663-71-2

0

1

0

1,4-Cyclohexanediol, 1-(1-hydroxy-1-methylethyl)-4methyl-, 4-acetate, (E)-

Name (per CA Collective Index)

Selected structures

II.A-2, V-3 II.A-2 II.A-2 CH3 OH

HO

II.A-2, V-3

CH3

H3C-COO

88663-72-3

Chapter Table

CH3

0

1

0

1,4-Cyclohexanediol, 1-(1-hydroxy-1-methylethyl)-4methyl-, 4-acetate, (Z)-

II.A-2, V-3

0

1

0

1,4-Cyclohexanediol, 1-methyl-4-(1-methylethenyl)-, 1-acetate, (Z)-

II.A-2

59632-87-0

0

1

0

1,4-Cyclohexanediol, 1-methyl-4-(1-methylethenyl)-, 1-acetate, (E)-

II.A-2

765-87-7

0

1

0

1,2-Cyclohexanedione

III-13

O

O

1

0

0

1,2-Cyclohexanedione, 4-methyl-

III-13

3008-43-3

0

1

0

1,2-Cyclohexanedione, 6-methyl-

III-13

1919-64-8

0

1

0

1,3-Cyclohexanedione, 5,5-dimethyl-2-propyl-

III-13

1193-55-1

1

1

1

1,3-Cyclohexanedione, 2-methyl-

III-13

637-88-7

1

1

1

1,4-Cyclohexanedione

20547-99-3

1

1

1

1,4-Cyclohexanedione, 2,2,6-trimethyl{4-ketodihydroisophorone}

13487-27-9

0

1

0

Cyclohexanemethanol, D-methyl-, acetate

O

O

III-13 III-13 V-3

CH3 OOC-CH3

639-99-6

0

1

0

Cyclohexanemethanol, 4-ethenyl-D,D,4-trimethyl-3(1-methylethenyl)-, [1R-(1D,3D,4E)]-

II.A-5

2451-01-6

1

0

0

Cyclohexanemethanol, 4-hydroxy-D,D,4-trimethyl-, monohydrate, cis{terpin hydrate}

II.A-5

104153-60-8

0

1

0

1,2,3-Cyclohexanetriol, 1-methyl-4-(1-methylethyl)-

II.A-5

108-93-0

1

0

0

Cyclohexanol

II.A-5

60759-94-6

0

1

0

Cyclohexanol, 1-(3-hydroxy-1-butenyl)-2,2-dimethyl6-methylene-

II.A-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1555

11/24/08 1:55:58 PM

1556

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

586-81-2

0

1

0

Cyclohexanol, 1-methyl-4-(1-methylethylidene)-

II.A-5

10235-63-9

0

1

0

Cyclohexanol, 1-methyl-4-(1-methylethylidene)-, acetate

V-3

22567-22-2

0

1

0

Cyclohexanol, 2-methyl-5-(1-methylethenyl)-, [1R(1D,2D,5E)]-

II.A-5

51773-45-6

0

1

0

Cyclohexanol, 2-methyl-5-(1-methylethenyl)-, [1R(1D,2D,5D)]-

II.A-5

88437-32-5

0

1

0

Cyclohexanol, 4-(2-hydroxy-1-methylethylidene)-1methyl-, 1-acetate

89-79-2

0

1

0

Cyclohexanol, 5-methyl-2-(1-methylethenyl)-, [1R(1D,2E,5D)]-

1490-04-6

0

1

0

Cyclohexanol, 5-methyl-2-(1-methylethyl)-

89-78-1

1

1

1

Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1D,2E,5D){menthol}

V-3 II.A-5 II.A-5 II.A-5

CH3

OH H3C

CH3

1

1

1

Cyclohexanol, 5-methyl-2-(1-methylethyl)-, 14 14 (1D,2E,5D)- C(U), labeled with C 14 { C-menthol (U)}

II.A-5

2216-51-5

0

1

0

Cyclohexanol, 5-methyl-2-(1-methylethyl)-, [1R(1D,2E,5D)]-

II.A-5

16409-45-3

0

1

0

Cyclohexanol, 5-methyl-2-(1-methylethyl)-, acetate

V-3

108-94-1

1

0

0

Cyclohexanone

III-13

2816-57-1

0

1

0

Cyclohexanone, 2,6-dimethyl-

III-13

71607-84-6

1

0

0

Cyclohexanone, ethenylmethyl-

III-13

50874-76-5

0

1

0

Cyclohexanone, trimethyl-

III-13

7500-42-7

0

1

0

Cyclohexanone, 2-hydroxy-2,6,6-trimethyl-

38462-22-5

0

1

0

Cyclohexanone, 2-(1-mercapto-1-methylethyl)-5methyl-

II.A-5, III-13 III-13, XVIII.A-1

O CH3 H3C

SH CH3

0

1

0

Cyclohexanone, 2-methyl-

III-13

7764-50-3

1

0

0

Cyclohexanone, 2-methyl-5-(1-methylethenyl)-

III-13

6909-25-7

0

1

0

Cyclohexanone, 2-methyl-5-(1-methylethenyl)-, (2Scis)-

III-13

5948-04-9

0

1

0

Cyclohexanone, 2-methyl-5-(1-methylethenyl)-, trans-

III-13

491-07-6

0

1

0

Cyclohexanone, 2-methyl-5-(1-methylethyl)-, (E){dl-isomenthone}

III-13

0

1

0

Cyclohexanone, 2-(1-methylethyl)-

III-13

15189-14-7

0

1

0

Cyclohexanone, 2,2,5,5-tetramethyl-

III-13

2408-37-9

0

1

0

Cyclohexanone, 2,2,6-trimethyl{2,6,6-trimethylcyclohexanone}

III-13

0

1

0

Cyclohexanone, 2,4,4-trimethyl-3-(1-oxobutyl)-

III-13

1

0

0

Cyclohexanone, 3-methyl-

III-13

591-24-2

{two isomers}

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1556

11/24/08 1:55:58 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1557

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

60026-21-3

0

1

0

Cyclohexanone, 3,3,5-trimethyl-4-(3-oxo-1-butenyl)-

III-13

123716-12-1

1

0

0

Cyclohexanone, 4-(1-methylethyl)-3-(2-oxopropyl)-

III-13

72491-45-3

0

1

0

Cyclohexanone, 4-(2-butenylidene)-3,3,5-trimethyl-

III-13

20548-02-1

0

1

0

Cyclohexanone, 4-hydroxy-2,2,6-trimethyl-

III-13

20548-03-2

0

1

0

Cyclohexanone, 4-hydroxy-3,3,5-trimethyl-

III-13

529-00-0

0

1

0

Cyclohexanone, 5-methyl-2-(1-methylethenyl){isopulegone}

III-13

89-80-5

1

1

1

Cyclohexanone, 5-methyl-2-(1-methylethyl)-, trans{menthone}

III-13

89-82-7

0

1

0

Cyclohexanone, 5-methyl-2-(1-methylethylidene)-, (R){pulegone}

III-13

110-83-8

1

0

0

Cyclohexene

74423-06-6

0

1

0

Cyclohexene, 2-(1,3-butadienyl)-1,3,3-trimethyl-, (E){megastigmatriene}

I.C-1 H3C

I.C-1

CH3 CH2 CH3

70941-91-2

0

1

0

Cyclohexene, 6-(3,7-dimethyl-1,3,5,7-octatetraenyl)1,5,5-trimethyl-, (E,E,E)-

I.C-1

495-62-5

0

1

0

Cyclohexene, 4-(1,5-dimethyl-4-hexenylidene)-1methyl{bisabolene}

I.C-1

25168-07-4

0

1

0

Cyclohexene, ethenyl-

I.C-1

1

0

0

Cyclohexene, 3-ethenyl-1,3-di(4',8',12'trimethyltridecyl)-

I.C-1

100-40-3

1

0

0

Cyclohexene, 4-ethenyl-

I.C-1

20307-84-0

0

1

0

Cyclohexene, 4-ethenyl-4-methyl-3-(1methylethenyl)-1-(1-methylethyl)- {į-elemene}

I.C-1

1

0

0

Cyclohexene, 4-ethenyl-1,4-di(4',8',12'trimethyltridecyl)-

I.C-1

1611-21-8

1

0

0

Cyclohexene, 5-ethenyl-1,5-dimethyl-

I.C-1

591-49-1

1

0

0

Cyclohexene, 1-methyl-

I.C-1

38738-60-2

1

0

0

Cyclohexene, 1-methyl-3-(1-methylethenyl){sylvestrene}

I.C-1

138-86-3

1

1

1

Cyclohexene, 1-methyl-4-(1-methylethenyl){limonene; p-mentha-1,8-diene}

5989-27-5

1

0

0

Cyclohexene, 1-methyl-4-(1-methylethenyl)-, (R){d-limonene}

I.C-1

5502-88-5

1

1

1

Cyclohexene, 1-methyl-4-(1-methylethyl)-

I.C-1

586-62-9

0

1

0

Cyclohexene, 1-methyl-4-(1-methylethylidene){terpinolene}

I.C-1

1461-27-4

I.C-1

0

1

0

Cyclohexene, 1-methyl-5-(1-methylethenyl)-, (R)-

I.C-1

1

0

0

Cyclohexene, 3-methyl-

I.C-1

586-67-4

1

0

0

Cyclohexene, 4-methyl-1-(1-methylethenyl){3,8-menthadiene}

I.C-1

5256-65-5

1

0

0

Cyclohexene, 3-methyl-6-(1-methylethyl)-

I.C-1

23733-91-7

0

1

0

Cyclohexene, 3-methylene-4-(1-methylethenyl)-, (R)-

I.C-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1557

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1558

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke S

T

S T

1

0

0

Cyclohexene, 3-(1"-methylene-5",9",13"trimethyltetradecyl)-1-(4',8',12'-trimethyltridecyl)-

I.C-1

1

0

0

Cyclohexene, 4-(1"-methylene-5",9",13"trimethyltetradecyl)-1-(4',8',12'-trimethyltridecyl)-

I.C-1

1192-88-7

1

0

0

1-Cyclohexene-1-carboxaldehyde

III-12

432-25-7

0

1

0

1-Cyclohexene-1-carboxaldehyde, 2,6,6-trimethyl{ȕ-cyclocitral}

III-12

471-90-9

0

1

0

1-Cyclohexene-1-carboxylic acid, 2,6,6-trimethyl{cyclogeranic acid}

IV.A-3

138-59-0

0

1

0

1-Cyclohexene-1-carboxylic acid, 3,4,5-trihydroxy-, [3R-(3D,4D,5E)]{shikimic acid}

6082-44-6

0

1

0

1-Cyclohexene-1-carboxylic acid, 3-[[3-(3,4dihydroxyphenyl)-1-oxo-2-propenyl]oxy]-4,5dihydroxy-, (3D,4D,5E)-

38073-89-1

0

1

0

3-Cyclohexene-1-carboxylic acid, 6-(1-methylethyl)-, cis-

IV.A-3

19894-91-8

0

1

0

1-Cyclohexene-1,4-dimethanol, D4,D4-dimethyl-, (S)-

II.A-5

CAS No.

Name (per CA Collective Index)

Selected structures

Chapter Table

II.A-5, IV.A-3 II.A-5, IV.A-3, V-3, IX.A-22

1

1

1

2-Cyclohexene, 1-(2-oxopropyl) 3,5,5-trimethyl-

35692-98-9

0

1

0

2-Cyclohexene-1,4-dione, 2-hydroxy-3,5,5-trimethyl-

III-13

1125-21-9

1

1

1

2-Cyclohexene-1,4-dione, 2,6,6-trimethyl{4-ketoisophorone; 4-oxoisophorone}

88663-73-4

0

1

0

1-Cyclohexene-1-methanol, 4-(acetyloxy)-D,D,4trimethyl-

42370-41-2

0

1

0

3-Cyclohexene-1-methanol, 5-hydroxy-D,D,4trimethyl-, trans-

II.A-5

498-71-5

0

1

0

3-Cyclohexene-1-methanol, 5-hydroxy-D,D,4trimethyl-

II.A-5

98-55-5

1

1

1

3-Cyclohexene-1-methanol, D,D,4-trimethyl{D-terpineol}

II.A-5, III-13 III-13 II.A-5, V-3

CH3 H3C

II.A-5

OH CH3

10482-56-1

1

1

1

3-Cyclohexene-1-methanol, D,D,4-trimethyl-, (S)-

II.A-5

80-26-2

1

1

1

3-Cyclohexene-1-methanol, D,D,4-trimethyl-, acetate {D-terpinyl acetate}

II.A-5, V-3

822-67-3

1

1

1

2-Cyclohexen-1-ol

II.A-5

536-30-1

0

1

0

2-Cyclohexen-1-ol, 2-methyl-5-(1-methylethyl)-, (1SZ)-

II.A-5

27185-80-4

0

1

0

2-Cyclohexen-1-ol, 3-(3-hydroxy-1-butenyl)-2,4,4trimethyl-

II.A-5

470-99-5

0

1

0

2-Cyclohexen-1-ol, 3,5,5-trimethyl-

II.A-5

0

1

0

2-Cyclohexen-1-ol, 3,5,5-trimethyl-4-methylene-

II.A-5

0

1

0

2-Cyclohexen-1-ol, 4-(2-butenylidene)-3,5,5trimethyl{megastigmatrienol}

II.A-5

13215-90-2

{isophorol}

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1558

11/24/08 1:55:59 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1559

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

62660-03-1

0

1

0

Name (per CA Collective Index)

Chapter Table

Selected structures

2-Cyclohexen-1-ol, 4-(3-hydroxy-1-butenyl)-3,5,5trimethyl-

H3C 5

.

OH

CH3

II.A-5

CH3

4 3

1

HO

CH3

2

H3C

CH3

OH 7

6

9

CH3

8

3

5

HO

CH3

4

Nomenclature by Enzell et al. 68831-80-1

0

1

0

2-Cyclohexen-1-ol, 4-(3-hydroxy-1-butenyl)-3,5,5trimethyl-, [1S-[1D,4D(1E,3S*)]]-

II.A-5

68831-81-2

0

1

0

2-Cyclohexen-1-ol, 4-(3-hydroxy-1-butenyl)-3,5,5trimethyl-, [1S-[1D,4D(1E,3R*)]]-

II.A-5

78830-91-8

0

1

0

3-Cyclohexen-1-ol, 1-(3-hydroxy-1-butenyl)-6,6dimethyl-2-methylene-

CH3 5 4

33759-63-6

0

1

0

3-Cyclohexen-1-ol, 4-(3-hydroxy-1-butenyl)-3,5,5trimethyl-

H3C

0

1

0

3-Cyclohexen-1-ol, 4-(3-hydroxy-1-butenyl)-3,5,5trimethyl-, (E)-

31162-45-5 58023-72-6

1

1

1

3-Cyclohexen-1-ol, 4-(3-hydroxy-1-butynyl)-3,5,5trimethyl-

6

3

1 2

CH3

OH CH2

II.A-5

OH

CH3

CH3 HO

121269-03-2

II.A-5

OH

H3C

CH3

II.A-5 II.A-5 OH

HO

562-74-3

1

1

1

3-Cyclohexen-1-ol, 4-methyl-1-(1-methylethyl){4-carvomenthol}

II.A-5

23811-18-9

0

1

0

3-Cyclohexen-1-ol, 3,5,5-trimethyl-, (±)-

II.A-5

930-68-7

1

1

1

2-Cyclohexen-1-one

74051-80-2

0

1

0

2-Cyclohexen-1-one, 2-[1-(ethoximino)butyl]-5-[2(ethylthio)-propyl]-3-hydroxy{Sethoxydim®}

III-13

10316-66-2

1

0

0

2-Cyclohexen-1-one, 2-hydroxy-

II.A-5, III-13

490-03-9

0

1

0

2-Cyclohexen-1-one, 2-hydroxy-3-methyl{diosphenol}

II.A-5, III-13

65310-49-1

1

0

0

2-Cyclohexen-1-one, 2-hydroxy-3-propyl-

II.A-5, III-13

1121-18-2

1

0

0

2-Cyclohexen-1-one, 2-methyl-

III-13

99-49-0

1

1

1

2-Cyclohexen-1-one, 2-methyl-5-(1-methylethenyl){l-carvone}

III-13

2244-16-8

0

1

0

2-Cyclohexen-1-one, 2-methyl-5-(1-methylethenyl){d-carvone}

III-13

1

0

0

2-Cyclohexen-1-one, 2-propyl-3-methyl- {2 isomers}

III-13

1

0

0

2-Cyclohexen-1-one, 2,4,4-trimethyl-3-(1,3butadienyl)-

III-13

II.A-5, III-13, XXI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1559

11/24/08 1:56:00 PM

1560

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

27185-77-9

0

1

0

2-Cyclohexen-1-one, 2,4,4-trimethyl-3-(3-oxo-1butenyl)-

III-13

20013-73-4

0

1

0

2-Cyclohexen-1-one, 2,6,6-trimethyl-

III-13

Name (per CA Collective Index)

Selected structures

Chapter Table

5220-49-5

1

0

0

2-Cyclohexen-1-one, 3-amino-

67401-25-6

0

1

0

2-Cyclohexen-1-one, 3-(2-butenyl)-2,4,4-trimethyl-, (Z)-

III-13, XII-2 III-13

1193-18-6

1

0

0

2-Cyclohexen-1-one, 3-methyl-

III-13

89-81-6

0

1

0

2-Cyclohexen-1-one, 3-methyl-6-(1-methylethyl){D-piperitone}

III-13

0

1

0

2-Cyclohexen-1-one, 3-methyl-2-(1,3-pentadienyl)-

III-13

78-59-1

1

1

1

2-Cyclohexen-1-one, 3,5,5-trimethyl{isophorone}

III-13

133304-85-5

1

0

0

2-Cyclohexen-1-one, 3,4-dimethyl-2-hydroxy-

II.A-5, III-13

2748-09-6

1

0

0

2-Cyclohexen-1-one, 3,5-dimethyl-2-hydroxy-

II.A-5, III-13

2748-08-5

1

0

0

2-Cyclohexen-1-one, 3,6-dimethyl-2-hydroxy-

II.A-5, III-13

41577-83-7

1

0

0

2-Cyclohexen-1-one, 3-ethyl-2-hydroxy-

II.A-5, III-13

51771-56-3

1

1

1

2-Cyclohexen-1-one, 3,5,5-trimethyl-2-(1methylethenyl)-

III-13

53398-09-7

0

1

0

2-Cyclohexen-1-one, 3,5,5-trimethyl-4-(1-oxo-2butenyl)-

III-13

60026-25-7

1

1

1

2-Cyclohexen-1-one, 3,5,5-trimethyl-4-(1-propenyl)-

III-13

33601-06-8

0

1

0

2-Cyclohexen-1-one, 3,5,5-trimethyl-4-(3-oxo-1butenyl)-, (R)-(+)-

III-13

20548-00-9

0

1

0

2-Cyclohexen-1-one, 3,5,5-trimethyl-4-methylene{methyleneisophorone}

III-13

5896-02-6

1

1

1

2-Cyclohexen-1-one, 4-(1,3-butadienyl)-3,5,5trimethyl-

III-13 O

38818-55-2

1

0

0

2-Cyclohexen-1-one, 4-(1,3-butadienyl)-3,5,5trimethyl-, (E)-

77761-55-8

0

1

0

2-Cyclohexen-1-one, 4-(2,3-dihydroxybutylidene)3,5,5-trimethyl-

II.A-5, III-13

77842-24-1

0

1

0

2-Cyclohexen-1-one, 4-(2,3-dihydroxybutylidene)3,5,5-trimethyl{isomer}

II.A-5, III-13

1

0

0

2-Cyclohexen-1-one, 4-(1,3-butadienyl)-3,5,5triethyl-

III-13

1

0

0

2-Cyclohexen-1-one, 4-(1,3-butadienyl)-3,5,5trimethyl-

III-13

1

0

0

2-Cyclohexen-1-one, 4-(2-butenyl)-3,5,5-trimethyl-

III-13

13215-88-8

1

1

1

2-Cyclohexen-1-one, 4-(2-butenylidene)-3,5,5trimethyl-

III-13

5164-78-3

1

1

1

2-Cyclohexen-1-one, 4-(2-butenylidene)-3,5,5trimethyl-, (E,E){megastigmatrienone} {trans-, trans-K1a}

5896-02-6

5298-13-5

1

1

1

2-Cyclohexen-1-one, 4-(2-butenylidene)-3,5,5trimethyl-, (E,Z){trans-,cis-K2a}

III-13

III-13 O

III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1560

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1561

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

5492-79-5

1

1

1

2-Cyclohexen-1-one, 4-(2-butenylidene)-3,5,5trimethyl-, (Z,E){cis-, trans-K1b}

III-13

5164-79-4

1

1

1

2-Cyclohexen-1-one, 4-(2-butenylidene)-3,5,5trimethyl-, (Z,Z){cis-, cis-K2b}

III-13

1

1

1

2-Cyclohexen-1-one, 4-(3-butenylidene)-3,5,5trimethyl-

III-13

0

1

0

2-Cyclohexen-1-one, 4-ethyl-

III-13

62512-22-5

0

1

0

2-Cyclohexen-1-one, 4-[3-(E-D-glucopyranosyloxy)1-butenyl]-3,5,5-trimethyl-

II.A-5, III-13, X-2

77699-19-5

0

1

0

2-Cyclohexen-1-one, 4-[3-(E-D-glucopyranosyloxy)1-butenyl]-3,5,5-trimethyl-, [R-[R*,R*-(E)]]-

II.A-5, III-13, X-2

159813-37-3

0

1

0

2-Cyclohexen-1-one, 4-[3-(E-D-glucopyranosyloxy)1-butenyl]-3,5,5-trimethyl-, [4R-[4R*(1E,3S*)]]-

II.A-5, III-13, X-2

54835-70-0

0

1

0

2-Cyclohexen-1-one, 4-[3-(E-D-glucopyranosyloxy)1-butenyl]-4-hydroxy-3,5,5-trimethyl-, [R-[R*,S*(E)]]-

II.A-5, III-13, X-2

62512-23-6

0

1

0

2-Cyclohexen-1-one, 4-[3-(E-Dglucopyranosyloxy)butyl]-3,5,5-trimethyl-

II.A-5, III-13, X-2

91048-13-4

0

1

0

2-Cyclohexen-1-one, 4-[3-(E-Dglucopyranosyloxy)butylidene]-3,5,5-trimethyl-

II.A-5, III-13, X-2

34318-21-3

1

1

1

2-Cyclohexen-1-one, 4-(3-hydroxy-1-butenyl)-3,5,5trimethyl{4-keto-D-ionol}

Name (per CA Collective Index)

Selected structures

H3C

II.A-5, III-13

OH

CH3

Chapter Table

CH3 CH3

O

52210-15-8

1

1

1

2-Cyclohexen-1-one, 4-(3-hydroxy-1-butenyl)-3,5,5trimethyl-, [R-[R*,R*-(E)]]-

II.A-5, III-13

68759-08-0

1

1

1

2-Cyclohexen-1-one, 4-(3-hydroxy-1-butenyl)-3,5,5trimethyl-, [S-[R*,S*-(E)]]-

II.A-5, III-13

60047-19-0

1

1

1

2-Cyclohexen-1-one, 4-(3-hydroxybutyl)-3,5,5trimethyl{4-ketodihydro-D-ionol}

II.A-5, III-13

36151-02-7

1

1

1

2-Cyclohexen-1-one, 4-(3-hydroxybutyl)-3,5,5trimethyl-, [R-(R*,R*)]-

II.A-5, III-13

60026-24-6

1

1

1

2-Cyclohexen-1-one, 4-(3-hydroxybutylidene)-3,5,5trimethyl-

II.A-5, III-13

19620-37-2

0

1

0

2-Cyclohexen-1-one, 4-hydroxy-2,6,6-trimethyl-

14203-59-9

0

1

0

2-Cyclohexen-1-one, 4-hydroxy-3,5,5-trimethyl-

II.A-5, III-13

24427-77-8

1

0

0

2-Cyclohexen-1-one, 4-hydroxy-4-(3-hydroxy-1butenyl)-3,5,5-trimethyl{vomifoliol}

II.A-5, III-13

II.A-5, III-13

0

1

0

2-Cyclohexen-1-one, 4-(1-methylethyl)-

III-13

51171-72-3

1

0

0

2-Cyclohexen-1-one, 4-phenyl-

III-13

1073-13-8

1

0

0

2-Cyclohexen-1-one, 4,4-dimethyl-

III-13

5715-25-3

0

1

0

2-Cyclohexen-1-one, 4,5-dimethyl-

7712-46-1

0

1

0

2-Cyclohexen-1-one, 5-(1-hydroxy-1-methylethyl)-2methyl-

III-13 II.A-5, III-13

O

OH

56691-69-1

0

1

0

2-Cyclohexen-1-one, 5-[1-(acetyloxy)-1methylethyl]-2-methyl-, (R)-

499-74-1

1

0

0

2-Cyclohexen-1-one, 6-methyl-3-(1-methylethyl)-

III-13, V-3 III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1561

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1562

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 4096-34-8

S

T

S T

Name (per CA Collective Index)

Chapter Table

Selected structures

1

0

0

3-Cyclohexen-1-one

III-13

0

1

0

3-Cyclohexen-1-one, 4-(1-butenyl)-3,5,5-trimethyl-

III-13

471-01-2

1

0

0

3-Cyclohexen-1-one, 3,5,5-trimethyl-

III-13

4657-58-3

0

1

0

9,19-Cyclolanostan-3-ol, (3E)-

II.B-2

26955-76-0

0

1

0

9,19-Cyclolanostan-3-ol, 24,25-epoxy-, (3E)-

II.B-2

1449-09-8

0

1

0

9,19-Cyclolanostan-3-ol, 24-methylene-, (3E)-

469-38-5

1

0

0

9,19-Cyclolanost-24-en-3-ol, (3E)-

II.B-2 CH3

{cycloartenol}

CH3

CH3 CH3 HO H3C

CH3

CH3

II.B-2 25692-13-1

0

1

0

9,19-Cyclolanost-24-en-3-ol, 24-methyl-, (3E)-

II.B-2

51088-90-5

0

1

0

9,19-Cyclolanost-25-en-3-ol, 24-methyl-, (3E,24S)-

II.B-2

511-61-5

0

1

0

9,19-Cyclolanost-25-en-3-ol, 24-methyl-, (3E,24S)-

II.B-2

124713-05-9

0

1

0

9,19-Cyclolanost-5-en-3-ol, 24-methylene-, (3E)-

II.B-2

629-20-9

1

0

0

1,3,5,7-Cyclooctatetraene

I.C-1

149331-19-1

0

1

0

Cyclononane, 1,1,4,4,7,7-hexamethyl-

I.C-1

202-98-2

1

0

0

4H-Cyclopenta[def]chrysene {4,5-methylenechrysene}

I.E-6

126458-49-9

0

1

0

4HCyclopenta[3',4']cycloocta[1',2':1,5]cyclopent[1,2b]oxiren-4-one, 1,2,2a,5,6,8,9,10,10a,10bdecahydro-2,6,10a-trimethyl-8-(1-methylethyl)-, [2aS-(2aD,3aS*,6E,8E,10aE,10bE)]-

III-13

86154-08-7

0

1

0

4HCyclopenta[3',4']cycloocta[1',2':1,5]cyclopent[1,2b]oxiren-4-one, 1,2,2a,7,7a,8,9,10,10a,10bdecahydro-2a,6,10a-trimethyl-8-(1-methylethyl)-, (2aD,3aR*,7aE,8E,10aE,10bE)-

III-13

142750-43-4

0

1

0

Cyclopentacycloundecene, tetradecahydro-1,4,8trimethyl-11-(1-methylethyl)-

I.C-1

142750-40-1

0

1

0

4,10(1H,5H)-Cyclopentacycloundecenedione, 2,3,3a,6,7,11,12,12a-octahydro-1,3,12-trihydroxy3,8,12-trimethyl-5-(1-methylethyl)-, (1R*,3S*,3aR*,5S*,8Z,12R*,12aR*)-(-)-

III-13

541-91-3

0

1

0

Cyclopentadecanone, 3-methyl-

III-13

542-92-7

1

0

0

1,3-Cyclopentadiene

1

0

0

1,3-Cyclopentadiene, dimethyl-

I.C-1

1

0

0

1,3-Cyclopentadiene, ethyl-

I.C-1

26519-92-6

{pyropentylene}

I.C-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1562

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1563

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

26519-91-5

1

0

0

1,3-Cyclopentadiene, methyl-

I.C-1

33320-27-3

1

0

0

1,3-Cyclopentadiene-1-carboxaldehyde

III-12

4784-86-5

1

0

0

1,3-Cyclopentadiene, 1,2-dimethyl-

I.C-1

4045-53-8

1

0

0

1,3-Cyclopentadiene, 1,3-dimethyl-

I.C-1

96-39-9

1

0

0

1,3-Cyclopentadiene, 1-methyl-

I.C-1

96-38-8

1

0

0

1,3-Cyclopentadiene, 5-methyl-

I.C-1

497-20-1

Name (per CA Collective Index)

1

0

0

1,3-Cyclopentadiene, 5-methylene-

1

0

0

2,4-Cyclopentadien-1-one, 2,3-dimethyl-4-hydroxy-

Selected structures

{fulvene}

Chapter Table

I.C-1 II.A-5, III-13

94618-71-0

1

0

0

2,4-Cyclopentadien-1-one, 2-methyl-

III-13

193-54-4

1

0

0

Cyclopenta[cd]fluoranthene

I.E-6

0

1

0

Cyclopenta[b]furan, 3-acetyl-4-pentyl-

C5H11

III-13, X-2

COCH3

O

1

1

1

Cyclopenta[b]furan-6-one, 4,5-dihydro-2-methyl-

CH3

III-13, X-2

O O

1162-65-8

0

1

0

Cyclopenta[c]furo[3',2':4,5]furo[2,3-h][1]benzopyran1,11-dione, 2,3,6a,9a-tetrahydro-4-methoxy-, (6aR-cis){aflatoxin B1}

O

O

III-13, VI-3, X-2

O O O

7220-81-7

0

1

0

Cyclopenta[c]furo[3',2':4,5]furo[2,3-h][1]benzopyran1,11-dione, 2,3,6a,8,9,9a-hexahydro-4-methoxy-, (6aR-cis){aflatoxin B2}

287-92-3

1

0

0

Cyclopentane

2452-99-5

1

0

0

Cyclopentane, 1,2-dimethyl-, cis-

{pentamethylene}

OCH3

III-13, VI-3, X-2

I.C-1 I.C-1

822-50-4

1

0

0

Cyclopentane, 1,2-dimethyl-, trans-

I.C-1

96-37-7

1

0

0

Cyclopentane, methyl-

I.C-1

53366-54-4

1

0

0

Cyclopentane, (2-methylbutylidene)-

I.C-1

53366-58-8

1

0

0

Cyclopentane, (2-methylpropylidene)-

I.C-1

79637-61-9

1

0

0

Cyclopentane, propenyl-

I.C-1

1

0

0

Cyclopentane, propyl-

I.C-1

30498-64-7

1

0

0

Cyclopentane, trimethyl-

I.C-1

20497-93-2

0

1

0

Cyclopentanecarboxaldehyde, 2-hydroxy-1-methyl{2 isomers}

III-12

3400-45-1

0

1

0

Cyclopentanecarboxylic acid {cyclopentanoic acid}

IV.A-3

38655-27-5

0

1

0

Cyclopentanecarboxylic acid, 1-methyl-3-(1methylethenyl)-

IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1563

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1564

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

66016-71-5

0

1

0

1,2-Cyclopentanedicarboxylic acid, 1-methyl-3-(1methylethyl)-

28473-29-2

1

0

0

Cyclopentanedione

3008-40-0

Name (per CA Collective Index)

{2 isomers}

Selected structures

Chapter Table IV.A-3 III-13

1

1

1

1,2-Cyclopentanedione

III-13

0

1

0

1,2-Cyclopentanedione, 4-acetyl-

III-13

1

0

0

1,2-Cyclopentanedione, 3,4-diethyl-

III-13

54362-49-1

1

0

0

1,2-Cyclopentanedione, 3,5-diethyl-

III-13

72692-92-3

1

1

1

1,2-Cyclopentanedione, 3,3-dimethyl-

III-13

13494-06-9

1

1

1

1,2-Cyclopentanedione, 3,4-dimethyl-

III-13

13494-07-0

1

1

1

1,2-Cyclopentanedione, 3,5-dimethyl-

III-13

13494-08-1

71608-11-2

1

0

0

1,2-Cyclopentanedione, 3-ethyl-

III-13

1

0

0

1,2-Cyclopentanedione, 3-ethyl-3-methyl-

III-13

1

0

0

1,2-Cyclopentanedione, 3-ethyl-4-methyl-

III-13

1

0

0

1,2-Cyclopentanedione, 3-ethyl-5-methyl- = 1,2Cyclopentanedione, 5-ethyl-3-methyl-

III-13

1

0

0

1,2-Cyclopentanedione, hydroxy-

II.A-5, III-13

765-70-8

1

1

1

1,2-Cyclopentanedione, 3-methyl-

60386-55-2

1

0

0

1,2-Cyclopentanedione, 3-(1-methylethyl)-

{cyclotene}

III-13

72693-09-5

1

0

0

1,2-Cyclopentanedione, 4-(1-methylethyl)-

III-13

71608-12-3

1

0

0

1,2-Cyclopentanedione, 3-methyl-5-propyl-

III-13

69745-71-7

1

0

0

1,2-Cyclopentanedione, 3-phenyl-

III-13

III-13

4542-64-7

1

0

0

1,2-Cyclopentanedione, 4-phenyl-

III-13

23747-37-7

1

0

0

1,2-Cyclopentanedione, 3-propyl-

III-13

3859-41-4

0

1

0

1,3-Cyclopentanedione

III-13

34598-80-6

1

0

0

1,3-Cyclopentanedione, 2,4-dimethyl-

III-13

823-36-9

1

0

0

1,3-Cyclopentanedione, 2-ethyl-

III-13

765-69-5

1

0

0

1,3-Cyclopentanedione, 2-methyl-

III-13

120-92-3

1

1

1

Cyclopentanone

55713-44-5

0

1

0

Cyclopentanone, 2,2-dimethyl-4-(2-oxopropyl)-

{adipic ketone}

III-13 III-13

4041-09-2

1

0

0

Cyclopentanone, 2,5-dimethyl-

III-13

4971-18-0

1

0

0

Cyclopentanone, 2-ethyl-

III-13

10264-55-8

1

0

0

Cyclopentanone, 3-ethyl-

III-13

1

0

0

Cyclopentanone, 2-ethylidene-

III-13

1

0

0

Cyclopentanone, 2-hydroxy-

III-13

28631-88-1

1

0

0

Cyclopentanone, methyl-

III-13

1120-72-5

1

0

0

Cyclopentanone, 2-methyl-

III-13

1

0

0

Cyclopentanone, 2-(1-methylpropyl)-

III-13

1

0

0

Cyclopentanone, 3-methyl-

III-13

1757-42-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1564

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1565

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

189-01-5

1

0

0

1

0

1

0

1

0

1 219-07-8

Name (per CA Collective Index)

Selected structures

Chapter Table

Cyclopenta[cd]perylene

I.E-6

0

Cyclopenta[cd]perylene, methyl-

I.E-6

0

Cyclopenta[a]phenalene

I.E-6

0

Cyclopentaphenanthrene {at least 2 isomers in MSS}

I.E-6

0

0

Cyclopentaphenanthrene, methyl{at least 2 isomers in MSS}

I.E-6

1

0

0

15H-Cyclopenta[a]phenanthrene

I.E-6

482-66-6

1

0

0

15H-Cyclopenta[a]phenanthrene, 16,17-dihydro-

I.E-6

219-08-9

1

0

0

17H -Cyclopenta[a]phenanthrene

I.E-6

71277-92-4

1

0

0

17H -Cyclopenta[a]phenanthrene, ethyl-

I.E-6

71277-93-5

1

0

0

17H -Cyclopenta[a]phenanthrene, methyl-

I.E-6

203-64-5

1

0

0

4H -Cyclopenta[def]phenanthrene {4,5-methylenephenanthrene}

I.E-6

71277-91-3

1

0

0

4H-Cyclopenta[def]phenanthrene, dimethyl-

I.E-6

65319-51-9

1

0

0

4H-Cyclopenta[def]phenanthrene, ethyl-

I.E-6

58548-39-3

1

0

0

4H-Cyclopenta[def]phenanthrene, methyl-

I.E-6

1

0

0

Cyclopenta[l]phenanthrene, dihydro-

I.E-6

1

0

0

5H-Cyclopentapyrazine

211-95-0

25042-83-5

5

XVII.E-6

4

N

3

6 2 7

38917-63-4

1

0

0

5H-Cyclopentapyrazine, 6,7-dihydro-2,3-dimethyl-

N 1

XVII.E-6

1

0

0

5H-Cyclopentapyrazine, 6,7-dihydro-5,7-dimethyl-

XVII.E-6

38917-60-1

1

0

0

5H-Cyclopentapyrazine, 6,7-dihydro-2-ethyl-

XVII.E-6

23747-46-8

1

1

1

5H-Cyclopentapyrazine, 6,7-dihydro-2-methyl-

XVII.E-6

23747-48-0

1

1

1

5H-Cyclopentapyrazine, 6,7-dihydro-5-methyl-

XVII.E-6

© 2009 by Taylor & Francis Group, LLC

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1566

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

61891-57-4

1

0

0

5H-Cyclopentapyrazine, dimethyl-

42315-22-0

1

0

0

Cyclopenta[a]pyrene

XVII.E-6 I.E-6

1

0

0

Cyclopenta[a]pyrene, 3,4-dihydro{sometimes listed as 3,4-Trimethylenepyrene}

I.E-6

1

0

0

Cyclopenta[a]pyrene, 3,4-dihydromethyl-

I.E-6

27208-37-3

1

0

0

Cyclopenta[cd]pyrene

I.E-6

25732-74-5

1

0

0

Cyclopenta[cd]pyrene, 3,4-dihydro-

I.E-6

64760-18-5

1

0

0

Cyclopenta[cd]pyrene, 3,4-dihydromethyl-

I.E-6

23992-32-7

1

0

0

4H-Cyclopenta[def]triphenylene {4,5-methylenetriphenylene}

I.E-6

142-29-0

1

0

0

Cyclopentene

0

1

0

Cyclopentene, 2-acetyl-4-hydroxy-4-(1-methylethyl)-

0

1

0

Cyclopentene, 2,3-diacetyl-1-(1-methylethyl)-

I.C-1

II.A-5, III-13 H3C

III-13

CH3 1

CO-CH3

2 3

4

CO-CH3

0

1

0

Cyclopentene, 2,3-diacetyl-4-(1-methylethyl)-

H3C 4

1

III-13

CH3

3

CO-CH3

2

CO-CH3

1 28638-58-6 2146-38-5

0

0

Cyclopentene, ethenyl-

I.C-1

1

0

0

Cyclopentene, 1-ethenyl-

I.C-1

1

0

0

Cyclopentene, ethyl-

I.C-1

1

0

0

Cyclopentene, 1-ethyl-

I.C-1

693-89-0

1

0

0

Cyclopentene, 1-methyl-

I.C-1

1120-62-3

1

0

0

Cyclopentene, 3-methyl-

I.C-1

1759-81-5

1

0

0

Cyclopentene, 4-methyl-

I.C-1

3074-61-1

1

0

0

Cyclopentene, 1-propyl-

56169-12-1

0

1

0

1-Cyclopentene-1-carboxylic acid, 2-methyl-5-(1methylethyl)-

I.C-1 COOH

CH3

IV.A-3

H3C CH3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1566

11/24/08 1:56:02 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1567

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 28750-51-8 2687-69-6

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

3-Cyclopentene-1,2-dione

III-13

1

0

0

3-Cyclopentene-1,2-dione, 3,4-dimethyl-

III-13

1

0

0

3-Cyclopentene-1,2-dione, 3,5-dimethyl-

III-13

1

0

0

3-Cyclopentene-1,2-dione, 3-ethyl-4-methyl-

III-13

10130-95-7

1

0

0

3-Cyclopentene-1,2-dione, 3-methyl-

III-13

66309-79-3

1

0

0

3-Cyclopentene-1,2-dione, 4-methyl-

III-13

930-60-9

0

1

0

4-Cyclopentene-1,3-dione

III-13

18515-43-0

1

0

0

4-Cyclopentene-1,3-dione, 4,5-dimethyl-

III-13

53109-18-5

0

1

0

1-Cyclopentene-1-pentanoic acid, G-hydroxy-3,5bis(1-methylpropyl)-E-oxo-

III-13

28982-58-3

1

0

0

Cyclopentenone

III-13

930-30-3

1

0

0

2-Cyclopenten-1-one

24105-07-5

1

0

0

2-Cyclopenten-1-one, C3-alkyl-

{cyclopenten-3-one}

III-13 III-13

1

0

0

2-Cyclopenten-1-one, C4-alkyl-

III-13

72692-71-8

1

0

0

2-Cyclopenten-1-one, dimethyl-

III-13

61205-39-8

1

0

0

2-Cyclopenten-1-one, ethyl-2-hydroxy-

II.A-5, III-13

21835-01-8

1

0

0

2-Cyclopenten-1-one, 3-ethyl-2-hydroxy-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, ethyl-methyl-

III-13

1

0

0

2-Cyclopenten-1-one, methyl-

III-13

1

0

0

2-Cyclopenten-1-one, phenyl-

III-13

1

0

0

2-Cyclopenten-1-one, trimethyl-

17190-74-8

0

1

0

2-Cyclopenten-1-one, 2-(2-butenyl)-4-hydroxy-3methyl-

78210-65-8

1

0

0

2-Cyclopenten-1-one, 2-(2-furanyl)-

61892-84-0

1

0

0

2-Cyclopenten-1-one, 2-(2-oxopropyl)-

80-72-8

1

0

0

2-Cyclopenten-1-one, 2,3-dihydroxy{reductic acid}

III-13 II.A-5, III-13 III-13, X-2 III-13 II.A-5, III-13 O

HO OH

1121-05-7

1

1

1

2-Cyclopenten-1-one, 2,3-dimethyl-

III-13

3779-64-4

1

0

0

2-Cyclopenten-1-one, 2,3-dimethyl-4-(1methylethyl)-

III-13

61893-14-9

0

1

0

2-Cyclopenten-1-one, 2,3-dimethyl-5-(1methylethyl)-

III-13

28790-86-5

1

0

0

2-Cyclopenten-1-one, 2,3,4-trimethyl-

III-13

5456-24-5

1

0

0

2-Cyclopenten-1-one, 2,3,5-trimethyl-

III-13

66309-82-8

1

0

0

2-Cyclopenten-1-one, 2,4,5-trimethyl-

III-13

23048-13-7

1

0

0

2-Cyclopenten-1-one, 2,4-dimethyl-

III-13

4041-11-6

1

0

0

2-Cyclopenten-1-one, 2,5-dimethyl-

III-13

2931-10-4

1

0

0

2-Cyclopenten-1-one, 2-ethyl-

III-13

5682-72-4

1

0

0

2-Cyclopenten-1-one, 2-ethyl-3-methyl-

III-13

78210-64-7

1

0

0

2-Cyclopenten-1-one, 2-ethyl-5-methyl-

III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-3-(1-butyl)-

II.A-5, III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1567

11/24/08 1:56:02 PM

1568

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

80-71-7

1

1

1

2-Cyclopenten-1-one, 2-hydroxy-3-methyl{methylcyclopentenolone}

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-3-(2-methylbutyl)-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-3-(3-methylbutyl)-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-3-methyl-4-(1methylethyl)-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-3-(1-methylethyl)-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-3-(1-methylpropyl)-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-3-(2-methylpropyl)-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-3-methyl-4-propyl-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-3-methyl-5-propyl-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-4-methyl-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-4-methyl-3-propyl-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-3-pentyl-

II.A-5, III-13

25684-04-2

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-3-propyl-

II.A-5, III-13

82147-26-0

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-4-propyl-

II.A-5, III-13

61205-40-1

Name (per CA Collective Index)

Selected structures

Chapter Table

1

1

1

2-Cyclopenten-1-one, 2-hydroxypropyl-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-hydroxy-3,4,5-trimethyl-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 2-methoxy-

III-13, X-2

14189-85-6

1

0

0

2-Cyclopenten-1-one, 2-methoxy-3-methyl-

III-13, X-2

1120-73-6

1

0

0

2-Cyclopenten-1-one, 2-methyl-

5760-58-7

1

0

0

2-Cyclopenten-1-one, 2-methyl-3-propyl-

III-13

61892-83-9

1

0

0

2-Cyclopenten-1-one, 2-methyl-4-(1-methylethyl)-

III-13

III-13

31089-17-5

1

0

0

2-Cyclopenten-1-one, 2-methyl-5-(1-methylethyl)-

III-13

66309-80-6

1

0

0

2-Cyclopenten-1-one, 2-methyl-5-methylene-

III-13

24105-07-5 1619-28-9

1

0

0

2-Cyclopenten-1-one, 2-propyl-

III-13

1

0

0

2-Cyclopenten-1-one, 3-(2-furanyl)-

III-13

1

0

0

2-Cyclopenten-1-one, 3-(1-methylethyl)-

1

0

0

2-Cyclopenten-1-one, 3,4-diethyl-2-hydroxy-

1

0

0

2-Cyclopenten-1-one, 3,4-dimethyl-

1

0

0

2-Cyclopenten-1-one, 3,4-dimethyl-2-hydroxy-

0

1

0

2-Cyclopenten-1-one, 3,4-dimethyl-2-(1methylethyl)-

1

0

0

2-Cyclopenten-1-one, 3,5-diethyl-2-hydroxy-

1

1

1

2-Cyclopenten-1-one, 3,5-dimethyl-

1

0

0

2-Cyclopenten-1-one, 3,5-dimethyl-2-4-ethylhydroxy-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 3,5-dimethyl-2-hydroxy-

II.A-5, III-13

0

1

0

2-Cyclopenten-1-one, 3,5-dimethyl-2-(1methylethyl)-

III-13

5682-69-9

1

0

0

2-Cyclopenten-1-one, 3-ethyl-

III-13

21835-01-8

1

0

0

2-Cyclopenten-1-one, 3-ethyl-2-hydroxy{ethylcyclopentenolone}

30434-64-1 72692-76-3

931-22-6

III-13 II.A-5, III-13 III-13 II.A-5, III-13 III-13 II.A-5, III-13 III-13

II.A-5, III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1568

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1569

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

41496-77-9 78210-63-6

5870-63-3

S

T

S T

1

0

0

2-Cyclopenten-1-one, 3-ethyl-2-hydroxy-4-methyl-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 3-ethyl-2-hydroxy-5-methyl-

II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 3-ethyl-2-methoxy-

III-13

1

1

1

2-Cyclopenten-1-one, 3-ethyl-2-methyl-

III-13

Name (per CA Collective Index)

Chapter Table

Selected structures

1

0

0

2-Cyclopenten-1-one, 3-ethyl-4-hydroxy-

III-13

1

0

0

2-Cyclopenten-1-one, 3-ethyl-4-methyl-

III-13

1

0

0

2-Cyclopenten-1-one, 3-ethyl-5-methyl-

0

1

0

2-Cyclopenten-1-one, 3-hydroxy-2-methyl-

III-13 II.A-5, III-13

2758-18-1

1

1

1

2-Cyclopenten-1-one, 3-methyl-

III-13

3727-35-3

1

1

1

2-Cyclopenten-1-one, 3-methyl-2-(2-oxopropyl)-

III-13

1

0

0

2-Cyclopenten-1-one, 3-methyl-2-(1,3-pentadienyl)-

III-13

488-10-8

0

1

0

2-Cyclopenten-1-one, 3-methyl-2-(2-pentenyl)-, (Z)-

III-13

1

0

0

2-Cyclopenten-1-one, 3-(2-oxopropyl)-

III-13

3810-26-2

1

0

0

2-Cyclopenten-1-one, 3-phenyl-

III-13

35953-18-5

1

0

0

2-Cyclopenten-1-one, 3-propyl-

III-13

30434-65-2

0

1

0

2-Cyclopenten-1-one, 3,4,4-trimethyl-

1

0

0

2-Cyclopenten-1-one, 4-ethyl-2-hydroxy-

II.A-5, III-13

III-13 II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 4-ethyl-2-hydroxy-3-methyl-

71278-13-2

1

0

0

2-Cyclopenten-1-one, 4-ethyl-2-methyl-

10288-24-1

1

0

0

2-Cyclopenten-1-one, 4-hydroxy-3-methyl-

23415-96-7

1

0

0

2-Cyclopenten-1-one, 4-methyl-

III-13

66309-81-7

1

0

0

2-Cyclopenten-1-one, 4-methyl-3-(1-propenyl)-

III-13

III-13 II.A-5, III-13

1

0

0

2-Cyclopenten-1-one, 5-ethyl-2-hydroxy-3-methyl-

II.A-5, III-13

70919-26-5

1

0

0

2-Cyclopenten-1-one, 5-hydroxy-

II.A-5, III-13

70919-27-6

1

0

0

2-Cyclopenten-1-one, 5-hydroxy-3-methyl-

II.A-5, III-13

14963-40-7

1

0

0

2-Cyclopenten-1-one, 5-methyl-

14320-37-7

III-13

1

0

0

3-Cyclopenten-1-one

III-13

0

1

0

3-Cyclopenten-1-one, 3-(1-methylethyl)-

III-13

1630-94-0

1

0

0

Cyclopropane, 1,1-dimethyl-

I.C-1

2511-95-7

1

0

0

Cyclopropane, 1,2-dimethyl-

I.C-1

930-18-7

1

0

0

Cyclopropane, 1,2-dimethyl-, (Z)-

I.C-1

2402-06-4

1

0

0

Cyclopropane, 1,2-dimethyl-, (E)-

22059-21-8

0

1

0

Cyclopropanecarboxylic acid, 1-amino-

91465-08-6

0

1

0

Cyclopropanecarboxylic acid, 3-(2-chloro-3,3,3trifluoro-1-propenyl)-2,2-dimethyl-, cyano(3phenoxyphenyl)methyl ester {Ȝ-Cyhalothrin®}

52315-07-8

0

1

0

Cyclopropanecarboxylic acid, 3-(2,2dichloroethenyl)-2,2-dimethyl-, cyano(3phenoxyphenyl)methyl ester {Cypermethrin®}

I.C-1 IV.A-3, XII-2 V-3, XI-1, XVIII.B-3, XXI-3

Cl

H3C

CH3

O

O

Cl O

CN

V-3, X-2, XI-1, XVIII.B-3, XXI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1569

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1570

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

67375-30-8

0

1

0

Cyclopropanecarboxylic acid, 3-(2,2dichloroethenyl)-2,2-dimethyl-, cyano(3phenoxyphenyl)methyl ester {Į-Cypermethrin®}

121-29-9

0

1

0

Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(3methoxy-2-methyl-3-oxo-1-propenyl)-, 2-methyl-4oxo-3-(2,4-pentadienyl)-2-cyclopenten-1-yl ester {Pyrethrin II®}

7696-12-0

0

1

0

Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2methyl-1-propenyl)-, (1-cyclohexene-1,2dicarboximido)methyl ester {Tetramethrin®}

Name (per CA Collective Index)

Chapter Table

Selected structures

V-3, X-2, XI-1, XVIII.B-3, XXI-3

V-3, XXI-3

O CH3

CH3

H3C

N

O

H3C

O O

V-3, X-2, XXI-3 121-21-1

0

1

0

Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2methyl-1-propenyl)-, 2-methyl-4-oxo-3-(2,4pentadienyl)-2-cyclopenten-1-yl ester {Pyrethrin I®}

10453-86-8

0

1

0

Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2methylpropenyl)-, (5-phenylmethyl-3furanyl)methyl ester {Resmethrin®}

52918-63-5

0

1

0

Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2,2dibromoethenyl)-, cyano(3-phenoxyphenyl)methyl ester {Deltamethrin®}

V-3, XVIII.B-3, XXI-3

XXI-3

Br

H3C

CH3

O

O

Br

CN

O

V-3, X-2, XI-1, XVIII.B-3, XXI-3 52645-53-1

0

1

0

Cyclopropanecarboxylic acid, 2,2-dimethyl-3dichloroethenyl-, (3-phenoxyphenyl)methyl ester {Permethrin®; Spartan®}

Cl

H3C

CH3

O

O

Cl O

V-3, X-2, XVIII.B-3, XXI-3 68359-37-5

0

1

0

Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2,2dichloroethenyl)-, cyano(4-fluoro-3phenoxyphenyl)methyl ester {Cyfluthrin®}

F Cl

H3C

CH3

O

O

Cl

CN

O

V-3, X-2, XI-1, XVIII.B-3, XXI-3 97-41-6

0

1

0

Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2methylpropenyl)-, ethyl ester

V-3

5460-63-9

0

1

0

Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2methylpropenyl)-, methyl ester

V-3

25402-06-6

0

1

0

Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2methyl-1-propenyl)-, 3-(2-butenyl)-2-methyl-4-oxo2-cyclopenten-1-yl ester {Cinerin I®}

XXI-3

4466-14-2

0

1

0

Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2methyl-1-propenyl)-, 2-methyl-4-oxo-3-(2pentenyl)-2-cyclopenten-1-yl ester {Jasmolin 1®}

XXI-3

584-79-2

0

1

0

Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2methylpropenyl)-, 2-(1-propenyl)-4-hydroxy-3methyl-2-cyclopenten-1-one ester {Allethrin®}

O

O

O

V-3, XXI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1570

11/24/08 1:56:03 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1571

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

66841-25-6

0

1

0

Cyclopropanecarboxylic acid, 2,2-dimethyl-3(1,2,2,2-tetrabromoethyl)-, cyano(3phenoxyphenyl)methyl ester {Tralomethrin®}

39515-41-8

1

1

1

Cyclopropanecarboxylic acid, 2,2,3,3-tetramethyl cyano(3-phenoxyphenyl)methyl ester {Fenpropathrin®, Danitol®}

Name (per CA Collective Index)

Selected structures

Chapter Table XI-2, XXI-3

XI-2, XXI-3 82657-04-3

0

1

0

Cyclopropanecarboxylic acid, 3-[(1Z)-2-chloro-3,3,3trifluoro-1-propenyl]-2,2-dimethyl-, (2-methyl[1,1'biphenyl]-3-yl)methyl ester, (1R,3R)-rel{Bifenthrin®, Biphenthrin®}

17219-23-7

0

1

0

Cyclopropanecarboxylic acid, 2,3-dimethyl-

32809-16-8

0

1

0

1,2-Cyclopropanedicarboximide, N (3,5dichlorophenyl)-1,2-dimethyl{Procymidone®}

XXI-3

IV.A-3 O

N

Cl

O

18383-59-0

0

1

0

XVIII.B-3, XXI-3

Cl

Cyclopropanemethanol, 2,2-dimethyl-3-(2methylpropenyl){chrysanthemyl alcohol}

50906-50-8

0

1

0

9,19-Cyclostigmast-24(28)-en-3-ol, 4,14-dimethyl-, (3E,4D,5D,24Z)-

89288-59-5

0

1

0

4,13-Cyclotetradecadiene-1,3-diol, 8-hydroperoxy1,5-dimethyl-9-methylene-12-(1-methylethyl)-, [1S(1R*,3S*,4E,8R*,12R*,13E)]-

II.A-5 OH

II.B-2 H3C H2C

OH

9

11

8

6

HOO

12

7

1

13 4

5

0

1

0

4,13-Cyclotetradecadiene-1,3-diol, 8-hydroperoxy1,5-dimethyl-9-methylene-12-(1-methylethyl)-, [1R(1R*,3R*,4E,8S*,12S*,13E)]-

H3 C

OH

9

11 6

0

1

0

5,10-Cyclotetradecadiene-1,2,7,9-tetrol, 1,5,9trimethyl-12-(1-methylethyl)-, [1S(1R*,2R*,5E,7S*,9R*,10E,12R*)]-

7

4

H3C

OH 12

9 6

7

0

1

0

4,13-Cyclotetradecadiene-1,3,8-triol, 1,5-dimethyl-9methylene-12-(1-methylethyl)-, [1R(1R*,3R*,4E,8S*,12S*,13E)]-

1 4

5

OH

89362-09-4

II.A-5

CH3

10

8

CH3

2

3

OH

H3C OH

1

13 5

CH3

102734-57-6

II.A-5

CH3

12

8

HOO

CH3

OH

10

H2C

2

3

CH3

89362-05-0

II.A-5

CH3

10

2

CH3 OH

3

CH3

II.A-5 9

11

8

6

HO

14

12

10

7

1

13 4

5

OH 2

3

OH

91200-13-4

0

1

0

II.A-5

4,13-Cyclotetradecadiene-1,3,8-triol, 1,5-dimethyl-9methylene-12-(1-methylethyl)-, [1S(1R*,3S*,4E,8S*,12R*,13E)]HO

9

11

8

6 7

14

12

10

1

13 5

4

3

OH 2

OH

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1571

11/24/08 1:56:04 PM

1572

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

80802-00-2

0

1

0

Name (per CA Collective Index)

Selected structures

Chapter Table II.A-5

4,13-Cyclotetradecadiene-1,3,8-triol, 1,5-dimethyl-9methylene-12-(1-methylethyl)-

14

12

10 9

11

8

13

6

HO

1

4

5

7

OH 2

3

OH

91163-46-1

0

1

0

5,9-Cyclotetradecadiene-1,4,8-triol, 4,8-dimethyl-14methylene-11-(1-methylethyl)-, [1S(1R*,4R*,5E,8S*,9E,11R*)]-

H3C H2C

OH

9

13 14

12

1

3

HO

II.A-5

CH3

11

8

10 5

4

2

OH

H3C

CH3

7 6

90660-18-7

0

1

0

4,9-Cyclotetradecadien-1-one, 6,8-dihydroxy-4,8dimethyl-14-methylene-11-(1-methylethyl)-, [6R(4E,6R*,

II.A-5, III-13

119613-98-8

0

1

0

5,10-Cyclotetradecadien-1-one, 7,9-dihydroxy-7,11dimethyl-4-(1-methylethyl)-, [4S(4R*,5E,7R*,9S*,10E)]-

II.A-5, III-13

1786-12-5

0

1

0

Cyclotetradecane, 1,7,11-trimethyl-4-(1methylethyl)-

H3C

I.C-1

CH3

6

H3C

2

7

4

5 10

8

1

3

CH3

11

9

CH3

150405-76-8

0

1

0

1,3,6,10-Cyclotetradecatetraene, 3,7,11-trimethyl-

I.C-1

101159-08-4

1

1

1

1,3,6,10-Cyclotetradecatetraene, 3,7,11-trimethyl14-(1-methylethyl){cembrene}

I.C-1

1898-13-1

0

1

0

1,3,6,10-Cyclotetradecatetraene, 3,7,11-trimethyl14-(1-methylethyl)-, [S- (E,Z,E,E)]-

I.C-1

0

1

0

1,3,6,11-Cyclotetradecatetraene, 3,7,11-trimethyl14-(1-methylethyl)-

I.C-1 11

14

3

1 6

7

0

1

0

I.C-1

5,8,11,14-Cyclotetradecatetraene, 1.5.9-trimethyl12-(1-methylethyl)-

14

9 11 8

101159-07-3

0

1

0

1,4,7,10-Cyclotetradecatetraene, 1,7,11-trimethyl-4(1-methylethenyl)-

39815-66-2

0

1

0

2,4,9,13-Cyclotetradecatetraen-1-ol, 3,9,13trimethyl-6-(1-methylethyl)-

1

12 5

I.C-1 H3C H3C

9

8 7 12

10

II.A-5

CH3

6

4 5

13

1

CH3

OH

CH3

3 2

11

57688-99-0 59284-87-6

1

0

0

2,6,11-Cyclotetradecatriene-1,5-diol, 1,5,11trimethyl-8-(1-methylethyl)-

II.A-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1572

11/24/08 1:56:05 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1573

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

84367-90-8

1

1

1

Name (per CA Collective Index)

Selected structures

II.A-5

2,6,11-Cyclotetradecatriene-1,5-diol, 1,5,11trimethyl-8-(1-methylethyl)-, [1S(1R*,2E,5R*,6E,8R*,11E)]-

10

8

11

5

1

0

2,6,11-Cyclotetradecatriene-1,5-diol, 1,5,11trimethyl-8-(1-methylethyl)-, [1R(1R*,2E,5S*,6E,8S*,11E)]-

89288-60-8

0

1

0

4,7,13-Cyclotetradecatriene-1,3-diol, 9hydroperoxy-1,5,9-trimethyl-12-(1-methylethyl)-, [1S-(1R*,3S*,4E,7E,9R*,12R*,13E)]-

4 3

OH

II.A-5

H3C H3C

OH 12

11

9

HOO

II.A-5

CH3

10

6

8

1

13 4

5

CH3

0

1

0

4,7,13-Cyclotetradecatriene-1,3-diol, 9hydroperoxy-1,5,9-trimethyl-12-(1-methylethyl)-, [1S-(1R*,3S*,4E,7E,9S*,12R*,13E)]-

OH

H3C H3C

OH 12

11 6

8

1

13 4

5

7

0

1

0

4,7,13-Cyclotetradecatriene-1,3-diol, 9hydroperoxy-1,5,9-trimethyl-12-(1-methylethyl)-, [1R-(1R*,3R*,4E,7E,9S*,12S*,13E)]-

OH

H3C 10

12

11

9

6

8

1

13 4

5

7

0

1

0

4,7,13-Cyclotetradecatriene-1,3,9-triol, 1,5,9trimethyl-12-(1-methylethyl)-, [1S(1R*,3S*,4E,7E,9R*,12R*,13E)]-

H3C

CH3

OH

II.A-5

CH3

CH3

CH3

10

12

11

9

HO

2

3

CH3

82003-46-1

II.A-5

CH3 OH

H3C HOO

CH3 2

3

CH3

89362-07-2

II.A-5

CH3

10 9

HOO

CH3 2

3

7

89362-06-1

OH

2 1

13

0

6

7

9 14

123

84367-92-0

Chapter Table

8

1

13

6

4

5

OH

2

3

7

OH

CH3

89362-10-7

0

1

0

4,7,13-Cyclotetradecatriene-1,3,9-triol, 1,5,9trimethyl-12-(1-methylethyl)-, [1S(1R*,3S*,4E,7E,9R*,12R*,13E)]-

H3 C

II.A-5

CH3

CH3

CH3

10

12

11

9

HO

1

13

6

8

4

5

OH

2

3

7

OH

CH3

89362-11-8

0

1

0

4,7,13-Cyclotetradecatriene-1,3,9-triol, 1,5,9trimethyl-12-(1-methylethyl)-, [1R(1R*,3R*,4E,7E,9R*,12R*,13E)]-

H3C

II.A-5

CH3

CH3

CH3

10 11

9

HO

6

8

12

1

13 4

5

OH

2

3

7

OH

CH3

91200-14-5

0

1

0

4,7,13-Cyclotetradecatriene-1,3,9-triol, 1,5,9trimethyl-12-(1-methylethyl)-, [1R(1R*,3R*,4E,7E,9R*,12R*,13E)]-

H3C

II.A-5

CH3

CH3

CH3

10 11

9

HO

6

8

12

1

13 5

4

3

2

OH

7

CH3

116348-80-2

0

1

0

4,8,13-Cyclotetradecatriene-1,3-diol, 1,5,9-trimethyl12-(1-methylethyl)-, [1R(1R*,3S*,4E,8E,12S*,13E)]-

OH

II.A-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1573

11/24/08 1:56:05 PM

1574

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

121916-90-3

0

1

0

4,8,13-Cyclotetradecatriene-1,3-diol, 1,5,9-trimethyl12-(1-methylethyl)-, [1S(1R*,3R*,4E,8E,12S*,13E)]-

II.A-5

122620-36-4

0

1

0

4,8,13-Cyclotetradecatriene-1,3-diol, 1,5,9-trimethyl12-(1-methylethyl)-, (1R*,3R*,4E,8E,12S*,13E)(r)-

II.A-5

57605-80-8

1

1

1

4,8,13-Cyclotetradecatriene-1,3-diol, 1,5,9-trimethyl12-(1-methylethyl)-, [1S(1R*,3S*,4E,8E,12S*,13E)]-

Name (per CA Collective Index)

Selected structures

H3C

II.A-5

CH3 OH

10

H3C 9

11 6

8

Chapter Table

12 5

1

13 4

2

3

CH3

7

CH3

57605-81-9

1

1

1

4,8,13-Cyclotetradecatriene-1,3-diol, 1,5,9-trimethyl12-(1-methylethyl)-, [1R1R*,3R*,4E,8E,12S*,13E)]-

H3C

OH

II.A-5

CH3 OH

10

H3C 9

11 6

8

12 5

1

13 4

3

2

CH3

7

CH3

OH

87554-04-9

0

1

0

4,8,13-Cyclotetradecatriene-1,3-diol, 1,5,9-trimethyl12-(1-methylethyl)-, [1S(1R*,3S*,4E,8E,12S*,13Z)]-

II.A-5

7220-78-2

1

1

1

4,8,13-Cyclotetradecatriene-1,3-diol, 1,5,9-trimethyl12-(1-methylethyl)-

II.A-5

2043-08-1

0

1

0

4,8,13-Cyclotetradecatriene-1,3-diol, 1,5,9-trimethyl12-(1-methylethyl)-, 3-acetate, [1S(1R*,3S*,4E,8E,12S*,13E)]-

II.A-5

146564-67-2

0

1

0

4,8,13-Cyclotetradecatriene-1,3-diol, 9(hydroxymethyl)-1,5-dimethyl-12-(1-methylethyl)-, [1S-(1R*,3S*,4E,8Z,12R*,13E)]-

II.A-5

1

1

1

4,8,13-Cyclotetradecatriene-1-ol-3-one,-1,5,9trimethyl-12-(1-methylethyl)-,

II.A-5

149403-67-8

0

1

0

4,8,13-Cyclotetradecatriene-1,3,7-triol, 1,5,9trimethyl-12-(1-methylethyl)-, [1S(1R*,3S*,4E,7S*,8E,12R*)]-

II.A-5

149403-68-9

0

1

0

4,8,13-Cyclotetradecatriene-1,3,7-triol, 1,5,9trimethyl-12-(1-methylethyl)-, [1S(1R*,3S*,4E,7R*,8E,12R*)]-

II.A-5

149403-69-0

0

1

0

4,8,13-Cyclotetradecatriene-1,3,7-triol, 1,5,9trimethyl-12-(1-methylethyl)-, [1R(1R*,3R*,4E,7R*,8E,12S*)]-

II.A-5

149403-70-3

0

1

0

4,8,13-Cyclotetradecatriene-1,3,7-triol, 1,5,9trimethyl-12-(1-methylethyl)-, [1R(1R*,3R*,4E,7S*,8E,12S*)]-

II.A-5

149403-71-4

0

1

0

4,8,13-Cyclotetradecatriene-1,3,7-triol, 1,5,9trimethyl-12-(1-methylethyl)-, [1R(1R*,3R*,4E,7S*,8Z,12S*)]-

II.A-5

146564-66-1

0

1

0

4,9,13-Cyclotetradecatriene-1,3,8-triol, 3,9,13trimethyl-6-(1-methylethyl)-, [1R(1R*,3R*,4E,6S*,8R*,9E,13E)]-

II.A-5

146609-95-2

0

1

0

4,9,13-Cyclotetradecatriene-1,3,8-triol, 3,9,13trimethyl-6-(1-methylethyl)-, [1R(1R*,3S*,4E,6S*,8R*,9E,13E)]-

II.A-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1574

11/24/08 1:56:06 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1575

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

60026-11-1

0

1

0

Name (per CA Collective Index)

Chapter Table

Selected structures

2,7,12-Cyclotetradecatrien-1-ol, 1,7-dimethyl-11methylene-4-(1-methylethyl)Chem. Abstracts numbering

II.A-5 H3C

CH3 CH3

H3C 7 8

6

4

5

12

10

9

3

11

2 13

1 14

OH

CH2

Chem. Abstracts numbering 87387-80-2

0

1

0

2,6,12-Cyclotetradecatrien-1-ol, 3,7,13-trimethyl-10(1-methylethenyl)-

II.A-5

119864-28-7

0

1

0

2,7,10-Cyclotetradecatrien-1-ol, 1,7,11-trimethyl-4(1-methylethyl)-, [1R- (1R*,2E,4S*,7E,10E)]-

II.A-5

119944-62-6

0

1

0

2,7,10-Cyclotetradecatrien-1-ol, 1,7,11-trimethyl-4(1-methylethyl)-, [1S-(1R*,2E,4R*,7E,10E)]-

II.A-5

25269-17-4

1

1

1

2,7,11-Cyclotetradecatrien-1-ol, 1,7,11-trimethyl-4(1-methylethyl)-, [1R-(1R*,2E,4S*,7E,11E)]-

H3C H3C

II.A-5

CH3 CH3

2

6 7

5

8

10 9

4

1

3

OH

12

11

13

CH3

80126-41-6

0

1

0

2,7,11-Cyclotetradecatrien-1-ol, 1,7,11-trimethyl-4(1-methylethyl)-, [1S-(1R*,2E,4R*,7E,11E)]-

H3C H3C

II.A-5

CH3 CH3

2

6 7

5

8

10 9

4 11

1

3

OH

12 13

CH3

149312-90-3

0

1

0

2,6,11-Cyclotetradecatrien-1-one, 5,13-dihydroxy3,7,13-trimethyl-10-(1-methylethyl)-, [5S(2E,5R*,6E,10R*,11E,13R*)]-

II.A-5, III-13

98064-74-5

0

1

0

2,5,11-Cyclotetradecatrien-1-one, 7,13-dihydroxy3,7,13-trimethyl-10-(1- methylethyl)-, [7S(2E,5E,7R*,10R*,11E,13R*)]-

II.A-5, III-13

149312-89-0

0

1

0

2,7,12-Cyclotetradecatrien-1-one, 9,11-dihydroxy3,9,13-trimethyl-6-(1-methylethyl)-, [6S(2E,6R*,7E,9R*,11S*,12E)]-

II.A-5, III-13

149403-72-5

0

1

0

2,7,12-Cyclotetradecatrien-1-one, 9,11-dihydroxy3,9,13-trimethyl-6-(1-methylethyl)-, [6S(2E,6R*,7E,9S*,11S*,12E)]-

II.A-5, III-13

41429-54-3

0

1

0

2,6,11-Cyclotetradecatrien-1-one, 13-hydroxy3,7,13-trimethyl-10-(1-methylethyl)-

II.A-5 12

11

13

HO

2

1

14

10

3

8

7

9 4

6

5

O

0

1

0

13-Cyclotetradecene-1,3,4,8-tetrol-1-methyl-5,9dimethylene-12-(1-methylethyl)-

H3C

OH

10

H2C

HO

II.A-5

CH3

9

11

8

6 7

12 5

1

13 4

CH2

OH

3

CH3 2

OH

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1575

11/24/08 1:56:06 PM

1576

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

0

1

0

Name (per CA Collective Index) 1-Cyclotetradecen-1-one, 3,6,13-triol-3,13-dimethyl7-methylene-10-(1-methylethyl)-

H3C H2C 7

HO

1

0

0

Cycloundecane, 1,1,2-trimethyl-

6753-98-6

0

1

0

1,4,8-Cycloundecatriene, 2,6,6,9-tetramethyl-, (E,E,E)-

II.A-5, III-13

CH3 12

8

6

62376-15-2

Chapter Table

Selected structures

9 4

5

10

H3C

13

11 2

3

CH3 OH

1

OH O

I.C-1 I.C-1

6

7 8

5

4

9 1

10

2

3

11

498-40-8

0

1

0

Cysteic acid

HO-SO2-CH2-CH(NH2)-COOH IV.B-7, XVIII.A-1

52-90-4

1

1

1

L-Cysteine {propanoic acid, 2-amino-3-mercapto- (R)}

HS-CH2-CH(NH2)-COOH

636-58-8

0

1

0

L-Cysteine, N-L-J-glutamyl-

24645-67-8

0

1

0

Cystine

65-46-3

0

1

0

Cytidine

IV.B-7, XVIII.A-1 IV.B-7, XVIII.A-1

{propanoic acid, 2-amino-3,3’-dithiobis-}

{S-CH2-CH(NH2)-COOH}2 IV.B-7, XVIII.A-1 II.A-5, X-2, XII-2, XVII.B-2

{2(1H)-pyrimidinone, 4-amino-1-ED-ribofuranosyl-} 65-47-4

0

1

0

Cytidine 5'-(tetrahydrogen triphosphate)

63-37-6

0

1

0

5'-Cytidylic acid

II.A-5, X-2, XII-2, XVII.B-2 II.A-5, X-2, XII-2, XVII.B-2

NH2 OH O

P OH

N O O

N

O

OH OH

9044-61-5

0

1

0

Cytochrome b 559

XXII-2

9035-46-5

0

1

0

Cytochrome c6

XXII-2

0

1

0

Cytochrome oxidase

XXII-2

62168-75-6

0

1

0

Deacylase

XXII-2

2363-88-4

0

1

0

2,4-Decadienal

III-12

25152-84-5

1

1

1

2,4-Decadienal, (E,E)-

III-12

63889-75-8

0

1

0

Decadienoic acid

59286-28-1

0

1

0

2,4-Decadienoic acid, 3-methyl-6-(1-methylethyl)-9oxo-, (Z,E)-

III-13, IV.A-3

58315-84-7

0

1

0

2,4-Decadienoic acid, 3-methyl-6-(1-methylethyl)-9oxo-, [S-(E,E)]-

III-13, IV.A-3

59262-52-1

0

1

0

2,7-Decadienoic acid, 3-methyl-6-(1-methylethyl)-9oxo-, (E,E)-

III-13, IV.A-3

158815-70-4

0

1

0

4,9-Decadienoic acid, 3-hydroxy-3-methyl-6-(1methylethyl)-9-(tetrahydro-5-oxo-2-furanyl)-

II.A-5, IV.A-3

160115-53-7

0

1

0

4,9-Decadienoic acid, 3-hydroxy-3-methyl-6-(1methylethyl)-9-(tetrahydro-5-oxo-2-furanyl)-, methyl ester

II.A-5, V-3

112-31-2

1

1

1

Decanal

{sebacic acid}

{capraldehyde}

IV.A-3

H3C-(CH2)8-CH=O

III-12

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1576

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1577

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Chapter Table

Selected structures

124-18-5

1

1

1

Decane

H3C-(CH2)8-CH3

I.A-10

61193-21-3

1

0

0

Decane, methyl-

C10H21-CH3

I.A-10

6975-98-0

0

1

0

Decane, 2-methyl-

H3C-CH(CH3)-(CH2)7-CH3

I.A-10

13151-34-3

1

0

0

Decane, 3-methyl-

H3C-CH2-CH(CH3)-(CH2)6-CH3

I.A-10

13151-35-4

1

0

0

Decane, 5-methyl-

H3C-(CH2)4-CH(CH3)-(CH2)3-CH3

I.A-10

111-20-6

1

1

1

Decanedioic acid

HOOC-(CH2)8-COOH

IV.A-3

110-40-7

0

1

0

Decanedioic acid, diethyl ester

334-48-5

1

1

1

Decanoic acid

H5C2-OOC-(CH2)8-COO-C2H5 {capric acid} {ethyl caprate}

H3C-(CH2)8-COOH

V-3

IV.A-3, XXI-3

110-38-3

1

1

1

Decanoic acid, ethyl ester

5601-60-5

0

1

0

Decanoic acid, 8-methyl-

H 3C-(CH2)8-COO-C2H5

V-3

110-42-9

0

1

0

Decanoic acid, methyl ester

70898-23-6

1

1

1

Decanoic acid, 3,7,11,15,19,23,27,31,35nonamethyl-2,6,10,14,18,22,26,30,34hexatriacontanonaenyl ester, (all-E)-

V-3

70898-24-7

0

1

0

Decanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester, [R-[R*,R*-(E)]]-

V-3

IV.A-3 H3C-(CH2)8-COO-CH3

{capric alcohol}

V-3

112-30-1

1

1

1

1-Decanol

693-54-9

1

1

1

2-Decanone

9027-22-9

0

1

0

Decarboxylase

XXII-2

9036-20-8

0

1

0

Decarboxylase, adenosylmethionine

XXII-2

9024-77-5

0

1

0

Decarboxylase, arginine

XXII-2

9024-58-2

0

1

0

Decarboxylase, glutamate

XXII-2

37259-67-9

0

1

0

Decarboxylase, glycine

XXII-2

9024-60-6

0

1

0

Decarboxylase, ornithine

XXII-2

9001-04-1

0

1

0

Decarboxylase, pyruvate

XXII-2

{methyl octyl ketone}

H3C-(CH2)8-CH2OH

II.A-5, XXI-3

H3C-(CH2)7-CO-CH3

III-13

9024-70-8

0

1

0

Decarboxylase, uroporphyrinogen

XXII-2

63892-04-6

0

1

0

2,7,9-Decatrienoic acid, 3,9-dimethyl-6-(1methylethyl)-, (E,E)-

IV.A-3

2497-25-8

0

1

0

2-Decenal, (Z)-

3913-71-1

0

1

0

2-Decenal, (E)-

872-05-9

1

1

1

1-Decene

H2C=CH-(CH2)7-CH3

1

0

0

1-Decene, 5-methyl-

H2C=CH-(CH2)2-CH(CH3)-(CH2)4-CH3 I.B-1

0

1

0

2-Decene

H3C-CH=CH-(CH2)6-CH3

6816-17-7

H3C-(CH2)6-CH=CH-CH=O

III-12 III-12

{3 isomers detected}

I.B-1 I.B-1

26446-27-5

0

1

0

Decenoic acid

60924-66-5

0

1

0

4-Decenoic acid, 3-hydroxy-3-methyl-6-(1methylethyl)-9-oxo-

II.A-5, III-13, IV.A-3

IV.A-3

129777-23-7

0

1

0

4-Decenoic acid, 3-hydroxy-3-methyl-6-(1methylethyl)-9-oxo-, [R-[R*,S*-(E)]]-

II.A-5, III-13, IV.A-3

77288-98-3

0

1

0

6-Decen-2-one, 8,10-dihydroxy-8-methyl-5-(1methylethyl)-

II.A-5, III-13, IV.A-3

9001-03-0

0

1

0

Dehydratase, carbonate

XXII-2

9024-34-4

0

1

0

Dehydratase, threonine

XXII-2

9035-82-9

0

1

0

Dehydrogenase

XXII-2

9001-40-5

0

1

0

Dehydrogenase, glucose 6-phosphate

XXII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1577

11/24/08 1:56:07 PM

1578

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

9001-46-1

0

1

0

Dehydrogenase, glutamate

XXII-2

9029-12-3

0

1

0

Dehydrogenase, glutamate (nicotinamide adenine dinucleotide (phosphate))

XXII-2

Name (per CA Collective Index)

Selected structures

Chapter Table

0

1

0

Dehydrogenase, glutamic acid

XXII-2

9026-38-4

0

1

0

Dehydrogenase, glutathione (ascorbate)

XXII-2

9001-50-7

0

1

0

Dehydrogenase, glyceraldehyde phosphate

XXII-2

9028-13-1

0

1

0

Dehydrogenase, homoserine

XXII-2

9001-58-5

0

1

0

Dehydrogenase, isocitrate

XXII-2

9028-48-2

0

1

0

Dehydrogenase, isocitrate (nicotinamide adenine dinucleotide phosphate)

XXII-2

9001-64-3

0

1

0

Dehydrogenase, malate

XXII-2

56941-16-3

0

1

0

Dehydrogenase, malate (decarboxylating) (nicotinamide adenine dinucleotide (phosphate))

XXII-2

37250-19-4

0

1

0

Dehydrogenase, malate (nicotinamide adenine dinucleotide phosphate)

XXII-2

9028-47-1

0

1

0

Dehydrogenase, malate (oxalacetatedecarboxylating) (nicotinamide adenine dinucleotide phosphate)

XXII-2

9029-14-5

0

1

0

Dehydrogenase, methylenetetrahydrofolate

XXII-2

37256-31-8

0

1

0

Dehydrogenase, nicotine

XXII-2

9001-82-5

0

1

0

Dehydrogenase, phosphogluconate

XXII-2

9073-95-4

0

1

0

Dehydrogenase, phosphogluconate (decarboxylating)

XXII-2

9050-70-8

0

1

0

Dehydrogenase, proline

XXII-2

9028-28-8

0

1

0

Dehydrogenase, quinate

XXII-2

9079-67-8

0

1

0

Dehydrogenase, reduced nicotinamide adenine dinucleotide

XXII-2

9032-20-6

0

1

0

Dehydrogenase, reduced nicotinamide adenine dinucleotide (phosphate) (quinone)

XXII-2

37256-36-3

0

1

0

Dehydrogenase, reduced nicotinamide adenine dinucleotide (quinone)

XXII-2

37256-37-4

0

1

0

Dehydrogenase, reduced nicotinamide adenine dinucleotide phosphate (quinone)

XXII-2

9001-68-7

0

1

0

Dehydrogenase, reduced nicotinamide adenine dinucleotide phosphate

XXII-2

9026-87-3

0

1

0

Dehydrogenase, shikimate

XXII-2

9002-02-2

0

1

0

Dehydrogenase, succinate

XXII-2

9054-84-6

0

1

0

Dehydrogenase, xanthine

XXII-2

159844-35-6

0

1

0

Deoxyribonucleic acid (Arabidopsis thaliana clone TAY029 gene UbcAt3 ubiquitin-carrier enzyme E 2 messenger RNA-complementary plus 5'- and 3'flanking region fragment)

XXII-2

141712-74-5

0

1

0

Deoxyribonucleic acid (Arabidopsis thaliana strain Heynhold glycerol phosphate acyltransferase messenger RNA-complementary)

XXII-2

140812-74-4

0

1

0

Deoxyribonucleic acid (Nicotiana plumbaginifolia gene pma1 plus 5'- and 3'-flanking region fragment)

XXII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1578

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1579

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

130061-32-4

0

1

0

Deoxyribonucleic acid (Nicotiana sylvestris clone NySS4 ribulose diphosphate carboxylase small subunit gene)

XXII-2

144997-82-0

0

1

0

Deoxyribonucleic acid (Nicotiana sylvestris clone yaDC12/yaDC17 gene psaDa protein D 2 messenger RNA-complementary)

XXII-2

155317-25-2

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum clone NeIF-4A11 protein formation initiation factor eIF 4A messenger RNA complementary plus 5'- and 3'-flanking region fragment)

XXII-2

155317-10-5

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum clone NeIF-4A13 protein formation initiation factor eIF 4A messenger RNA complementary plus 5'- and 3'-flanking region fragment)

XXII-2

155317-11-6

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum clone NeIF-4A14 protein formation initiation factor eIF 4A messenger RNA complementary plus 5'- and 3'-flanking region fragment)

XXII-2

155317-12-7

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum clone NeIF-4A15 protein formation initiation factor eIF 4A messenger RNA complementary plus 5'- and 3'-flanking region fragment)

XXII-2

155317-13-8

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum clone NeIF-4A6 protein formation initiation factor eIF 4A messenger RNA complementary plus 5'- and 3'flanking region fragment)

XXII-2

155317-14-9

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum clone NeIF-4A7 protein formation initiation factor eIF 4A messenger RNA complementary plus 5'- and 3'flanking region fragment)

XXII-2

155317-15-0

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum clone NeIF-4A9 protein formation initiation factor eIF 4A messenger RNA complementary plus 5'- and 3'flanking region fragment)

XXII-2

160074-66-8

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum clone Ubi.U4 gene Ubi.U4 polyubiquitin plus 5' and 3' flanking region fragment)

XXII-2

160075-53-6

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum cv. SR1 leaf clone Ntfad3 Z-3 fatty acid desaturase mRNAcomplementary plus 5' and 3' flanking region fragment)

XXII-2

131553-16-7

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum samsun 16.5-kilodalton protein messenger RNAcomplementary)

XXII-2

131553-15-6

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum samsun chitinase isoenzyme messenger RNAcomplementary)

XXII-2

143514-65-2

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum samsun clone NeIF-5A3 protein formation initiation factor eIF 5A isoform gene)

XXII-2

141093-81-4

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum samsun clone pMOG404 osmotin messenger RNAcomplementary)

XXII-2

Name (per CA Collective Index)

Selected structures

Chapter Table

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1579

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1580

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

143638-33-9

0

1

0

Deoxyribonucleic acid (Nicotiana tabacum samsun clone pTOL1 osmotin messenger RNAcomplementary)

XXII-2

143341-52-0

0

1

0

Deoxyribonucleic acid (tobacco 1-109-extensin-like protein precursor-specifying)

XXII-2

152619-15-3

0

1

0

Deoxyribonucleic acid (tobacco chitinase acidic isoenzyme III messenger RNA-complementary plus 5'- and 3'-flanking region fragment)

XXII-2

152619-16-4

0

1

0

Deoxyribonucleic acid (tobacco chitinase basic isoenzyme III messenger RNA-complementary plus 5'- and 3'-flanking region fragment)

XXII-2

142978-98-1

0

1

0

Deoxyribonucleic acid (tobacco chloroplast clone L27-1 ribosome protein L 27 messenger RNAcomplementary)

XXII-2

139872-58-5

0

1

0

Deoxyribonucleic acid (tobacco clone .lambda.5A gene RB7 plus 5'- and 3'-flanking region fragment)

XXII-2

139872-57-4

0

1

0

Deoxyribonucleic acid (tobacco clone .lambda.5A gene RB7)

XXII-2

128284-58-2

0

1

0

Deoxyribonucleic acid (tobacco clone .lambda.CHN17 chitinase basic isoenzyme gene)

XXII-2

156553-68-3

0

1

0

Deoxyribonucleic acid (tobacco clone 59 gene chi-V chitinase plus 5'- and 3'-flanking region fragment)

XXII-2

156553-69-4

0

1

0

Deoxyribonucleic acid (tobacco clone cA-3 gene chi-V chitinase messenger RNA-complementary plus 5'- and 3'-flanking region fragment)

XXII-2

155663-09-5

0

1

0

Deoxyribonucleic acid (tobacco clone cpb20-52 antifungal protein CPB 20 messenger RNAcomplementary plus 5'- and 3'-flanking region fragment)

XXII-2

124757-79-5

0

1

0

Deoxyribonucleic acid (tobacco clone E22 protein PR 5 gene)

XXII-2

148757-18-0

0

1

0

Deoxyribonucleic acid (tobacco clone G27.1/G27.2 gene Npg1 plus 5'- and 3'-flanking region fragment)

XXII-2

158928-85-9

0

1

0

Deoxyribonucleic acid (tobacco clone lambda TFLO 4 gene NFL2 exon 1 fragment)

XXII-2

158928-86-0

0

1

0

Deoxyribonucleic acid (tobacco clone lambda TFLO 4 gene NFL2 exon 2 fragment)

XXII-2

158928-87-1

0

1

0

Deoxyribonucleic acid (tobacco clone lambda TFLO 4 gene NFL2 exon 3 fragment)

XXII-2

145137-42-4

0

1

0

Deoxyribonucleic acid (tobacco clone NtDAHPS-1 phospho-2-keto-3-deoxyheptonate aldolase messenger RNA-complementary)

XXII-2

151876-45-8

0

1

0

Deoxyribonucleic acid (tobacco clone OMT3.4 catechol methyltransferase isoenzyme II messenger RNA-complementary plus 5'- and 3'flanking region fragment)

XXII-2

128512-15-2

0

1

0

Deoxyribonucleic acid (tobacco clone pBSGlu39.1 endo-1,3-E-glucanase isoenzyme gene coding region)

XXII-2

128512-16-3

0

1

0

Deoxyribonucleic acid (tobacco clone pBSGlu39.3 endo-1,3-E-glucanase isoenzyme gene coding region)

XXII-2

Name (per CA Collective Index)

Selected structures

Chapter Table

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1580

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1581

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

147626-92-4

0

1

0

Deoxyribonucleic acid (tobacco clone pcGS2-17 glutamine synthetase isoenzyme 2 messenger RNA-complementary)

XXII-2

128512-19-6

0

1

0

Deoxyribonucleic acid (tobacco clone pGL31 endo1,3-E-glucanase isoenzyme messenger RNAcomplementary)

XXII-2

128512-20-9

0

1

0

Deoxyribonucleic acid (tobacco clone pGL36 endo1,3-E-glucanase isoenzyme messenger RNAcomplementary)

XXII-2

128512-21-0

0

1

0

Deoxyribonucleic acid (tobacco clone pGL43 endo1,3-E-glucanase isoenzyme messenger RNAcomplementary)

XXII-2

103469-25-6

0

1

0

Deoxyribonucleic acid (tobacco clone PROB12 protein TL messenger RNA-complementary)

XXII-2

158928-82-6

0

1

0

Deoxyribonucleic acid (tobacco clone pTGF220 gene NFL1 exon 1 fragment)

XXII-2

158928-83-7

0

1

0

Deoxyribonucleic acid (tobacco clone pTGF220 gene NFL1 exon 2 fragment)

XXII-2

158928-84-8

0

1

0

Deoxyribonucleic acid (tobacco clone pTGF220 gene NFL1 exon 3 fragment)

XXII-2

141002-75-7

0

1

0

Deoxyribonucleic acid (tobacco clone pVK5 osmotin messenger RNA-complementary)

XXII-2

150001-42-6

0

1

0

Deoxyribonucleic acid (tobacco clone TSC81 ribosome protein L 17 messenger RNAcomplementary plus 5'- and 3'-flanking region fragment)

XXII-2

128512-25-4

0

1

0

Deoxyribonucleic acid (tobacco endo-1,3-Eglucanase isoenzyme messenger RNAcomplementary)

XXII-2

143341-55-3

0

1

0

Deoxyribonucleic acid (tobacco extensin-like protein 107-amino acid fragment-specifying)

XXII-2

143341-56-4

0

1

0

Deoxyribonucleic acid (tobacco extensin-like protein 81-amino acid fragment-specifying)

XXII-2

160936-44-7

0

1

0

Deoxyribonucleic acid (tobacco leaf curl virus coat protein gene)

XXII-2

141004-11-7

0

1

0

Deoxyribonucleic acid (tobacco ribosome protein L 2 messenger RNA-complementary plus 5'- and 3'flanking region fragment)

XXII-2

143513-68-2

0

1

0

Deoxyribonucleic acid (tobacco strain NK326 gene oee2-A plus 5'- and 3'-flanking region fragment)

XXII-2

143513-69-3

0

1

0

Deoxyribonucleic acid (tobacco strain NK326 gene oee2-A)

XXII-2

149309-58-0

0

1

0

Deoxyribonucleic acid (tobacco thioredoxin h2 gene plus 5'- and 3'-flanking region fragment)

XXII-2

140114-22-3

0

1

0

Deoxyribonucleic acid (tobacco thioredoxin messenger RNA-complementary plus 5'- and 3'flanking region fragment)

XXII-2

141712-75-6

0

1

0

Deoxyribonucleic acid, (Arabidopsis thaliana strain Heynhold glycerol phosphate acyltransferase messenger RNA-complementary plus 5'- and 3'flanking region fragment)

XXII-2

Name (per CA Collective Index)

Selected structures

Chapter Table

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1581

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1582

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

148037-15-4

0

1

0

Deoxyribonucleic acid, (Arabidopsis thaliana thioredoxin h messenger RNA-complementary plus 5'- and 3'-flanking region fragment)

XXII-2

147533-09-3

0

1

0

Deoxyribonucleic acid, (Nicotiana alata clone NaPRP3g12 proline-rich protein PRP 3 gene plus 5'- and 3'-flanking region fragment)

XXII-2

139860-37-0

0

1

0

Deoxyribonucleic acid, (Nicotiana plumbaginifolia clone NeIF-4A2 protein formation initiation factor eIF 4A messenger RNA-complementary plus 5'and 3'-flanking region fragment)

XXII-2

146150-24-5

0

1

0

Deoxyribonucleic acid, (Nicotiana plumbaginifolia clone NeIF-4A2 protein formation initiation factor eIF 4A messenger RNA-complementary)

XXII-2

140095-89-2

0

1

0

Deoxyribonucleic acid, (Nicotiana plumbaginifolia clone NeIF-4A3 protein formation initiation factor eIF 4A messenger RNA-complementary plus 5'and 3'-flanking region fragment)

XXII-2

146150-26-7

0

1

0

Deoxyribonucleic acid, (Nicotiana plumbaginifolia clone NeIF-4A3 protein formation initiation factor eIF 4A messenger RNA-complementary)

XXII-2

140360-04-9

0

1

0

Deoxyribonucleic acid, (Nicotiana plumbaginifolia clone NeIF-5A2 protein formation initiation factor eIF 5A isoform messenger RNA-complementary plus 5'- and 3'-flanking region fragment)

XXII-2

143514-64-1

0

1

0

Deoxyribonucleic acid, (Nicotiana plumbaginifolia clone NeIF-5A2 protein formation initiation factor eIF 5A isoform messenger RNA-complementary)

XXII-2

141374-52-9

0

1

0

Deoxyribonucleic acid, (Nicotiana plumbaginifolia clone pSOD3 copper-zinc superoxide dismutase messenger RNA-complementary plus 5'- and 3'flanking region fragment)

XXII-2

143348-77-0

0

1

0

Deoxyribonucleic acid, (Nicotiana plumbaginifolia clone pSOD3 copper-zinc superoxide dismutase messenger RNA-complementary)

XXII-2

144997-81-9

0

1

0

Deoxyribonucleic acid, (Nicotiana sylvestris clone yaDC12/yaDC17 gene psaDa protein D 2 messenger RNA-complementary plus 5'- and 3'flanking region fragment)

XXII-2

140110-39-0

0

1

0

Deoxyribonucleic acid, (Nicotiana tabacum samsun clone NeIF-5A3 protein formation initiation factor eIF 5A isoform gene plus 5'- and 3'-flanking region fragment)

XXII-2

141093-82-5

0

1

0

Deoxyribonucleic acid, (Nicotiana tabacum samsun clone pMOG404 osmotin messenger RNAcomplementary plus 5'- and 3'-flanking region fragment)

XXII-2

141093-84-7

0

1

0

Deoxyribonucleic acid, (Nicotiana tabacum samsun clone pMOG4041-226-osmotin-specifying plus 5'and 3'-flanking region fragment)

XXII-2

142978-99-2

0

1

0

Deoxyribonucleic acid, (tobacco chloroplast clone L27-1 ribosome protein L 27 messenger RNAcomplementary plus 5'- and 3'-flanking region fragment)

XXII-2

Name (per CA Collective Index)

Selected structures

Chapter Table

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1582

11/24/08 1:56:09 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1583

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

145093-14-7

0

1

0

Deoxyribonucleic acid, (tobacco clone EPSPS-1 5enolpyruvoylshikimate 3-phosphate synthase messenger RNA-complementary plus 5'- and 3flanking region fragment)

XXII-2

139837-73-3

0

1

0

Deoxyribonucleic acid, (tobacco clone NtDAHPS-1 phospho-2-keto-3-deoxyheptonate aldolase messenger RNA-complementary plus 5'- and 3'flanking region fragment)

XXII-2

128512-17-4

0

1

0

Deoxyribonucleic acid, (tobacco clone pBSGlu39.1 endo-1,3-E-glucanase isoenzyme gene coding region plus 5'- and 3'-flanking region fragment)

XXII-2

128512-18-5

0

1

0

Deoxyribonucleic acid, (tobacco clone pBSGlu39.3endo-1,3-E-glucanase isoenzyme gene coding region plus 5'- and 3'-flanking region fragment)

XXII-2

145735-56-4

0

1

0

Deoxyribonucleic acid, (tobacco clone pcGS2-17 glutamine synthetase isoenzyme 2 messenger RNA-complementary plus 5'- and 3'-flanking region fragment)

XXII-2

128512-22-1

0

1

0

Deoxyribonucleic acid, (tobacco clone pGL31 endo1,3-E- glucanase isoenzyme messenger RNAcomplementary plus 5'- and 3'-flanking region fragment)

XXII-2

128512-23-2

0

1

0

Deoxyribonucleic acid, (tobacco clone pGL36 endo1,3-E-glucanase isoenzyme messenger RNAcomplementary plus 5'- and 3'-flanking region fragment)

XXII-2

128512-24-3

0

1

0

Deoxyribonucleic acid, (tobacco clone pGL43 endo1,3-E-glucanase isoenzyme messenger RNAcomplementary plus 5'- and 3'-flanking region fragment)

XXII-2

143341-58-6

0

1

0

Deoxyribonucleic acid, (tobacco clone pMG15 extensin-like protein messenger RNAcomplementary plus 5'- and 3'-flanking region fragment)

XXII-2

128512-26-5

0

1

0

Deoxyribonucleic acid, (tobacco endo-1,3-Eglucanase isoenzyme messenger RNAcomplementary plus 5'- and 3'-flanking region fragment)

XXII-2

143341-53-1

0

1

0

Deoxyribonucleic acid, (tobacco extensin-like protein 171-amino acid C-terminal fragmentspecifying plus 3'-flanking region fragment)

XXII-2

143341-54-2

0

1

0

Deoxyribonucleic acid, (tobacco extensin-like protein 264-amino acid C-terminal fragmentspecifying plus 3'-flanking region fragment)

XXII-2

143341-57-5

0

1

0

Deoxyribonucleic acid, (tobacco extensin-like protein 393-amino acid C-terminal fragmentspecifying plus 3'-flanking region fragment)

XXII-2

139637-37-9

0

1

0

Deoxyribonucleic acid, d(A-T-G-T-T-C-T-C-T-C-T-TT-T-A-A-T-G-G-T-G-G-T-T-C-T-T-T-A-G)

XXII-2

152789-83-8

0

1

0

Deoxyribonucleic acid, d(C-A-T-C-A-C-G-T-G-A-GA-T-A-A-G-A-G-C-C-G-C-C-A), double-stranded complementary

XXII-2

Name (per CA Collective Index)

Selected structures

Chapter Table

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1583

11/24/08 1:56:09 PM

1584

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

152789-84-9

0

1

0

Deoxyribonucleic acid, d(T-A-A-A-G-T-C-A-A-A-GA-A-T-T-T-C-A-A-T-G-T-C-A-C-A), doublestranded complementary

Name (per CA Collective Index)

Selected structures

Chapter Table XXII-2

67880-95-9

0

1

0

Desaturase, fatty acid Z3-

XXII-2

159965-67-0

0

1

0

Desaturase, fatty acid Z3- (tobacco clone Ntfad3)

XXII-2

107544-21-8

0

1

0

Desaturase, phytoene

XXII-2

9004-53-9

0

1

0

Dextrin

37340-89-9

0

1

0

Diaphorase

II.A-5, VIII-3

5385-75-1

1

0

0

Dibenz[a,e]aceanthrylene {dibenzo[a,e]fluoranthene}

I.E-6

189-75-3

1

0

0

Dibenz[j,mno]aceanthrylene

I.E-6

71630-69-8

1

0

0

Dibenz[j,mno]aceanthrylene, methyl-

226-36-8

1

0

0

Dibenz[a,h]acridine

226-92-6

1

0

0

Dibenz[a,i]acridine

XVII.E-6

224-42-0

1

0

0

Dibenz[a,j]acridine

XVII.E-6

224-53-3

1

0

0

Dibenz[c,h]acridine

XVII.E-6

67775-07-9

1

0

0

Dibenzanthracene

53-70-3

1

0

0

Dibenz[a,h]anthracene

224-41-9

1

0

0

Dibenz[a,j]anthracene

4607-33-4

1

0

0

Dibenzo[b,h][1]benzopyrano[2,3,4de][1,6]naphthyridine

XVII.E-8

34442-52-9

1

0

0

1H-Dibenzo[a,c]carbazole

XVII.E-6

XXII-2

I.E-6 XVII.E-6

I.E-6 {DB[a,h]A}

I.E-6

I.E-6

c

g f

h

a

i

N H

207-84-1

1

1

1

7H-Dibenzo[a,g]carbazole

XVII.E-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1584

11/24/08 1:56:09 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1585

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

239-64-5

1

0

0

Name (per CA Collective Index)

Selected structures

13H-Dibenzo[a,i]carbazole

XVII.E-6

c

g f

h

Chapter Table

a

i

N H

194-59-2

1

0

0

7H-Dibenzo[c,g]carbazole

XVII.E-6 c

g f

h

a

i

N H

28641-62-5

1

0

0

5H-Dibenzo[c,g]carbazole

189-64-0

1

0

0

Dibenzo[b,def]chrysene

191-26-4

1

0

0

Dibenzo[def,mno]chrysene

64760-24-3

1

0

41699-10-9

1

XVII.E-6 {dibenzo[a,h]pyrene}

I.E-6

{anthanthrene}

I.E-6

0

Dibenzo[def,mno]chrysene, dimethyl{at least 2 isomers in MSS}

I.E-6

0

0

Dibenzo[def,mno]chrysene, methyl{at least 2, possibly 3, isomers in MSS}

I.E-6

1

0

0

Dibenzo[def,mno]chrysene, 6-methyl-

I.E-6

191-30-0

1

0

0

Dibenzo[def,p]chrysene

I.E-6

191-68-4

1

0

0

Dibenzo[g,p]chrysene

1210-35-1

1

0

0

5H-Dibenzo[a,d]cyclohepten-5-one, 10,11-dihydro-

262-12-4

1

0

0

Dibenzo[b,e][1,4]dioxin

{dibenzo[a,l]pyrene}

I.E-6

III-13 8

O

7 6

35822-46-9

1

0

0

Dibenzo[b,e][1,4]dioxin, polychloro-

1

1

1

Dibenzo[b,e][1,4]dioxin, 1,2,3,4,6,7,8-heptachloro-

2 3

O

5

X-2

1

4

X-2, XVIII.B-3 X-2, XVIII.B-3

Cl Cl

Cl

O

Cl

O Cl

Cl Cl

1

0

0

Dibenzo[b,e][1,4]dioxin, 1,2,3,4,6,7,9-heptachloro-

X-2, XVIII.B-3

39227-28-6

1

0

0

Dibenzo[b,e][1,4]dioxin, 1,2,3,4,7,8-hexachloro-

X-2, XVIII.B-3

57653-85-7

1

0

0

Dibenzo[b,e][1,4]dioxin, 1,2,3,6,7,8-hexachloro-

X-2, XVIII.B-3

19408-74-3

1

0

0

Dibenzo[b,e][1,4]dioxin, 1,2,3,7,8,9-hexachloro-

X-2, XVIII.B-3

40321-76-4

1

0

0

Dibenzo[b,e][1,4]dioxin, 1,2,3,7,8-pentachloro-

X-2, XVIII.B-3

1746-01-6

1

1

1

Dibenzo[b,e][1,4]dioxin, 2,3,7,8-tetrachloro-

X-2, XVIII.B-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1585

11/24/08 1:56:10 PM

1586

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

37871-00-4

1

0

0

Dibenzo[b,e][1,4]dioxin, heptachloro-

X-2, XVIII.B-3

34465-46-8

1

0

0

Dibenzo[b,e][1,4]dioxin, hexachloro-

X-2, XVIII.B-3

Name (per CA Collective Index)

Selected structures

Chapter Table

3268-87-9

1

0

0

Dibenzo[b,e][1,4]dioxin, octachloro-

X-2, XVIII.B-3

36088-22-9

1

0

0

Dibenzo[b,e][1,4]dioxin, pentachloro-

X-2, XVIII.B-3

41903-57-5

1

0

0

Dibenzo[b,e][1,4]dioxin, tetrachloro-

X-2, XVIII.B-3

60382-88-9

1

0

0

Dibenzofluoranthene {at least two isomers in MSS}

I.E-6

203-18-9

1

0

0

Dibenzo[j,l]fluoranthene

I.E-6

239-60-1

1

0

0

13H-Dibenzo[a,i]fluorene

I.E-6

132-64-9

1

1

1

Dibenzofuran

{2,2’-biphenylene oxide}

1

X-2

2 3

O

4

1

0

0

Dibenzofuran, dimethyl-

X-2

1

0

0

Dibenzofuran, methyl-

1

0

0

Dibenzofuran, polychloro-

67562-39-4

1

1

1

Dibenzofuran, 1,2,3,4,6,7,8-heptachloro-

X-2, XVIII.B-3

55673-89-7

1

0

0

Dibenzofuran, 1,2,3,4,7,8,9-heptachloro-

X-2, XVIII.B-3

70648-26-9

1

0

0

Dibenzofuran, 1,2,3,4,7,8-hexachloro-

X-2, XVIII.B-3

X-2 {dioxins}

X-2, XVIII.B-3

91538-84-0

1

0

0

Dibenzofuran, 1,2,3,4,7,9-hexachloro-

X-2, XVIII.B-3

67517-48-0

1

0

0

Dibenzofuran, 1,2,3,4,8-pentachloro-

X-2, XVIII.B-3

57117-44-9

1

0

0

Dibenzofuran, 1,2,3,6,7,8-hexachloro-

X-2, XVIII.B-3

72918-21-9

1

0

0

Dibenzofuran, 1,2,3,7,8,9-hexachloro-

X-2, XVIII.B-3

57117-41-6

1

0

0

Dibenzofuran, 1,2,3,7,8-pentachloro-

X-2, XVIII.B-3

7320-50-5

1

0

0

Dibenzofuran, 1-methyl-

60851-34-5

1

0

0

Dibenzofuran, 2,3,4,6,7,8-hexachloro-

57117-31-4

1

0

0

Dibenzofuran, 2,3,4,7,8-pentachloro-

X-2, XVIII.B-3

83704-32-9

1

0

0

Dibenzofuran, 2,3,4,8-tetrachloro-

X-2, XVIII.B-3 X-2, XVIII.B-3

51207-31-9

X-2 X-2, XVIII.B-3

1

0

0

Dibenzofuran, 2,3,7,8-tetrachloro-

1

0

0

Dibenzofuran, 1-methyl-

X-2

7320-51-6

1

0

0

Dibenzofuran, 2-methyl-

X-2

7320-52-7

1

0

0

Dibenzofuran, 3-methyl-

X-2

7320-53-8

1

0

0

Dibenzofuran, 4-methyl-

X-2

9062-95-1

1

0

0

Dibenzofuran, dimethyl-

X-2

38998-75-3

1

0

0

Dibenzofuran, heptachloro-

X-2, XVIII.B-3

55684-94-1

1

0

0

Dibenzofuran, hexachloro-

X-2, XVIII.B-3

60826-62-2

1

0

0

Dibenzofuran, methyl-

X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1586

11/24/08 1:56:10 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1587

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

39001-02-0

1

0

0

Dibenzofuran, octachloro-

X-2, XVIII.B-3

30402-15-4

1

0

0

Dibenzofuran, pentachloro-

X-2, XVIII.B-3

30402-14-3

1

0

0

Dibenzofuran, tetrachloro-

3693-22-9

1

0

0

2-Dibenzofuranamine

4106-66-5

1

0

0

3-Dibenzofuranamine

216-00-2

1

0

0

Dibenzo[a,c]naphthacene

I.E-6

227-04-3

1

0

0

Dibenzo[a,j]naphthacene

I.E-6

193-09-9

1

0

0

Dibenzo[de,qr]naphthacene {naphtho[2,3-d]pyrene}

I.E-6

192-51-8

1

0

0

Dibenzo[fg,op]naphthacene

Name (per CA Collective Index)

Selected structures

Chapter Table

X-2, XVIII.B-3 X-2, XII-2

NH2

O

X-2, XII-2

I.E-6 {dibenzo[e,l]pyrene}

26894-49-5

0

1

0

6H-Dibenzo[b,d]pyran-6-one, 3,7(3,9 or 7,9)dihydroxy-9(7 or 3)-methoxy-1-methyl-

VI-3, X-2, IX.A-22

OCH3

OH HO

29752-43-0

0

1

0

O

O

6H-Dibenzo[b,d]pyran-6-one, 9-methoxy-4a-methyl2,3,4,4a-tetrahydro-2,3,7-trihydroxy- (2D,3E,4aE)-

VI-3, X-2, IX.A-22

OCH3

HO

OH

HO

O

O CH3

641-38-3

0

1

0

6H-Dibenzo[b,d]pyran-6-one, 1-methyl-3,7,9trihydroxy-

VI-3, IX.A-22

OH CH3 OH HO

O

O

58615-36-4

1

0

0

Dibenzopyrene

132-65-0

1

1

1

Dibenzothiophene

XVIII.A-1

I.E-6

70021-47-5

0

1

0

Dibenzothiophene, dimethyl{at least four isomers detected}

XVIII.A-1

30995-64-3

1

1

1

Dibenzothiophene, methyl{at least four isomers detected}

XVIII.A-1

© 2009 by Taylor & Francis Group, LLC

78836_C030.indd 1587

11/24/08 1:56:11 PM

1588

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

188-94-3

1

0

0

Diindeno[1,2,3-cd:1',2',3'-lm]perylene

309-00-2

1

1

1

1,4:5,8-Dimethanonaphthalene, 1,2,3,4,10,10hexachloro-1,4,4a,5,8,8a-hexahydro-, (1D,4D,4aE,5D,8D,8aE)- [endo, endo] {Aldrin®}

Name (per CA Collective Index)

Selected structures

Chapter Table I.E-6

XVIII.B-3, XXI-3

Cl Cl Cl

CCl2

CH2

Cl

465-73-6

0

1

0

1,4:5,8-Dimethanonaphthalene, 1,2,3,4,10,10hexachloro-1,4,4a,5,8,8a-hexahydro-, (1D,4D,4aE,5E,8E,8aE)- [endo, exo] {Isodrin®}

XVIII.B-3, , XXI-3

60-57-1

1

1

1

2,7:3,6-Dimethanonaphth[2,3-b]oxirene, 3,4,5,6,9,9hexachloro-1a,2,2a,3,6,6a,7,7a-octahydro-, (1aD,2E,2aD,3E,6E,6aD,7E,7aD){Dieldrin®}

X-2, XVIII.B-3, XXI-3

72-20-8

1

1

1

2,7:3,6-Dimethanonaphth[2,3-b]oxirene, 3,4,5,6,9,9hexachloro-1a,2,2a,3,6,6a,7,7a-octahydro-, (1aD,2E,2aE,3D,6D,6aE,7E,7aD){Endrin®}

X-2, XVIII.B-3, XXI-3

119973-29-4

1

0

0

26,27-Dinorergosta-3,5-diene

I.C-1

119973-31-8

1

0

0

26,27-Dinorergosta-3,5,22-triene, (22E)-

I.C-1 I.C-1

119973-30-7

1

0

0

26,27-Dinorergost-3-ene, (5D)-

117210-53-4

0

1

0

2,7-Dioxabicyclo[2.2.1]heptane, 1,3-dimethyl-3-(4methyl-3-pentenyl)-, endo-

X-2

117305-90-5

0

1

0

2,7-Dioxabicyclo[2.2.1]heptane, 1,3-dimethyl-3-(4methyl-3-pentenyl)-, exo-

X-2

121927-15-9

0

1

0

13,14-Dioxabicyclo[10.2.2]hexadec-6-ene-2,3,5triol, 1,5-dimethyl-11-methylene-8-(1-methylethyl)-, [1R-(1R*,2S*,3R*,5S*,

II.A-5, X-2

52886-15-4

0

1

0

2,9-Dioxabicyclo[3.3.1]nonan-4-ol, 1,3,3-trimethyl-6(1-methylethyl){2 isomers reported}

II.A-5, X-2

0

1

0

6,8-Dioxabicyclo[3.2.1]octane, 1,5-dimethyl{frontalin}

0

1

0

6,8-Dioxabicyclo[3.2.1]octane-7-methanol, 2-(1methylethyl)-D,5-dimethyl- [1D,2E,5D,7D(R*)]

58001-00-6

X-2 II.A-5, X-2

CH3 O O HO

CH3

CH3

CH3

58001-10-8

0

1

0

6,8-Dioxabicyclo[3.2.1]octane-7-methanol, 2-(1methylethyl)-D,D,5-trimethyl-, (2-endo,7-exo)-(±)-

II.A-5, X-2

CH3 O O HO H3C

52992-36-6

0

1

0

6,8-Dioxabicyclo[3.2.1]octane-7-methanol, 2-(1methylethyl)-D,D,5-trimethyl-

CH3

CH3

CH3

II.A-5, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1588

11/24/08 1:56:12 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1589

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

37112-31-5

1

1

1

Name (per CA Collective Index) 6,8-Dioxabicyclo[3.2.1]oct-2-en-4-one, (1S){levoglucosenone}

16279-34-8

1

0

0

1,4-Dioxane, 2-methyl-

162188-91-2

1

0

0

1,4-Dioxaspiro[4.5]decan-8-one, 7-(acetyloxy)7,9,9-trimethyl-, (r)-

Selected structures O

X-2 O

H3C

8

9

5

O

1

1

0

1,6-Dioxaspiro[4.5]dec-3-en-2-one, 3,4,7-trimethyl-

0

1,3-Dioxalane-4-methanol, 2,2-dimethyl-

5 1

1

0

0

1,3-Dioxalan-2-one

{ethylene glycol carbonate}

4

CH3

H3C

5 4

O CH3

3

II.A-5, X-2

CH 2OH

O

H3C

96-49-1

III-13

CH3

O

0

O

3

6

2

1

CH3

6

7

O

100-79-8

III-13

OOC-CH3 7

4

2

0

III-13, X-2

O

O

H3C

41059-94-3

Chapter Table

O

V-3

1 O O

2 O 3

931-40-8

1

0

0

1,3-Dioxalan-2-one, 4-(hydroxymethyl){glycerol carbonate}

V-3

108-32-7

1

1

1

1,3-Dioxalan-2-one, 4-methyl{1,2-propylene glycol carbonate}

V-3

9025-33-6

0

1

0

Dipeptidase, prolyl

1

0

0

Dipropoxymethane

1

0

0

Dipyrido[1,2-a:3',2'-d]imidazol-2-amine {Glu-P-2}

67730-10-3

XXII-2 (C3H7O)2=CH2 N

X-2 NH2

XVII.F-6

N N

67730-11-4

1

0

0

Dipyrido[1,2-a:3',2'-d]imidazol-2-amine, 6-methyl{Glu-P-1}

N

NH2

XVII.F-6

N N CH3

484-73-1

1

0

0

5H,10H-Dipyrrolo[1,2-a:1',2'-d]pyrazine-5,10-dione {pyrocoll}

XVII.E-8

O N N O

59017-02-6

1

0

0

5H,10H-Dipyrrolo[1,2-a:1',2'-d]pyrazine-5,10-dione, 1,2,3,5a,8,10a-hexahydro-, (5aS-cis)-

XVII.E-8

1

0

0

5H,10H-Dipyrrolo[1,2-a:1',2'-d]pyrazine-5,10-dione, 1,2,3,5a,8,10a-hexahydro-3-methyl-

XVII.E-8

71277-95-7

1

0

0

5H,10H-Dipyrrolo[1,2-a:1',2'-d]pyrazine-5,10-dione, methyl-

XVII.E-8

6708-06-1

1

0

0

5H,10H-Dipyrrolo[1,2-a:1',2'-d]pyrazine-5,10-dione, octahydro-

XVII.E-8

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1589

11/24/08 1:56:12 PM

1590

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

9054-89-1

0

1

0

Dismutase, superoxide

XXII-2

143352-40-3

0

1

0

Dismutase, superoxide (Nicotiana plumbaginifolia clone pSOD3 copper-zinc protein moiety reduced)

XXII-2

5905-46-4

1

0

0

Disulfide, 1-propenyl propyl

110-81-6

1

0

0

Disulfide, diethyl

H3C-CH2-S-CH2-CH3

XVIII.A-1

624-92-0

1

1

1

Disulfide, dimethyl

H3C-S-S-CH3

XVIII.A-1

XVIII.A-1

20333-39-5

1

0

0

Disulfide, ethyl methyl

XVIII.A-1

5905-47-5

1

0

0

Disulfide, methyl 1-propenyl

XVIII.A-1

2179-60-4

1

0

0

Disulfide, methyl propyl

21548-32-3

0

1

0

1,3-Dithietan-2-ylidenephosphoramidic acid, diethyl ester {Fosthietan®}

XVIII.A-1 OC2H5

S N

O

P

S

947-02-4

0

1

0

Dithiolan-2-ylidenephosphoramidic acid, diethyl ester {Cyolane®; Phosfolan®}

XVIII.A-1, XXI-3

OC2H5

XVIII.A-1, XXI-3

O

S N

P

OC2H5

S OC2H5

2439-01-2

0

1

0

1,3-Dithiolo[4,5-b]quinoxalin-2-one, 6-methyl{Quinomethionate®}

N

S O

N

S

29564-66-7

0

1

0

Docosadienoic acid, (Z,Z)-

629-97-0

1

1

1

Docosane

H3C-(CH2)20-CH3

XVIII.A-1, XXI-3 IV.A-3 I.A-10

1560-81-2

1

1

1

Docosane, 2-methyl-

(H3C)=CH-(CH2)19-CH3

I.A-10

72227-00-0

1

1

1

Docosane, 3-methyl-

H3C-CH2-CH(CH3)-(CH2)18-CH3

I.A-10

112-85-6

1

1

1

Docosanoic acid

H3C-(CH2)20-COOH

IV.A-3

17671-27-1

1

1

1

Docosanoic acid, docosyl ester

H3C-(CH2)20-COO-(CH2)21-CH3

V-3

42233-07-8

1

1

1

Docosanoic acid, dodecyl ester

H3C-(CH2)20-COO-(CH2)11-CH3

V-3

{behenic acid}

42233-14-7

1

1

1

Docosanoic acid, eicosyl ester

H3C-(CH2)20-COO-(CH2)19-CH3

V-3

5908-87-2

1

0

0

Docosanoic acid, ethyl ester

H3C-(CH2)20-COO-CH2-CH3

V-3

42233-15-8

1

1

1

Docosanoic acid, heneicosyl ester

H3C-(CH2)20-COO-(CH2)20-CH3

V-3

121877-99-4

1

1

1

Docosanoic acid, heptacosyl ester

H3C-(CH2)20-COO-(CH2)26-CH3

V-3

42233-12-5

1

1

1

Docosanoic acid, heptadecyl ester

H3C-(CH2)20-COO-(CH2)16-CH3

V-3

55136-77-1

1

1

1

Docosanoic acid, hexacosyl ester

H3C-(CH2)20-COO-(CH2)25-CH3

V-3

42233-11-4

1

1

1

Docosanoic acid, hexadecyl ester

H3C-(CH2)20-COO-(CH2)15-CH3

V-3

42233-13-6

1

1

1

Docosanoic acid, nonadecyl ester

H3C-(CH2)20-COO-(CH2)18-CH3

V-3

21511-31-9

1

1

1

Docosanoic acid, octacosyl ester

H3C-(CH2)20-COO-(CH2)27-CH3

V-3

24271-12-3

1

1

1

Docosanoic acid, octadecyl ester

H3C-(CH2)20-COO-(CH2)17-CH3

V-3

1

1

1

Docosanoic acid, pentacosyl ester

H3C-(CH2)20-COO-(CH2)24-CH3

V-3

42233-10-3

1

1

1

Docosanoic acid, pentadecyl ester

H3C-(CH2)20-COO-(CH2)14-CH3

V-3

42233-17-0

1

1

1

Docosanoic acid, tetracosyl ester

H3C-(CH2)20-COO-(CH2)23-CH3

V-3

H3C-(CH2)20-COO-(CH2)13-CH3

V-3

42233-09-0

1

1

1

Docosanoic acid, tetradecyl ester

1

0

0

Docosanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester

42233-16-9

1

1

1

Docosanoic acid, tricosyl ester

H3C-(CH2)20-COO-(CH2)32-CH3

V-3

42233-08-9

1

1

1

Docosanoic acid, tridecyl ester

H3C-(CH2)20-COO-(CH2)12-CH3

V-3

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1590

11/24/08 1:56:13 PM

1591

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Chapter Table

Selected structures

36332-95-3

0

1

0

Docosanoic acid, 20-methyl-

H3C-CH2 CH(CH3)-(CH2)18-COOH

121877-76-7

1

1

1

Docosanoic acid, 20-methyl-, docosyl ester

121877-62-1

1

1

1

Docosanoic acid, 20-methyl-, eicosyl ester

H3C-CH2-CH(CH3)-(CH2)18-COO-(CH2)21-CH3 V-3 H3C-CH2-CH(CH3)-(CH2)18-COO-(CH2)19-CH3 V-3

121877-71-2

1

1

1

Docosanoic acid, 20-methyl-, heneicosyl ester

59708-74-6

0

1

0

Docosanoic acid, 21-methyl-

661-19-8

1

1

1

1-Docosanol

0

1

0

1-Docosanol, 20-methyl-

0

1

0

1-Docosanol, 21-methyl-

1

0

0

1-Docosene

H3C-(CH2)19-CH=CH2

I.B-1

1

0

0

1-Docosene, 2-methyl-

H2C=C(CH3)-(CH2)19-CH3

I.B-1

1

0

0

2-Docosene, (Z)-

H3C-CH=CH-(CH2)18-CH3

I.B-1

1

0

0

2-Docosene, (E)-

1

0

0

2-Docosene, 2-methyl-

H3C-C(CH3)=CH-(CH2)18-CH3

1

0

0

2-Docosene, 20-methyl-, (Z)-

H3C-CH=CH-(CH2)16-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Docosene, 20-methyl-, (E)-

1

0

0

2-Docosene, 21-methyl-, (Z)-

1599-67-3

{behenyl alcohol}

IV.A-3

H3C-CH2-CH(CH3)-(CH2)18-COO-(CH2)20-CH3 V-3 (H3C)2=CH-(CH2)19-COOH

IV.A-3

H3C-(CH2)20-CH2OH

II.A-5 II.A-5 II.A-5

I.B-1 I.B-1

I.B-1 H3C-CH=CH-(CH2)17-CH(CH3)2

I.B-1

1

0

0

2-Docosene, 21-methyl-, (E)-

112-86-7

0

1

0

13-Docosenoic acid, (Z)-

I.B-1

65596-29-4

0

1

0

3,6-Dodecadienedioic acid, 10-hydroxy-4,9dimethyl-

II.A-5, IV.A-3

40596-69-8

1

1

1

2,4-Dodecadienoic acid, 11-methoxy-3,7,11trimethyl-, 1-methylethyl ester, (E,E){Methoprene®; Altoside®}

IV.A-3, XXI-3

0

1

0

2,4-Dodecadienoic acid, 3-methyl-6-(1-methylethyl)9-oxo-

III-13, IV.A-3

7226-86-0

1

0

0

2,6-Dodecadien-1-ol, 3,7,11-trimethyl-

117232-64-1

0

1

0

5,10-Dodecadien-2-one, 9-hydroxy-6,11-dimethyl-

112-40-3

1

1

1

Dodecane

H3C-(CH2)10-CH3

I.A-10

1560-97-0

1

0

0

Dodecane, 2-methyl-

H3C-(CH2)9-CH=(CH3)2

I.A-10

17312-57-1

1

1

1

Dodecane, 3-methyl-

3891-98-3

1

1

1

Dodecane, 2,6,10-trimethyl-

IV.A-3

II.A-5 II.A-5, III-13

H3C-(CH2)8-CH(CH3)-CH2-CH3 (farnesane)

I.A-10 I.A-10

693-23-2

1

0

0

Dodecanedioic acid

143-07-7

1

1

1

Dodecanoic acid

71278-23-4

1

1

1

Dodecanoic acid, 3,7,11,15,19,23,27,31,35nonamethyl-2,6,10,14,18,22,26,30,34hexatriacontanonaenyl ester

V-3

71278-24-5

1

0

0

Dodecanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester

V-3

36617-18-2

1

1

1

Dodecanoic acid, eicosyl ester

106-33-2

0

1

0

Dodecanoic acid, ethyl ester

111-82-0

0

1

0

Dodecanoic acid, methyl ester

HOOC-(CH2)10-COOH {lauric acid}

{ethyl laurate}

H 3C-(CH2)10-COOH

IV.A-3 IV.A-3, XXI-3

H3C-(CH2)10-COO-(CH2)19-CH3

V-3

H 3C-(CH2)10-COO-C2H5

V-3

H3C-(CH2)10-COO-CH3

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1591

11/24/08 1:56:13 PM

1592

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

7416-57-1

0

1

0

Dodecanoic acid, 10-methyl-

H3C-CH2 CH(CH3)-(CH2)8-COOH

121877-15-4

1

1

1

Dodecanoic acid, 10-methyl-, eicosyl ester

H3C-CH2-CH(CH3)-(CH2)8-COO-(CH2)19-CH3 V-3

Name (per CA Collective Index)

Chapter Table

Selected structures

IV.A-3

121877-10-9

1

1

1

Dodecanoic acid, 11-methyl-, eicosyl ester

(H3C)2=CH-(CH2)9-COO-(CH2)19-CH3

112-53-8

1

1

1

1-Dodecanol

H3C-(CH2)10-CH2OH

6750-34-1

0

1

0

1-Dodecanol, 3,7,11-trimethyl- {hexahydrofarnesol}

6175-49-1

0

1

0

2-Dodecanone

502-61-4

1

0

0

1,3,6,10-Dodecatetraene, 3,7,11-trimethyl-, (E,E){D-farnesene}

I.B-1

1

0

0

2,6,9,11-Dodecatetraen-1-ol, 2,6,10-trimethyl-, (2E,6E,9E){Į-sinensol}

II.A-5

1

0

0

2,6,10,?-Dodecatetraenol

{dehydrofarnesol}

II.A-5

1

0

0

1,6,10-Dodecatriene, 7,11-dimethyl-3-methylene-, (E){E-farnesene}

I.B-1

18794-84-8 3899-18-1

{lauryl alcohol}

V-3

II.A-5, XXI-3 II.A-5

H3C-(CH2)9-CO-CH3

III-13

1

0

0

2,6,10-Dodecatriene, 2,6,10-trimethyl-, (E,E)-

I.B-1

1

0

0

2,6,10-Dodecatriene, 3,7,11-trimethyl-

I.B-1

7548-13-2

0

1

0

2,6,10-Dodecatrienoic acid, 3,7,11-trimethyl-

7212-44-4

1

1

1

1,6,10-Dodecatrien-3-ol, 3,7,11-trimethyl{nerolidol}

II.A-5

142-50-7

0

1

0

1,6,10-Dodecatrien-3-ol, 3,7,11-trimethyl-, [S-(Z)]-

II.A-5

4602-84-0 3790-71-4

1

1

1

2,6,10-Dodecatrien-1-ol, 3,7,11-trimethyl{sinensol; farnesol}

II.A-5, XXI-3

1

0

0

2,6,10-Dodecatrien-1-ol, 3,7,11-trimethyl{farnesol isomer}

II.A-5

1

1

1

2,6,10-Dodecatrien-1-ol, 3,7,11-trimethyl-, acetate {farnesyl acetate}

V-3

0

1

0

2,6,10-Dodecatrien-1-ol, 3,7,11-trimethyl-, formate {farnesyl formate}

V-3

25378-22-7

1

0

0

Dodecene

112-41-4

1

0

0

1-Dodecene

H2C=CH-(CH2)9-CH3

I.B-1

1

0

0

1-Dodecene, 2-methyl-

H2C=C(CH3)-(CH2)9-CH3

I.B-1

1

0

0

2-Dodecene, 2-methyl-

H3C-C(CH3)=CH-(CH2)8-CH3

I.B-1

1

0

0

2-Dodecene, 10-methyl-, (Z)-

H3C-CH=CH-(CH2)6-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Dodecene, 10-methyl-, (E)-

1

0

0

2-Dodecene, 11-methyl-, (Z)-

1

0

0

2-Dodecene, 11-methyl-, (E)-

1

0

0

Dodecenoic acid

4412-16-2

0

1

0

2-Dodecenoic acid

544-85-4

1

1

1

Dotriacontane

H3C-(CH2)30-CH3

29548-30-9

IV.A-3

I.B-1

I.B-1 H3C-CH=CH-(CH2)7-CH(CH3)2

I.B-1 I.B-1 IV.A-3 IV.A-3 I.A-10

1720-11-2

1

1

1

Dotriacontane, 2-methyl-

H3C-(CH2)29-CH=(CH3)2

I.A-10

20129-49-1

1

1

1

Dotriacontane, 3-methyl-

H3C-(CH2)28-CH(CH3)-CH2-CH3

I.A-10

16753-27-8

1

1

1

Dotriacontane-16,17- C2, labeled with C

3625-52-3

1

0

0

Dotriacontanoic acid

H3C-(CH2)30-COOH

121878-06-6

1

1

1

Dotriacontanoic acid, eicosyl ester

H3C-(CH2)30-COO-(CH2)19-CH3

14

14

I.A-10 IV.A-3 V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1592

11/24/08 1:56:14 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1593

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

66309-89-5

1

0

0

2,6,10,14,18,22,26,30-Dotriacontaoctaene, 2,6,10,14,18,22,26,30-octamethyl-, (all-E)-

I.B-1

85792-05-8

1

0

0

Dotriacontene

I.B-1

18435-55-7

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

1-Dotriacontene

H2C=CH-(CH2)29-CH3

I.B-1

1

0

0

2-Dotriacontene, (Z)-

H3C-CH=CH-(CH2)28-CH3

I.B-1

1

0

0

2-Dotriacontene, (E)-

7429-91-6

1

1

1

Dysprosium

9007-57-2

0

1

0

Edestin

I.B-1 Dy

25448-01-5

0

1

0

Eicosadienoic acid

2400-66-0

0

1

0

Eicosanal

H3C-(CH2)18-CH=O H3C-(CH2)18-CH3

112-95-8

XX-5 XXII-2 IV.A-3 III-12

1

1

1

Eicosane

0

1

0

Eicosane, methyl-

I.A-10

1

0

0

Eicosane, 2-methyl-

H3C-(CH2)17-CH=(CH3)2

I.A-10

0

1

0

Eicosane, 3-methyl-

H3C-(CH2)16-CH(CH3)-CH2-CH3

I.A-10

4616-73-3

1

0

0

Eicosanenitrile

H3C-(CH2)18-CN

I.A-10

{arachidic acid}

H3C-(CH2)18-COOH

XI-2

506-30-9

1

1

1

Eicosanoic acid

42232-87-1

1

1

1

Eicosanoic acid, docosyl ester

H3C-(CH2)18-COO-(CH2)21-CH3

IV.A-3 V-3

42232-82-6

1

1

1

Eicosanoic acid, dodecyl ester

H3C-(CH2)18-COO-(CH2)11-CH3

V-3

22432-80-0

1

1

1

Eicosanoic acid, eicosyl ester

H3C-(CH2)18-COO-(CH2)19-CH3

V-3

42218-26-8

1

1

1

Eicosanoic acid, heneicosyl ester

H3C-(CH2)18-COO-(CH2)20-CH3

V-3

121877-87-0

1

1

1

Eicosanoic acid, heptacosyl ester

H3C-(CH2)18-COO-(CH2)26-CH3

V-3

36610-58-9

1

1

1

Eicosanoic acid, heptadecyl ester

H3C-(CH2)18-COO-(CH2)16-CH3

V-3

17318-45-5

1

1

1

Eicosanoic acid, hexacosyl ester

H3C-(CH2)18-COO-(CH2)25-CH3

V-3

22413-05-4

1

1

1

Eicosanoic acid, hexadecyl ester

H3C-(CH2)18-COO-(CH2)15-CH3

V-3

1120-28-1

1

0

0

Eicosanoic acid, methyl ester

H3C-(CH2)18-COO-CH3

V-3

36610-60-3

1

1

1

Eicosanoic acid, nonadecyl ester

H3C-(CH2)18-COO-(CH2)18-CH3

V-3

55309-61-0

1

1

1

Eicosanoic acid, octacosyl ester

H3C-(CH2)18-COO-(CH2)27-CH3

V-3

22432-79-7

1

1

1

Eicosanoic acid, octadecyl ester

H3C-(CH2)18-COO-(CH2)17-CH3

V-3

121877-79-0

1

1

1

Eicosanoic acid, pentacosyl ester

H3C-(CH2)18-COO-(CH2)24-CH3

V-3

36665-69-7

1

1

1

Eicosanoic acid, pentadecyl ester

H3C-(CH2)18-COO-(CH2)14-CH3

V-3

42232-89-3

1

1

1

Eicosanoic acid, tetracosyl ester

H3C-(CH2)18-COO-(CH2)23-CH3

V-3

22413-04-3

1

1

1

Eicosanoic acid, tetradecyl ester

H3C-(CH2)18-COO-(CH2)13-CH3

V-3

71278-14-3

1

0

0

Eicosanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester

V-3

42232-88-2

1

1

1

Eicosanoic acid, tricosyl ester

H3C-(CH2)18-COO-(CH2)32-CH3

V-3

36610-55-6

1

1

1

Eicosanoic acid, tridecyl ester

H3C-(CH2)18-COO-(CH2)12-CH3

V-3

36332-93-1

1

1

1

Eicosanoic acid, 18-methyl-

H3C-CH2-CH(CH3)-(CH2)16-COOH IV.A-3

121877-60-9

1

1

1

Eicosanoic acid, 18-methyl-, docosyl ester

H3C-CH2-CH(CH3)-(CH2)16-COO-(CH2)21-CH3 V-3

59708-73-5

0

1

0

Eicosanoic acid, 19-methyl-

(H3C)2=CH-(CH2)17-COOH

629-96-9

1

1

1

1-Eicosanol

0

1

0

1-Eicosanol, 18-methyl-

{arachic alcohol}

H3C-(CH2)18-CH2OH

IV.A-3 II.A-5 II.A-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1593

11/24/08 1:56:14 PM

1594

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

0

1

0

1-Eicosanol, 19-methyl-

II.A-5

4340-76-5

1

0

0

2-Eicosanol

II.A-5

7431-92-7

1

0

0

2,6,10,14,18-Eicosapentaene, 2,6,10,14,18pentamethyl-, (all-E)-

75581-03-2

1

0

0

2,6,10,14,18-Eicosapentaene, 2,6,10,14,18pentamethyl-

I.B-1

1

0

0

2,6,10,14,18-Eicosapentaene, 2,6,10,14,18pentamethyl{isomer}

I.B-1

506-32-1

1

1

1

5,8,11,14-Eicosatetraenoic acid, (all-Z){arachidonic acid}

IV.A-3

55682-88-7

0

1

0

11,14,17-Eicosatrienoic acid, methyl ester

1

0

0

Eicosene

1

1

1

1-Eicosene

H2C=CH-(CH2)17-CH3

I.B-1

1

0

0

1-Eicosene, 2-methyl-

H2C=C(CH3)-(CH2)17-CH3

I.B-1

1

0

0

2-Eicosene, (Z)-

H3C-CH=CH-(CH2)16-CH3

I.B-1

3452-07-1

26764-41-0

H-[CH2-C(CH3)=CH-CH2]5-H

I.B-1

V-3 I.B-1

1

0

0

2-Eicosene, (E)-

1

0

0

2-Eicosene, 2-methyl-

H3C-C(CH3)=CH-(CH2)16-CH3

I.B-1

1

0

0

2-Eicosene, 18-methyl-, (Z)-

H3C-CH=CH-(CH2)14-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Eicosene, 18-methyl-, (E)-

1

0

0

2-Eicosene, 19-methyl-, (Z)-

1

0

0

2-Eicosene, 19-methyl-, (E)-

1

1

1

Eicosenoic acid

I.B-1 I.B-1

H3C-CH=CH-(CH2)15-CH(CH3)2

I.B-1 I.B-1 IV.A-3

22104-85-4

0

1

0

2-Eicosen-1-ol

159844-36-7

0

1

0

Enzyme E 2 (Arabidopsis thaliana clone TAY029 gene UbcAt3 ubiquitin-carrier)

H3C-(CH2)16-CH=CH-CH2OH

II.A-5

38419-69-1

0

1

0

6H-3,10b-Epoxy-1H-naphtho[2,1-b]pyran, decahydro-3,4a,7,7,10a-pentamethyl-, [3S(3D,4aE,6aD,10aE,10bD)]-

7440-52-0

1

1

1

Erbium

474-62-4

1

1

1

Ergost-5-en-3-ol, (3E,24R)-

26047-31-4

0

1

0

Ergost-7-en-3-ol, (3E)-

II.B-2

17105-75-8

1

0

0

Ergost-7-en-3-ol, (3E,24[)-

II.B-2

33860-48-9

0

1

0

Ergost-8-en-3-ol, 14-methyl-, (3E,5D)-

II.B-2

16910-33-1

0

1

0

Ergost-8-en-3-ol, 4,14-dimethyl-, (3E,4D,5D)-

II.B-2

70116-48-2

0

1

0

Ergost-8-en-3-ol, 4,14-dimethyl-, (3E,4D,5D,24[)-

II.B-2

77327-07-2

1

0

0

Ergosta-3,5,7-triene, (24[)-

XXII-2 X-2

XX-5 II.B-2

{campesterol}

I.C-1 R

R = -(CH2)2-CH(CH3)-CH(CH3)2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1594

11/24/08 1:56:15 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1595

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

19254-69-4

0

1

0

Name (per CA Collective Index)

Chapter Table

Selected structures

Ergosta-4,6,8(14),22-tetraen-3-one, (22E)-

III-13 CH3 H3C

1

CH3

H3C

2

H3C

8 3

O

4

CH3

5

7 6

474-67-9

0

1

0

Ergosta-5,22-dien-3-ol, (3E,22E)-

II.B-2

474-63-5

0

1

0

Ergosta-5,24(28)-dien-3-ol, (3E)-

II.B-2

52936-69-3

0

1

0

Ergosta-5,25-dien-3-ol, (3E)-

II.B-2

57-87-4

1

1

1

Ergosta-5,7,22-trien-3-ol, (3E,22E)-

II.B-2

{ergosterol} CH3 H3C

CH3 CH3

H3C H3C

HO

21490-25-5

0

1

0

Ergosta-7,24(28)-dien-3E-ol, 4E-methyl-

II.B-2

474-68-0

0

1

0

Ergosta-7,24(28)-dien-3-ol, (3E,5D)-

II.B-2

1176-52-9

0

1

0

Ergosta-7,24(28)-dien-3-ol, 4-methyl-, (3E,4D,5D)-

II.B-2

74635-33-9

0

1

0

Ergosta-8,14,24(28)-trien-3-ol, 4-methyl-, (3E,4D,5D)-

II.B-2

23839-47-6

0

1

0

Ergosta-8,14-dien-3-ol, (3E,5D)-

II.B-2

33886-74-7

0

1

0

Ergosta-8,24(28)-dien-3-ol, 14-methyl-, (3E,5D)-

II.B-2

16910-32-0

0

1

0

Ergosta-8,24(28)-dien-3-ol, 4,14-dimethyl-, (3E,4D,5D)-

II.B-2

80736-41-0

0

1

0

Ergostan-6-one, 2,3,22,23-tetrahydroxy-, (2D,3D,5D,22R, 23R,24S)-

III-13, II.B-2

121468-15-3

0

1

0

Ergostan-6-one, 2,3,22,23-tetrahydroxy-, (2D,3E,5D,22R,23R,24S)-

III-13, II.B-2

92751-21-8

0

1

0

Ergostan-6-one, 3,22,23-trihydroxy-, (3E,5D,22R,23R,24S)-

III-13, II.B-2

87734-68-7

0

1

0

Ergostan-6-one, 3,22,23-trihydroxy-, (3D,5D,22R,23R,24S)-

III-13, II.B-2

0

1

0

Erlose (a trisaccharide)

9013-79-0

0

1

0

Esterase

XXII-2

9025-98-3

0

1

0

Esterase, pectin

XXII-2

75-04-7

1

1

1

Ethanamine

51-75-2

1

0

0

Ethanamine, 2-chloro-N-(2-chloroethyl)-N-methyl-

(Cl-CH2-CH2)2=N-CH3

121-44-8

1

1

1

Ethanamine, N,N-diethyl-

(H3C-CH2)3ŁN

XII-2

(H3C-CH2)2=NH

XII-2

(H3C-CH2)2=N-NO

XV-8

H3C-CH2-NH-CH3

XII-2

H3C-CH2-N(NO)-CH3

XV-8

II.A-5

{ethylamine} {triethylamine}

1

0

0

Ethanamine, N,1-dimethyl-N-nitroso-

109-89-7

1

1

1

Ethanamine, N-ethyl-

55-18-5

1

1

1

Ethanamine, N-ethyl-N-nitroso-

624-78-2

1

1

1

Ethanamine, N-methyl-

10595-95-6

1

1

1

Ethanamine, N-methyl-N-nitroso-

H3C-CH2-NH2

XII-2 XII-2, XVIII.B-3 XV-8

{diethylamine} {NDEA} {NEMA}

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1595

11/24/08 1:56:15 PM

1596

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

97190-07-3

0

1

0

Ethanaminium, 2-[[(2,3dihydroxypropoxy)hydroxyphosphinyl]oxy]-N,N,Ntrimethyl-, hydroxide, inner salt, monooctadecadienoate monooctadecatrienoate, (all-Z)-

XII-2

97190-09-5

0

1

0

Ethanaminium, 2-[[(2,3dihydroxypropoxy)hydroxyphosphinyl]oxy]-N,N,Ntrimethyl-, hydroxide, inner salt, monohexadecanoate monooctadecatrienoate, (Z,Z,Z)-

XII-2

97190-10-8

0

1

0

Ethanaminium, 2-[[(2,3dihydroxypropoxy)hydroxyphosphinyl]oxy]-N,N,Ntrimethyl-, hydroxide, inner salt, monohexadecanoate monooctadecadienoate, (Z,Z)-

XII-2

97190-12-0

0

1

0

Ethanaminium, 2-[[(2,3dihydroxypropoxy)hydroxyphosphinyl]oxy]-N,N,Ntrimethyl-, hydroxide, inner salt, monooctadecadienoate

XII-2

62-49-7 123-41-1

0

1

0

Ethanaminium, 2-hydroxy-N,N,N-trimethyl{choline}

8002-43-5

0

1

0

Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, phosphatidyl{lecithin}

74-84-0

1

0

0

Ethane

0

1

0

Ethane, bis(4-methylphenyl)-

624-89-5

Name (per CA Collective Index)

Selected structures

+

HO-(CH2)2-N Ł(CH3)3

Chapter Table

XII-2 XII-2

H3C-CH3

I.A-10 I.D-1

1

0

0

Ethane, (methylthio)-

1

1

1

Ethane, 1-chloro-2-bromotetrafluoro{Freon® 114b1}

ClF2C-CF2Br

XVIII.B-3

XVIII.A-1

75-88-7

1

1

1

Ethane, 1-chloro-2,2,2-trifluoro-

ClCH2-CF3

XVIII.B-3

60-29-7

1

1

1

Ethane, 1,1'-oxybis-

352-93-2

1

0

0

Ethane, 1,1'-thiobis-

106-93-4

0

1

0

Ethane, 1,2-dibromo{ethylene dibromide, EDB®, Bromofume®}

{Freon® 133a} {ethyl ether}

X-2 XVIII.A-1

107-06-2

1

0

0

Ethane, 1,2-dichloro-

306-83-2

1

1

1

Ethane, 2,2-dichloro-1,1,1-trifluoro- {Freon® 123}

Br-CH2-CH2-Br

XVIII.B-3, XXI-3 XVIII.B-3

Cl 2CH-CF3

XVIII.B-3

104-66-5

0

1

0

Ethane, 1,2-diphenoxy-

C6H5-O-CH2CH2-OC6H5

75-00-3

1

0

0

Ethane, chloro-

C2H5-Cl

540-67-0

1

0

0

Ethane, methoxy-

C2H5-O-CH3

79-24-3

1

0

0

Ethane, nitro-

C2H5-NO2

71-55-6

1

0

0

Ethane, 1,1,1-trichloro-

H3C-CŁCl3

72-43-5

0

1

0

Ethane, 1,1,1-trichloro-2,2-bis(4-methoxyphenyl){Methoxychlor®}

X-2 XVIII.B-3 X-2 XVI-1 XVIII.B-3

O

O

CCl3

X-2, XVIII.B-3, XXI-3 811-97-2

1

1

1

Ethane, 1,1,1,2-tetrafluoro-

{Freon® 134a}

25323-89-1

0

1

0

Ethane, 1,2,2-trichloro-

151-67-7

1

1

1

Ethane, 1,1,1-trifluoro-2-bromo-2-chloro{Freon® 123b1, Halothane}

FCH2-CF3

XVIII.B-3 XVIII.B-3, XXI-3

ClBrCH-CF3

XVIII.B-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1596

11/24/08 1:56:16 PM

1597

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

107-22-2

1

1

1

Ethanedial

460-19-5

1

0

0

Ethanedinitrile

0

1

0

Ethanedioate

1

1

1

Ethanedioic acid

1

1

1

Ethanedioic acid, labeled with C 14 {oxalic acid- C}

14258-49-2

0

1

0

Ethanedioic acid, ammonium salt

17787-48-3

0

1

0

Ethanedioic acid, calcium salt (1:1), hydrate (2:5)

XX-6

25454-23-3

0

1

0

Ethanedioic acid, calcium salt

XX-6

144-62-7

Name (per CA Collective Index)

Chapter Table

Selected structures

{glyoxal} {cyanogen}

O=CH-CH=O

III-12

NC-CN

XI-2

{oxalate} {oxalic acid}

XX-6 HOOC-COOH

IV.A-3

14

XXV-29 XX-6

95-92-1

0

1

0

Ethanedioic acid, diethyl ester

583-52-8

0

1

0

Ethanedioic acid, dipotassium salt

XX-6

6018-94-6

0

1

0

Ethanedioic acid, nickel salt

XX-6

17480-26-1

0

1

0

Ethanedioic acid, tin salt

542-10-9

1

0

0

1,1-Ethanediol, diacetate

107-21-1

1

1

1

1,2-Ethanediol

111-55-7

1

0

0

1,2-Ethanediol, diacetate

V-3

{stannous oxalate}

XX-6 V-3

{ethylene glycol}

HOCH2-CH2OH

II.A-5 V-3

534-82-7

0

1

0

1,2-Ethanediol, 1-(4-hydroxy-3-methoxyphenyl)-

542-59-6

1

0

0

1,2-Ethanediol, monoacetate {acetic acid, 2-hydroxyethyl ester}

HO-(CH2) 2-OOC-CH3

134-81-6

1

0

0

Ethanedione, diphenyl-

107-35-7

0

1

0

Ethanesulfonic acid, 2-amino-

C6H5-CO-CO-C6H5 H2N-(CH2)2-SO3H

{benzil} {taurine} {ethyl mercaptan}

II.A-5 II.A-5, V-3 III-13 XII-2, XVIII.A-1

75-08-1

1

0

0

Ethanethiol

40460-44-4

0

1

0

1,1,2-Ethanetriol

C2H5-SH

XVIII.A-1

23135-22-0

0

1

0

Ethanimidothioic acid, 2-(dimethylamino)-N[[(methylamino)carbonyl]oxy]-2-oxo-, methyl ester {Oxamyl®}

(H3C)2=N-CO-C(S-CH3)=N-OOC-NH-CH3 V-3, XXI-3

59669-26-0

0

1

0

Ethanimidothioic acid, N',N'(thiobis((methylimino)carbonyloxy))bis-, dimethyl ester {Thiodicarb®}

S=[NH-COO-N=C(CH3)-SCH3]2

XXI-3

64-17-5

1

1

1

Ethanol

H3C-CH2OH

II.A-5

108-01-0

1

0

0

Ethanol, 2-(dimethylamino)-

II.A-5

{ethyl alcohol}

109-83-1

0

1

0

Ethanol, 2-(methylamino)-

1116-54-7

1

1

1

Ethanol, 2,2'-(nitrosoimino)bis-

112-27-6

1

1

1

Ethanol, 2,2'-(1,2-ethanediylbis(oxy))bis{triethylene glycol}

111-21-7

1

1

1

Ethanol, 2,2'-[1,2-ethanediylbis(oxy)]bis-, diacetate

112-60-7

0

1

0

Ethanol, 2,2'-[oxybis(2,1-ethanediyloxy)]bis{tetraethylene glycol}

30934-97-5

1

0

0

Ethanol, 2,2-dimethoxy-

111-42-2

1

1

1

Ethanol, 2,2'-iminobis-

111-46-6

1

1

1

Ethanol, 2,2'-oxybis-

{NDELA}

(H3C)2=N-CH2-CH2OH

II.A-5, XII-2

H3C-NH-CH2-CH2OH

II.A-5, XII-2

(HO-CH 2CH2)2=N-NO

XV-8

HO-(CH2) 2-O-(CH2) 2-O-(CH2) 2-OH II.A-5 V-3 II.A-5 II.A-5, X-2

{diethanolamine}

(HO-CH 2CH2)2=NH

II.A-5, XII-2

{diethylene glycol}

(HO-CH 2CH2)2=O

II.A-5

{ethanolamine}

HO-CH2CH2-NH2

II.A-5, XII-2

141-43-5

0

1

0

Ethanol, 2-amino-

1071-23-4

0

1

0

Ethanol, 2-amino-, dihydrogen phosphate (ester)

78-51-3

1

0

0

Ethanol, 2-butoxy-, phosphate (3:1)

XII-2 [H3C-(CH2)3-O-(CH2)2]3ŁP=O

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1597

11/24/08 1:56:16 PM

1598

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

110-80-5

1

1

1

Ethanol, 2-ethoxy-

HO-CH2CH2-O-CH2CH3

II.A-5, X-2

109-86-4

1

1

1

Ethanol, 2-methoxy-

HO-CH2CH2-O-CH3

II.A-5, X-2

C6H5O-CH2CH2-OH

II.A-5, X-2

Name (per CA Collective Index)

122-99-6

0

1

0

Ethanol, 2-phenoxy-

1321-27-3

1

1

1

Ethanol, phenyl-: Previously listed as 60-12-8 Benzeneethanol

115-32-2

0

1

0

Ethanol, 2,2,2-trichloro-1,1-bis(4-chlorophenyl){Dicofol®}

Selected structures

Chapter Table

II.A-5 Cl

Cl

Cl3C

XVIII.B-3, XXI-3

OH

1

0

0

Ethanone, 1-(alkyl-1H-pyrrolyl)-

III-13, XVII.A-4

78210-69-2

1

0

0

Ethanone, 1-(1,2-dihydro-2-methyl-3-pyridinyl)-

III-13, XVII.B-2

117210-49-8

0

1

0

Ethanone, 1-(1,4,4a,5,6,7,8,8a-octahydro-4a,8,8trimethyl-2-naphthalenyl)-, (4aR-trans)-

III-13

932-66-1

1

0

0

Ethanone, 1-(1-cyclohexen-1-yl)-

III-13

1

0

0

Ethanone, 1-(dimethylphenyl){dimethylacetophenone}

III-13

1

0

0

Ethanone, 1-(methylphenyl){methylacetophenone}

III-13

1

0

0

Ethanone, 1-(methyl-1H-pyrrolyl)-

III-13, XVII.A-4

20583-33-9

0

1

0

Ethanone, 1-(1H-pyrazol-3-yl)-

III-13, XVII.A-4

25016-16-4

0

1

0

Ethanone, 1-(1H-pyrazol-4-yl)-

III-13, XVII.A-4

1072-83-9

1

1

1

Ethanone, 1-(1H-pyrrol-2-yl){2-acetylpyrrole; methyl 2-pyrrolyl ketone}

III-13, XVII.A-4

1072-82-8

1

1

1

Ethanone, 1-(1H-pyrrol-3-yl){3-acetylpyrrole; methyl 3-pyrrolyl ketone}

III-13, XVII.A-4

26444-19-9

711-79-5

1

1

1

Ethanone, 1-(1-hydroxy-2-naphthalenyl)-

III-13

20970-50-7

1

0

0

Ethanone, 1-(1-methyl-1H-imidazol-5-yl)-

III-13, XVII.A-4

37687-18-6

1

0

0

Ethanone, 1-(1-methyl-1H-pyrazol-4-yl)-

III-13, XVII.A-4

932-16-1

1

1

1

Ethanone, 1-(1-methyl-1H-pyrrol-2-yl)-

III-13, XVII.A-4 III-13, XVII.A-4

932-62-7

1

1

1

Ethanone, 1-(1-methyl-1H-pyrrol-3-yl)-

70987-81-4

1

1

1

Ethanone, 1-(1,2,3-trimethyl-2-cyclopenten-2-yl)-

779-90-8

0

1

0

Ethanone, 1,1’,1”-(1,3,5-benzenetriyl)tris{1,3,5-triacetylbenzene}

III-13 III-13

CO-CH3

H3C-CO

CO-CH3

1

0

0

Ethanone, 1-(2-alkylphenyl)-

55041-85-5

1

1

1

Ethanone, 1-(2,3-dihydro-1H-pyrrolizin-5-yl)-

III-13, XVII.A-4

19005-95-9

1

0

0

Ethanone, 1-(2,4,5-trimethyl-1H-pyrrol-3-yl)-

III-13, XVII.A-4

85213-22-5

0

1

0

Ethanone, 1-(2,5-dihydro-1H-pyrrol-2-yl){2-acetylpyrroline}

III-13, XVII.A-4

1

0

0

Ethanone, 1-(2,5-dihydro-5-methyl-1H-pyrrol-3-yl)-

1

0

0

Ethanone, 1-(2,5-dihydroxyphenyl)-

490-78-8

III-13

III-13, XVII.A-4 III-13, IX.A-22

OH 3 2

4 5

CO-CH3

HO

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1598

11/24/08 1:56:17 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1599

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

1500-94-3

1

0

0

Ethanone, 1-(2,5-dimethyl-1H-pyrrol-3-yl)-

1197-92-8

0

1

0

Ethanone, 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-

699-83-2

1

0

0

Ethanone, 1-(2,6-dihydroxyphenyl)-

1192-62-7

1

1

1

Ethanone, 1-(2-furanyl)-

Selected structures

III-13, XVII.A-4 III-13 III-13, IX.A-22

{2-acetylfuran}

III-13, X-2 O

19859-79-1

1

0

0

Ethanone, 1-(2-furanyl)-2-(acetyloxy)-

17678-19-2

1

0

0

Ethanone, 1-(2-furanyl)-2-hydroxy-

Chapter Table

CO-CH3

III-13, X-2 III-13, X-2 O

703-98-0

1

0

0

Ethanone, 1-(2-hydroxy-3-methoxyphenyl)-

6921-64-8

0

1

0

Ethanone, 1-(2-hydroxy-4-methylphenyl)-

1450-72-2

1

0

0

Ethanone, 1-(2-hydroxy-5-methylphenyl)-

703-23-1

1

0

0

Ethanone, 1-(2-hydroxy-6-methoxyphenyl)-

CO-CH2OH

III-13, IX.A-22, X-2 III-13, IX.A-22 III-13, IX.A-22 III-13, IX.A-22, X-2

0

1

0

Ethanone, 1-(2-hydroxy-6-methylphenyl)-

III-13, IX.A-22

118-93-4

1

1

1

Ethanone, 1-(2-hydroxyphenyl)-

III-13, IX.A-22

78210-66-9

1

0

0

Ethanone, 1-(2-methyl-1H-imidazol-4-yl)-

577-16-2

1

1

1

Ethanone, 1-(2-methylphenyl){2-methylacetophenone}

III-13

0

1

0

Ethanone, 1-[2-methyl-5-(1-methylethyl)-phenyl]-

III-13

III-13, XVII.A-4

1122-62-9

1

1

1

Ethanone, 1-(2-pyridinyl)-

{2-acetylpyridine}

III-13, XVII.B-2

60026-20-2

1

1

1

Ethanone, 1-(2-pyrrolidinyl)- {2-acetylpyrrolidine}

III-13, XVII.A-4

24295-03-2

0

1

0

Ethanone, 1-(2-thiazolyl)-

88-15-3

0

1

0

Ethanone, 1-(2-thienyl)-

{2-acetylthiazole}

III-13, XVIII.A-1

{2-acetylthiophene}

III-13, XVIII.A-1

0

1

0

Ethanone, 1-[2,3-dihydro-2-(1-methylethyl)-inden-4yl]-

III-13

0

1

0

Ethanone, 1-[3,4-dihydro-6-(1-methylethyl)-inden-4yl]-pyran-2-yl]-

III-13

0

1

0

Ethanone, 1-(3,4-dihydro-4-methylpyrazin-2-yl)-

1197-09-7

1

0

0

Ethanone, 1-(3,4-dihydroxyphenyl)-

1131-62-0

1

0

0

Ethanone, 1-(3,4-dimethoxyphenyl)-

4478-63-1

0

1

0

Ethanone, 1-(3,3-dimethyloxiranyl){mesityl oxide epoxide}

III-13, XVII.B-2 III-13, IX.A-22 III-13 H3C

O

III-13, X-2 CO-CH3

H3C

3637-01-2

1

0

0

Ethanone, 1-(3,4-dimethylphenyl)-

III-13

51863-60-6

0

1

0

Ethanone, 1-(3,5-dihydroxyphenyl)-

117210-50-1

0

1

0

Ethanone, 1-(3a,4,5,6,7,7a-hexahydro-3a,7,7trimethyl-1H-inden-2-yl)-, (3aR-trans)-

66611-15-2

1

0

0

Ethanone, 1-(3-benzofuranyl)-

22699-70-3

1

0

0

Ethanone, 1-(3-ethylphenyl)-

14313-09-8

1

0

0

Ethanone, 1-(3-furanyl)-

3420-59-5

III-13, IX.A-22 III-13 III-13, X-2 III-13 III-13, X-2

0

1

0

Ethanone, 1-(3-hydroxy-2-furanyl)-

1

0

0

Ethanone, 1-(3-hydroxy-2-methoxyphenyl)-

{isomaltol}

III-13, IX.A-22, X-2 III-13, IX.A-22, X-2

6100-74-9

1

0

0

Ethanone, 1-(3-hydroxy-4-methoxyphenyl)-

33414-49-2

1

0

0

Ethanone, 1-(3-hydroxy-4-methylphenyl)-

II.A-5, III-13, X-2

III-13, IX.A-22

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1599

11/24/08 1:56:17 PM

1600

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

121-71-1

1

0

0

Ethanone, 1-(3-hydroxyphenyl)-

III-13, IX.A-22

586-37-8

1

0

0

Ethanone, 1-(3-methoxyphenyl)-

III-13, X-2

72693-15-3

1

0

0

Ethanone, 1-(3-methyl-3H-pyrazol-4-yl)-

III-13, XVII.A-4

72709-76-3

1

0

0

Ethanone, 1-(3-methyl-3H-pyrazol-4-yl)-

III-13, XVII.A-4

585-74-0

1

1

1

Ethanone, 1-(3-methylphenyl){3-methylacetophenone}

23787-80-6

1

1

1

Ethanone, 1-(3-methylpyrazinyl){2-acetyl-3-methylpyrazine}

Name (per CA Collective Index)

Selected structures

Chapter Table

III-13 N

CO-CH3

N

CH3

III-13, XVII.B-2

350-03-8

1

1

1

Ethanone, 1-(3-pyridinyl){3-acetylpyridine or methyl 3-pyridyl ketone}

III-13, XVII.B-2

25343-57-1

0

1

0

Ethanone, 1-[3-(1,4,5,6-tetrahydropyridinyl)]-

III-13, XVII.B-2

27300-27-2

0

1

0

Ethanone, 1-[3-(3,4,5,6-tetrahydropyridinyl)]-

III-13, XVII.B-2

59576-31-7

1

0

0

Ethanone, 1-(4,6-dimethyl-2-pyridinyl)-

III-13, XVII.B-2

37920-25-5

1

0

0

Ethanone, 1-(4-butylphenyl)-

1676-63-7

1

0

0

Ethanone, 1-(4-ethoxyphenyl)-

III-13 III-13, X-2

66309-77-1

1

0

0

Ethanone, 1-(4-ethyl-2,3-dimethylphenyl)-

493-33-4

1

0

0

Ethanone, 1-(4-hydroxy-2-methoxyphenyl)-

III-13, IX.A-22, X-2

III-13

2478-38-8

1

0

0

Ethanone, 1-(4-hydroxy-3,5-dimethoxyphenyl)-

III-13, IX.A-22, X-2

498-02-2

1

1

1

Ethanone, 1-(4-hydroxy-3-methoxyphenyl){acetovanillone}

III-13, IX.A-22, X-2

99-93-4

1

1

1

Ethanone, 1-(4-hydroxyphenyl)-

III-13, IX.A-22

100-06-1

1

1

1

Ethanone, 1-(4-methoxyphenyl)-

2524-90-5

1

0

0

Ethanone, 1-(4-methyl-1H-imidazol-2-yl)-

{acetanisole}

122-00-9

1

1

1

Ethanone, 1-(4-methylphenyl){4-methylacetophenone}

III-13, X-2 III-13, XVII.A-4 III-13

59576-26-0

1

0

0

Ethanone, 1-(4-methyl-2-pyridinyl)-

III-13, XVII.B-2

1122-54-9

1

1

1

Ethanone, 1-(4-pyridinyl)-

{4-acetylpyridine}

III-13, XVII.B-2

38205-66-2

1

0

0

Ethanone, 1-(4-thiazolyl)-

{4-acetylthiazole}

III-13, XVIII.A-1

6982-72-5

1

1

1

Ethanone, 1-(5-methyl-1H-pyrrol-2-yl){2-acetyl-5-methylpyrrole}

1193-79-9

1

1

1

Ethanone, 1-(5-methyl-2-furanyl){2-acetyl-5-methylfuran}

42972-46-3

1

1

1

Ethanone, 1-(5-methyl-3-pyridinyl)-

22047-27-4

1

1

1

Ethanone, 1-(5-methylpyrazinyl){2-acetyl-5-methylpyrazine}

III-13, XVII.A-4 III-13, X-2 III-13, XVII.B-2 N

H3C

CO-CH3

III-13, XVII.B-2

N

78210-67-0

1

0

0

Ethanone, 1-(5-propyl-1H-imidazol-4-yl)-

III-13, XVII.A-4

6940-57-4

1

0

0

Ethanone, 1-(6-methyl-2-pyridinyl)-

III-13, XVII.B-2

36357-38-7

1

0

0

Ethanone, 1-(6-methyl-3-pyridinyl)-

III-13, XVII.B-2

22047-26-3

1

1

1

Ethanone, 1-(6-methylpyrazinyl){2-acetyl-6-methylpyrazine}

III-13, XVII.B-2

61891-76-7

1

0

0

Ethanone, 1-(dihydro-3,4-dimethylpyrrol-2-yl)-

III-13, XVII.A-4

78249-86-2

1

0

0

Ethanone, 1-(dimethylpyridinyl)-

III-13, XVII.B-2

25496-14-4

1

0

0

Ethanone, 1-(ethylphenyl)-

III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1600

11/24/08 1:56:17 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1601

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

25154-45-4

1

0

0

Ethanone, 1-(furanyl)-

692-73-0

1

0

0

Ethanone, 1-(hydroxymethylphenyl)-

70587-92-7

1

0

0

Ethanone, 1-(hydroxyphenyl)-

71278-10-9

1

0

0

Ethanone, 1-(methyl-2-furanyl)-

74430-25-4

Name (per CA Collective Index)

Selected structures

Chapter Table III-13, X-2 III-13 III-13, IX.A-22 III-13

1

0

0

Ethanone, 1-(methylfuranyl)-

1

0

0

Ethanone, 1-(methylpyridinyl)-

{2 isomers}

III-13, XVII.B-2

III-13

1333-52-4

1

1

1

Ethanone, 1-(naphthalenyl){methyl naphthyl ketone}

III-13

25252-64-6

1

0

0

Ethanone, 1-(tetrahydro-2-furanyl)-

121198-50-3

1

0

0

Ethanone, 1-(tetrahydrofuranyl)-

III-13, X-2

13678-73-4

0

1

0

Ethanone, 1-[1-(2-furanylmethyl)-1H-pyrrol-2-yl]-

III-13, X-2

22583-61-5

1

0

0

Ethanone, 1-[2-(1,1-dimethylethyl)phenyl]-

III-13

112523-81-6

0

1

0

Ethanone, 1-[2,3,3a,4,6a,7,8,9,9a,9b-decahydro5,9a-dimethyl-7-(1-methylethyl)-1Hcyclopent[a]azulen-3-yl]-, [3R(3D,3aD,6aE,7E,9aD,9bE)]-

III-13

152186-01-1

0

1

0

Ethanone, 1-[2,3,3a,4,6a,7,8,9,9a,9b-decahydro5,9a-dimethyl-7-(1-methylethyl)-1Hcyclopent[a]azulen-3-yl]-, (3D,3aD,6aE,7E,9aD,9bE)-(r)-

III-13

III-13, X-2

1767-84-6

0

1

0

Ethanone, 1-(2-methyl-2-cyclopenten-1-yl)-

III-13

94390-73-5

1

0

0

Ethanone, 1-[2-methyl-5-(1-methylethyl)-2,5cyclohexadien-1-yl]-

III-13

1202-08-0

0

1

0

Ethanone, 1-[2-methyl-5-(1-methylethyl)phenyl]-

III-13

51297-35-9

0

1

0

Ethanone, 1-[3-(1-ethyl-2-methylpropyl)oxiranyl]-

III-13

31577-86-3 43219-68-7

0

1

0

Ethanone, 1-[3-(1-methylethenyl)cyclopentyl]{two isomers}

III-13

120056-06-6

0

1

0

Ethanone, 1-[3-(decahydro-2-hydroxy-2,5,5,8atetramethyl-1-naphthalenyl) oxiranyl]-, [1S[1D(2S*,3R*),2E,4a

1

0

0

Ethanone, 1-[4-(2,6-dimethylpyridinyl)]-

55087-82-6

1

0

0

Ethanone, 1-[5-(hydroxymethyl)-2-furanyl]-

52812-41-6

0

1

0

Ethanone, 1-[5-methyl-2-(1-methylethyl)-6,8dioxabicyclo[3.2.1]oct-7-yl]-

III-13, X-2

57934-85-7

0

1

0

Ethanone, 1-[5-methyl-2-(1-methylethyl)-6,8dioxabicyclo[3.2.1]oct-7-yl]-, (exo,exo)-(±)-

III-13, X-2

123695-66-9

1

0

0

Ethanone, 1-[6-hydroxy-6-methyl-3-(1-methylethyl)2-cyclohexen-1-yl]-

823-76-7

0

1

0

Ethanone, 1-cyclohexyl-

57276-33-2

1

0

0

Ethanone, 1-cyclopropyl-2-(3-pyridinyl)-

III-13, X-2

III-13, XVII.B-2 II.A-5, III-13

II.A-5, III-13 III-13 III-13, XVII.B-2

98-86-2

1

1

1

Ethanone, 1-phenyl-

2243-35-8

0

1

0

Ethanone, 1-phenyl-2-(acetyloxy)-

{acetophenone}

III-13

22047-25-2

1

1

1

Ethanone, 1-pyrazinyl-

{acetylpyrazine}

III-13, XVII.B-2

574-06-1

1

0

0

Ethanone, 1,2-diphenyl-2-(acetyloxy){benzoin acetate}

III-13, V-3

593-67-9

1

0

0

Ethenamine

III-13

H2C=CH-NH2

XII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1601

11/24/08 1:56:18 PM

1602

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

74-85-1

1

1

1

Ethene

75-01-4

0

1

0

Ethene, chloro-

{vinyl chloride}

79-38-9

1

1

1

Ethene, chlorotrifluoro-

79-35-6

1

1

1

0

1

0

Ethene, 1-(4-hydroxyphenyl)-2-(3,5dihydroxyphenyl){resveratrol}

IX.A-22

102-61-4

0

1

0

Ethene, 1-(phenyl)-2-(3,5-dihydroxyphenyl){pinosylvin}

IX.A-22

127-18-4

1

0

0

Ethene, tetrachloro-

Cl2C=CCl2

XVIII.B-3

79-01-6

1

0

0

Ethene, trichloro-

Cl2C=CHCl

XVIII.B-3

Name (per CA Collective Index) {ethylene}

Selected structures H2C=CH2

Chapter Table I.B-1, XXI-3

H2C=CH-Cl

XVIII.B-3

{Freon® 1113}

ClFC=CF2

XVIII.B-3

Ethene, 1,1-dichloro-2,2-difluoro- {Freon® 1112a}

Cl2C=CF2

XVIII.B-3

463-51-4

1

0

0

Ethenone

2154-50-9

1

0

0

Ethoxyl radical

{ketene} {acetylene}

H2C=CO

III-13

OCH2CH3

XXVII-1

74-86-2

1

0

0

Ethyne

HCŁCH

I.B-1

7440-53-1

1

1

1

Europium

Eu

XX-5

378750-46-0

1

1

1

Europium, isotope of mass 152

152

9040-09-9

0

1

0

Ferredoxins

29732-48-7

0

1

0

Flavylium, 3-[[O-(6-deoxymannosyl)-Dglucosyl]oxy]-3',4',5,5',7-pentahydroxy-, chloride

0

1

0

Flavylium, 3-[[O-(6-deoxymannosyl)-Dglucosyl]oxy]-3',4',5,7-tetrahydroxy-, chloride

1

0

0

Fluoraninene, ethylmethyl-

2693-46-1

1

0

0

3-Fluoranthenamine

206-44-0

1

1

1

Fluoranthene

Eu

XX-5 XXII-2 II.A-5, XVIII.B-3 II.A-5, IIIXVIII.B-3 I.E-6 XII-2 1

I.E-6

2

10

3

9 8

4 7 6

5

1

0

0

Fluoranthene, alkyl-

I.E-6

41593-24-2

1

0

0

Fluoranthene, dihydro-

I.E-6

71278-25-6

1

0

0

Fluoranthene, dihydromethyl-

I.E-6

60826-74-6

1

0

0

Fluoranthene, dimethyl{at least 4 isomers in MSS}

I.E-6

25889-63-8

1

0

0

Fluoranthene, 8,9-dimethyl-

I.E-6

55220-72-9

1

0

0

Fluoranthene, ethyl-

I.E-6

71277-96-8

1

0

0

Fluoranthene, ethylmethyl-

I.E-6

71277-97-9

1

0

0

Fluoranthene, hexamethyl-

I.E-6

30997-39-8

1

0

0

Fluoranthene, methyl-

I.E-6

25889-60-5

1

0

0

Fluoranthene, 1-methyl-

I.E-6

33543-31-6

1

1

1

Fluoranthene, 2-methyl-

I.E-6

1706-01-0

1

0

0

Fluoranthene, 3-methyl-

I.E-6

23339-05-1

1

0

0

Fluoranthene, 7-methyl-

I.E-6

20485-57-8

1

0

0

Fluoranthene, 8-methyl-

I.E-6

71277-98-0

1

0

0

Fluoranthene, pentamethyl{at least 2 isomers in MSS}

I.E-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1602

11/24/08 1:56:18 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1603

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

55220-69-4

1

0

0

Fluoranthene, propyl-

I.E-6

71277-99-1

1

0

0

Fluoranthene, tetramethyl-

I.E-6

41637-87-0

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

Fluoranthene, trimethyl-

I.E-6

1

0

0

Fluorenamine

XII-2

64294-96-8

1

0

0

9H-Fluorenamine

XII-2

6344-63-4

1

0

0

9H-Fluoren-1-amine

XII-2

153-78-6

1

0

0

9H-Fluoren-2-amine

XII-2

1

0

0

9H-Fluoren-4-amine

XII-2

525-03-1

1

0

0

9H-Fluoren-9-amine

86-73-7

1

1

1

9H-Fluorene

XII-2 9

8

I.E-6

1

7

2 6

30582-01-5

5

3

4

1

1

1

9H-Fluorene, dimethyl{at least 5 isomers in MSS}

I.E-6

1

0

0

9H-Fluorene, ?,9-dimethyl-

I.E-6

17057-98-6

1

0

0

9H-Fluorene, 1,9-dimethyl-

I.E-6

4612-63-9

1

1

1

9H-Fluorene, 2,3-dimethyl-

I.E-6

4569-45-3

1

0

0

9H-Fluorene, 9,9-dimethyl-

I.E-6

71278-00-7

1

0

0

9H-Fluorene, dimethylethyl-

I.E-6

65319-49-5

1

0

0

9H-Fluorene, ethyl-

1207-20-1

1

0

0

9H-Fluorene, 2-ethyl-

I.E-6

{at least 2 isomers in MSS}

I.E-6

2294-82-8

1

0

0

9H-Fluorene, 9-ethyl-

I.E-6

71278-01-8

1

0

0

9H-Fluorene, ethylmethyl{at least 2 isomers in MSS}

I.E-6

26914-17-0

1

1

1

9H-Fluorene, methyl-

I.E-6

1730-37-6

1

0

0

9H-Fluorene, 1-methyl-

I.E-6

1430-97-3

1

0

0

9H-Fluorene, 2-methyl-

I.E-6

2523-39-9

1

0

0

9H-Fluorene, 3-methyl-

I.E-6

1556-99-6

1

0

0

9H-Fluorene, 4-methyl-

I.E-6

2523-37-7

1

0

0

9H-Fluorene, 9-methyl-

I.E-6

4425-82-5

1

0

0

9H-Fluorene, 9-methylene-

I.E-6

63372-50-9

1

0

0

9H-Fluorene, tetramethyl-

I.E-6

30582-02-6

1

0

0

9H-Fluorene, trimethyl-

I.E-6

6276-03-5

1

1

1

9H-Fluorene-1-carboxylic acid

27134-14-1

1

0

0

Fluoren-9-one, ethyl-

27134-15-2

1

0

0

Fluoren-9-one, ethylmethyl-

486-25-9

1

1

1

9H-Fluoren-9-one

IV.A-3 III-13 III-13 8 7

1 9

2 3

6 5

27134-13-0 5501-37-1

III-13

O

4

1

0

0

9H-Fluoren-9-one, dimethyl {5 isomers detected}

III-13

1

0

0

9H-Fluoren-9-one, methyl- {2 isomers detected}

III-13

1

0

0

9H-Fluoren-9-one, 1-methyl-

III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1603

11/24/08 1:56:19 PM

1604

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

2840-51-9

1

1

1

9H-Fluoren-9-one, 2-methyl-

III-13

1705-89-1

1

0

0

9H-Fluoren-9-one, 3-methyl-

III-13

Name (per CA Collective Index)

4269-05-0

1

0

0

9H-Fluoren-9-one, 4-methyl-

16984-48-8

1

0

0

Fluoride

Selected structures

Chapter Table

III-13 -1

F

XVIII.B-3, XX-5 XVIII.B-3, XX-5

7782-41-4

1

1

1

Fluorine

F2

50-00-0

1

1

1

Formaldehyde

H-CH=O

III-12

75-12-7

1

0

0

Formamide

H-CO-NH2

XIII-1

871-71-6

1

0

0

Formamide, N-butyl-

H-CO-NH-(CH2)3-CH3

XIII-1

H-CO-N=(CH3)2

68-12-2

1

1

1

Formamide, N,N-dimethyl-

72693-10-8

1

0

0

Formamide, N-(2-furanylmethyl)-

123-39-7

1

0

0

Formamide, N-methyl-

10285-87-7

1

0

0

Formamide, N-(3-methylbutyl)-

2591-79-9

1

0

0

Formamide, N-pentyl-

XIII-1 X-2, XIII-1

H-CO-NH-CH3

XIII-1

H-CO-NH-(CH2)4-CH3

XIII-1

XIII-1

103-70-8

1

0

0

Formamide, N-phenyl-

XIII-1

6343-54-0

1

0

0

Formamide, N-(phenylmethyl)-

XIII-1

56625-04-8

1

0

0

Formamide, N-(3-pyridinylmethyl)-

1

0

0

Formate

XIII-3, XVII.B-2 XX-6

64-18-6

1

1

1

Formic acid

105-86-2

0

1

0

Formic acid, 3,7-dimethyl-2,6-octadien-1-yl ester

109-94-4

1

0

0

Formic acid, ethyl ester

33467-73-1

0

1

0

Formic acid, 3-hexenyl ester

629-33-4

0

1

0

Formic acid, hexyl ester

107-31-3

H-COOH

IV.A-3 V-3

H-COO-CH2-CH3

V-3 V-3

H-COO-(CH2)5-CH3 {methyl formate}

H-COO-CH 3

V-3

1

1

1

Formic acid, methyl ester

0

1

0

Formic acid, 3-methylbutyl ester

V-3

625-55-8

1

0

0

Formic acid, 1-methylethyl ester

H-COO-CH=(CH3)2

V-3

638-49-3

0

1

0

Formic acid, pentyl ester

H-COO-(CH2)4-CH3

V-3

104-62-1

0

1

0

Formic acid, 2-phenylethyl ester

H-COO-(CH2)2-C6H5

V-3

104-57-4

0

1

0

Formic acid, phenylmethyl ester {benzyl formate}

H-COO-CH 2-C6H5

V-3

HC(O)O

V-3

1

0

0

Formyl radical

9037-90-5

0

1

0

D-Fructan

10247-46-8

0

1

0

D-Fructofuranose

71385-82-5

0

1

0

E-D-Fructofuranose, 1-deoxy-1-[2-(3-pyridinyl)-1pyrrolidinyl]-, (S)-

79082-92-1

0

1

0

E-D-Fructofuranose, 2,6-bis(dihydrogen phosphate)

9001-57-4

0

1

0

E-Fructofuranosidase

79886-47-8

0

1

0

E-D-Fructopyranose, 1-deoxy-1-[2-(3-pyridinyl)-1pyrrolidinyl]-, (S)-

57-48-7

1

1

1

D-Fructose

XXVII-1 II.A-5, VIII-3 II.A-5, VIII-3 II.A-5, VIII-3, XVII.B-4 II.A-5, VIII-3 XXII-2 VIII-3, XVII.B-4

{levulose}

OH O

CH2OH

II.A-5, VIII-3, X-2

OH

OH OH

51767-72-7

0

1

0

13

D-Fructose, labeled with C

3

{D-Fructose- C}

II.A-5, VIII-3, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1604

11/24/08 1:56:19 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1605

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

29118-61-4

0

1

0

D-Fructose, 1-(2-carboxy-1-pyrrolidinyl)-1-deoxy-, (S)-

488-69-7

0

1

0

D-Fructose, 1,6-bis(dihydrogen phosphate)

70954-04-0

0

1

0

D-Fructose, 1-[(1-carboxy-2-hydroxypropyl)amino]1-deoxy-, [R-(R*,S*)]-

VIII-3

34393-27-6

0

1

0

D-Fructose, 1-[(3-amino-1-carboxy-3oxopropyl)amino]-1-deoxy-, (S)-

VIII-3

10003-63-1

0

1

0

D-Fructose, 1-[(3-carboxypropyl)amino]-1-deoxy-

70906-15-9

0

1

0

D-Fructose, 1-deoxy-1-[2-(3-pyridinyl)-1pyrrolidinyl]-, (S)-

643-13-0

0

1

0

D-Fructose, 6-(dihydrogen phosphate)

VIII-3

36119-15-0

Name (per CA Collective Index)

Selected structures

Chapter Table

II.A-5, VIII-3, XVII.A-4 II.A-5, VIII-3

VIII-3 II.A-5, VIII-3, XVII.B-4

0

1

0

D-Fructose, mono(dihydrogen phosphate)

VIII-3

0

1

0

Fructosidase

XXII-2

9033-47-0

0

1

0

ȕ-Fructosidase

XXII-2

2438-80-4

0

1

0

Fucose

VIII-3

110-00-9

1

0

0

Furan

X-2 O

0 64079-00-1

1

0

Furan, C3-alkyl-

{3 isomers detected}

0

1

0

Furan, butyl-

0

1

0

Furan, 2,3-diacetyl-5-methyl-

X-2 X-2 O

H3C 4

2

CO-CH3

X-2

3

CO-CH3

28802-49-5

1

0

0

Furan, dimethyl-

X-2

27252-25-1

0

1

0

Furan, ethyl-

X-2

1

0

0

Furan, ethenyl-methyl-

X-2

1

0

0

Furan, hexenyl-methyl-

X-2

27137-41-3

1

0

0

Furan, methyl-

X-2

64079-01-2

0

1

0

Furan, pentyl-

X-2

27252-26-2

0

1

0

Furan, propyl-

X-2

109-99-9

1

1

1

Furan, tetrahydro-

X-2

0

1

0

Furan, tetrahydro-2-methyl-2-(4-hydroxy-1pentenyl)-

II.A-5, X-2

OH O

CH3

0

1

0

Furan, tetrahydro-2-(3-phenylpropyl)-

X-2

13678-51-8

1

0

0

Furan, 2-(2-furanylmethyl)-5-methyl-

X-2

10504-11-7

1

0

0

Furan, 2-(2-methyl-1-propenyl)-

X-2

4868-20-6

1

0

0

Furan, 2-(3-hexenyl)-5-methyl-, (Z)-

X-2

1197-40-6

1

0

0

Furan, 2,2'-methylenebis-

X-2

110484-93-0

1

0

0

Furan, 2,2'-methylenebis[5-ethyl-

X-2

13679-43-1

1

0

0

Furan, 2,2'-methylenebis[5-methyl-

X-2

121213-25-0

1

0

0

Furan, 2,3-dihydro-2-methoxy-

X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1605

11/24/08 1:56:19 PM

1606

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

34314-83-5

1

0

0

Furan, 2,3-dihydro-4-methyl-

X-2

14920-89-9

1

0

0

Furan, 2,3-dimethyl-

X-2

Name (per CA Collective Index)

Selected structures

Chapter Table

1708-29-8

1

0

0

Furan, 2,5-dihydro-

X-2

13314-90-4

1

0

0

Furan, 2,5-dihydro-2,5-bis(methylene)-

X-2

13436-43-6

1

0

0

Furan, 2,5-dihydro-2-methoxy-

X-2

1708-30-1

1

0

0

Furan, 2,5-dihydro-2-methyl-

X-2

0

1

0

Furan, 2,5-diethyl-

X-2

625-86-5

1

1

1

Furan, 2,5-dimethyl-

X-2

110484-94-1

1

0

0

Furan, 2-[1-(5-ethyl-2-furanyl)ethyl]-5-methyl-

X-2

4466-24-4

1

1

1

Furan, 2-butyl-

X-2

1487-18-9

1

1

1

Furan, 2-ethenyl-

X-2

1

0

0

Furan, 2-ethenyl-5-methyl-

X-2

13679-86-2

0

1

0

Furan, 2-ethenyltetrahydro-2-methyl-5-(1methylethenyl)-

X-2

3208-16-0

1

1

1

Furan, 2-ethyl-

X-2

1703-52-2

1

0

0

Furan, 2-ethyl-5-methyl-

X-2

534-22-5

1

1

1

Furan, 2-methyl-

X-2

0

1

0

Furan, 2-methyl-5 (1-methylethenyl)-

X-2

96-47-9

1

0

0

Furan, 2-methyltetrahydro-

X-2

3777-69-3

0

1

0

Furan, 2-pentyl-

X-2

17113-33-6

1

0

0

Furan, 2-phenyl-

X-2

55484-04-3

1

0

0

Furan, 2-(4-pyridyl)-

42933-00-6 54869-11-3

1

1

1

Furan, 3-(4,8,12-trimethyltridecyl)-

X-2, XVII.B-2 {phytofuran}

X-2

930-27-8

1

1

1

Furan, 3-methyl-

X-2

13679-41-9

0

1

0

Furan, 3-phenyl-

X-2

2745-26-8

1

0

0

2-Furanacetic acid

IV.A-3, X-2

617-90-3

1

0

0

2-Furancarbonitrile

X-2, XI-2

13714-86-8

1

0

0

2-Furancarbonitrile, 5-methyl-

X-2, XI-2

39276-09-0

1

0

0

Furancarboxaldehyde

98-01-1

1

1

1

2-Furancarboxaldehyde {furfural; 2-furaldehyde}

III-12 X-2 4

III-12 X-2

3

5 O

CHO

1

0

0

2-Furancarboxaldehyde, hydroxy-

II.A-5, III-12, X-2

25376-49-2

0

1

0

2-Furancarboxaldehyde, (hydroxymethyl)-

II.A-5, III-12, X-2

26895-04-5

1

0

0

2-Furancarboxaldehyde, methyl-

33342-48-2

1

0

0

2-Furancarboxaldehyde, 3-methyl-

III-12, X-2

32529-53-6

1

1

1

2-Furancarboxaldehyde, 5-acetyl-

III-12, X-2

10551-58-3

0

1

0

2-Furancarboxaldehyde, 5-[(acetyloxy)methyl]-

67-47-0

1

1

1

2-Furancarboxaldehyde, 5-(hydroxymethyl)-

21300-07-2

III-12, X-2

III-12, V-3, X-2 II.A-5, III-12, X-2

0

1

0

2-Furancarboxaldehyde, 5-methoxy-

III-12 X-2

0

1

0

2-Furancarboxaldehyde, 5-methoxy-?-methyl-

III-12 X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1606

11/24/08 1:56:20 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1607

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

1917-64-2

0

1

0

2-Furancarboxaldehyde, 5-(methoxymethyl)-

620-02-0

1

1

1

2-Furancarboxaldehyde, 5-methyl-

Name (per CA Collective Index)

Selected structures

Chapter Table III-12 X-2 III-12, X-2

498-60-2

1

1

1

3-Furancarboxaldehyde

III-12, X-2

29988-76-9

1

1

1

Furancarboxamide

X-2, XIII-1

609-38-1

1

1

1

2-Furancarboxamide

X-2, XIII-1

26447-28-9

1

1

1

Furancarboxylic acid

IV.A-4, X-2

88-14-2

1

1

1

2-Furancarboxylic acid

61892-61-3

1

0

0

2-Furancarboxylic acid, 2-(acetyloxy)ethyl ester

{furoic acid}

IV.A-4, X-2 V-3, X-2

614-99-3

0

1

0

2-Furancarboxylic acid, ethyl ester {ethyl 2-furoate}

V-3, X-2

71278-16-5

0

1

0

2-Furancarboxylic acid, 3-hydroxy-

II.A-5, IV.A-3, X-2

6338-41-6

1

0

0

2-Furancarboxylic acid, 5-(hydroxymethyl)-

II.A-5, IV.A-3, X-2

1917-15-3

1

0

0

2-Furancarboxylic acid, 5-methyl-

611-13-2

1

1

1

2-Furancarboxylic acid, methyl ester {methyl 2-furoate}

V-3, X-2

3885-29-8

1

0

0

2-Furancarboxylic acid, tetrahydro-5-oxo-, methyl ester

V-3, VI-3, X-2

488-93-7

1

0

0

3-Furancarboxylic acid

6947-94-0

1

0

0

3-Furancarboxylic acid, 2-methyl-

IV.A-4, X-2

636-44-2

1

0

0

3-Furancarboxylic acid, 2,5-dimethyl-

IV.A-4, X-2

IV.A-4, X-2

IV.A-4, X-2

4412-96-8

1

0

0

3-Furancarboxylic acid, 3-methyl-

IV.A-4, X-2

21984-93-0

1

0

0

3-Furancarboxylic acid, 5-methyl-

IV.A-4, X-2

13129-23-2

0

1

0

3-Furancarboxylic acid, methyl ester

5204-91-1

1

0

0

3-Furancarboxylic acid, tetrahydro-5-oxo-, methyl ester

823-82-5

1

1

1

2,5-Furandicarboxaldehyde

61892-94-2

1

0

0

3,4-Furandiol, tetrahydro-3-methyl-

108-31-6

1

1

1

2,5-Furandione

V-3, X-2 V-3, VI-3, X-2 III-12, X-2 X-2

{maleic anhydride}

3 O

33765-37-6

0

1

0

2,5-Furandione, 3,4-diethyldihydro-, (E)-

1 O

5

o

VII-1

108-30-5

1

1

1

2,5-Furandione, dihydro-

17347-61-4

1

1

1

2,5-Furandione, dihydro-3,3-dimethyl-

VII-1

7475-92-5

1

1

1

2,5-Furandione, dihydro-3,4-dimethyl{pyrocinchonic anhydride}

VII-1

4100-80-5

1

0

0

2,5-Furandione, dihydro-3-methyl-

VII-1

766-39-2

1

1

1

2,5-Furandione, 3,4-dimethyl-

VII-1

3552-33-8

1

1

1

2,5-Furandione, 3-ethyl-4-methyl-

VII-1

616-02-4

1

0

0

2,5-Furandione, 3-methyl-

VII-1

72693-16-4

1

0

0

2,5-Furandione, 3-methyl-4-(phenylmethyl)-

VII-1

16493-20-2

1

0

0

2,5-Furandione, 3-methyl-4-propyl-

VII-1

61679-89-8

1

0

0

2,5-Furandione, 3-propyl-

98-02-2

0

1

0

2-Furanmethanethiol

40795-25-3

1

0

0

Furanmethanol

{succinic anhydride}

2

VII-1

4

VII-1

VII-1 X-2, XVIII.A-1 II.A-5, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1607

11/24/08 1:56:20 PM

1608

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

98-00-0

1

1

1

Name (per CA Collective Index) 2-Furanmethanol

Selected structures

5

II.A-5, X-2

3

4

{furfuryl alcohol}

2

CH2OH

1

O

623-17-6

1

1

1

2-Furanmethanol, acetate

Chapter Table

V-3, X-2

1

0

0

2-Furanmethanol, 2,3-dihydro-5-methoxy-

II.A-5, X-2

60047-17-8

0

1

0

2-Furanmethanol, 5-ethenyltetrahydro-D,D,5trimethyl-

II.A-5, X-2

5989-33-3

0

1

0

2-Furanmethanol, 5-ethenyltetrahydro-D,D,5trimethyl-, (Z){cis-linalool oxide}

II.A-5, X-2

23007-29-6

0

1

0

2-Furanmethanol, 5-ethenyltetrahydro-D,D,5trimethyl-, (E){trans-linalool oxide}

II.A-5, X-2

13493-97-5

0

1

0

2-Furanmethanol, formate

V-3, X-2

55664-77-2

0

1

0

2-Furanmethanol, methyl-

II.A-5, X-2

3857-25-8

1

1

1

2-Furanmethanol, 5-methyl-

II.A-5, X-2

54774-28-6

0

1

0

2-Furanmethanol, 5-methyltetrahydro-

II.A-5, X-2

61481-02-5

1

0

0

2-Furanmethanol, 5-(1-pyrrolidinylmethyl)-

97-99-4

1

1

1

2-Furanmethanol, tetrahydro-

II.A-5, X-2 II.A-5, X-2

4412-91-3

1

0

0

3-Furanmethanol

29848-46-2

1

0

0

3-Furanol, tetrahydro-5,5-dimethyl-

66607-70-3

0

1

0

3-Furanol, tetrahydro-5-[6-hydroxy-3-(1methylethyl)-1-heptenyl]-5-methyl-

II.A-5, X-2, XVII.A-4

II.A-5, X-2 II.A-5, X-2

OH OH

CH3 O

CH3 H3C

20825-71-2

1

1

1

2(3H)-Furanone

{butenolide}

5 4

517-23-7

CH3

VI-3

1 O O 3

1

0

0

2(3H)-Furanone, acetyl-

III-13, VI-3

1

0

0

2(3H)-Furanone, 3-acetyldihydro-

III-13, VI-3

7400-67-1

1

0

0

2(3H)-Furanone, 4-acetyldihydro-

III-13, VI-3

29393-32-6

1

1

1

2(3H)-Furanone, 5-acetyldihydro-

III-13, VI-3

19405-99-3

1

0

0

2(3H)-Furanone, 3-(acetyloxy)dihydro-

V-3, VI-3

19405-98-2

1

0

0

2(3H)-Furanone, 4-(acetyloxy)dihydro-

V-3, VI-3

26817-24-3

1

0

0

2(3H)-Furanone, 5-(acetyloxy)dihydro-

V-3, VI-3

61892-43-1

1

0

0

2(3H)-Furanone, 3-(acetyloxy)dihydro-4-hydroxy-

II.A-5, V-3, VI-3

61892-44-2

1

0

0

2(3H)-Furanone, 5-(acetyloxy)dihydro-4-hydroxy-

II.A-5, V-3, VI-3

160115-54-8

0

1

0

2(3H)-Furanone, 3-(acetyloxy)dihydro-5-methyl-5[3-(1-methylethyl)-6-oxo-1-heptenyl]-, [3R[3D,5E(1E,3S*)]]-

III-13, V-3, VI-3

160224-93-1

0

1

0

2(3H)-Furanone, 3-(acetyloxy)dihydro-5-methyl-5[3-(1-methylethyl)-6-oxo-1-heptenyl]-, [3R[3D,5D(1E,3S*)]]-

III-13, V-3, VI-3

1192-20-7

1

0

0

2(3H)-Furanone, 3-aminodihydro-

0

1

0

2(3H)-Furanone, 3-(3-butenyl)-dihydro-

VI-3

0

1

0

2(3H)-Furanone, 5-butyldihydro-

VI-3

104-50-7

VI-3, XII-2 {J-octalactone}

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1608

11/24/08 1:56:21 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1609

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

CAS No.

S 0

1

0

2(3H)-Furanone, 5-butyldihydro-4-methyl-

VI-3

96-48-0

1

1

1

2(3H)-Furanone, dihydro-

VI-3

13092-55-2

1

0

0

2(3H)-Furanone, dihydro-3,4-dihydroxy-

II.A-5, VI-3

17675-99-9

1

0

0

2(3H)-Furanone, dihydro-3,4-dihydroxy-, (Z)-

II.A-5, VI-3

1

0

0

2(3H)-Furanone, dihydro-3,4-dihydroxy-5(hydroxymethyl)-

II.A-5, VI-3

61892-57-7

1

0

0

2(3H)-Furanone, dihydro-3,4-dihydroxy-5(hydroxymethyl)-4-methyl-

II.A-5, VI-3

18465-71-9

1

0

0

2(3H)-Furanone, dihydro-3,4-dihydroxy-3-methyl-, (3R-Z)-

II.A-5, VI-3

1

0

0

2(3H)-Furanone, dihydro-3,4-dihydroxy-4-methyl-

II.A-5, VI-3

72693-07-3

1

0

0

2(3H)-Furanone, dihydro-3,4-dimethyl-

VI-3

5145-01-7

1

1

1

2(3H)-Furanone, dihydro-3,5-dimethyl-

VI-3

13861-97-7

0

1

0

2(3H)-Furanone, dihydro-4,4-dimethyl-

VI-3

6971-63-7

1

1

1

2(3H)-Furanone, dihydro-4,5-dimethyl-

VI-3

3123-97-5

0

1

0

2(3H)-Furanone, dihydro-5,5-dimethyl-

VI-3

38273-97-1

0

1

0

2(3H)-Furanone, dihydro-3,3-dimethyl-5-(2oxopropyl)-

VI-3

0

1

0

2(3H)-Furanone, dihydro-5-(1,4-dimethyl-1pentenyl)-

VI-3

1073-11-6

0

1

0

2(3H)-Furanone, dihydro-5-ethenyl-5-methyl-

VI-3

16496-51-8

0

1

0

2(3H)-Furanone, dihydro-4-ethyl-

VI-3

695-06-7

1

1

1

2(3H)-Furanone, dihydro-5-ethyl- {J-hexalactone}

VI-3

2610-98-2

0

1

0

2(3H)-Furanone, dihydro-5-ethyl-3-methyl-

VI-3

{butyrolactone}

2865-82-9

0

1

0

2(3H)-Furanone, dihydro-5-ethyl-5-methyl-

VI-3

158815-74-8

0

1

0

2(3H)-Furanone, dihydro-5-(3-ethyl-4-methyl-1pentenyl)-3-hydroxy-5-methyl-

VI-3

61892-46-4

1

0

0

2(3H)-Furanone, dihydro-4-ethynyl-5-hydroxy-3methyl-

VI-3

0

1

0

2(3H)-Furanone, dihydro-5-(5-heptenyl)-

VI-3

104-67-6

0

1

0

2(3H)-Furanone, dihydro-5-heptyl{J-undecalactone}

VI-3

706-14-9

0

1

0

2(3H)-Furanone, dihydro-5-hexyl-

VI-3

1

0

0

2(3H)-Furanone, dihydro(hydroxy)-

II.A-5, VI-3

1

0

0

2(3H)-Furanone, dihydro(hydroxymethyl)-

II.A-5, VI-3

18132-98-4

1

0

0

2(3H)-Furanone, dihydro-3-(hydroxymethyl)-

II.A-5, VI-3

1608-63-5

0

1

0

2(3H)-Furanone, dihydro-3-(1-methylethyl)-

60016-73-1

1

1

1

2(3H)-Furanone, dihydro-(2-oxopropyl)-

25600-22-0

1

0

0

2(3H)-Furanone, dihydro-3-(1-oxopropoxy)-

{J-decalactone}

VI-3 III-13, VI-3 OOC-CH2CH3 4 5

V-3, VI-3

3 1

O

2

O

71385-84-7

1

1

1

2(3H)-Furanone, dihydro-3-(2-oxopropyl)-

III-13, VI-3

65331-00-2

1

0

0

2(3H)-Furanone, dihydro-4-(2-oxopropyl)-

III-13, VI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1609

11/24/08 1:56:21 PM

1610

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

61892-49-7

1

0

0

2(3H)-Furanone, dihydro-5-(1-oxopropyl)-

III-13, VI-3

53155-68-3

0

1

0

2(3H)-Furanone, dihydro-3,4,5-trimethyl-, (3D,4D,5D)-

VI-3

19444-84-9

1

0

0

2(3H)-Furanone, dihydro-3-hydroxy-

II.A-5, VI-3

19444-86-1

1

0

0

2(3H)-Furanone, dihydro-3-hydroxy-3(hydroxymethyl)-

II.A-5, VI-3

1192-42-3

1

0

0

2(3H)-Furanone, dihydro-3-hydroxy-3-methyl-

II.A-5, VI-3

6969-43-3

0

1

0

2(3H)-Furanone, dihydro-3-hydroxy-4,4,5-trimethyl-

II.A-5, VI-3

52126-90-6

1

1

1

2(3H)-Furanone, dihydro-3-hydroxy-4,4-dimethyl-

II.A-5, VI-3

599-04-2

1

1

1

2(3H)-Furanone, dihydro-3-hydroxy-4,4-dimethyl-, (R)-

II.A-5, VI-3

1

0

0

2(3H)-Furanone, dihydro-3-hydroxy-5-(1hydroxyethyl)-

II.A-5, VI-3

61892-52-2

1

0

0

2(3H)-Furanone, dihydro-3-hydroxy-5-(2hydroxyethyl)-

II.A-5, VI-3

61892-50-0

1

0

0

2(3H)-Furanone, dihydro-3-hydroxy-5-(2hydroxyethyl)-5-methyl-

II.A-5, VI-3

53561-62-9

1

0

0

2(3H)-Furanone, dihydro-3-hydroxy-5-methyl{2 isomers}

II.A-5, VI-3

158815-71-5

0

1

0

2(3H)-Furanone, dihydro-3-hydroxy-5-methyl-5-[3(1-methylethyl)-6-oxo-1-heptenyl]-, [3R[3D,5E(1E,3S*)]]-

5469-16-9

1

1

1

2(3H)-Furanone, dihydro-4-hydroxy-

II.A-5, VI-3

3285-47-0

1

0

0

2(3H)-Furanone, dihydro-4-hydroxy-3,3-dimethyl-

II.A-5, VI-3

61892-45-3

1

0

0

2(3H)-Furanone, dihydro-4-hydroxy-3(hydroxymethyl)-

II.A-5, VI-3

36679-81-9

1

1

1

2(3H)-Furanone, dihydro-4-(hydroxymethyl)-

II.A-5, VI-3

34945-05-6

1

0

0

2(3H)-Furanone, dihydro-4-hydroxy-4-methyl-

II.A-5, VI-3

0

1

0

2(3H)-Furanone, dihydro-4-(2,5,6-trimethyl-5,6epoxyoctanyl)-

50768-69-9

1

0

0

2(3H)-Furanone, dihydro-5-hydroxy-

II.A-5, VI-3

27610-27-1

1

1

1

2(3H)-Furanone, dihydro-5-(1-hydroxyethyl)-

II.A-5, VI-3

61892-47-5

1

0

0

2(3H)-Furanone, dihydro-5-hydroxy-4-methyl-

II.A-5, VI-3

10374-51-3

1

1

1

2(3H)-Furanone, dihydro-5-(hydroxymethyl)-

II.A-5, VI-3

1679-47-6

0

1

0

2(3H)-Furanone, dihydro-3-methyl-

VI-3

1679-49-8

1

1

1

2(3H)-Furanone, dihydro-4-methyl-

VI-3

108-29-2

1

1

1

2(3H)-Furanone, dihydro-5-methyl{J-valerolactone}

VI-3

0

1

0

2(3H)-Furanone, dihydro-5-methyl-5-(3-methyl-1butenyl)-

VI-3

0

1

0

2(3H)-Furanone, dihydro-5-methyl-5-(3-oxobutyl)-

III-13, VI-3

0

1

0

2(3H)-Furanone, dihydro-5-(3-methyl-1-butenyl)-

80797-69-9

Selected structures

Chapter Table

II.A-5, III-13, VI-3

VI-3, X-2

VI-3

2429-94-9

0

1

0

2(3H)-Furanone, dihydro-5-(3-methylbutyl)-

VI-3

10547-88-3

0

1

0

2(3H)-Furanone, dihydro-4-(1-methylethyl)-

VI-3

38624-29-2

0

1

0

2(3H)-Furanone, dihydro-5-(1-methylethyl)-

VI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1610

11/24/08 1:56:21 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1611

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke S

T

S T

0

1

0

2(3H)-Furanone, dihydro-5-(1-methylethyl)-5-(3methyl-1,2-butadienyl)-

VI-3

129742-48-9

0

1

0

2(3H)-Furanone, dihydro-5-(1-methylethyl)-5-(3oxo-1-butenyl)-, (E)-(+)-

III-13, VI-3

2305-05-7

0

1

0

2(3H)-Furanone, dihydro-5-octyl{J-dodecalactone}

VI-3

76710-90-2

0

1

0

2(3H)-Furanone, dihydro-5-(2-pentenyl)-, (Z)-

VI-3

104-61-0

0

1

0

2(3H)-Furanone, dihydro-5-pentyl{J-nonalactone}

VI-3

105-21-5

1

1

1

2(3H)-Furanone, dihydro-5-propyl{J-heptalactone}

VI-3

20971-79-3

1

0

0

2(3H)-Furanone, dihydro-5-(3-pyridinyl)-

61892-55-5

1

0

0

2(3H)-Furanone, dihydro-5-(hydroxymethyl)-4methyl-

II.A-5, VI-3

72507-34-7

0

1

0

2(3H)-Furanone, dihydro-5-[1-methyl-4-(1methylethyl)-7-oxo-2-octenyl]-

III-13, VI-3

102734-52-1

0

1

0

2(3H)-Furanone, dihydro-5-[4-hydroxy-4-methyl-7(1-methylethyl)-10-oxo-1,5-undecadienyl]-5methyl-, [5S-[5R*(1E,4R*,5E,7R*)]]-

CAS No.

Name (per CA Collective Index)

Chapter Table

Selected structures

VI-3, XVII.B-2

II.A-5, III-13, VI-3 H3C

CH3 OH

O

CH3

CH3 O

CH3

O

102734-53-2

0

1

0

2(3H)-Furanone, dihydro-5-[4-hydroxy-4-methyl-7(1-methylethyl)-10-oxo-1,5-undecadienyl]-5methyl-, [5S-[5R*(1E,4S*,5E,7R*)]]-

II.A-5, III-13, VI-3

102734-54-3

0

1

0

2(3H)-Furanone, dihydro-5-[4-hydroxy-4-methyl-7(1-methylethyl)-10-oxo-1,5-undecadienyl]-5methyl-, [5R-[5R*(1E,4S*,5E,7S*)]]-

II.A-5, III-13, VI-3

102734-55-4

0

1

0

2(3H)-Furanone, dihydro-5-[4-hydroxy-4-methyl-7(1-methylethyl)-10-oxo-1,5-undecadienyl]-5methyl-, [5R-[5R*(1E,4R*,5E,7S*)]]-

II.A-5, III-13, VI-3

80744-25-8

0

1

0

2(3H)-Furanone, dihydro-5-[4-hydroxy-4-methyl-7(1-methylethyl)-10-oxo-1,5-undecadienyl]-5methyl-

II.A-5, III-13, VI-3

0

1

0

2(3H)-Furanone, dihydro-5-methyl-5-(5-methyl-2furanyl)-

60646-31-3

1

0

0

2(3H)-Furanone, dihydro-5-methyl-5-(1methylethyl)-, (S)-

57213-51-1

0

1

0

2(3H)-Furanone, dihydro-5-methyl-5-[3-(1methylethyl)-6-oxo-1-heptenyl]-

VI-3, X-2 VI-3 III-13, VI-3 O

CH3

H3C

H3C

O

O

CH3

3284-93-3

0

1

0

2(3H)-Furanone, dihydro-5-methyl-5-propyl-

VI-3

10008-73-8

1

0

0

2(3H)-Furanone, dihydro-5-methylene-

VI-3

0

1

0

2(3H)-Furanone, dihydro-5-(1,1,3-trimethyl-2butenyl)-

VI-3

64291-81-2

0

1

0

2(3H)-Furanone, dihydrodimethyl-

VI-3

0

1

0

2(3H)-Furanone, 3,3-dimethyl-

VI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1611

11/24/08 1:56:22 PM

1612

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

1

1

1

2(3H)-Furanone, 3,4-dimethyl-

61892-58-8

1

0

0

2(3H)-Furanone, 3-(hydroxymethyl)-5-methyl-

591-12-8

1

1

1

2(3H)-Furanone, 5-methyl-

Selected structures

Chapter Table VI-3 II.A-5, VI-3 VI-3

{4-hydroxy-3-pentenoic acid lactone; D-angelica lactone} 497-23-4

1

1

1

2(5H)-Furanone

{crotonolactone}

5 4

VI-3

1 O O 3

1

0

0

2(5H)-Furanone, acetyl-

III-13, VI-3

80436-91-5

1

0

0

2(5H)-Furanone, 3-acetyl-

III-13, VI-3

38260-27-4

1

0

0

2(5H)-Furanone, 4-acetyl-

III-13, VI-3

61892-53-3

1

0

0

2(5H)-Furanone, 5-acetyl-

III-13, VI-3 III-13, VI-3

61892-42-0 14668-67-8 1575-46-8

1

0

0

2(5H)-Furanone, 3-acetyl-4-methyl-

1

0

0

2(5H)-Furanone, 5-butylidene-

VI-3

1

0

0

2(5H)-Furanone, 3,5-diethyl-

VI-3

1

0

0

2(5H)-Furanone, 3,4-dihydroxy-

VI-3

1

0

0

2(5H)-Furanone, 3,4-dimethyl-

VI-3

5584-69-0

1

1

1

2(5H)-Furanone, 3,5-dimethyl-

VI-3

10547-85-0

1

1

1

2(5H)-Furanone, 4,5-dimethyl-

VI-3

20019-64-1 6067-11-4

0

1

0

2(5H)-Furanone, 5,5-dimethyl-

VI-3

0

1

0

2(5H)-Furanone, 5,5-dimethyl-4-ethyl-

VI-3

0

1

0

2(5H)-Furanone, 3,4-dimethyl-5-hydroxy-5-pentyl-

II.A-5, VI-3

OH

O

O

14300-74-4

1

0

0

2(5H)-Furanone, 3,4-dimethyl-5-methylene-

VI-3

10547-84-9

1

1

1

2(5H)-Furanone, 3,4-dimethyl-5-pentyl{dihydrobovolide}

VI-3 O

774-64-1

1

1

1

O

2(5H)-Furanone, 3,4-dimethyl-5-pentylidene{bovolide}

VI-3 O

O

7935-59-1

0

1

0

2(5H)-Furanone, 3,4-dimethyl-5-pentylidene-, dihydro derivative

VI-3

66309-74-8

1

0

0

2(5H)-Furanone, 3,4-dimethyl-5-(1-propenyl)-

VI-3

66309-75-9

2407-43-4

1

0

0

2(5H)-Furanone, 5-ethenyl-

VI-3

0

1

0

2(5H)-Furanone, 5-ethenyl-3-methyl-

VI-3

0

1

0

2(5H)-Furanone, 4-ethyl-

VI-3

1

1

1

2(5H)-Furanone, 5-ethyl-

VI-3

0

1

0

2(5H)-Furanone, 4-ethyl-5,5-dimethyl-

VI-3

698-10-2

0

1

0

2(5H)-Furanone, 5-ethyl-3-hydroxy-4-methyl-

VI-3

14668-66-7

1

0

0

2(5H)-Furanone, 3-ethyl-5-methyl-

VI-3

54467-53-7

0

1

0

2(5H)-Furanone, 4-ethyl-5-methyl-

VI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1612

11/24/08 1:56:22 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1613

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

26329-68-0

1

0

0

2(5H)-Furanone, 5-ethyl-3-methyl-

VI-3

52945-87-6

1

0

0

2(5H)-Furanone, 5-ethyl-4-methyl-

VI-3

Name (per CA Collective Index)

Selected structures

Chapter Table

6066-62-2

1

0

0

2(5H)-Furanone, 5-ethylidene-3,4-dimethyl-

VI-3

71126-48-2

1

0

0

2(5H)-Furanone, 5-ethylidene-3-methyl-, (Z)-

VI-3

28664-35-9 54621-96-4

0

1

0

2(5H)-Furanone, 3-hydroxy-4,5-dimethyl-

VI-3

1

0

0

2(5H)-Furanone, 3-hydroxy-5-(1-hydroxyethyl)-

IVI-3

1

0

0

2(5H)-Furanone, 5-(1-hydroxyethyl)-, [R-(R*,S*)]-

1

0

0

2(5H)-Furanone, 3-(hydroxymethyl)-

II.A-5, VI-3 VI-3

80904-75-2

1

0

0

2(5H)-Furanone, 4-(hydroxymethyl)-

II.A-5, VI-3

22122-36-7

1

1

1

2(5H)-Furanone, 3-methyl-

VI-3

6124-79-4

1

1

1

2(5H)-Furanone, 4-methyl-

VI-3

591-11-7

1

1

1

2(5H)-Furanone, 5-methyl-

{ȕ-angelica lactone}

VI-3

108-28-1

1

1

1

2(5H)-Furanone, 5-methylene- {protoanemonin}

VI-3

7754-93-0

0

1

0

2(5H)-Furanone, 3-(1-methylethyl)-

VI-3

10547-89-4

1

1

1

2(5H)-Furanone, 4-(1-methylethyl)-

VI-3

61892-54-4

1

1

1

2(5H)-Furanone, 3-methyl-5-methylene-

VI-3

0

1

0

2(5H)-Furanone, 5-methyl-5-(1-methylethyl)-

VI-3

0

1

0

2(5H)-Furanone, 4-methyl-5-(3-oxobutyl)

III-13, VI-3

0

1

0

2(5H)-Furanone, 5-methyl-4-(3-oxo-4-methylpentyl)-

III-13, VI-3

0

1

0

2(5H)-Furanone, 4-(4-methyl-1-pentyl)-

VI-3

77267-30-2

0

1

0

2(5H)-Furanone, 5-(2-pentenyl)-, (Z)-

VI-3

1963-26-8 21963-26-8

0

1

0

2(5H)-Furanone, 5-pentyl-

VI-3

33488-51-6

1

1

1

2(5H)-Furanone, 3,4,5-trimethyl-

VI-3

50598-50-0

0

1

0

2(5H)-Furanone, 3,5,5-trimethyl-

VI-3

4182-41-6

0

1

0

2(5H)-Furanone, 4,5,5-trimethyl-

3511-31-7

1

0

0

3(2H)-Furanone

22929-52-8

3188-00-9

VI-3 III-13, X-2

1

0

0

3(2H)-Furanone, dihydro-

III-13, X-2

1

0

0

3(2H)-Furanone, dihydro-2,5-dimethyl-, (E)-

III-13, X-2

1

0

0

3(2H)-Furanone, dihydro-2,5-dimethyl-, (Z)-

III-13, X-2

1

1

1

3(2H)-Furanone, dihydro-2-methyl{2-methyltetrahydrofuran-3-one}

III-13, X-2 O

O CH3

89364-27-2

1

0

0

3(2H)-Furanone, dihydro-4-methyl-

III-13, X-2

0

1

0

3(2H)-Furanone, dihydro-5-methyl-5-propyl-

III-13, X-2

14400-67-0

1

0

0

3(2H)-Furanone, 2,5-dimethyl-

III-13, X-2

27538-09-6

0

1

0

3(2H)-Furanone, 3-ethyl-4-hydroxy-5-methyl-

III-13, X-2

17678-20-5

1

0

0

3(2H)-Furanone, 4-hydroxy-2-(hydroxymethyl)-5methyl-

II.A-5, III-13, X-2

3658-77-3

1

1

1

3(2H)-Furanone, 4-hydroxy-2,5-dimethyl{furaneol}

II.A-5, III-13, X-2

484-20-8

0

1

0

7H-Furo[3,2-g][1]benzopyran-7-one, 4-methoxy-

X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1613

11/24/08 1:56:23 PM

1614

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

0

1

0

Name (per CA Collective Index) Furo[3,2-b]furan, tetrahydro-2-acetyl-3a-methyl-5(1-methylethyl)-

Chapter Table

Selected structures

III-13, X-2 H3 C CO-CH3 O

H3C

O CH3

0

1

0

Furo[3,2-b]furan-2(3H)-methanol, tetrahydro-Į,Į,3atrimethyl-5-(1-methylethyl)-

II.A-5, III-13, X-2 H3C

CH3 OH O

H3C

CH3

O CH3

60026-27-9

0

1

0

Furo[3,2-b]furan-2(3H)-one, tetrahydro-3a-methyl-

VI-3, X-2

O O

O CH3

0

1

0

Furo[3,2-b]furan-2(3H)-one, tetrahydro-3a-methyl-5(1-methylethenyl)-

VI-3, X-2

H2C O O

H3C

O CH3

0

1

0

Furo[3,2-b]furan-2(3H)-one, tetrahydro-3a-methyl-5(1-methylethenyl)-

VI-3, X-2

H2C O H3C

O

O CH3

0

1

0

Furo[3,2-b]furan-2(3H)-one, tetrahydro-3a-methyl-5(1-methylethyl)-

VI-3, X-2

H3C O O

H3C

O CH3

0

1

0

Furo[3,2-b]furan-2(3H)-one, tetrahydro-3a-methyl-5(1-methylethyl)-

VI-3, X-2

H3C O O

H3C

O CH3

61893-05-8

1

0

0

1H-Furo[2,3-d]imidazole, 2-methyl-

X-2, XVII.A-4

H N CH3 O

N

72686-97-6

0

1

0

2H-Furo[3,2-c]isobenzofuran-8-methanol, octahydro-2-methoxy-D,D,3a,5a-tetramethyl-, (2D,3aD,5aE,8E,9aS*)-

II.A-5, X-2

72747-21-8

0

1

0

2H-Furo[3,2-c]isobenzofuran-8-methanol, octahydro-2-methoxy-D,D,3a,5a-tetramethyl-, [2R(2D,3aE,5aD,8D,9aR*)]-

II.A-5, X-2

37209-50-0

0

1

0

3aH-Furo[3,2-c]isobenzofuran-8-methanol, 5,5a,6,7,8,9-hexahydro-D,D,3a,5a-tetramethyl-, acetate, [3aR-(3aD,5aE,8E,9aR*)]-

II.A-5, X-2

56857-64-8

0

1

0

3aH-Furo[3,2-c]isobenzofuran-8-methanol, 5,5a,6,7,8,9-hexahydro-D,D,3a,5a-tetramethyl-, [3aR-(3aD,5aE,8E,9aR*)]-

II.A-5, X-2

7440-54-2

1

1

1

Gadolinium

9037-55-2

1

1

1

D-Galactan

526-99-8

Gd

XX-5 VIII-3

0

1

0

Galactaric acid

HOOC-(CHOH)4-COOH

0

1

0

Galactitol, 2,3-di-O-methyl-

HOH2C-[CH(OCH3]2-(CHOH)2-CH2OH II.A-5

IV.A-3

0

1

0

Galactitol, 2,4-di-O-methyl-

II.A-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1614

11/24/08 1:56:23 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1615

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

0

1

0

Galactitol, 2,6-di-O-methyl-

0

1

0

Galactitol, 2-O-methyl-

II.A-5, X-2

Name (per CA Collective Index)

Selected structures

Chapter Table

HOH2C-CH(OCH3)-(CHOH)3-CH2OCH3 II.A-5

0

1

0

Galactitol, 3-O-methyl-

II.A-5, X-2

0

1

0

Galactitol, 2,3,4,6-tetra-O-methyl-

II.A-5, X-2

0

1

0

Galactitol, 2,3,4-tri-O-methyl-

II.A-5, X-2

0

1

0

Galactitol, 2,3,6-tri-O-methyl-

II.A-5, X-2

0

1

0

Galactitol, 2,4,6-tri-O-methyl-

II.A-5, X-2

9036-66-2

1

1

1

D-Galacto-L-arabinan

II.A-5, X-2

33818-21-2

1

0

0

D-D-Galactofuranose, 1,6-anhydro-

II.A-5, X-2

9040-29-3

0

1

0

D-Galacto-D-gluco-D-mannan

II.A-5, X-2

644-76-8

1

0

0

E-D-Galactopyranose, 1,6-anhydro-

II.A-5, X-2

26656-33-7

0

1

0

D-Galactopyranuronic acid, homopolymer

1948-54-5

0

1

0

Galactose, 2-amino-2-deoxy-

II.A-5, X-2 II.A-5, X-2, XII-2

35381-83-0

0

1

0

Galactose, diether with 1,2,3-propanetriol (1:2)

II.A-5, X-2

59-23-4

1

1

1

D-Galactose

II.A-5, X-2

7535-00-4

0

1

0

D-Galactose, 2-amino-2-deoxy-

II.A-5, X-2, XII-2

{galactosamine}

1949-89-9

0

1

0

D-Galactose, 2-deoxy-

9001-34-7

0

1

0

Galactosidase

II.A-5, X-2

97234-09-8

0

1

0

D-Galactoside, [(1-oxohexadecatrienyl)oxy][(1oxooctadecatrienyl)oxy]propyl, (all-Z)-

II.A-5, X-2

97234-10-1

0

1

0

D-Galactoside, [(1-oxohexadecyl)oxy][(1oxooctadecatrienyl)oxy]propyl, (Z,Z,Z)-

II.A-5, X-2

97276-55-6

0

1

0

D-Galactoside, [(1-oxooctadecadienyl)oxy][(1oxooctadecatrienyl)oxy]propyl, (all-Z)-

II.A-5, X-2

97232-94-5

0

1

0

D-Galactoside, 2,3-bis[(1oxooctadecadienyl)oxy]propyl O-D-galactosyl-, (all-Z)-

II.A-5, X-2

97170-15-5

0

1

0

D-Galactoside, 2,3-bis[(1oxooctadecadienyl)oxy]propyl, (all-Z)-

II.A-5, X-2

97233-43-7

0

1

0

D-Galactoside, 2,3-bis[(1oxooctadecatrienyl)oxy]propyl O-D-galactosyl-, (all-Z)-

II.A-5, X-2

97170-14-4

0

1

0

D-Galactoside, 2,3-bis[(1oxooctadecatrienyl)oxy]propyl, (all-Z)-

II.A-5, X-2

97275-71-3

0

1

0

D-Galactoside, 2,3-dihydroxypropyl, 2'(or 3')hexadecanoate 3' (or 2')-octadecadienoate, (Z,Z)-

II.A-5, X-2

14982-50-4

0

1

0

Galacturonic acid

XXII-2

II.A-5, IV.A-3, X-2

COOH HO OH

O

OH OH

25990-10-7

0

1

0

Galacturonic acid, homopolymer

II.A-5, IV.A-3, X-2

685-73-4

1

1

1

D-Galacturonic acid

II.A-5, IV.A-3, X-2

34150-36-2

0

1

0

D-Galacturonic acid, anhydro-

II.A-5, IV.A-3, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1615

11/24/08 1:56:24 PM

1616

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

25249-06-3

0

1

0

D-Galacturonic acid, homopolymer

7440-55-3

1

1

1

Gallium

XX-5

152347-17-6

0

1

0

GenBank D16204

XXII-2

152347-18-7

0

1

0

GenBank D16205

XXII-2

152347-16-5

0

1

0

GenBank D16206

XXII-2

143787-54-6

0

1

0

GenBank L02124

XXII-2

150472-46-1

0

1

0

GenBank L13439

XXII-2

150472-47-2

0

1

0

GenBank L13440

XXII-2

150472-48-3

0

1

0

GenBank L13441

XXII-2

150472-49-4

0

1

0

GenBank L13442

XXII-2

150472-50-7

0

1

0

GenBank L13443

XXII-2

149241-78-1

Name (per CA Collective Index)

Selected structures

Chapter Table

II.A-5, IV.A-3, X-2

0

1

0

GenBank L14953

XXII-2

0

1

0

GenBank M73791

XXII-2

144680-39-7

0

1

0

GenBank M74102

XXII-2

144680-37-5

0

1

0

GenBank M74103

XXII-2

142693-30-9

0

1

0

GenBank M84650

XXII-2

145767-36-8

0

1

0

GenBank M87838

XXII-2

145767-40-4

0

1

0

GenBank M87839

XXII-2

141683-31-0

0

1

0

GenBank M94135

XXII-2

0

1

0

GenBank X58527

XXII-2

139854-77-6

0

1

0

GenBank X60057

XXII-2

140352-16-5

0

1

0

GenBank X61113

XXII-2

140352-17-6

0

1

0

GenBank X61114

XXII-2

139857-64-0

0

1

0

GenBank X61750

XXII-2

0

1

0

GenBank X61826

XXII-2

140360-05-0

0

1

0

GenBank X62339

XXII-2

141005-27-8

0

1

0

GenBank X62368

XXII-2

140104-46-7

0

1

0

GenBank X62395

XXII-2

0

1

0

GenBank X62500

XXII-2

142965-21-7

0

1

0

GenBank X63078

XXII-2

145905-43-7

0

1

0

GenBank X63607

XXII-2

139867-08-6

0

1

0

GenBank X64398

XXII-2

139869-01-5

0

1

0

GenBank X64399

XXII-2

140830-68-8

0

1

0

GenBank X64423

XXII-2

0

1

0

GenBank X64621

XXII-2

141164-37-6

0

1

0

GenBank X65117

XXII-2

141164-36-5

0

1

0

GenBank X65118

XXII-2

147904-32-3

0

1

0

GenBank X65982

XXII-2

144031-18-5

0

1

0

GenBank X66145

XXII-2

143341-50-8

0

1

0

GenBank X67158

XXII-2

151468-68-7

0

1

0

GenBank X69971

XXII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1616

11/24/08 1:56:24 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1617

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 148757-17-9

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

0

1

0

GenBank X71015

XXII-2

0

1

0

GenBank Z11803

XXII-2

142914-46-3

0

1

0

GenBank Z12619

XXII-2

142914-45-2

0

1

0

GenBank Z12623

XXII-2

152651-60-0

0

1

0

GenBank Z14079

XXII-2

152651-59-7

0

1

0

GenBank Z14080

XXII-2

152651-58-6

0

1

0

GenBank Z14081

XXII-2

152651-57-5

0

1

0

GenBank Z14082

XXII-2

152651-61-1

0

1

0

GenBank Z14085

XXII-2

148544-79-0

0

1

0

GenBank Z16403

XXII-2

148544-80-3

0

1

0

GenBank Z16404

XXII-2

554-91-6

0

1

0

Gentiobiose

7440-56-4

1

1

1

Germanium

II.A-5, X-2

19147-78-5

0

1

0

Gibbane-1,10-dicarboxylic acid, 2,3-epoxy-4a,7dihydroxy-1-methyl-8-methylene-, 1,4a-lactone, (1D,2E,3E,4aD,4bE,10E)-

II.A-5, VI-3

545-97-1

0

1

0

Gibbane-1,10-dicarboxylic acid, 2,4a,7-trihydroxy-1methyl-8-methylene-, 1,4a-lactone, (1D,2E,4aD,4bE,10E)-

II.A-5, VI-3

468-44-0

0

1

0

Gibbane-1,10-dicarboxylic acid, 2,4a-dihydroxy-1methyl-8-methylene-,1,4a-lactone, (1D,2E,4aD,4bE,10E)-.

Ge

XX-5

II.A-5, VI-3 COOH

H2C

O

O CH3

OH

561-56-8

0

1

0

Gibb-2-ene-1,10-dicarboxylic acid, 4a,7-dihydroxy1-methyl-8-methylene-, 1,4a-lactone, (1D,4aD,4bE,10E)-

77-06-5

0

1

0

Gibb-3-ene-1,10-dicarboxylic acid, 2,4a,7trihydroxy-1-methyl-8-methylene-, 1,4a-lactone, (1D,2E,4aD,4bE,10E){gibberellic acid}

II.A-5, VI-3

II.A-5, VI-3 O HO

OH

O

COOH

125-67-7

0

1

0

Gibb-3-ene-1,10-dicarboxylic acid, 2,4a,7trihydroxy-1-methyl-8-methylene-, 1,4a-lactone, potassium salt {gibberellic acid, potassium salt}

II.A-5, VI-3, XXI-3 O HO

OH

O

COOH

510-75-8

0

1

0

Gibb-3-ene-1,10-dicarboxylic acid, 2,4a-dihydroxy1-methyl-8-methylene-, 1,4a-lactone, (1D,2E,4aD,4bE,10E)-

II.A-5, VI-3

9007-83-4

0

1

0

Globulins, J-

9037-91-6

0

1

0

Glucan

II.A-5, VIII-3

9051-97-2

0

1

0

E-D-Glucan, (1o3)-

II.A-5, VIII-3

9044-93-3

0

1

0

E-1,3-Glucanase

XXII-2

128512-83-4

0

1

0

Glucanase, endo-1,3-E-(tobacco clone pGL31 isoenzyme)

XXII-2

XXII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1617

11/24/08 1:56:25 PM

1618

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

128512-84-5

0

1

0

Glucanase, endo-1,3-E- (tobacco clone pGL36 isoenzyme)

XXII-2

128512-85-6

0

1

0

Glucanase, endo-1,3-E- (tobacco clone pGL43 isoenzyme)

XXII-2

128512-86-7

0

1

0

Glucanase, endo-1,3-E- (tobacco isoenzyme)

XXII-2

62213-14-3

0

1

0

Glucanase, endo-1,3(4)-E-

XXII-2

128475-00-3

0

1

0

Glucanase, preproendo-1,3-E- (tobacco clone pBSGlu39.1 isoenzyme signal peptide)

XXII-2

128475-01-4

0

1

0

Glucanase, preproendo-1,3-E- (tobacco clone pBSGlu39.1 isoenzyme signal peptide) 26-Lthreonine-28-L-glutamic acid

XXII-2

128512-87-8

0

1

0

Glucanase, preproendo-1,3-E- (tobacco clone pBSGlu39.1 isoenzyme protein moiety)

XXII-2

128512-88-9

0

1

0

Glucanase, preproendo-1,3-E- (tobacco clone pBSGluc39.3 isoenzyme protein moiety)

XXII-2

128512-89-0

0

1

0

Glucanase, preproendo-1,3-E- (tobacco clone pGL31 isoenzyme protein moiety)

XXII-2

128512-90-3

0

1

0

Glucanase, preproendo-1,3-E- (tobacco clone pGL36 isoenzyme protein moiety)

XXII-2

128512-91-4

0

1

0

Glucanase, preproendo-1,3-E- (tobacco clone pGL43 isoenzyme protein moiety)

XXII-2

128512-92-5

0

1

0

Glucanase, preproendo-1,3-E- (tobacco isoenzyme protein moiety)

XXII-2

7425-74-3

1

1

1

E-D-Glucofuranose, 1,6-anhydro-

66537-22-2

1

1

1

Glucometasaccharinic acid, J-lactone

492-62-6

0

1

0

D-D-Glucopyranose

Name (per CA Collective Index)

Selected structures

Chapter Table

II.A-5, X-2 II.A-5, VI-3, X-2 II.A-5, X-2

OH OH

O

HO

HOCH2 OH

492-61-5

28977-67-5

0

1

0

E-D-Glucopyranose

II.A-5, X-2

0

1

0

Į-D-Glucopyranose, 1-acetate 2,3,4,6-tetrakis((+)-3methylbutanoate)

V-3

1

1

1

E-D-Glucopyranose, 6-acetate 2,3,4-tris((+)-3methylvalerate)

V-3

E-D-Glucopyranose, 6-acetate 2,3,4-tris((+)-3methylpentanoate) 25545-13-5

0

1

0

D-Glucopyranose, 4-(4-hydroxybenzoate)

V-3

23445-11-6

0

1

0

E-D-Glucopyranose, 1-(2,5-dihydroxybenzoate)

V-3 V-3

41682-52-4

0

1

0

E-D-Glucopyranose, 1-(3-phenyl-2-propenoate)

59-56-3

0

1

0

D-D-Glucopyranose, 1-(dihydrogen phosphate)

498-07-7

1

1

1

E-D-Glucopyranose, 1,6-anhydro- {levoglucosan}

V-3 HO

HO

OH

II.A-5, X-2

O O

61891-55-2

1

0

0

E-D-Glucopyranose, 1,6-anhydro-, monoacetate

V-3

10139-18-1

0

1

0

D-D-Glucopyranose, 1,6-bis(dihydrogen phosphate)

V-3

21056-52-0

0

1

0

E-D-Glucopyranose, 1-benzoate

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1618

11/24/08 1:56:25 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1619

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

33-99-3

0

1

0

E-D-Glucopyranose, 4-O-D-D-glucopyranosyl-

II.A-5, X-2

4482-75-1

0

1

0

D-D-Glucopyranose, 4-O-D-D-glucopyranosyl-

II.A-5, X-2

0

1

0

Į-D-Glucopyranose, 1,2,3,4,5-penta((+)-3methylbutanoate)

V-3

64461-84-3

Name (per CA Collective Index)

Chapter Table

Selected structures

0

1

0

E-D-Glucopyranose, 6-(3-phenyl-2-propenoate)

V-3

0

1

0

Į-D-Glucopyranose, 1,3,4,6-tetrakis((+)-3methylbutanoate)

V-3

0

1

0

Į-D-Glucopyranose, 2,3,4,5-tetrakis((+)-3methylbutanoate)

V-3

0

1

0

ȕ-D-Glucopyranose, 2,3,4,5-tetrakis((+)-3methylbutanoate)

V-3

7724-09-6

0

1

0

E-D-Glucopyranoside, (2-hydroxyphenyl)methyl-

7073-61-2

1

1

1

E-D-Glucopyranoside, (3E)-cholest-5-en-3-yl{cholesteryl glucoside}

II.A-5, X-2

1

1

1

E-D-Glucopyranoside, (3E)-ergost-5-en-3-yl{campesteryl glucoside}

II.A-5, X-2

0

1

0

E-D-Glucopyranoside, 3-hexen-1-yl{3-hexen-1-yl glucoside; leaf acid glucoside}

II.A-5, X-2

1

1

1

E-D-Glucopyranoside, (3E)-stigmast-5-en-3-yl{E-sitosteryl glucoside}

474-58-8

II.A-5, IX.A-22, X-2

II.A-5, X-2 CH3 H3C

C2H5

CH-CH2CH2-CH-CH=(CH3)2

H3C

HOCH2

O

O OH

OH

HO

19716-26-8

1

1

1

E-D-Glucopyranoside, (3E,22E)-stigmasta-5,22dien-3-yl{stigmasteryl glucoside}

CH3

C2H5

II.A-5, X-2

CH-CH=CH-CH-CH=(CH3)2

H3C H3C

HOCH2

O

O

OH OH

HO

51064-38-1

1

1

1

II.A-5, X-2

E-D-Glucopyranoside, (3E,24S)-stigmast-5-en-3-yl{Ȗ-sitosteryl glucoside}

CH3 H 3C

CH-CH2CH2-CH-CH=(CH 3)2 C2H5

H3C

HOCH2

O

O

OH OH

HO

57-50-1

1

1

1

D-D-Glucopyranoside, E-D-fructofuranosyl{sucrose}

II.A-5, X-2 HOH2C O

HOH2C

HO

O

CH2OH

O OH HO

126-14-7

0

1

0

D-D-Glucopyranoside, E-D-fructofuranosyl-, octaacetate

OH

HO

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1619

11/24/08 1:56:26 PM

1620

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

470-55-3

0

1

0

D-D-Glucopyranoside, E-D-fructofuranosyl-O-D-Dgalactopyranosyl-(1o6)-O-D-D-galactopyranosyl(1o6)-

II.A-5, X-2

512-69-6

0

1

0

D-D-Glucopyranoside, E-D-fructofuranosyl-O-D-Dgalactopyranosyl-(1o6){raffinose}

II.A-5, X-2

13101-54-7

0

1

0

D-D-Glucopyranoside, E-D-fructofuranosyl-O-D-Dglucopyranosyl-(1o4)-

II.A-5, X-2

25954-44-3

0

1

0

D-D-Glucopyranoside, E-D-fructofuranosyl-O-E-Dglucopyranosyl-(1o6)-

II.A-5, X-2

98913-58-7

0

1

0

D-D-Glucopyranoside, E-D-fructofuranosyl-, 3methylpentanoate

II.A-5, V-3, X-2

154063-13-5

0

1

0

D-D-Glucopyranoside, E-D-fructofuranosyl-, 6acetate 2,3,4-tris(2-methylbutanoate)

II.A-5, V-3, X-2

97614-61-4

0

1

0

D-D-Glucopyranoside, E-D-fructofuranosyl-, 6acetate 2,3,4-tris(3-methylpentanoate)

II.A-5, V-3, X-2

106033-38-9

0

1

0

D-D-Glucopyranoside, E-D-fructofuranosyl-, 6acetate 2,3,4-tris(3-methylpentanoate), [2(S),3(S),4(S)]-

II.A-5, V-3, X-2

41055-68-9

0

1

0

D-D-Glucopyranoside, E-D-fructofuranosyl-, labeled 13 with C

II.A-5, X-2

21291-36-1

0

1

0

D-D-Glucopyranoside, E-D-fructofuranosyl-O-D-Dglucopyranosyl-(1o6)-

II.A-5, X-2

88848-61-7

0

1

0

E-D-Glucopyranoside, 1,2,3,4,5,6,7,8-octahydro-3hydroxy-1-methyl-7-(1-methylethenyl)-2naphthalenyl 2-O-E-D-glucopyranosyl-, [1S(1D,2E,3D,7E)]-

II.A-5, X-2

99499-89-5

0

1

0

E-D-Glucopyranoside, 1,2,3,4,5,6,7,8-octahydro-3hydroxy-1-methyl-7-(1-methylethenyl)-2naphthalenyl O-6-deoxy-D-L-mannopyranosyl(1o4)-O-E-D-glucopyranosyl-(1o4)-, [1S(1D,2E,3D,7E)]-

II.A-5, X-2

138-52-3

0

1

0

E-D-Glucopyranoside, 2-(hydroxymethyl)phenyl-

II.A-5, X-2

136448-99-2

0

1

0

E-D-Glucopyranoside, 2-[5-(acetyloxy)1,2,3,5,6,7,8,8a-octahydro-8,8a-dimethyl-2naphthalenyl]-2-hydroxypropyl-, 2,3,4,6tetraacetate, [2R-[2D(S*),5D,8E,8aD]]-

II.A-5, V-3, X-2

75039-16-6

0

1

0

E-D-Glucopyranoside, 2-methyl-4-(1H-purin-6ylamino)-2-butenyl-, mono(dihydrogen phosphate) (ester), (E)-

II.A-5, V-3, X-2

62512-96-3

0

1

0

E-D-Glucopyranoside, 2-methyl-4-(1H-purin-6ylamino)butyl-

78081-83-1

0

1

0

E-D-Glucopyranoside, 3-(4-hydroxy-2,2,6-trimethyl7-oxabicyclo[4.1.0]hept-1-yl)-1-methyl-2-propenyl-

II.A-5, X-2

63648-83-9

0

1

0

D-D-Glucopyranoside, 3-O-acetyl-E-Dfructofuranosyl-

II.A-5, X-2

470-57-5

0

1

0

D-D-Glucopyranoside, O-D-D-galactopyranosyl(1o6)-E-D-fructofuranosyl{theanderose}

II.A-5, X-2

1464-44-4

0

1

0

E-D-Glucopyranoside, phenyl-

II.A-5, X-2

Name (per CA Collective Index)

Selected structures

Chapter Table

II.A-5, X-2, XII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1620

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1621

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

1405-86-3

0

1

0

Name (per CA Collective Index)

Chapter Table

Selected structures

II.A-5, III-13, IV.A-3, X-2

2-O-E-D-Glucopyranuronysyl-D-Dglucopyranosiduronic acid, (3E,20E)-20-carboxy11-oxo-30-norolean-12-en-3-yl{glycyrrhizic acid; glycyrrhizin}

H3C

COOH

O CH3

H3C

CH3

CH3 O HOOC

H3C

O

O OH

HO HO

53596-04-0

0

1

0

2-O-E-D-Glucopyranuronysyl-D-Dglucopyranosiduronic acid, ammoniated (3E,20E)20-carboxy-11-oxo-30-norolean-12-en-3-yl-, ammoniated {glycyrrhizic acid ammoniated; glycyrrhizin ammoniated}

50-99-7 26655-34-5

1

1

1

D-D-Glucose

0

1

0

D-D-Glucose, labeled with C {D-D-Glucose- C}

0

1

0

OH

OH

CH3

O

COOH

X-2

II.A-5, X-2

14

13

Glucose, labeled with C

154-17-6

0

1

0

D-Glucose, 2-deoxy-

3416-24-8

0

1

0

D-Glucose, 2-deoxy-, 2-amino-

14

XXV-29

13

{Glucose- C}

VIII-3

{glucosamine}

II.A-5, X-2, XII-2

II.A-5, X-2

1398-61-4

0

1

0

D-Glucose, ȕ-(1,4)-2-acetamido-2-deoxy-

28905-12-6

1

1

1

E-D-Glucose

9001-22-3

0

1

0

Glucosidase, E-

II.A-5, X-2, XIII-1 II.A-5, X-2 XXII-2

9001-42-7

0

1

0

Glucosidase, D-

XXII-2

9012-47-9

0

1

0

Glucosidase, amylo-1,6-

XXII-2

9031-48-5

0

1

0

Glucosyltransferase

XXII-2

9027-19-4

0

1

0

Glucosyltransferase, uridine diphosphoglucose-1,4E-glucan

XXII-2

50812-18-5

0

1

0

Glucosyltransferase, uridine diphosphoglucoseflavonol 3-O-glucoside

XXII-2

9030-05-1

0

1

0

Glucosyltransferase, uridine diphosphoglucosefructose

XXII-2

9030-06-2

0

1

0

Glucosyltransferase, uridine diphosphoglucosefructose phosphate

XXII-2

146480-37-7

0

1

0

Glucosyltransferase, uridine diphosphoglucosesalicylate 3-

XXII-2

37294-28-3

0

1

0

Glucoxylan

576-37-4

0

1

0

Glucuronic acid

II.A-5, VIII-3 HOOC

OH

OH

II.A-5, IV.A-3, X-2

O HO OH

28905-07-9

0

1

0

D-D-Glucuronic acid, methyl ester

9001-45-0

0

1

0

Glucuronidase, E-

II.A-5, V-3, X-2 XXII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1621

11/24/08 1:56:27 PM

1622

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

32449-92-6

0

1

0

Name (per CA Collective Index)

Selected structures

II.A-5, VI-3, X-2

OH

D-Glucurono-3,6-lactone

Chapter Table

O O

OH O OH

62930-75-0

0

1

0

Glucuronomannan

II.A-5, VIII-3

77272-02-7

0

1

0

Glucuronomannoarabinan

II.A-5, VIII-3

6899-05-4

1

1

1

Glutamic acid

56-86-0

0

1

0

L-Glutamic acid

IV.A-3, IV.B-7, XII-2

HOOC-(CH2)2-CH(NH2)-COOH IV.A-3, IV.B-7, XII-2

997-68-2

0

1

0

L-Glutamic acid, N-(5-amino-5-carboxypentyl)-, (S)-

IV.A-3, IV.B-7, XII-2

58-05-9

0

1

0

L-Glutamic acid, N-[4-[[(2-amino-5-formyl1,4,5,6,7,8-hexahydro-4-oxo-6pteridinyl)methyl]amino]benzoyl]-

IV.A-3, IV.B-7, XII-2

1116-22-9

0

1

0

L-Glutamic acid, N-L-J-glutamyl-

IV.A-3, IV.B-7, XII-2

3929-61-1

0

1

0

L-Glutamic acid, N-L-D-glutamyl-

IV.A-3, IV.B-7, XII-2

6899-04-3

0

1

0

Glutamine

56-85-9

1

1

1

L-Glutamine

9046-27-9

0

1

0

Glutamyltransferase, J-

H2N-OC-(CH2)2-CH(NH2)-COOH IV.A-3, IV.B-7, XII-2, XIII-1 IV.A-3, IV.B-7, XII-2

9061-41-0

0

1

0

Glutenin

56-40-6

1

1

1

Glycine

18875-39-3

0

1

0

Glycine, labeled with C

0

1

0

Glycine, N-(1-deoxy-D-fructos-1-yl)-

XXII-2 XXII-2 H2N-CH2-COOH

14

IV.A-3, IV.B-7, XII-2 IV.A-3, IV.B-7, XII-2

II.A-5, IV.A-3, IV.B-7, XII-2

88476-94-2

0

1

0

Glycine, N-(1-nitroso-L-prolyl)-

IV.A-3, IV.B-7, XV-8, XVII.A-4

70-18-8

0

1

0

Glycine, N-(N-L-J-glutamyl-L-cysteinyl){glutathione}

IV.A-3, IV.B-7, XII-2, XVIII.A-1

1071-83-6

0

1

0

Glycine, N-(phosphonomethyl)-

IV.A-3, IV.B-7, XII-2

1118-68-9

0

1

0

Glycine, N,N-dimethyl-

73360-07-3

0

1

0

Glycine, N-[2-(2-aminoethoxy)ethenyl]-

(H3C)2=N-CH2-COOH IV.A-3, IV.B-7, XII-2

19246-18-5

0

1

0

Glycine, N-L-cysteinyl-

20661-60-3

0

1

0

Glycine, N-methyl-N-nitro-

13256-22-9

1

1

1

Glycine, N-methyl-N-nitroso-

1

1

1

Glycine, N-methyl-N-nitroso-, methyl ester

0

1

0

Glycosidase

IV.A-3, IV.B-7, X-1, XII-2 IV.A-3, IV.B-7, XII-2, XVIII.A-1 XVI-1 {NSAR}

H3C-N(NO)-CH2-COOH IV.A-3, IV.B-7, XII-2, XV-8 H3C-N(NO)-CH2-COO CH3 V-3, XII-2, XV-8 XXII-2

9001-97-2

0

1

0

Glycosyltransferase, D-glucan-branching

XXII-2

37347-76-5

0

1

0

Glyoxalase

XXII-2

7440-57-5

1

1

1

Gold

306-60-5

0

1

0

Guanidine, (4-aminobutyl)-

Au

XX-5 XII-2

86-01-1

0

1

0

Guanosine 5'-(tetrahydrogen triphosphate)

7440-58-6

1

1

1

Hafnium

XII-2, XVII.E-8

9034-32-6

0

1

0

Hemicellulose

VIII-3

63100-39-0

0

1

0

Hemicellulose A

VIII-3

Hf

XX-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1622

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1623

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

63100-40-3

0

1

0

Hemicellulose B

VIII-3

65058-12-0

0

1

0

Hemicellulose C

VIII-3

629-94-7

Name (per CA Collective Index)

Selected structures

Chapter Table

1

1

1

Heneicosane

H3C-(CH2)19-CH3

I.A-10

1

0

0

Heneicosane, 2-methyl-

H3C-CH(CH3)-(CH2)18-CH3

I.A-10

1

0

0

Heneicosane, 3-methyl-

H3C-CH2-CH(CH3)-(CH2)17-CH3

I.A-10

2363-71-5

1

1

1

Heneicosanoic acid

H3C-(CH2)19-COOH

4.A-3

42233-02-3

1

1

1

Heneicosanoic acid, docosyl ester

H3C-(CH2)19-COO-(CH2)21-CH3

V-3

42232-93-9

1

1

1

Heneicosanoic acid, dodecyl ester

H3C-(CH2)19-COO-(CH2)11-CH3

V-3

42233-00-1

1

1

1

Heneicosanoic acid, eicosyl ester

H3C-(CH2)19-COO-(CH2)19-CH3

V-3

42233-01-2

1

1

1

Heneicosanoic acid, heneicosyl ester

H3C-(CH2)19-COO-(CH2)20-CH3

V-3

1

1

1

Heneicosanoic acid, heptacosyl ester

H3C-(CH2)19-COO-(CH2)26-CH3

V-3

42232-98-4

1

1

1

Heneicosanoic acid, heptadecyl ester

H3C-(CH2)19-COO-(CH2)16-CH3

V-3

1

0

0

Heneicosanoic acid, hexacosyl ester

H3C-(CH2)19-COO-(CH2)25-CH3

V-3

42232-97-3

1

1

1

Heneicosanoic acid, hexadecyl ester

H3C-(CH2)19-COO-(CH2)15-CH3

V-3

42232-99-5

1

1

1

Heneicosanoic acid, nonadecyl ester

H3C-(CH2)19-COO-(CH2)18-CH3

V-3

121878-00-0

1

1

1

Heneicosanoic acid, octacosyl ester

H3C-(CH2)19-COO-(CH2)27-CH3

V-3

1

0

0

Heneicosanoic acid, octadecyl ester

H3C-(CH2)19-COO-(CH2)17-CH3

V-3

1

1

1

Heneicosanoic acid, pentacosyl ester

H3C-(CH2)19-COO-(CH2)24-CH3

V-3

42232-96-2

1

1

1

Heneicosanoic acid, pentadecyl ester

H3C-(CH2)19-COO-(CH2)14-CH3

V-3

42233-04-5

1

1

1

Heneicosanoic acid, tetracosyl ester

H3C-(CH2)19-COO-(CH2)23-CH3

V-3

42232-95-1

1

1

1

Heneicosanoic acid, tetradecyl ester

H3C-(CH2)19-COO-(CH2)13-CH3

V-3

42233-03-4

1

1

1

Heneicosanoic acid, tricosyl ester

H3C-(CH2)19-COO-(CH2)22-CH3

V-3

42232-94-0

1

1

1

Heneicosanoic acid, tridecyl ester

H3C-(CH2)19-COO-(CH2)12-CH3

36332-94-2

1

1

1

Heneicosanoic acid, 19-methyl-

H3C-CH2-CH(CH3)-(CH2)17-COOH

121877-70-1

1

1

1

Heneicosanoic acid, 19-methyl-, docosyl ester

H3C-CH2-CH(CH3)-(CH2)17-COO-(CH2)21-CH3 V-3

121877-61-0

1

1

1

Heneicosanoic acid, 19-methyl-, heneicosyl ester

H3C-CH2-CH(CH3)-(CH2)17-COO-(CH2)20-CH3 V-3 (H3C)2=CH-(CH2)18-COOH

6704-01-4

1

1

1

Heneicosanoic acid, 20-methyl-

71278-17-6

1

0

0

Heneicosanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester

15594-90-8

1

1

1

1-Heneicosanol

H3C-(CH2)19-CH2OH

1599-68-4

28984-67-0

V-3 IV.A-3

IV.A-3 V-3 II.A-5

1

0

0

1-Heneicosene

H3C-(CH2)18-CH=CH2

I.B-1

1

0

0

1-Heneicosene, 2-methyl-

H2C=C(CH3)-(CH2)18-CH3

I.B-1

1

0

0

2-Heneicosene, (Z)-

H3C-CH=CH-(CH2)17-CH3

I.B-1

1

0

0

2-Heneicosene, (E)-

1

0

0

2-Heneicosene, 2-methyl-

H3C-C(CH3)H=CH-(CH2)17-CH3

1

0

0

2-Heneicosene, 19-methyl-,(Z)-

H3C-CH=CH-(CH2)15-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Heneicosene, 19-methyl-, (E)-

1

0

0

2-Heneicosene, 20-methyl-, (Z)-

1

0

0

2-Heneicosene, 20-methyl-, (E)-

1

1

1

Heneicosenoic acid

I.B-1 I.B-1 I.B-1 H3C-CH=CH-(CH2)16-CH(CH3)2

I.B-1 I.B-1 IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1623

11/24/08 1:56:28 PM

1624

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

66288-40-2

1

0

0

Heneicosenoic acid, 19-methyl-

IV.A-3

66288-41-3

1

0

0

Heneicosenoic acid, 20-methyl-

IV.A-3

Name (per CA Collective Index)

Selected structures

H3C-(CH2)39-CH3

Chapter Table

1

0

0

Hentetracontane

6704-02-5

1

0

0

5,9,13,17,21,25,29-Hentriacontaheptaen-2-one, 6,10,14,18,22,26,30-heptamethyl-

I.A-10

630-04-6

1

1

1

Hentriacontane

H3C-(CH2)29-CH3

1720-12-3

1

1

1

Hentriacontane, 2-methyl-

(H3C)2=CH-(CH2)28-CH3

I.A-10

4981-99-1

1

1

1

Hentriacontane, 3-methyl-

H3C-CH2-CH(CH3)-(CH2)27-CH3

I.A-10 IV.A-3

III-13 I.A-10

67537-80-8

1

0

0

Hentriacontanoic acid

H3C-(CH2)29-COOH

71278-18-7

1

0

0

Hentriacontanoic acid, hentriacontyl ester

H3C-(CH2)29-COO-(CH2)30-CH3

V -3

H3C-(CH2)14-CO-(CH2)14-CH3

III-13

502-73-8

1

1

1

16-Hentriacontanone

77046-64-1

1

1

1

Hentriacontene

18435-54-6

I.B-1

1

0

0

1-Hentriacontene

H3C-(CH2)28-CH=CH2

I.B-1

1

0

0

1-Hentriacontene, 2-methyl-

H2C=C(CH3)-(CH2)28-CH3

I.B-1

1

0

0

2-Hentriacontene, (Z)-

H3C-CH=CH-(CH2)27-CH3

I.B-1

1

0

0

2-Hentriacontene, (E)-

1

1

1

2-Hentriacontene, 2-methyl-

H3C-C(CH3)=CH-(CH2)27-CH3

I.B-1

1

0

0

2-Hentriacontene, 29-methyl-, (Z)-

H3C-CH=CH-(CH2)25-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Hentriacontene, 29-methyl-, (E)-

I.B-1

1

0

0

2-Hentriacontene, 30-methyl-, (Z)-

1

0

0

2-Hentriacontene, 30-methyl-, (E)-

H3C-CH=CH-(CH2)26-CH(CH3)2

I.B-1

I.B-1 I.B-1

7719-93-9

1

1

1

Heptacontane

32304-17-9

1

1

1

5,9,13,17,21,25-Heptacosahexaen-2-one, 6,10,14,18,22,26-hexamethyl-, (all-E)-

H3C-(CH2)35-CH3

593-49-7

1

1

1

Heptacosane

H3C-(CH2)25-CH3

I.A-10 III-13 I.A-10

1561-00-8

1

1

1

Heptacosane, 2-methyl-

(H3C)2=CH-(CH2)24-CH3

I.A-10

14167-66-9

1

1

1

Heptacosane, 3-methyl-

H3C-CH2-CH(CH3)-(CH2)23-CH3

I.A-10

7138-40-1

1

0

0

Heptacosanoic acid

H3C-(CH2)25-COOH

121877-96-1

1

1

1

Heptacosanoic acid, docosyl ester

H3C-(CH2)25-COO-(CH2)21-CH3

V-3

1

1

1

Heptacosanoic acid, dodecyl ester

H3C-(CH2)25-COO-(CH2)11-CH3

V-3

1

1

1

Heptacosanoic acid, eicosyl ester

H3C-(CH2)25-COO-(CH2)19-CH3

V-3

1

1

1

Heptacosanoic acid, heneicosyl ester

H3C-(CH2)25-COO-(CH2)20-CH3

V-3

1

1

1

Heptacosanoic acid, heptacosyl ester

H3C-(CH2)25-COO-(CH2)26-CH3

V-3

1

1

1

Heptacosanoic acid, heptadecyl ester

H3C-(CH2)25-COO-(CH2)16-CH3

V-3

1

1

1

Heptacosanoic acid, hexacosyl ester

H3C-(CH2)25-COO-(CH2)25-CH3

V-3

1

1

1

Heptacosanoic acid, hexadecyl ester

H3C-(CH2)25-COO-(CH2)15-CH3

V-3

1

1

1

Heptacosanoic acid, nonadecyl ester

H3C-(CH2)25-COO-(CH2)18-CH3

V-3

1

1

1

Heptacosanoic acid, octadecyl ester

H3C-(CH2)25-COO-(CH2)17-CH3

V-3

1

1

1

Heptacosanoic acid, pentacosyl ester

H3C-(CH2)25-COO-(CH2)24-CH3

V-3

1

1

1

Heptacosanoic acid, pentadecyl ester

H3C-(CH2)25-COO-(CH2)14-CH3

V-3

1

1

1

Heptacosanoic acid, tetracosyl ester

H3C-(CH2)25-COO-(CH2)231-CH3

V-3

117063-83-9

IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1624

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1625

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

1

1

1

1

1

1

Selected structures

Chapter Table

Heptacosanoic acid, tetradecyl ester

H3C-(CH2)25-COO-(CH2)13-CH3

V-3

Heptacosanoic acid, tricosyl ester

H3C-(CH2)25-COO-(CH2)22-CH3

V-3 V-3

Name (per CA Collective Index)

1

1

1

Heptacosanoic acid, tridecyl ester

H3C-(CH2)25-COO-(CH2)12-CH3

121878-01-1

1

1

1

Heptacosanoic acid, 25-methyl-, docosyl ester

H3C-CH2CH(CH3)-(CH2)23-COO-(CH2)21-CH3 V-3

121877-93-8

1

1

1

Heptacosanoic acid, 25-methyl-, heneicosyl ester

H3C-CH2CH(CH3)-(CH2)23-COO-(CH2)20-CH3 V-3

2004-39-9

0

1

0

1-Heptacosanol

H3C-(CH2)25-CH2OH

II.A-5

63785-26-2

0

1

0

1-Heptacosanol, 26-methyl-

(H3C)2=CH-(CH2)24-CH2OH

II.A-5

542-50-7

0

1

0

14-Heptacosanone

H3C-(CH2)12-CO-(CH2)12-CH3

III-13

67537-80-8

1

0

0

Heptacosene

15306-27-1

1

0

0

1-Heptacosene

H3C-(CH2)24-CH=CH2

1

0

0

2-Heptacosene, (Z)-

H3C-CH=CH-(CH2)23-CH3

1

0

0

2-Heptacosene, (E)-

1

0

0

2-Heptacosene, 2-methyl-

H3C-C(CH3)=CH-(CH2)23-CH3

1

0

0

2-Heptacosene, 25-methyl-, (Z)-

H3C-CH=CH-(CH2)21-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Heptacosene, 25-methyl-, (E)-

I.B-1

1

0

0

2-Heptacosene, 26-methyl-, (Z)-

1

0

0

2-Heptacosene, 26-methyl-, (E)-

I.B-1

56797-42-3

0

1

0

8,11-Heptadecadienal, (Z,Z)-

III-12

37822-80-3

0

1

0

Heptadecadienoic acid, methyl ester

I.B-1 I.B-1 I.B-1

H3C-CH=CH-(CH2)22-CH(CH3)2

I.B-1

I.B-1

V-3

629-90-3

0

1

0

Heptadecanal

H3C-(CH2)15-CH=O

629-78-7

1

1

1

Heptadecane

H3C-(CH2)15-CH3

1560-89-0

I.B-1

III-12 I.A-10

1

1

1

Heptadecane, 2-methyl-

H3C-(CH2)14-CH=(CH3)2

I.A-10

0

1

0

Heptadecane, 3-methyl-

H3C-(CH2)13-CH(CH3)-CH2-CH3

I.A-10

13287-23-5

1

0

0

Heptadecane, 8-methyl-

H3C-(CH2)6-CH(CH3)-(CH2)8-CH3

I.A-10

506-12-7

1

1

1

Heptadecanoic acid

H3C-(CH2)15-COOH

IV.A-3

42218-25-7

1

1

1

Heptadecanoic acid, docosyl ester

H3C-(CH2)15-COO-(CH2)21-CH3

V-3

42232-43-9

1

1

1

Heptadecanoic acid, dodecyl ester

H3C-(CH2)15-COO-(CH2)11-CH3

V-3

36617-53-5

1

1

1

Heptadecanoic acid, eicosyl ester

H3C-(CH2)15-COO-(CH2)19-CH3

V-3

42232-52-0

1

1

1

Heptadecanoic acid, heneicosyl ester

H3C-(CH2)15-COO-(CH2)20-CH3

V-3

1

1

1

Heptadecanoic acid, heptacosyl ester

H3C-(CH2)15-COO-(CH2)26-CH3

V-3

36617-50-2

1

1

1

Heptadecanoic acid, heptadecyl ester

H3C-(CH2)15-COO-(CH2)16-CH3

V-3

121877-64-3

1

1

1

Heptadecanoic acid, hexacosyl ester

H3C-(CH2)15-COO-(CH2)25-CH3

V-3

36617-49-9

1

1

1

Heptadecanoic acid, hexadecyl ester

H3C-(CH2)15-COO-(CH2)15-CH3

V-3

1731-92-6

1

1

1

Heptadecanoic acid, methyl ester

H3C-(CH2)15-COO-CH3

V-3

36617-52-4

1

1

1

Heptadecanoic acid, nonadecyl ester

H3C-(CH2)15-COO-(CH2)18-CH3

V-3

36617-51-3

1

1

1

Heptadecanoic acid, octadecyl ester

H3C-(CH2)15-COO-(CH2)17-CH3

V-3

1

1

1

Heptadecanoic acid, pentacosyl ester

H3C-(CH2)15-COO-(CH2)24-CH3

V-3

36617-48-8

1

1

1

Heptadecanoic acid, pentadecyl ester

H3C-(CH2)15-COO-(CH2)14-CH3

V-3

42232-54-2

1

1

1

Heptadecanoic acid, tetracosyl ester

H3C-(CH2)15-COO-(CH2)23-CH3

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1625

11/24/08 1:56:29 PM

1626

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

36617-47-7

1

1

1

42232-53-1

1

1

1

Selected structures

Chapter Table

Heptadecanoic acid, tetradecyl ester

H3C-(CH2)15-COO-(CH2)13-CH3

V-3

Heptadecanoic acid, tricosyl ester

H3C-(CH2)15-COO-(CH2)22-CH3

V-3 V-3

Name (per CA Collective Index)

36617-46-6

1

1

1

Heptadecanoic acid, tridecyl ester

H3C-(CH2)15-COO-(CH2)12-CH3

29709-08-8

1

1

1

Heptadecanoic acid, 15-methyl-

H3C-CH2-CH(CH3)-(CH2)13-COOH IV.A-3

121877-42-7

1

1

1

Heptadecanoic acid, 15-methyl-, heneicosyl ester

H3C-CH2-CH(CH3)-(CH2)13-COO-(CH2)20-CH3 V-3

121877-68-7

1

1

1

Heptadecanoic acid, 15-methyl-, hexacosyl ester

H3C-CH2-CH(CH3)-(CH2)13-COO-(CH2)25-CH3 V-3

121877-81-4

1

1

1

Heptadecanoic acid, 15-methyl-, octacosyl ester

H3C-CH2-CH(CH3)-(CH2)13-COO-(CH2)27-CH3 V-3

121877-52-9

1

1

1

Heptadecanoic acid, 15-methyl-, tricosyl ester

H3C-CH2-CH(CH3)-(CH2)13-COO-(CH2)22-CH3 V-3 (H3C)2=CH-(CH2)14-COOH

2724-58-5

1

1

1

Heptadecanoic acid, 16-methyl-

150462-99-0

0

1

0

Heptadecanoic acid, 16-methyl-, 2-(acetyloxy)-1(hydroxymethyl)ethyl ester

II.A-5, V-3

IV.A-3

150462-98-9

0

1

0

Heptadecanoic acid, 16-methyl-, 3-(acetyloxy)-2hydroxypropyl ester

II.A-5, V-3

121877-46-1

1

1

1

Heptadecanoic acid, 16-methyl-, docosyl ester

(H3C)2=CH-(CH2)14-COO-(CH2)21-CH3 V-3

52458-35-2

0

1

0

Heptadecanoic acid, 16-methyl-, ethyl ester

(H3C)2=CH-(CH2)14-COO-C2H5

V-3

121877-36-9

1

1

1

Heptadecanoic acid, 16-methyl-, heneicosyl ester

(H3C)2=CH-(CH2)14-COO-(CH2)20-CH3

V-3

5129-61-3

0

1

0

Heptadecanoic acid, 16-methyl-, methyl ester

(H3C)2=CH-(CH2)14-COO-CH3

V-3

121877-50-7

1

1

1

Heptadecanoic acid, 16-methyl-, tricosyl ester

(H3C)2=CH-(CH2)14-COO-(CH2)22-CH3 V-3

71278-19-8

0

1

0

Heptadecanoic acid, 3,7,11,15,19,23,27,31,35nonamethyl-2,6,10,14,18,22,26,30,34hexatriacontanonaenyl ester

V-3

1

0

0

Heptadecanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester

V-3

1454-85-9

1

1

1

1-Heptadecanol

H3C-(CH2)15-CH2OH

II.A-5

41744-75-6

1

0

0

1-Heptadecanol, 16-methyl-

(H3C)2=CH-(CH2)14-CH2OH

II.A-5

56797-44-5

0

1

0

8,11,14-Heptadecatrienal, (Z,Z,Z)-

37822-82-5

0

1

0

Heptadecatrienoic acid, methyl ester

26266-05-7

1

1

1

Heptadecene

H-(CH2)15-n-CH=CH-(CH2)n-H

I.B-1

6765-39-5

1

0

0

1-Heptadecene

H3C-(CH2)14-CH=CH2

I.B-1

1

0

0

1-Heptadecene, 2-methyl-

H2C=C(CH3)-(CH2)14-CH3

I.B-1

1

0

0

2-Heptadecene, (Z)-

H3C-CH=CH-(CH2)13-CH3

I.B-1 I.B-1

36232-39-0

III-12 V-3

1

0

0

2-Heptadecene, (E)-

1

0

0

2-Heptadecene, 2-methyl-

H3C-C(CH3)=CH-(CH2)13-CH3

I.B-1

1

0

0

2-Heptadecene, 15-methyl-, (Z)-

H3C-CH=CH-(CH2)11-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Heptadecene, 15-methyl-, (E)-

1

0

0

2-Heptadecene, 16-methyl-, (Z)-

1

0

0

2-Heptadecene, 16-methyl-, (E)-

1

0

0

2-Heptadecene, 4-methylene-8,12,16-trimethyl-

I.B-1 H3C-CH=CH-(CH2)12-CH(CH3)2

I.B-1 I.B-1

H3C-CH=CH-C(=CH2)-CH2-{(CH2)2-CH(CH3)CH2}3-H I.B-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1626

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1627

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

26265-99-6

1

1

1

Heptadecenoic acid

H-(CH2)14-n-CH=CH-(CH2)n-COOH IV.A-3

31424-16-5

0

1

0

Heptadecenoic acid, methyl ester

H-(CH2)14-n-CH=CH-(CH2)n-COO-CH3 V-3

4313-03-5 5910-85-0

0

1

0

2,4-Heptadienal

O=CH-CH=CH-CH=CH-CH2-CH=O

51945-98-3

0

1

0

1,5-Heptadiene-3,4-diol

H3C-CH=CH-CHOH-CHOH-CH=CH2 II.A-5

74630-29-8

0

1

0

1,5-Heptadiene, 3,3,5-trimethyl-

H3C-CH=C(CH3)-CH2-C(CH3)2-CH=CH2 I.B-1

1

0

0

2,4-Heptadiene, 2,6-dimethyl-

72693-11-9

1

1

1

2,5-Heptadienoic acid, 2,3-dimethyl-

IV.A-3

54557-55-0

0

1

0

4,6-Heptadienoic acid, 6-methyl-3-(1-methylethyl)-, (E)-

IV.A-3

54557-57-2

0

1

0

4,6-Heptadienoic acid, 6-methyl-3-(1-methylethyl)-, methyl ester, (E)-

V-3

77411-76-8

0

1

0

3,5-Heptadien-2-ol, 2,6-dimethyl-

II.A-5

57935-33-8

0

1

0

4,6-Heptadien-1-ol, 6-methyl-3-(1-methylethyl)-, (E)-

II.A-5

79-78-7

0

1

0

1,6-Heptadien-3-one, 1-(2,6,6-trimethyl-2cyclohexen-1-yl){allylionone}

III-13

0

1

0

3,5-Heptadien-2-one, 6-methyl-, (Z)-

1

1

1

3,5-Heptadien-2-one, 6-methyl-, (E)-

0

1

0

4,6-Heptadien-2-one, 5-(1-methylethyl)-7(tetrahydro-2-methylfuranyl)-

3511-27-1

1

0

0

1,5-Heptadien-3-yne

H3C-CH=CH-CŁC-CH=CH2

I.B-1

111-71-7

1

0

0

Heptanal

H3C-(CH2)5-CH=O

III-12

111-68-2

1

1

1

1-Heptanamine

H3C-(CH2)6-NH2

XII-2

142-82-5

1

0

0

Heptane

H3C-(CH2)5-CH3

I.A-10

H3C-(CH2)5-CH2Cl

1604-28-0

629-06-1 2213-23-2

Name (per CA Collective Index)

Chapter Table

Selected structures

III-12

I.B-1

III-13 (H3C)2=C=CH-CH=CH-CO-CH3

III-13 III-13, X-2

1

0

0

Heptane, 1-chloro-

1

0

0

Heptane, dimethyl-

XVIII.B-3 I.A-10

0

1

0

Heptane, 2,4-dimethyl-

I.A-10

592-27-8

1

0

0

Heptane, 2-methyl-

H3C-(CH2)4-CH=(CH3)2

I.A-10

15869-80-4

1

0

0

Heptane, 3-ethyl-

H3C-(CH2)3-CH=(C2H5)2

I.A-10 I.A-10

589-81-1

1

0

0

Heptane, 3-methyl-

H3C-(CH2)3-CH(CH3)-CH2-CH3

1632-16-2

0

1

0

Heptane, 3-methylene-

H3C-(CH2)3-C(=CH2)-CH2-CH3

646-20-8

1

0

0

Heptanedinitrile

111-16-0

1

0

0

Heptanedioic acid

NC-(CH2)5-CN {pimelic acid}

I.B-1 XI-2

HOOC-(CH2)5-COOH

IV.A-3

535-24-0

0

1

0

Heptanedioic acid, 2,6-diamino-3-hydroxy-

96-04-8

1

0

0

2,3-Heptanedione

H3C-(CH2)3-CO-CO-CH3

III-13

7307-02-0

1

0

0

2,4-Heptanedione

H3C-(CH2)2-CO-CH2-CO-CH3

III-13

(H3C)2=CH-CH2-CO-CH2-CO-CH3

3002-23-1

II.A-5, IV.A-3, XII-2

0

1

0

2,4-Heptanedione, 6-methyl-

0

1

0

2,5-Heptanedione, 4-(1-methylethyl)-

III-13

13901-85-4

0

1

0

2,5-Heptanedione, 6-methyl-

(H3C)2=CH-CO-(CH2)2-CO-CH3

III-13

13505-34-5

1

1

1

2,6-Heptanedione

H3C-CO-(CH2)3-CO-CH3

III-13

0

1

0

2,6-Heptanedione, 3-methyl-

H3C-CO-CH(CH3)-(CH2)2-CO-CH3

III-13

III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1627

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1628

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 111-14-8

S

T

S T

Name (per CA Collective Index) {enanthic acid}

Chapter Table

Selected structures

1

1

1

Heptanoic acid

0

1

0

Heptanoic acid, 2-ethyl-

H 3C-(CH2)5-COOH

IV.A-3

59262-53-2

0

1

0

Heptanoic acid, 3-(1-methylethyl)-6-oxo-, (S)-

39815-78-6

0

1

0

Heptanoic acid, 3-oxo-, methyl ester

1070-68-4

0

1

0

Heptanoic acid, 5-methyl-

42330-36-9

0

1

0

Heptanoic acid, 5-methyl-, (S)-

IV.A-3

929-10-2

0

1

0

Heptanoic acid, 6-methyl-

IV.A-3

IV.A-3 III-13, IV.A-3 H3C-(CH2)3-CO-CH2-COO-CH3 III-13, V-3 IV.A-3

3128-07-2

1

0

0

Heptanoic acid, 6-oxo-

98188-02-4

0

1

0

Heptanoic acid, 7-(2-furanyl)-, methyl ester

H3C-CO-(CH2)4-COOH

III-13, IV.A-3 V-3, X-2

106-30-9

0

1

0

Heptanoic acid, ethyl ester

H3C-(CH2)5-COO-C2H5

V-3

106-73-0

0

1

0

Heptanoic acid, methyl ester

H3C-(CH2)5-COO-CH3

V-3

111-70-6

1

1

1

1-Heptanol

H3C-(CH2)5-CH2OH

1653-40-3

0

1

0

1-Heptanol, 6-methyl-

543-49-7

0

1

0

2-Heptanol

II.A-5 H3C-(CH2)4-CHOH-CH3

110-43-0

1

1

1

2-Heptanone

52812-44-9

1

0

0

2-Heptanone, 5-(3-acetyloxiranyl)-6-methyl-

52812-43-8

0

1

0

2-Heptanone, 5-[3-(1-hydroxy-1methylethyl)oxiranyl]-6-methyl-

0

1

0

2-Heptanone, 5-(2,3-dihydro-4-methyl-6-pyranyl)-6methyl-

0

1

0

2-Heptanone, 5-(5,6-dihydro-4-methyl-2-pyranyl)-6methyl-

{methyl pentyl ketone}

0

1

0

2-Heptanone, 6-(5-methyl-2-furanyl)-

72693-12-0

1

0

0

2-Heptanone, 6-hydroxy-

928-68-7

1

1

1

2-Heptanone, 6-methyl-

41059-93-2

0

1

0

2-Heptanone, 6-methyl-5-(4-methyl-2-furanyl){solanofuran}

106-35-4

1

0

0

3-Heptanone

19549-83-8

1

0

0

3-Heptanone, 2,6-dimethyl-

123-19-3

1

0

0

4-Heptanone

III-13 III-13 II.A-5, III-13, X-2 III-13, X-2 III-13, X-2

H3C O CH3 O

121269-00-9

II.A-5

H3C-(CH2)4-CO-CH3

H3C

108-83-8

II.A-5

CH3

III-13, X-2 H3C-CHOH-(CH2)3-CO-CH3

II.A-5, III-13 III-13

{ethyl butyl ketone} {butyrone; dipropyl ketone}

O

O

H3C-CH2-CO-(CH2)3-CH3

III-13, X-2

III-13 III-13

H3C-(CH2)2-CO-(CH2)2-CH3

III-13

1

0

0

4-Heptanone, 2,6-dimethyl-

1

1

1

Heptatriacontane

III-13

24587-25-5

1

0

0

1,3,5-Heptatriene

H3C-(CH=CH)2-CH=CH2

2463-63-0

0

1

0

2-Heptenal

H3C-(CH2)3-CH=CH-CH=O

III-12

30567-26-1

1

0

0

2-Heptenal, 2-methyl-

H3C-(CH2)3-CH=C(CH3)-CH=O

III-12

H3C-(CH2)35-CH3

I.A-10 I.B-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1628

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1629

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

34098-52-7

0

1

0

D-xylo-Hept-2-enaric acid, 2,6-anhydro-3-deoxy{2H-pyran-2,4-dicarboxylic acid, 3,4-dihydro-3,4dihydroxy-}

592-76-7

1

0

0

1-Heptene

Name (per CA Collective Index)

Chapter Table

Selected structures

II.A-5

H2C=CH-(CH2)4-CH3

I.B-1 I.B-1

592-77-8

1

0

0

2-Heptene

H3C-CH=CH-(CH2)3-CH3

77288-93-8

0

1

0

2-Heptene-1,6-diol, 3-(1-methylethyl)-, (E)-

H3C-CHOH-(CH2)2-C[CH(CH3)2] =CH-CH2OH II.A-5

21504-51-8

0

1

0

3-Heptene-2,5-dione, 6-methyl-

25377-46-2

1

1

1

Heptenoic acid

III-13

18999-28-5

0

1

0

2-Heptenoic acid

H3C-(CH2)3-CH=CH-COOH

499-84-3

0

1

0

2-Heptenoic acid, 3-(1-methylethyl)-6-oxo-

H3C-CO-(CH2)2-C[CH(CH3)2]=CH-COOH III-13, IV.A-3

41654-06-2

0

1

0

2-Heptenoic acid, 3-(1-methylethyl)-6-oxo-, (E)-

63892-03-5

0

1

0

2-Heptenoic acid, 3-(1-methylethyl)-6-oxo-, (Z)-

35194-37-7

0

1

0

4-Heptenoic acid

IV.A-3 IV.A-3

III-13, IV.A-3 III-13, IV.A-3 H3C-CH2-CH=CH-(CH2)2-COOH

IV.A-3

41653-95-6

0

1

0

4-Heptenoic acid, (Z)-

105728-84-5

0

1

0

4-Heptenoic acid, 6-hydroxy-

41654-07-3

0

1

0

4-Heptenoic acid, 3-(1-methylethyl)-6-oxo-, (E)-

H3C-CO-CH=CH-CH[CH(CH3)2]-CH2-COOH III-13, IV.A-3

1119-60-4

0

1

0

6-Heptenoic acid

H2C=CH-(CH2)4-COOH

IV.A-3

0

1

0

6-Heptenoic acid, 5-methyl-

H2C=CH-CH(CH3)-(CH2)3-COOH

IV.A-3

0

1

0

6-Heptenoic acid, 3-oxo-, methyl ester

H2C=CH-(CH2)2-CO-CH2-COO-CH3

30414-57-4

IV.A-3 II.A-5, IV.A-3

V-3 1335-09-7

0

1

0

Heptenol, methyl-

33467-78-4

0

1

0

2-Hepten-1-ol (E)

II.A-5 H3C-(CH2)3-CH=CH-CH2OH

II.A-5

55454-22-3

0

1

0

2-Hepten-1-ol (Z)

II.A-5

70898-26-9

0

1

0

3-Hepten-2-ol, 5-ethyl-2,6-dimethyl-

II.A-5

0

1

0

3-Hepten-2-ol, 5-(1-methylethy)-2-methyl-

II.A-5

58927-84-7

0

1

0

4-Hepten-2-ol, 6-methyl-, (E)-

II.A-5

1569-60-4

0

1

0

5-Hepten-2-ol, 6-methyl-

II.A-5

42201-30-9

0

1

0

6-Hepten-2-ol, 4-methylene-

57782-61-3

0

1

0

6-Hepten-2-ol, 5-(1-methylethyl)-7-(tetrahydro-2methyl-2-furanyl)-

409-02-9

0

1

0

Heptenone, methyl-

II.A-5 II.A-5, X-2 III-13

1119-44-4

0

1

0

3-Hepten-2-one

129742-47-8

0

1

0

3-Hepten-2-one, 5-ethyl-5-hydroxy-6-methyl-, [R(E)]-

57283-79-1

0

1

0

3-Hepten-2-one, 5-ethyl-6-methyl-

III-13

50767-76-5

H3C-(CH2)2-CH=CH-CO-CH3

III-13 II.A-5, III-13

0

1

0

3-Hepten-2-one, 5-ethyl-6-methyl-, (E)-

III-13

0

1

0

3-Hepten-2-one, 5-(1-methylethyl)-

III-13

2009-74-7

1

1

1

3-Hepten-2-one, 6-methyl-

152209-54-6

0

1

0

3-Hepten-2-one, 5-(1-methylethyl)-7-[2-methyl-3-(3methyl-5-oxo-3-hexenyl)oxiranyl]-, [2S[2D(3E,5R*),3E(E)]]-

III-13 III-13, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1629

11/24/08 1:56:31 PM

1630

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

110-93-0

1

1

1

5-Hepten-2-one, 6-methyl-

57782-60-2

0

1

0

6-Hepten-2-one, 5-(1-methylethyl)-7-(tetrahydro-2methyl-2-furanyl)-

Selected structures

Chapter Table III-13 III-13, X-2

CH3 O

CH=CH-CH-(CH2)2-CO-CH3

H3C

CH3

104669-35-4

0

1

0

6-Hepten-2-one, 5-(1-methylethyl)-7-(tetrahydro-4hydroxy-2-methyl-2-furanyl)-

II.A-5, III-13, X-2

160115-55-9

0

1

0

6-Hepten-2-one, 7-[4-(acetyloxy)tetrahydro-5hydroxy-2-methyl-2-furanyl]-5-(1-methylethyl)-

II.A-5, III-13, X-2

117210-48-7

0

1

0

6-Hepten-2-one, 7-[tetrahydro-2-methyl-5-(1methylethyl)-2-furanyl]-

II.A-5, III-13, X-2

628-71-7

1

0

0

1-Heptyne

H3C-(CH2)4-CŁCH

I.B-1

2586-89-2

1

0

0

3-Heptyne

H3C-(CH2)2-CŁC-CH2-CH3

I.B-1

630-01-3

1

1

1

Hexacosane

H3C-(CH2)24-CH3

I.A-10

1561-02-0

1

1

1

Hexacosane, 2-methyl-

(H3C)2=CH-(CH2)23-CH3

I.A-10

65820-56-6

0

1

0

Hexacosane, 3-methyl-

506-46-7

1

1

1

Hexacosanoic acid

108657-23-4 121877-83-6

{cerotinic acid}

H3C-CH2-CH(CH3)-(CH2)22-CH3

I.A-10

H3C-(CH2)24-COOH

IV.A-3

1

1

1

Hexacosanoic acid, docosyl ester

H3C-(CH2)24-COO-(CH2)21-CH3

V-3

1

1

1

Hexacosanoic acid, dodecyl ester

H3C-(CH2)24-COO-(CH2)11-CH3

V-3

1

1

1

Hexacosanoic acid, eicosyl ester

H3C-(CH2)24-COO-(CH2)19-CH3

V-3

1

1

1

Hexacosanoic acid, ester with olean-12-en-3-ol, (3E){ȕ-amyrenyl hexacosanoate)

V3

121877-89-2

1

1

1

Hexacosanoic acid, heneicosyl ester

H3C-(CH2)24-COO-(CH2)20-CH3

V-3

75696-56-9

1

1

1

Hexacosanoic acid, heptacosyl ester

H3C-(CH2)24-COO-(CH2)26-CH3

V-3

1

1

1

Hexacosanoic acid, heptadecyl ester

H3C-(CH2)24-COO-(CH2)16-CH3

V-3

1

1

1

Hexacosanoic acid, hexacosyl ester

H3C-(CH2)24-COO-(CH2)25-CH3

V-3

1

1

1

Hexacosanoic acid, hexadecyl ester

H3C-(CH2)24-COO-(CH2)15-CH3

V-3

1

1

1

Hexacosanoic acid, nonadecyl ester

H3C-(CH2)24-COO-(CH2)18-CH3

V-3

1

1

1

Hexacosanoic acid, octadecyl ester

H3C-(CH2)24-COO-(CH2)17-CH3

V-3

1

1

1

Hexacosanoic acid, pentacosyl ester

H3C-(CH2)24-COO-(CH2)24-CH3

V-3

1

1

1

Hexacosanoic acid, pentadecyl ester

H3C-(CH2)24-COO-(CH2)14-CH3

V-3

1

1

1

Hexacosanoic acid, tetracosyl ester

H3C-(CH2)24-COO-(CH2)23-CH3

V-3

1

1

1

Hexacosanoic acid, tetradecyl ester

H3C-(CH2)24-COO-(CH2)193-CH3

V-3

121877-97-2

1

1

1

Hexacosanoic acid, tricosyl ester

H3C-(CH2)24-COO-(CH2)22-CH3

V-3

1

1

1

Hexacosanoic acid, tridecyl ester

H3C-(CH2)24-COO-(CH2)12-CH3

V-3

121877-92-7

1

1

1

Hexacosanoic acid, 24-methyl-, docosyl ester

V-3

121877-90-5

1

1

1

Hexacosanoic acid, 24-methyl-, heneicosyl ester

V-3

506-52-5

0

1

0

1-Hexacosanol

63785-25-1

0

1

0

1-Hexacosanol, 24-methyl-

H3C-(CH2)24-CH2OH

II.A-5

II.A-5

0

1

0

1-Hexacosanol, 25-methyl-

II.A-5

84808-91-9

1

0

0

Hexacosene

I.B-1

18835-33-1

1

0

0

1-Hexacosene

H2C=CH-(CH2)23-CH3

I.B-1

1

0

0

1-Hexacosene, 2-methyl-

H2C=C(CH3)-(CH2)23-CH3

I.B-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1630

11/24/08 1:56:32 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1631

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

1

0

0

2-Hexacosene, (Z)-

1

0

0

2-Hexacosene, (E)-

1

0

0

2-Hexacosene, 2-methyl-

H3C-C(CH3)=CH-(CH2)22-CH3

1

0

0

2-Hexacosene, 24-methyl-, (Z)-

H3C-CH=CH-(CH2)20-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Hexacosene, 24-methyl-, (E)-

1

0

0

2-Hexacosene, 25-methyl-, (Z)-

Name (per CA Collective Index)

Selected structures H3C-CH=CH-(CH2)22-CH3

Chapter Table I.B-1 I.B-1 I.B-1

I.B-1 H3C-CH=CH-(CH2)21-CH(CH3)2

I.B-1

1

0

0

2-Hexacosene, 24-methyl-, (E)-

30917-33-0

1

0

0

1,3-Hexadecadiene, 2,6,10,14-tetramethyl-

H[CH2CH2CH(CH3)CH2] 3-CH=CHC(CH3)=CH2

I.B-1

21980-71-2

1

0

0

1,3-Hexadecadiene, 3,7,11,15-tetramethyl{phytadiene}

H[CH2CH(CH3)CH2CH2] 3-CH=CHC(CH3)=CH2

I.B-1

1

0

0

1,3-Hexadecadiene, 2,6,10-trimethyl-

I.B-1

0

1

0

2,4-Hexadexadiene, 3,7,11,15-tetramethyl-

I.B-1

25377-52-0

1

1

1

Hexadecadienoic acid

29961-54-4

0

1

0

Hexadecadienoic acid, methyl ester

629-80-1

0

1

0

Hexadecanal

H3C-(CH2)14-CH=O

III-12

544-76-3

1

1

1

Hexadecane

H3C-(CH2)14-CH3

I.A-10

1560-92-5

I.B-1

{palmitolenic acid}

IV.A-3 V-3

0

1

0

Hexadecane, 2-methyl-

H3C-(CH2)13-CH=(CH3)2

I.A-10

0

1

0

Hexadecane, 3-methyl-

H3C-(CH2)12-CH(CH3)-CH2-CH3

I.A-10

638-36-8

1

1

1

Hexadecane, 2,6,10,14-tetramethyl-

36232-38-9

1

0

0

Hexadecane, 2,6,10-trimethyl-14-methylene-

60922-91-0

1

0

0

Hexadecane, mixt. with pentane

505-54-4

0

1

0

Hexadecanedioic acid

57-10-3

1

1

1

Hexadecanoic acid

{phytane}

I.A-10 I.B-1 I.A-10

{palmitic acid}

HOOC-(CH2)14-COOH

IV.A-3

H3C-(CH2)14-COOH

IV.A-3

42232-33-7

1

1

1

Hexadecanoic acid, docosyl ester

H3C-(CH2)14-COO-(CH2)21-CH3

V-3

42232-29-1

1

1

1

Hexadecanoic acid, dodecyl ester

H3C-(CH2)14-COO-(CH2)11-CH3

V-3

80252-38-6

1

1

1

Hexadecanoic acid, dotriacontyl ester

H3C-(CH2)14-COO-(CH2)31-CH3

V-3

22413-01-0

1

1

1

Hexadecanoic acid, eicosyl ester

H3C-(CH2)14-COO-(CH2)19-CH3

V-3

628-97-7

1

1

1

Hexadecanoic acid, ethyl ester

H3C-(CH2)14-COO-CH2-CH3

V-3

{ethyl palmitate}

42232-32-6

1

1

1

Hexadecanoic acid, heneicosyl ester

H3C-(CH2)14-COO-(CH2)20-CH3

V-3

94632-82-3

1

1

1

Hexadecanoic acid, heptacosyl ester

H3C-(CH2)14-COO-(CH2)26-CH3

V-3

18466-06-3

1

1

1

Hexadecanoic acid, heptadecyl ester

H3C-(CH2)14-COO-(CH2)16-CH3

V-3

60007-87-6

1

1

1

Hexadecanoic acid, hexacosyl ester

H3C-(CH2)14-COO-(CH2)25-CH3

V-3

540-10-3

1

1

1

Hexadecanoic acid, hexadecyl ester

H3C-(CH2)14-COO-(CH2)15-CH3

V-3

23470-00-0

1

0

0

Hexadecanoic acid, 2-hydroxy-1(hydroxymethyl)ethyl ester

H3C-(CH2)14-COO-CH=(CH2OH)2

V-3

28801-93-6

1

1

1

Hexadecanoic acid, methyl-

112-39-0

IV.A-3

1

1

1

Hexadecanoic acid, methyl ester

1

1

1

Hexadecanoic acid, (1-methylethyl) ester

H3C-(CH2)14-COO-CH3

V-3

36617-44-4

1

1

1

Hexadecanoic acid, nonadecyl ester

H3C-(CH2)14-COO-(CH2)18-CH3

V-3

78509-52-1

1

1

1

Hexadecanoic acid, octacosyl ester

H3C-(CH2)14-COO-(CH2)27-CH3

V-3

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1631

11/24/08 1:56:33 PM

1632

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

2598-99-4

1

1

1

Hexadecanoic acid, octadecyl ester

H3C-(CH2)14-COO-(CH2)17-CH3

V-3

94632-81-2

1

1

1

Hexadecanoic acid, pentacosyl ester

H3C-(CH2)14-COO-(CH2)24-CH3

V-3

18299-77-9

1

1

1

Hexadecanoic acid, pentadecyl ester

H3C-(CH2)14-COO-(CH2)14-CH3

V-3

42232-35-9

1

1

1

Hexadecanoic acid, tetracosyl ester

H3C-(CH2)14-COO-(CH2)33-CH3

V-3

4536-26-9

1

1

1

Hexadecanoic acid, tetradecyl ester

H3C-(CH2)14-COO-(CH2)13-CH3

V-3

84461-48-3

1

1

1

Hexadecanoic acid, tetratriacontyl ester

H3C-(CH2)14-COO-(CH2)33-CH3

V-3

6027-71-0

1

1

1

Hexadecanoic acid, triacontyl ester

H3C-(CH2)14-COO-(CH2)29-CH3

V-3

42232-34-8

1

1

1

Hexadecanoic acid, tricosyl ester

H3C-(CH2)14-COO-(CH2)22-CH3

V-3

H3C-(CH2)14-COO-(CH2)13-CH3

V-3

36617-38-6

1

1

1

Hexadecanoic acid, tridecyl ester

3233-90-7

0

1

0

Hexadecanoic acid, 10,16-dihydroxy-

5918-29-6

1

1

1

Hexadecanoic acid, 14-methyl-

H3C-CH2-CH(CH3)-(CH2)12-COOH IV.A-3

121877-41-6

1

1

1

Hexadecanoic acid, 14-methyl-, docosyl ester

H3C-CH2-CH(CH3)-(CH2)12-COO-(CH2)21-CH3 V-3

121877-33-6

1

1

1

Hexadecanoic acid, 14-methyl-, heneicosyl ester

H3C-CH2-CH(CH3)-(CH2)12-COO-(CH2)20-CH3 V-3

121877-67-6

1

1

1

Hexadecanoic acid, 14-methyl-, heptacosyl ester

H3C-CH2-CH(CH3)-(CH2)12-COO-(CH2)26-CH3 V-3

121877-58-5

1

1

1

Hexadecanoic acid, 14-methyl-, hexacosyl ester

H3C-CH2-CH(CH3)-(CH2)12-COO-(CH2)25-CH3 V-3

2490-49-5

1

1

1

Hexadecanoic acid, 14-methyl-, methyl ester

H3C-CH2-CH(CH3)-(CH2)12-COO-CH3 V-3

121877-74-5

1

1

1

Hexadecanoic acid, 14-methyl-, octacosyl ester

H3C-CH2-CH(CH3)-(CH2)12-COO-(CH2)27-CH3 V-3

1603-03-8

1

1

1

Hexadecanoic acid, 15-methyl-

(H3C)2=CH-(CH2)13-COOH

121877-39-2

1

1

1

Hexadecanoic acid, 15-methyl-, docosyl ester

(H3C)2=CH-(CH2)13-COO-(CH2)21-CH3 V-3

6929-04-0

0

1

0

Hexadecanoic acid, 15-methyl-, methyl ester

(H3C)2=CH-(CH2)13-COO-CH3

506-13-8

0

1

0

Hexadecanoic acid, 16-hydroxy-

HOCH2-(CH2)14-COOH

IV.A-3

27147-71-3

0

1

0

Hexadecanoic acid, 2-methyl-

H3C-(CH2)13-CH(CH3)-COOH

IV.A-3

42172-35-0

0

1

0

Hexadecanoic acid, 3-methyl-

H3C-(CH2)12-CH(CH3)-CH2-COOH IV.A-3

71607-94-8

1

1

1

Hexadecanoic acid, 3,7,11,15,19,23,27,31,35nonamethyl-2,6,10,14,18,22,26,30,34-hexatria contanonaenyl ester

V-3

1118-77-0

0

1

0

Hexadecanoic acid, 3,7,11,15-tetramethyl-, methyl ester

V-3

53950-58-6

1

1

1

Hexadecanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester, [R-[R*,R*- (E)]]-

V-3

124-29-8

1

1

1

1-Hexadecanol

2490-43-9

0

1

0

1-Hexadecanol, 14-methyl-

645-72-7

1

1

1

1-Hexadecanol, 3,7,11,15-tetramethyl{dihydrophytol}

II.A-5, IV.A-3

IV.A-3 V-3

H3C-(CH2)14-CH2OH

H3C

II.A-5 II.A-5 II.A-5

CH3 CH3

CH2OH

H[CH2-CH(CH3)-CH2-CH2]4-OH

H3C CH3

60054-55-9

0

1

0

1-Hexadecanol, 7,11,15-trimethyl-3-methylene-

18787-63-8

1

1

1

2-Hexadecanone

H3C-(CH2)13-CO-CH3

II.A-5 III-13

34083-18-6

1

0

0

2,6,10,14-Hexadecatetraene, 2,6,10,14-tetramethyl-

H-[CH2-C(CH3)=CH-CH2]4-H

I.B-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1632

11/24/08 1:56:33 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1633

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

70901-63-2

0

1

0

1,6,10,14-Hexadecatetraene, 7,11,15-trimethyl-3methylene-, (E,E)-

I.B-1

76540-54-0

0

1

0

1,6,10,14-Hexadecatetraene-3,9-diol, 3,7,11,15tetramethyl-

II.A-5

76540-55-1

0

1

0

2,6,10,15-Hexadecatetraene-1,14-diol, 2,6,10,14tetramethyl-, [S-(Z,E,E)]-

II.A-5

25377-56-4

0

1

0

Hexadecatrienoic acid

IV.A-3

32839-24-0

0

1

0

Hexadecatrienoic acid, (Z,Z,Z)-

IV.A-3

37822-81-4

0

1

0

Hexadecatrienoic acid, methyl ester

26952-14-7

0

1

0

Hexadecene

629-73-2

1

0

0

1-Hexadecene

Name (per CA Collective Index)

Selected structures

Chapter Table

V-3 I.B-1 {1-cetene}

H2C=CH-(CH2)13-CH3 H2C=C(CH3)-(CH2)13-CH3

I.B-1

1

0

0

1-Hexadecene, 2-methyl-

71278-20-1

1

0

0

1-Hexadecene, 2,6,10-trimethyl-

I.B-1

504-96-1

1

1

1

1-Hexadecene, 3-methylene-7,11,15-trimethyl{neophytadiene}

0

1

0

1-Hexadecene, 3,7,11,15-tetramethyl-

1

0

0

2-Hexadecene, (Z)-

1

0

0

2-Hexadecene, (E)-

1

0

0

2-Hexadecene, 2-methyl-

H3C-C(CH3)=CH-(CH2)12-CH3

1

0

0

2-Hexadecene, 14-methyl-, (Z)-

H3C-CH=CH-(CH2)10-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Hexadecene, 14-methyl-, (E)-

1

0

0

2-Hexadecene, 15-methyl-, (Z)-

I.B-1 H2C=CH-C(=CH2)-CH2-{(CH2)2CH(CH3)CH2}3-H

I.B-1 I.B-1

H3C-CH=CH-(CH2)12-CH3

I.B-1 I.B-1 I.B-1

I.B-1 H3C-CH=CH-(CH2)11-CH(CH3)2

I.B-1

1

0

0

2-Hexadecene, 15-methyl-, (E)-

51806-25-8

0

1

0

4-Hexadecene, 3-methylene-7,11,15-trimethyl-

I.B-1

25447-95-4

1

1

1

Hexadecenoic acid

IV.A-3

28039-99-8

0

1

0

Hexadecenoic acid, (Z)-

IV.A-3

1686-10-8

0

1

0

3-Hexadecenoic acid, (E)-

IV.A-3

H3C-CH2-C(=CH2)-CH=CH-CH2-CH(CH3)CH2-{(CH2)2-CH(CH3)-CH2}2-H I.B-1

373-49-9

1

1

1

9-Hexadecenoic acid, (Z)-

{palmitoleic acid}

H3C-(CH2)7-CH=CH-(CH2)5-COOH IV.A-3

10030-73-6 2091-29-4

1

1

1

9-Hexadecenoic acid, (E)-

{palmitelaidic acid}

H3C-(CH2)7-CH=CH-(CH2)5-COOH IV.A-3

1120-25-8

0

1

0

9-Hexadecenoic acid, methyl ester, (Z)-

505-32-8

1

1

1

1-Hexadecen-3-ol, 3,7,11,15-tetramethyl{isophytol}

22104-83-2

0

1

0

2-Hexadecen-1-ol

102608-53-7

0

1

0

2-Hexadecen-1-ol, 3,7,11,15-tetramethyl-

150-86-7

1

1

1

2-Hexadecen-1-ol, 3,7,11,15-tetramethyl-, [R[R*,R*-(E)]]{phytol}

H3C-(CH2)7-CH=CH-(CH2)5-COO-CH3 V-3 II.A-5 H3C-(CH2)12-CH=CH-CH2OH

II.A-5 II.A-5

H3C

II.A-5

CH3 CH3

CH2OH

H3C CH3

60026-26-8

0

1

0

7-Hexadecen-6-one, 3,7,11,15-tetramethyl-

80466-34-8

0

1

0

2,4-Hexadienal

III-13 H3C-(CH=CH)2-CH=O

III-12

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1633

11/24/08 1:56:34 PM

1634

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

142-83-6

1

1

1

2,4-Hexadienal, (E,E)-

III-12

54612-24-7

1

0

0

Hexadiene, dimethyl-

I.B-1

1

0

0

Hexadiene, methyl-

I.B-1

1

0

0

1,3-Hexadiene, 3-ethyl-2,5-dimethyl-

I.B-1

927-97-9

1

0

0

1,4-Hexadiene, 2,5-dimethyl-

I.B-1

764-13-6

1

0

0

2,4-Hexadiene, 2,5-dimethyl-

I.B-1

1

0

0

2,4-Hexadiene, 3,4-dimethyl-

110-44-1

1

1

1

2,4-Hexadienoic acid, (E,E)-

I.B-1

590-00-1 24634-61-5

0

1

0

2,4-Hexadienoic acid, potassium salt

90-65-3

1

0

0

2,5-Hexadienoic acid, 3-methoxy-5-methyl-4-oxo-

10420-90-3

1

0

0

1,3-Hexadien-5-yne

{sorbic acid}

H3C-(CH=CH)2-COOH

IV.A-3

H3C-(CH=CH)2-COOK

XX-6 III-13, IV.A-3, X-2

HCŁC-CH=CH-CH=CH2

821-08-9

1

0

0

1,5-Hexadien-3-yne

66-25-1

1

1

1

Hexanal

15303-46-5

0

1

0

Hexanal, 2-(1-methylethyl)-5-oxo-

2363-84-0

1

0

0

Hexanal, 2-oxo-

H3C-(CH2)3-CO-CH=O

III-12, III-13

0

1

0

Hexanal, 4-oxo-

H3C-CH2-CO-(CH2)2-CH=O

III-12, III-13

1

0

0

Hexanamide

H3C-(CH2)4-CO-NH2 H3C-(CH2)5-NH2

628-02-4

{divinylacetylene} {caproic aldehyde}

H2C=CH-CŁC-CH=CH2

I.B-1

H3C-(CH2)4-CH=O

I.B-1 III-12 III-12, III-13

111-26-2

1

1

1

1-Hexanamine

28056-87-3

1

0

0

1-Hexanamine, 2-ethyl-N,N-dimethyl-

XIII-1 XII-2 XII-2

110-54-3

1

1

1

Hexane

33240-56-1

1

0

0

Hexane, 1-chloro-5-methyl-

H3C-(CH2)4-CH3

I.A-10

28777-67-5

1

0

0

Hexane, dimethyl-

I.A-10

XVIII.B-3

1

0

0

Hexane, 2,4-dimethyl-

I.A-10

592-13-2

1

0

0

Hexane, 2,5-dimethyl-

I.A-10

50-70-4

1

1

1

Hexane, hexahydroxy-

585-88-6

0

1

0

Hexane, hexahydroxy-, 4-O-ȕ-D-glucopyranosyl{maltitol; 4-O-ȕ-D-glucopyranosyl-D-glucitol}

{sorbitol; glucitol}

HOCH2-(CHOH)4-CH2OH

II.A-5 II.A-5, X-2

OH HO

OH

HO

O

OH

O

HO OH

589-34-4

OH

OH

0

1

0

Hexane, hexahydroxy-, 2,6-di-O-methyl-

0

1

0

Hexane, hexahydroxy-, 2,3,6-tri-O-methyl-

II.A-5, X-2

0

1

0

Hexane, hexahydroxy-, 2,3,4,6-tetra-O-methyl-

II.A-5, X-2

1

0

0

Hexane, 3-methyl-

1071-81-4

1

0

0

Hexane, 2,2,5,5-tetramethyl-

124-04-9

1

0

0

Hexanedioic acid

542-32-5

0

1

0

Hexanedioic acid, 2-amino-

123-79-5

1

0

0

Hexanedioic acid, dioctyl ester

II.A-5, X-2

I.A-10 {adipic acid}

103-23-1

1

0

0

Hexanedioic acid, bis(2-ethylhexyl) ester

3184-35-8

1

1

1

Hexanedioic acid, 2-oxo-

77289-00-0

0

1

0

1,5-Hexanediol, 2-(1-methylethyl)-, [S-(R*,R*)]-

(H3C)3ŁC-(CH2)2-CŁ(CH3)3

I.A-10

HOOC-(CH2)4-COOH

IV.A-3 IV.A-3, XII-2 V-3 V-3 III-13, IV.A-3 II.A-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1634

11/24/08 1:56:34 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1635

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

2935-44-6

1

1

1

2,5-Hexanediol

29044-06-2

0

1

0

2,5-Hexanediol, 2-methyl-

Chapter Table

Selected structures H3C-CHOH (CH2)2-CHOH-CH3

II.A-5 II.A-5

3848-24-6

1

0

0

2,3-Hexanedione

110-13-4

1

1

1

2,5-Hexanedione

1

0

0

2,5-Hexanedione, 3-hydroxy-

III-13

1

0

0

2,5-Hexanedione, 3-methyl-

III-13

1

0

0

3,4-Hexanedione

1

0

0

3,4-Hexanedione, 2-methyl-

4437-50-7

H3C-CO-CO-(CH2)3-CH3

III-13

H3C-CH2-CO-CO-CH2-CH3

III-13 III-13

628-73-9

1

0

0

Hexanenitrile

64350-07-8

1

0

0

Hexanenitrile, 2-hydroxy-

111-31-9

1

0

0

1-Hexanethiol

18990-98-2

1

0

0

1,3,6-Hexanetriol

142-62-1

1

1

1

Hexanoic acid

60308-81-8

0

1

0

Hexanoic acid, 4,5-dimethyl-

123-66-0

1

1

1

Hexanoic acid, ethyl ester

1

1

1

Hexanoic acid, 2,6-di-(methylnitrosamino)-

1

1

1

Hexanoic acid, 2-ethyl-

149-57-5

III-13

{acetonylacetone}

{capronitrile}

H3C-(CH2)4-CN

XI-1 II.A-5, XI-1

H3C-(CH2)5-SH

XVIII.A-1 II.A-5

{caproic acid}

H 3C-(CH2)4-COOH

IV.A-3, XXI-3 IV.A-3

{ethyl caproate}

H3C-(CH2)4-COO-C2H5

V-3

R-(CH2)4-CH(R)-COOH where R = H3C-N(NO)IV.A-3, XV-8 IV.A-3

1

0

0

Hexanoic acid, hydroxy-

II.A-5, IV.A-3

6064-63-7

0

1

0

Hexanoic acid, 2-hydroxy-

II.A-5, IV.A-3

1191-25-9

1

0

0

Hexanoic acid, 6-hydroxy-

II.A-5, IV.A-3

40309-49-7

0

1

0

Hexanoic acid, 3-hydroxy-5-methyl-

II.A-5, IV.A-3

0

1

0

Hexanoic acid, cis-3-hexenyl ester

V-3

106-70-7

0

1

0

Hexanoic acid, methyl ester

4536-23-6

1

1

1

Hexanoic acid, 2-methyl- {2-methylhexanoic acid}

H3C-(CH2)4-COO-CH3

IV.A-3

V-3

3780-58-3

0

1

0

Hexanoic acid, 3-methyl-

IV.A-3

1561-11-1

0

1

0

Hexanoic acid, 4-methyl-

IV.A-3

628-46-6

0

1

0

Hexanoic acid, 5-methyl-

30414-55-2

0

1

0

Hexanoic acid, 5-methyl-3-oxo-, methyl ester

IV.A-3

41654-04-0

0

1

0

Hexanoic acid, 5-methyl-4-oxo-

III-13, IV.A-3

2543-54-6

0

1

0

Hexanoic acid, 2-(1-methylethyl)-5-oxo-

III-13, IV.A-3

16825-90-4

1

0

0

Hexanoic acid, 2-(1-methylethyl)-5-oxo-, (S)-

III-13, IV.A-3

1842-56-4

0

1

0

Hexanoic acid, 2-(1-methylethyl)-5-oxo-, methyl ester

1117-74-4

1

1

1

Hexanoic acid, 4-oxo-

3128-06-1

1

0

0

Hexanoic acid, 5-oxo-

540-07-8

0

1

0

Hexanoic acid, pentyl ester

6290-37-5

0

1

0

Hexanoic acid, 2-phenylethyl ester

6938-45-0

0

1

0

Hexanoic acid, phenylmethyl ester

V-3

2051-49-2

0

1

0

Hexanoic anhydride

VII-1

25917-35-5

1

1

1

Hexanol

111-27-3

1

1

1

1-Hexanol

III-13, V-3

III-13, V-3 III-13, IV.A-3 III-13, IV.A-3 H3C-(CH2)4-COO-(CH2)4-C H3

V-3 V-3

II.A-5 {caproyl alcohol}

H3C-(CH2)4-CH2OH

II.A-5, XXI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1635

11/24/08 1:56:35 PM

1636

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

104-76-7

1

1

1

1-Hexanol, 2-ethyl-

61949-26-6

1

0

0

1-Hexanol, methyl-

818-49-5

0

1

0

1-Hexanol, 4-methyl-

627-98-5

0

1

0

1-Hexanol, 5-methyl-

(H3C)2=CH-(CH2)3-CH2OH H3C-(CH2)3-CHOH-CH3

626-93-7

1

1

1

2-Hexanol

0

1

0

2-Hexanol, 2-cyclohexanyl-

Chapter Table

Selected structures H3C-(CH2)3-CH(C2H5)-CH2OH

II.A-5 II.A-5 II.A-5 II.A-5 II.A-5 II.A-5

623-37-0

1

1

1

3-Hexanol

II.A-5

2180-43-0

1

0

0

3-Hexanol, 1-phenyl-

II.A-5

1

0

0

4-Hexanol, 1-phenyl-

14360-50-0

1

0

0

1-Hexanone, 1-(2-furanyl)-

II.A-5

591-78-6

1

1

1

2-Hexanone

72693-13-1

1

0

0

2-Hexanone, 5,6-dihydroxy-

II.A-5, III-13

56745-61-0

1

0

0

2-Hexanone, 5-hydroxy-

II.A-5, III-13

68208-73-1

1

0

0

2-Hexanone, 6-hydroxy-5-methyl-

589-38-8

1

1

1

3-Hexanone

71278-21-2

1

1

1

1,3,6,10,14,18,22,26,30,34-Hexatriacontadecaene, 3,7,11,15,19,23,27,31,35-nonamethyl{solanesene}

III-13, X-2 {butyl methyl ketone}

H3C-(CH2)3-CO-CH3

III-13

II.A-5, III-13

{ethyl propyl ketone}

III-13 I.B-1

630-06-8

1

1

1

Hexatriacontane

71278-22-3

1

0

0

1,6,10,14,18,22,26,30,34-Hexatriacontanonaene, 7,11,15,19,23,27,31,35-octamethyl-3-methylene-

H3C-(CH2)34-CH3

I.B-1

66327-99-9

1

0

0

2,6,10,14,18,22,26,30,34-Hexatriacontanonaene, 2,6,10,14,18,22,26,30,34-nonamethyl-, (all-E)-

I.B-1

60924-87-0

0

1

0

2,6,10,14,18,22,26,30,35-Hexatriacontanonaene1,34-diol, 3,7,11,15,19,23,27,31,35-nonamethyl-, (all-E)-

II.A-5

60924-86-9

0

1

0

2,6,10,14,18,22,26,30,33-Hexatriacontanonaene1,35-diol, 3,7,11,15,19,23,27,31,35-nonamethyl-, (all-E)-

II.A-5

101330-76-1

0

1

0

2,6,10,14,18,22,26,30,34-Hexatriacontanonaen-1ol, 3,7,11,15,19,23,27,31,35-nonamethyl-, labeled 14 with C, (Z,Z,Z)-

II.A-5

13190-97-1

1

1

1

2,6,10,14,18,22,26,30,34-Hexatriacontanonaen-1ol, 3,7,11,15,19,23,27,31,35-nonamethyl-, (all-E){solanesol}

29144-38-5

1

1

1

2,6,10,14,18,22,26,30,34-Hexatriacontanonaen-1ol, 3,7,11,15,19,23,27,31,35-nonamethyl-, acetate, stereoisomer {solanesyl acetate}

2235-12-3

1

0

0

1,3,5-Hexatriene

1

0

0

1,3,5-Hexatriene, 2-methyl-

I.B-1

1

0

0

1,3,5-Hexatriene, 3-methyl-

I.B-1

1335-39-3

0

1

0

Hexenal

505-57-7

1

1

1

2-Hexenal

H-[CH2-CH(CH3)-CH2-CH2]9-OH

I.A-10

II.A-5

V-3

H2C=CH-CH=CH-CH=CH2

I.B-1

III-12 H3C-(CH2)2-CH=CH-CH=O

III-12

6728-26-3

1

1

1

2-Hexenal, (E)-

III-12

16635-54-4

1

1

1

2-Hexenal, (Z)-

III-12

1

0

0

2-Hexenal, 2,5-dimethyl-

III-12

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1636

11/24/08 1:56:35 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1637

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 28467-88-1

S

T

S T

Name (per CA Collective Index)

1

0

0

2-Hexenal, 2-methyl-

1

0

0

2-Hexenal, 5-methyl-

21834-92-4

0

1

0

2-Hexenal, 5-methyl-2-phenyl-

25264-93-1

1

0

0

Hexene

Selected structures H3C-(CH2)2-CH=C(CH3)-CH=O

Chapter Table III-12 III-12 III-12

H-(CH2)n-CH=CH-(CH2)(4-n)-H

I.B-1

1

0

0

Hexene, diamino

592-41-6

1

0

0

1-Hexene

H3C-(CH2)3-CH=CH2

XII-2 I.B-1

3524-73-0

1

0

0

1-Hexene, 5-methyl-

(H3C)2=CH-(CH2)2-CH=CH2

I.B-1

4050-45-7

1

0

0

2-Hexene, (E)-

H3C-(CH2)2-CH=CH-CH3

I.B-1

7688-21-3

1

0

0

2-Hexene, (Z)-

3404-78-2

1

0

0

2-Hexene, 2,5-dimethyl-

H3C-CH(CH3)-CH2-CH=C(CH3)-CH3 I.B-1

I.B-1

2738-19-4

1

0

0

2-Hexene, 2-methyl-

H3C-(CH2)2-CH=C(CH3)-CH3

I.B-1

3404-62-4

1

0

0

2-Hexene, 5-methyl-

H3C-CH(CH3)-CH2-CH=CH-CH3

I.B-1

592-47-2

1

0

0

3-Hexene

H3C-CH2-CH=CH-CH2-CH3

I.B-1

13269-52-8

1

1

1

3-Hexene, (E)-

I.B-1

7642-09-3

1

0

0

3-Hexene, (Z)-

I.B-1

4436-75-3

0

1

0

3-Hexene, 2,5-dione

1289-40-3

1

0

0

Hexenoic acid

III-13

1191-04-4

0

1

0

2-Hexenoic acid

5309-52-4

0

1

0

2-Hexenoic acid, 2-ethyl-

41653-96-7

0

1

0

2-Hexenoic acid, 5-methyl-

51424-01-2

0

1

0

2-Hexenoic acid, 5-methyl-, (E)-

4219-24-3

1

1

1

3-Hexenoic acid

1775-43-5

0

1

0

3-Hexenoic acid, (Z)-

2396-78-3

0

1

0

3-Hexenoic acid, methyl ester

H3C-CH2-CH=CH-CH2-COO-CH3

35194-36-6

1

1

1

4-Hexenoic acid

H3C-CH=CH-(CH2)2-COOH

1577-20-4

1

1

1

4-Hexenoic acid, (E)-

5636-65-7

0

1

0

4-Hexenoic acid, 5-methyl-

IV.A-3

1577-22-6

0

1

0

5-Hexenoic acid

IV.A-3

IV.A-3 H3C-(CH2)2-CH=CH-COOH

IV.A-3 IV.A-3

(H3C)2=CH-CH2-CH=CH-COOH

IV.A-3 IV.A-3

{hydrosorbic acid}

H3C-CH2-CH=CH-CH2-COOH

IV.A-3 IV.A-3 V-3 IV.A-3 IV.A-3

928-95-0

0

1

0

2-Hexen-1-ol

2305-21-7

0

1

0

2-Hexen-1-ol, (E)-

2497-18-9

0

1

0

2-Hexen-1-ol, acetate, (E)-

544-12-7

0

1

0

3-Hexen-1-ol

II.A-5

928-97-2

0

1

0

3-Hexen-1-ol, (E)-

II.A-5

928-96-1

H3C-(CH2)2-CH=CH-CH2OH

II.A-5 II.A-5 V-3

1

1

1

3-Hexen-1-ol, (Z)-

{leaf alcohol}

II.A-5

1

1

1

3-Hexen-1-ol, (Z)-, labeled with C 14 {leaf alcohol- C}

XXV-29

1708-82-3

0

1

0

3-Hexen-1-ol, acetate

V-3

3681-71-8

0

1

0

3-Hexen-1-ol, acetate, (Z)-

V-3

25152-85-6

0

1

0

3-Hexen-1-ol, benzoate, (Z)-

V-3

2315-09-5

0

1

0

3-Hexen-1-ol, formate

V-3

33467-73-1

0

1

0

3-Hexen-1-ol, formate, (Z)-

763-93-9

1

0

0

3-Hexen-2-one

14

V-3 III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1637

11/24/08 1:56:36 PM

1638

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

5166-53-0

1

1

1

3-Hexen-2-one, 5-methyl-

III-13

1821-29-0

0

1

0

3-Hexen-2-one, 5-methyl-, (E)-

III-13

Name (per CA Collective Index)

109-49-9

1

1

1

5-Hexen-2-one

55615-04-8

0

1

0

5-Hexen-2-one, 4,5-dimethyl-

Selected structures

H2C=CH-(CH2)2-CO-CH3

Chapter Table

III-13 III-13

0

1

0

4-Hexen-3-one, 4,5-dimethyl-

121197-12-4

1

0

0

5-Hexen-3-one, 4,5-dihydroxy-

III-13

33124-69-5

0

1

0

threo-2,3-Hexodiulosonic acid, J-lactone

490-83-5

0

1

0

L-threo-2,3-Hexodiulosonic acid, J-lactone

61989-59-1

1

0

0

Hexonic acid, 2,3-dideoxy-, J-lactone, monoacetate

61892-51-1

1

0

0

Hexonic acid, 3,6-dideoxy-, J-lactone

II.A-5, III-13 VI-3 VI-3 V-3, VI-3 VI-3

61653-41-6

0

1

0

D-lyxo-Hexonic acid, 2-deoxy-, J-lactone

45009-62-9

0

1

0

Hexoses

VI-3

62446-36-0

0

1

0

Hexouronic acid

26856-30-4

1

0

0

Hexyne

H-(CH2)n-CŁC-(CH2)(4-n)-H

I.B-1

693-02-7

1

0

0

1-Hexyne

HCŁC-(CH2)3-CH3

I.B-1

II.A-5, VIII-3

2203-80-7

1

0

0

1-Hexyne, 5-methyl-

HCŁC-(CH2)2-CH(CH3)2

I.B-1

764-35-2

1

0

0

2-Hexyne

H3C-CŁC-(CH2)2-CH3

I.B-1

53566-37-3

1

0

0

2-Hexyne, 5-methyl-

H3C-CŁC-CH2-CH(CH3)2

I.B-1

928-49-4

1

0

0

3-Hexyne

H3C-CH2-CŁC-CH2-CH3

I.B-1

7006-35-1

0

1

0

Histidine

IV.A-3, IV.B-7, XII-2, XVII.A-4

71-00-1

0

1

0

L-Histidine

IV.A-3, IV.B-7, XII-2, XVII.A-4 NH2

N HN

332-80-9

1

1

1

L-Histidine, 1-methyl-

COOH

IV.A-3, IV.B-7, XII-2, XVII.A-4

1

1

1

L-Histidine, 3-methyl-

IV.A-3, IV.B-7, XII-2, XVII.A-4

62504-27-2

0

1

0

L-Histidine, N-(1-carboxyethyl)-, (R)-

IV.A-3, IV.B-7, XII-2, XVII.A-4

7440-60-0

1

1

1

Holmium

8064-26-4

0

1

0

Holocellulose

454-29-5

0

1

0

DL-Homocysteine

HS-(CH2)2-CH(NH2)-COOH IV.A-3, IV.B-7, XII-2, XVIII.A-1

498-19-1 672-15-1

1

1

1

Homoserine

HO-(CH2)2-CH(NH2)-COOH II.A-5, IV.A-3, IV.B-7, XII-2, XVIII.A-1

Ho

XX-5 VIII-3

{2-amino-4-hydroxybutanoic acid}

1415-93-6

0

1

0

Humic acids

IV.A-3

9024-25-3

0

1

0

Hydratase, aconitate

XXII-2

9032-88-6

0

1

0

Hydratase, fumarate

XXII-2

9014-08-8

0

1

0

Hydratase, phosphopyruvate

302-01-2

1

1

1

Hydrazine

XXII-2 H2N-NH2

XII-2

57-14-7

1

1

1

Hydrazine, 1,1-dimethyl-

H2N-N(CH3)2

XII-2

624-80-6

1

0

0

Hydrazine, ethyl-

H2N-NH-CH2-CH3

XII-2

60-34-4

1

0

0

Hydrazine, methyl-

74-90-8

1

1

1

Hydrocyanic acid

H2N-NH-CH3 {hydrogen cyanide}

HCN

XII-2 XI-2, XXI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1638

11/24/08 1:56:36 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1639

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

1333-74-0

1

0

0

Hydrogen

H2

XIX-5

7722-84-1

1

0

0

Hydrogen peroxide

H2O2

XXVII

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

Hydrogen peroxyl radical

OOH

XXVII-1

7783-06-4

1

0

0

Hydrogen sulfide

H2S

XVIII.A-1

9027-05-8

0

1

0

Hydrogenase

XXII-2

9027-41-2

0

1

0

Hydrolase

XXII-2

0

1

0

Hydropectin

1

0

0

Hydroquinone/semiquinone/quinone free radical

XXVII-1

3352-57-6

1

0

0

Hydroxide free radical

XXVII-1

120598-69-8

0

1

0

Hydroxycinnamoyltransferase, putrescine

XXII-2

0

1

0

Hydroxycinnamoyltransferase, quinate

XXII-2

VIII-3

73904-44-6

0

1

0

Hydroxycinnamoyltransferase, shikimate

XXII-2

128909-19-3

0

1

0

Hydroxycinnamoyltransferase, tyramine

XXII-2

60321-02-0

0

1

0

Hydroxycinnamyl-CoA:quinate hydroxycinnamyl transferase, quinate

XXII-2

7803-49-8

0

1

0

Hydroxylamine

0

1

0

Hydroxylase, cinnamete

HO-NH2

XII-2 XXII-2

0

1

0

Hydroxylase, glycine

XXII-2

9029-83-8

0

1

0

Hydroxymethyltransferase, serine

XXII-2

105827-78-9

0

1

0

1H-Imidazol-2-amine, ((6-chloro-3-pyridinyl)methyl)4,5-dihydro-N-nitro{Admire®}

NH-NO2 N

N

XVII.B-4, XXI-3

N

Cl

288-32-4

1

1

1

1H-Imidazole

{1,3-diazole}

1

5 4

2466-76-4

XVII.A-4

H N 2

N

3

0

1

0

1H-Imidazole, 1-acetyl-

1

0

0

1H-Imidazole, C3-alkyl-

{3 isomers detected}

XVII.A-4

XVII.A-4

1

0

0

1H-Imidazole, C4-alkyl-

{5 isomers detected}

XVII.A-4

1

0

0

1H-Imidazole, C5-alkyl-

{4 isomers detected}

XVII.A-4

1

0

0

1H-Imidazole, butyl-

XVII.A-4

1

0

0

1H-Imidazole, 2-butyl-

XVII.A-4

0

1

0

1H-Imidazole, 4,5-dihydro-2-ethyl-4-methyl-

XVII.A-4

1739-84-0

1

0

0

1H-Imidazole, 1,2-dimethyl-

XVII.A-4

6338-45-0

1

0

0

1H-Imidazole, 1,4-dimethyl-

XVII.A-4

10447-93-5

1

0

0

1H-Imidazole, 1,5-dimethyl-

XVII.A-4

930-62-1

1

0

0

1H-Imidazole, 2,4-dimethyl-

XVII.A-4

2302-39-8

1

0

0

1H-Imidazole, 4,5-dimethyl-

XVII.A-4

37455-73-5

1

0

0

1H-Imidazole, 1,4-dimethyl-2-(1-methylethyl)-

XVII.A-4

40688-28-6

1

0

0

1H-Imidazole, 2,4-dimethyl-5-(1-methylethyl)-

XVII.A-4

1

0

0

1H-Imidazole, 2,5-dimethyl-4-(1-methylethyl)-

XVII.A-4

1

0

0

1H-Imidazole, 1,4-dimethyl-5-phenyl-

XVII.A-4

1131-16-4

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1639

11/24/08 1:56:37 PM

1640

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

51-45-6

0

1

0

Name (per CA Collective Index)

Selected structures

1H-Imidazole-4-ethanamine

1

3

7098-07-9

XII-2, XVII.A-4

H N 2

Chapter Table

5

N CH2CH2-NH2

1

0

0

1H-Imidazole, ethyl-

XVII.A-4

1

0

0

1H-Imidazole, 1-ethyl-

XVII.A-4

1072-62-4

1

0

0

1H-Imidazole, 2-ethyl-

XVII.A-4

19141-85-6

1

0

0

1H-Imidazole, 4-ethyl-

XVII.A-4

21202-52-8

1

0

0

1H-Imidazole, 1-ethyl-2-methyl-

XVII.A-4

931-36-2

1

0

0

1H-Imidazole, 2-ethyl-4-methyl-

XVII.A-4

29239-89-2

1

0

0

1H-Imidazole, 4-ethyl-2-methyl-

XVII.A-4

37455-59-7

1

0

0

1H-Imidazole, 4-ethyl-2-(1-methylethyl)-

XVII.A-4

37455-56-4

1

0

0

1H-Imidazole, 4-ethyl-2-propyl-

XVII.A-4

1

0

0

1H-Imidazole, methyl-

XVII.A-4

616-47-7

1

0

0

1H-Imidazole, 1-methyl-

XVII.A-4

693-98-1

1

0

0

1H-Imidazole, 2-methyl-

XVII.A-4

822-36-6

1

0

0

1H-Imidazole, 4-methyl-

XVII.A-4

36947-68-9

1

0

0

1H-Imidazole, 2-(1-methylethyl)-

XVII.A-4

58650-48-9

1

0

0

1H-Imidazole, 4-(1-methylethyl)-

XVII.A-4

22509-02-0

1

0

0

1H-Imidazole, 1-methyl-2-(1-methylethyl)-

XVII.A-4

37455-52-0

1

0

0

1H-Imidazole, 2-methyl-4-(1-methylethyl)-

XVII.A-4

37455-58-6

1

0

0

1H-Imidazole, 4-methyl-2-(1-methylethyl)-

XVII.A-4

61893-07-0

1

0

0

1H-Imidazole, 4-methyl-2-(1-methylpropyl)-

XVII.A-4

61893-06-9

1

0

0

1H-Imidazole, 2-(1-methylpropyl)-

XVII.A-4

61893-08-1

1

0

0

1H-Imidazole, 4-(2-methylpropyl)-

XVII.A-4

1

0

0

1H-Imidazole, pentyl-

XVII.A-4

91491-09-7

1

0

0

1H-Imidazole, propyl-

XVII.A-4

1842-63-3

1

0

0

1H-Imidazole, 1,2,4-trimethyl-

XVII.A-4

822-90-2

1

0

0

1H-Imidazole, 2,4,5-trimethyl-

XVII.A-4

20185-22-2

1

0

0

1H-Imidazole, 1,4,5-trimethyl-

XVII.A-4

36734-19-7

0

1

0

1-Imidazolidinecarboxamide, 3-(3,5-dichlorophenyl)2,4-dioxo{Iprodione®}

XIII-1, XIV-1, XVII.A-4, XVIII.B-3, XXI-3 O

N

N

461-72-3

1

0

0

2,4-Imidazolidinedione

{hydantoin}

H N

N

O

O

O

Cl

Cl

XIV-1, XVII.A-4

NH O

61893-10-5

1

0

0

2,4-Imidazolidinedione, 1-(1-methylethyl)-

XIV-1, XVII.A-4

17374-27-5

1

0

0

2,4-Imidazolidinedione, 1,5-dimethyl-

XIV-1, XVII.A-4

61893-09-2

1

0

0

2,4-Imidazolidinedione, 1-ethyl-

XIV-1, XVII.A-4

16935-34-5

1

0

0

2,4-Imidazolidinedione, 5-(1-methylethyl)-

XIV-1, XVII.A-4

15414-82-1

1

0

0

2,4-Imidazolidinedione, 5-ethyl-

XIV-1, XVII.A-4

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1640

11/24/08 1:56:37 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1641

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

616-03-5

1

1

1

2,4-Imidazolidinedione, 5-methyl-

96-45-7

1

0

0

2-Imidazolidinethione

138261-41-3

1

1

1

Imidazolidinimine, 1-((6-chloro-3-pyridinyl)methyl)N-nitro{Imidacloprid®}

61892-75-9

1

0

0

4H-Imidazol-4-one, 1,5-dihydro-1-methyl-

60-27-5

0

1

0

4H-Imidazol-4-one, 2-amino-1,5-dihydro-1-methyl{creatinine}

Selected structures

Chapter Table XIV-1, XVII.A-4

{ethylenethiourea}

XVII.A-4 XVII.A-4, XVIII.B-3, XXI-3 XVII.A-4 XII-2, XVII.A-4

O 5 4

1

3N

N

CH3

2

NH2

274-76-0

1

0

0

Imidazo[1,2-a]pyridine

XVII.E-6

1

N

N 2

1

0

0

3

Imidazo[1,2-a]pyridine, C2-alkyl-

875-80-9

1

0

0

Imidazo[1,2-a]pyridine, 2,3-dimethyl-

105650-23-5

1

0

0

1H-Imidazo[4,5-b]pyridin-2-amine, 1-methyl-6phenyl{PhIP}

XVII.E-6 XVII.E-6 N 4

5 6

XVII.F-8

N 3 1 N

2

NH2

CH3

68175-07-5

1

0

0

1H-Imidazo[4,5-b]pyridine, methyl-

1

0

0

1H-Imidazo[4,5-b]pyridine, 2-methyl-

XVII.E-6 N 5 6

N

4 7

XVII.E-6

3

1

2

N H

27582-20-3

1

0

0

1H-Imidazo[4,5-b]pyridine, 7-methyl-

XVII.E-6

120293-52-9

0

1

0

1H-Imidazo[4,5-c]pyridine-4-propanoic acid, 4,6dicarboxy-4,5,6,7-tetrahydro-, (4R-cis)-

IV.A-3

77094-11-2

1

0

0

3H-Imidazo[4,5-f]quinolin-2-amine, 3,4-dimethyl{MeIQ}

2

1

3N

N

76180-96-6

1

0

0

3H-Imidazo[4,5-f]quinolin-2-amine, 3-methyl{IQ}

0

0

1H-Indazole

XVII.F-8

NH2 N

2

3N

CH3

4

N

1

CH3

CH3

1

271-44-3

XVII.F-8

NH2 N

XVII.E-6

H N

1

2

N 3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1641

11/24/08 1:56:38 PM

1642

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

34879-87-3

0

1

0

1H-Indazole, 1,6-dimethyl-

95-13-6

1

0

0

1H-Indene

Selected structures

XVII.E-6 7

1

4

3

6

1

0

0

1H-Indene, diethyl-

496-11-7

1

0

0

1H-Indene, 2,3-dihydro-

I.E-6 2

5

71278-05-2

Chapter Table

I.E-6 {indane}

7 6

I.E-6

1 2

5 4

3

53563-67-0

1

0

0

1H-Indene, 2,3-dihydrodimethyl{4 isomers detected}

I.E-6

17057-82-8

1

0

0

1H-Indene, 2,3-dihydro-1,2-dimethyl-

I.E-6

71278-02-9

1

0

0

1H-Indene, 2,3-dihydroethyl-

I.E-6

27133-93-3

1

0

0

1H-Indene, 2,3-dihydromethyl{4 isomers detected}

I.E-6

767-58-8

1

0

0

1H-Indene, 2,3-dihydro-1-methyl-

I.E-6

824-63-5

1

0

0

1H-Indene, 2,3-dihydro-2-methyl-

I.E-6

824-22-6

1

0

0

1H-Indene, 2,3-dihydro-4-methyl-

I.E-6

874-35-1

1

0

0

1H-Indene, 2,3-dihydro-5-methyl-

I.E-6

16204-57-2

0

1

0

1H-Indene, 2,3-dihydro 1,1,4,5-tetramethyl-

I.E-6

942-43-8

0

1

0

1H-Indene, 2,3-dihydro 1,1,5,6-tetramethyl-

I.E-6

36541-18-1

1

0

0

1H-Indene, 2,3-dihydrotrimethyl-

I.E-6

29348-63-8

1

0

0

1H-Indene, dimethyl-

I.E-6

71278-06-3

1

0

0

1H-Indene, dimethylethyl-

I.E-6

1

0

0

1H-Indene, 5,6-dimethyl-2-phenyl-

I.E-6

1

0

0

1H-Indene, 2-(3’,4’-dimethylphenyl)-

I.E-6

58924-35-9 71278-07-4

1

0

0

1H-Indene, ethyl-

I.E-6

1

0

0

1H-Indene, ethylmethyl-

I.E-6

1

0

0

1H-Indene, ethylpentamethyl-

I.E-6

1

0

0

1H-Indene, heptamethyl-

I.E-6

71278-08-5

1

0

0

1H-Indene, hexamethyl-

I.E-6

29036-25-7

1

0

0

1H-Indene, methyl{at least 3 isomers are present in MSS}

I.E-6

767-59-9

1

0

0

1H-Indene, 1-methyl-

I.E-6

2177-47-1

1

0

0

1H-Indene, 2-methyl-

I.E-6

767-60-2

1

0

0

1H-Indene, 3-methyl-

I.E-6

2471-84-3

1

0

0

1H-Indene, 1-methylene-

I.E-6

6596-86-7

1

0

0

2H-Indene, 2-methylene-

1

0

0

1H-Indene, 4-methyl-2-(2’-methylphenyl)-

I.E-6

1

0

0

1H-Indene, 5-methyl-2-(4-methylphenyl)-

I.E-6

1

0

0

1H-Indene, 6-methyl-2-(4-methylphenyl)-

I.E-6

1

0

0

1H-Indene, 7-methyl-2-(2’-methylphenyl)-

I.E-6

{benzofulvene}

I.E-6

© 2009 by Taylor & Francis Group, LLC

78836_C030.indd 1642

11/24/08 1:56:38 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1643

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

71278-09-6 38638-41-4

S

T

S T

1

0

0

1H-Indene, 7-(4’-methylphenyl)-

I.E-6

1

0

0

1H-Indene, pentamethyl-

I.E-6

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

1H-Indene, phenyl-

I.E-6

1

0

0

1H-Indene, 2-phenyl-

I.E-6

1

0

0

1H-Indene, phenyltrimethyl-

I.E-6

27135-78-0

1

0

0

1H-Indene, tetramethyl{at least 4 isomers present in MSS}

I.E-6

60826-61-1

1

0

0

1H-Indene, trimethyl{at least 3 isomers present in MSS}

I.E-6

37414-44-1

1

0

0

1H-Indene-2-carboxaldehyde, 2,3-dihydro-

III-12

30084-91-4

1

0

0

1H-Indene-5-carboxaldehyde, 2,3-dihydro-

III-12

606-23-5

1

0

0

1H-Indene-1,3(2H)-dione

668-30-4

1

0

0

Indeno[1,2,3,4-defg]chrysene

III-13 I.E-6

{also known as indeno[3,2,1,7-defg]chrysene; dibenzo[b,mno]fluoranthene; naphtho[1,2,3,4ghi]fluoranthene}

71277-94-6

1

0

0

Indeno[1,2,3,4-defg]chrysene, methyl{indeno[3,2,1,7-defg]chrysene, methyl-; dibenzo[b,mno]fluoranthene, methyl-; naphtho[1,2,3,4-ghi]fluoranthene, methyl-}

I.E-6

193-43-1

1

0

0

Indeno[1,2,3-cd]fluoranthene

I.E-6

41699-07-4

1

0

0

Indeno[1,2,3-cd]fluoranthene, methyl-

206-56-4

1

0

0

Indeno[1,2,3-ij]isoquinoline

I.E-6 XVII.E-6

N

{1-azafluoranthene}

56631-57-3

1

0

0

Indeno[1,2,3-ij]isoquinoline, dimethyl-

1

0

0

Indeno[1,2,3-ij]isoquinoline, methyl-

1

0

0

1H-Indenol [1H-Inden-4-ol]

XVII.E-6 XVII.E-6 IX.A-22

OH 3

5

2

6 7

1

72692-86-5

1

0

0

1H-Indenol, 2,3-dihydromethyl[1H-Inden-4-ol, 2,3-dihydromethyl-]

IX.A-22

73850-11-0

1

0

0

1H-Indenol, dimethyl[1H-Inden-4-ol, dimethyl-

IX.A-22

73850-20-1

1

0

0

1H-Indenol, ethylmethyl[1H-Inden-4-ol, ethylmethyl-]

IX.A-22

1

0

0

1H-Indenol, methyl[1H-Inden-4-ol, methyl-]

IX.A-22

1

0

0

1H-Indenol, tetramethyl[1H-Inden-4-ol, tetramethyl-]

IX.A-22

73850-09-6

© 2009 by Taylor & Francis Group, LLC

78836_C030.indd 1643

11/24/08 1:56:38 PM

1644

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

73850-10-9

1

0

0

1H-Indenol, trimethyl[1H-Inden-4-ol, trimethyl-]

IX.A-22

1641-41-4

1

0

0

1H-Indenol, 2,3-dihydro[1H-Inden-4-ol, 2,3-dihydro-]

IX.A-22

1470-94-6

1

0

0

1H-Inden-5-ol, 2,3-dihydro-

IX.A-22

30286-23-8

1

0

0

Indenone, dihydro-

72692-87-6

1

0

0

Indenone, 1,3(or 2,3)-dihydrodimethyl-

III-13

480-90-0

1

0

0

1H-Inden-1-one

III-13

83-33-0

1

0

0

1H-Inden-1-one, 2,3-dihydro-

Name (per CA Collective Index)

Selected structures

Chapter Table

III-13

III-13

4

{1-indanone}

5

3 2 1

6 7

O

71278-03-0

1

0

0

1H-Inden-1-one, 2,3-dihydrodimethyl{6 isomers detected}

III-13

66309-83-9

1

0

0

1H-Inden-1-one, 2,3-dihydro-2,6-dimethyl-

III-13

17714-57-7

1

0

0

1H-Inden-1-one, 2,3-dihydro-3,5-dimethyl-

III-13

5037-60-5

1

0

0

1H-Inden-1-one, 2,3-dihydro-4,7-dimethyl-

III-13

71278-04-1

1

0

0

1H-Inden-1-one, 2,3-dihydro-ethyl-

III-13

57878-30-5

0

1

0

1H-Inden-1-one, 2,3-dihydro-5-hydroxy-3-methyl-

III-13

72692-69-4

1

0

0

1H-Inden-1-one, 2,3-dihydro(methoxymethyl)-

III-13

65436-86-4

1

0

0

1H-Inden-1-one, 2,3-dihydromethyl{4 isomers detected}

III-13

17496-14-9

1

0

0

1H-Inden-1-one, 2,3-dihydro-2-methyl-

III-13

6072-57-7

1

0

0

1H-Inden-1-one, 2,3-dihydro-3-methyl-

III-13

24644-78-8

1

0

0

1H-Inden-1-one, 2,3-dihydro-4-methyl-

III-13

4593-38-8

1

0

0

1H-Inden-1-one, 2,3-dihydro-5-methyl-

III-13

24623-20-9

1

0

0

1H-Inden-1-one, 2,3-dihydro-6-methyl-

III-13

66288-51-5

1

0

0

1H-Inden-1-one, 2,3-dihydrotrimethyl{3 isomers detected}

III-13

54789-23-0

1

1

1

1H-Inden-1-one, 2,3-dihydro-3,3,5,7-tetramethyl-

III-13

35322-84-0

1

0

0

1H-Inden-1-one, 2,3-dihydro-3,4,7-trimethyl-

III-13

22303-81-7

1

0

0

1H-Inden-1-one, 3-methyl-

III-13

615-13-4

1

0

0

2H-Inden-2-one, 1,3-dihydro-

III-13

1

0

0

2H-Inden-2-one, dimethyl-

III-13

1

0

0

2H-Inden-2-one, methyl-

0

1

0

2H-Inden-2-one, 1,4,5,6,7,7a-hexahydro-1-hydroxy1,4,4,7a-tetramethyl-

39815-71-9

III-13 5 6

4

3

1

0

0

11H-Indeno[2,1-a]phenanthrene {11H-naphtho[2,1-a]fluorene}

2

1

7

H3C

220-97-3

II.A-5, III-13

CH3

H3 C

O OH

CH3

I.E-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1644

11/24/08 1:56:39 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1645

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

193-39-5

1

0

0

Indeno[1,2,3-cd]pyrene

{o-phenylenepyrene}

I.E-6

64158-99-2

1

0

0

Indeno[1,2,3-cd]pyrene, dimethyl{at least 2 isomers present in MSS}

I.E-6

64158-98-1

1

0

0

Indeno[1,2,3-cd]pyrene, methyl{at least 2 isomers present in MSS}

I.E-6

1

0

0

Indeno[1,2,3-cd]pyrene, trimethyl{at least 2 isomers present in MSS}

I.E-6

1

0

0

5H-Indeno[1,2-b]pyridine

244-99-5

Name (per CA Collective Index)

Selected structures

{4-azafluorene}

5

Chapter Table

XVII.E-6

4 3

N

2

1

1

0

0

5H-Indeno[1,2-b]pyridine, dimethyl-

XVII.E-6

1

0

0

5H-Indeno[1,2-b]pyridine, methyl-

XVII.E-6

7440-74-6

1

1

1

Indium

120-72-9

1

1

1

1H-Indole

In {2,3-benzopyrrole}

XX-5 7

6

XVII.E-6

H N 2

5 4

3

1

0

0

1H-Indole, alkyl-

XVII.E-6

5192-03-0

1

0

0

1H-Indole, 5-amino-

XVII.E-6

55191-12-3

1

0

0

1H-Indole, 1,3-dibutyl-

496-15-1

0

1

0

1H-Indole, 2,3-dihydro-

XVII.E-6 {indoline}

XVII.E-6

6872-06-6

0

1

0

1H-Indole, 2,3-dihydro-2-methyl-

XVII.E-6

78210-52-3

1

0

0

1H-Indole, 2,3-dihydro-3-(3-pyridinylmethyl)-

XVII.E-6

29930-57-2

1

0

0

1H-Indole, dimethyl-

XVII.E-6

875-79-6

1

0

0

1H-Indole, 1,2-dimethyl-

XVII.E-6

875-30-9

1

0

0

1H-Indole, 1,3-dimethyl-

XVII.E-6

27816-52-0

1

0

0

1H-Indole, 1,4-dimethyl-

XVII.E-6

27816-53-1

1

0

0

1H-Indole, 1,5-dimethyl-

XVII.E-6

5621-15-8

1

0

0

1H-Indole, 1,6-dimethyl-

XVII.E-6

5621-16-9

1

0

0

1H-Indole, 1,7-dimethyl-

XVII.E-6

91-55-4

1

0

0

1H-Indole, 2,3-dimethyl-

XVII.E-6

1196-79-8

1

0

0

1H-Indole, 2,5-dimethyl-

XVII.E-6

5621-14-7

1

0

0

1H-Indole, 3,7-dimethyl-

XVII.E-6

64844-47-9

1

0

0

1H-Indole, dimethylethyl-

XVII.E-6

64844-49-1

1

0

0

1H-Indole, dimethylpropyl-

XVII.E-6

97542-81-9

1

0

0

1H-Indole, ethyl-

XVII.E-6

10604-59-8

1

0

0

1H-Indole, 1-ethyl-

XVII.E-6

3484-18-2

1

0

0

1H-Indole, 2-ethyl-

XVII.E-6

1484-19-1

1

0

0

1H-Indole, 3-ethyl-

XVII.E-6

68742-28-9

1

0

0

1H-Indole, 5-ethyl-

XVII.E-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1645

11/24/08 1:56:39 PM

1646

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

64844-45-7

1

0

0

1H-Indole, ethylmethyl-

XVII.E-6

64844-50-4

1

0

0

1H-Indole, ethylpropyl-

XVII.E-6

27323-28-0

1

1

1

1H-Indole, methyl-

XVII.E-6

603-76-9

1

0

0

1H-Indole, 1-methyl-

XVII.E-6

95-20-5

1

1

1

1H-Indole, 2-methyl-

83-34-1

1

1

1

1H-Indole, 3-methyl-

16096-32-5

1

0

0

1H-Indole, 4-methyl-

XVII.E-6

614-96-0

1

0

0

1H-Indole, 5-methyl-

XVII.E-6

3420-02-8

1

0

0

1H-Indole, 6-methyl-

XVII.E-6

933-67-5

1

0

0

1H-Indole, 7-methyl-

XVII.E-6

1

0

0

1H-Indole, (1-methylethyl)-

XVII.E-6

1

0

0

1H-Indole, methylphenyl-

XVII.E-6

1

0

0

1H-Indole, methylpropyl-

XVII.E-6

64844-46-8

Name (per CA Collective Index)

Selected structures

Chapter Table

XVII.E-6 {skatole}

XVII.E-6

948-65-2

1

1

1

1H-Indole, 2-phenyl-

XVII.E-6

1504-16-1

1

0

0

1H-Indole, 3-phenyl-

XVII.E-6

64844-44-6

1

0

0

1H-Indole, propyl-

XVII.E-6

1859-92-3

1

0

0

1H-Indole, 3-propyl-

XVII.E-6

64844-48-0

1

0

0

1H-Indole, tetramethyl-

XVII.E-6

30642-36-5

1

0

0

1H-Indole, trimethyl-

XVII.E-6

1971-46-6

1

0

0

1H-Indole, 1,2,3-trimethyl-

XVII.E-6

21296-92-4

1

0

0

1H-Indole, 2,3,5-trimethyl-

XVII.E-6

54340-99-7

1

0

0

1H-Indole, 5,6,7-trimethyl-

XVII.E-6

31212-21-2

0

1

0

1H-Indoleacetamide

XIII-1

32536-43-9

0

1

0

1H-Indoleacetic acid

IV.A-3

0

1

0

1H-Indole-2-acetonitrile, 1-methyl-

87-51-4

0

1

0

1H-Indole-3-acetic acid

1912-33-0

0

1

0

1H-Indole-3-acetic acid, methyl ester

V-3

771-51-7

0

1

0

1H-Indole-3-acetonitrile

XI-2

133-32-4

0

1

0

1H-Indole-3-butanoic acid

0

1

0

1H-Indole-3-butanoic acid, methyl ester

487-89-8

0

1

0

1H-Indole-3-carboxaldehyde

771-50-6

0

1

0

1H-Indole-3-carboxylic acid

942-24-5

0

1

0

1H-Indole-3-carboxylic acid, methyl ester

XI-2 IV.A-3, XXI-3

IV.A-3, XXI-3 V-3 III-12 IV.A-3 7 6

V-3

H N 2

5 4

COO-CH3

61-54-1

0

1

0

1H-Indole-3-ethanamine

XII-2

526-55-6

0

1

0

1H-Indole-3-ethanol

II.A-5 IV.A-3

830-96-6

0

1

0

1H-Indole-3-propanoic acid

5548-09-4

0

1

0

1H-Indole-3-propanoic acid, methyl ester

35656-49-6

0

1

0

1H-Indolepropanoic acid, D-oxo-

III-13, IV.A-3

392-12-1

0

1

0

1H-Indole-3-propanoic acid, D-oxo-

III-13, IV.A-3

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1646

11/24/08 1:56:40 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1647

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

1761-10-0

0

1

0

Indolizine, 3-methyl-

XVII.E-6

1761-11-1

1

0

0

Indolizine, 6-methyl-

XVII.E-6

Name (per CA Collective Index)

Selected structures

Chapter Table

N

54906-44-4

1

1

1

8(5H)-Indolizinone, 5,6,7,8-tetrahydro{5-oxocyclohexa[a]pyrrole}

III-13

O

N

55041-88-8

0

1

0

8(5H)-Indolizinone, 6,7-dihydro-2-methyl-

50-67-9

0

1

0

1H-Indol-5-ol, 3-(2-aminoethyl)-

59-48-3

1

0

0

2H-Indol-2-one, 1,3-dihydro{phthalimidine; oxindole}

15379-45-0

III-13 XII-2 XVII.C-1 O N H

1

0

0

2H-Indol-2-one, 1,3-dihydro-3-ethyl-

XVII.C-1

1

0

0

2H-Indol-2-one, 1,3-dihydro-3-methyl-

XVII.C-1

20200-86-6

0

1

0

2H-Indol-2-one, 1,3-dihydro-1,3,3-trimethyl-

58074-25-2

0

1

0

3H-Indol-3-one, 2,3,4,5,6,7-hexahydro{4,5,6,7-tetrahydro-3-indolinone}

XVII.C-1 O

III-13

N H

6917-35-7

1

1

1

Inositol

87-89-8

1

1

1

myo-Inositol

II.A-5 II.A-5

OH HO

OH

OH

HO OH

3615-82-5

0

1

0

myo-Inositol, hexakis(dihydrogen phosphate), calcium magnesium salt

XX-6

71608-14-5

0

1

0

myo-Inositol, O-2-(acetylamino)-2-deoxy-D-Dglucopyranosyl-(1o4)-O-alpha-Dglucopyranuronosyl-(1o2)-, 1-[3,4-dihydroxy-2[(2-hydroxy-1-oxodocosyl)amino]octadecyl hydrogen phosphate], disodium salt

XX-6

71608-17-8

0

1

0

myo-Inositol, O-2-(acetylamino)-2-deoxy-D-Dglucopyranosyl-(1o4)-O-alpha-Dglucopyranuronosyl-(1o2)-, 1-[3,4-dihydroxy-1[(2-hydroxy-1-oxopentacosyl)amino]octadecyl hydrogen phosphate], disodium salt

XX-6

71608-15-6

0

1

0

myo-Inositol, O-2-(acetylamino)-2-deoxy-D-Dglucopyranosyl-(1o4)-O-alpha-Dglucopyranuronosyl-(1o2)-, 1-[3,4-dihydroxy-2[(2-hydroxy-1-oxotricosyl)amino]octadecyl hydrogen phosphate], disodium salt

XX-6

71608-16-7

0

1

0

myo-Inositol, O-2-(acetylamino)-2-deoxy-D-Dglucopyranosyl-(1o4)-O-alpha-Dglucopyranuronosyl-(1o2)-, 1-[3,4-dihydroxy-2[(2-hydroxy-1-oxotetracosyl)amino]octadecyl hydrogen phosphate], disodium salt

XX-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1647

11/24/08 1:56:40 PM

1648

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

71608-19-0

0

1

0

myo-Inositol, O-2-(acetylamino)-2-deoxy-D-Dglucopyranosyl-(1o4)-O-alpha-Dglucopyranuronosyl-(1o2)-, 1-[3,4-dihydroxy-2[(2-hydroxy-1-oxodocosyl)amino]-8-octadecenyl hydrogen phosphate], disodium salt

XX-6

71608-20-3

0

1

0

myo-Inositol, O-2-(acetylamino)-2-deoxy-D-Dglucopyranosyl-(1o4)-O-alpha-Dglucopyranuronosyl-(1o2)-, 1-[3,4-dihydroxy-2[(2-hydroxy-1-oxotricosyl)amino]-8-octadecenyl hydrogen phosphate], disodium salt

XX-6

71608-21-4

0

1

0

myo-Inositol, O-2-(acetylamino)-2-deoxy-D-Dglucopyranosyl-(1o4)-O-alpha-Dglucopyranuronosyl-(1o2)-, 1-[3,4-dihydroxy-2[(2-hydroxy-1-oxotetracosyl)amino]-8-octadecenyl hydrogen phosphate], disodium salt

XX-6

71608-22-5

0

1

0

myo-Inositol, O-2-(acetylamino)-2-deoxy-D-Dglucopyranosyl-(1o4)-O-alpha-Dglucopyranuronosyl-(1o2)-, 1-[3,4-dihydroxy-2[(2-hydroxy-1-oxopentacosyl)amino]-8octadecenyl hydrogen phosphate], disodium salt

XX-6

71608-23-6

0

1

0

myo-Inositol, O-2-(acetylamino)-2-deoxy-D-Dglucopyranosyl-(1o4)-O-alpha-Dglucopyranuronosyl-(1o2)-, 1-[3,4-dihydroxy-2[(2-hydroxy-1-oxohexacosyl)amino]-8-octadecenyl hydrogen phosphate], disodium salt

XX-6

Name (per CA Collective Index)

Selected structures

Chapter Table

89194-80-9

0

1

0

myo-Inositol, O-D-glucopyranosyl-

II.A-5

49741-70-0

0

1

0

D-myo-Inositol, O-D-glucopyranosyl-

II.A-5

0

1

0

myo-Inositol, phosphatidyl-

0

1

0

Iodide

20461-54-5

II.A-5 I

-1

XVIII.B-3, XX-5

7553-56-2

1

1

1

Iodine

I2

XVIII.B-3, XX-5

7439-88-5

1

1

1

Iridium

Ir

XX-5

7439-89-6

1

1

1

Iron

Fe

XX-5

15281-98-8

1

0

0

Iron carbonyl

Fe(CO)4

XX-6

15438-31-0

0

1

0

Iron, ion

Fe

XX-5

1332-37-2

0

1

0

Iron oxide

Fe2O3

XX-6

14596-12-4

1

1

1

Iron, isotope of mass 59

59

14484-64-1

0

1

0

Iron, tris(dimethylcarbamodithioato-S,S')-, (OC-611){Ferbam®}

+2

Fe

XX-5

-

S

H3C N

S-

H3C

0

1

0

1,3-Isobenzofurandione

Fe3+

-3

-

85-44-9

XXI-3

-

{phthalic anhydride}

VII-1

O

O

O

56-25-7

0

1

0

1,3-Isobenzofurandione, 3a,7a-dimethyl-4,7-epoxyhexahydro {cantharidin}

O

O

VII-1

O

O

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1648

11/24/08 1:56:41 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1649

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

87-41-2

0

1

0

Name (per CA Collective Index) 1(3H)-Isobenzofuranone

{phthalide}

Selected structures

Chapter Table VI-3

O

O

1

0

0

1(3H)-Isobenzofuranone, methyl-

VI-3

551-08-6

0

1

0

1(3H)-Isobenzofuranone, 3-butylidene-

VI-3

13277-77-5

0

1

0

1(3H)-Isobenzofuranone, 3,7-dihydroxy-3,4,5,6tetramethyl-

VI-3

66309-76-0

1

0

0

1(3H)-Isobenzofuranone, 4,5,6,7-tetrahydro-

VI-3

75-13-8

0

1

0

Isocyanic acid

52845-07-5

1

0

0

Isoeicosane

H-N=C=O

I.A-10

XIX-5

52655-10-4

0

1

0

Isoeicosanol

II.A-5

52845-08-6

1

0

0

Isoheneicosane

I.A-10

54365-40-1

1

1

1

Isoheptacosane

85-41-6

1

0

0

1H-Isoindole-1,3(2H)-dione

I.A-10 {phthalimide}

XIV-1

O

NH

O

66309-86-2

1

0

0

1H-Isoindole-1,3(2H)-dione, 4,5-dimethyl-

XIV-1

1

0

0

1H-Isoindole-1,3(2H)-dione, methyl-

XIV-1

7251-82-3

1

0

0

1H-Isoindole-1,3(2H)-dione, 4-methyl-

XIV-1

40314-06-5

1

0

0

1H-Isoindole-1,3(2H)-dione, 5-methyl-

133-06-2

1

1

1

1H-Isoindole-1,3(2H)-dione, 3a,4,7,7a-tetrahydro-2[(trichloromethyl)thio]{Captan®}

XIV-1 XIV-1, XVIII.A-1, XVIII.B-3, XXI-3 O

N

S-CCl3

O

133-07-3

0

1

0

1H-Isoindole-1,3(2H)-dione, 2[(trichloromethyl)thio]-

{Folpan®}

XIV-1, XVIII.A-1, XVIII.B-3, XXI-3 O

N

S-CCl3

O

480-91-1

1

0

0

1H-Isoindol-1-one, 2,3-dihydro-

XIV-1

6091-76-5

1

0

0

1H-Isoindol-1-one, 2,3-dihydro-3-methyl-

XIV-1

7004-09-3

0

1

0

Isoleucine

1509-34-8

0

1

0

Isoleucine, allo-

73-32-5

0

1

0

L-Isoleucine

139681-66-6

0

1

0

L-Isoleucine, N-[N-[N-(N-L-methionyl-L-valyl)-Lphenylalanyl]-L-leucyl]-

80449-01-0

0

1

0

Isomerase, deoxyribonucleate topo-

XXII-2

H3C-CH2-CH(CH3)-CH(NH2)-COOH IV.A-3, IV.B-7, XII-2 IV.A-3, IV.B-7, XII-2 H3C-CH2-CH(CH3)-CH(NH2)-COOH IV.A-3, IV.B-7, XII-2 IV.A-3, IV.B-7, XII-2, XVIII.A-1

9001-41-6

0

1

0

Isomerase, glucose phosphate

XXII-2

9055-95-2

0

1

0

Isomerase, pentose phosphate

XXII-2

9023-83-0

0

1

0

Isomerase, ribose phosphate

XXII-2

52701-70-9

0

1

0

Isopentacosane

I.A-10

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1649

11/24/08 1:56:41 PM

1650

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 27836-87-9

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

0

1

0

Isopentadecanoic acid

IV.A-3

0

1

0

Isoperoxidase A3

XXII-2

1

0

0

Isoquinolinamine

XII-2

1532-84-9

1

0

0

1-Isoquinolinamine

XII-2

119-65-3

1

1

1

Isoquinoline

64828-50-8

1

0

0

Isoquinoline, butyl-

XVII.E-6

7661-38-3

1

0

0

Isoquinoline, 1-butyl-

XVII.E-6

64973-79-1

1

0

0

Isoquinoline, dihydro-

XVII.E-6

65312-77-8

1

0

0

Isoquinoline, dihydroethyl-

XVII.E-6

65312-79-0

XVII.E-6

1

0

0

Isoquinoline, dihydromethyl-

XVII.E-6

1

0

0

Isoquinoline, dimethyl-

XVII.E-6

64828-51-9

1

0

0

Isoquinoline, ethyl-

XVII.E-6

61010-32-0

0

1

0

Isoquinoline, 1-[(4-methoxy-3-nitrophenyl)methyl]-, mononitrate

XVII.E-6

58853-80-8

1

0

0

Isoquinoline, methyl{several methylquinolines detected in MSS}

XVII.E-6

1721-93-3

1

0

0

Isoquinoline, 1-methyl-

XVII.E-6

1125-80-0

1

0

0

Isoquinoline, 3-methyl-

XVII.E-6

64828-49-5

1

0

0

Isoquinoline, (1-methylethyl)-

XVII.E-6

1

0

0

Isoquinoline, methyltetrahydro-

XVII.E-6

64849-98-5

1

0

0

Isoquinoline, propyl-

XVII.E-6

29832-78-8

1

0

0

Isoquinoline, tetrahydro-

XVII.E-6

64849-99-6

1

0

0

Isoquinolinecarbonitrile

1198-30-7

55713-38-7

XI-2

1

0

0

1-Isoquinolinecarbonitrile

0

1

0

5,6-Isoquinolinedione, 7,8-dihydro-1,3,7,7tetramethyl-

XI-2

0

1

0

8(5H)-Isoquinolinone, 6,7-dihydro-1,3,6,6tetramethyl- [6,7-dihydro- or 5,6,7,8-tetrahydro-?]

III-13 CH3 N

CH3

H3C

27137-10-6

1

0

0

Isotetradecanoic acid, methyl ester

556-61-6

0

1

0

Isothiocyanic acid, methyl-

CH3

V-3 {Trapex®}

288-16-4

1

0

0

Isothiazole

34425-19-9

1

0

0

Isotriacontane

288-14-2

0

1

0

Isoxazole

300-87-8

0

1

0

Isoxazole, 3,5-dimethyl-

10557-82-1

1

0

0

Isoxazole, trimethyl- = Isoxazole, 3,4,5-trimethyl-

H 3C-N=S

0

1

0

3-Isoxazolidinone 2-((2-chlorophenyl)methyl)-4,4dimethyl{Clomazone®}

XVIII.A-1, XXI-3 XVIII.A-1 I.A-10 XVII.D-2 XVII.D-2 CH3

H3C

XVII.D-2

N

H3C

81777-89-1

III-13

O

O Cl

O N O

XVII.D-2, XVIII.B-3, XXI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1650

11/24/08 1:56:42 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1651

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

9013-02-9

0

1

0

Kinase (phosphorylating), adenylate

XXII-2

9012-50-4

0

1

0

Kinase (phosphorylating), aspartate

XXII-2

Name (per CA Collective Index)

Chapter Table

Selected structures

9026-67-9

0

1

0

Kinase (phosphorylating), choline

XXII-2

9001-36-9

0

1

0

Kinase (phosphorylating), gluco-

XXII-2

9026-62-4

0

1

0

Kinase (phosphorylating), glucurono-

XXII-2

9001-51-8

0

1

0

Kinase (phosphorylating), hexo-

XXII-2

9032-66-0

0

1

0

Kinase (phosphorylating), nicotinamide adenine dinucleotide

XXII-2

9001-80-3

0

1

0

Kinase (phosphorylating), phosphofructo-

XXII-2

9032-96-6

0

1

0

Kinase (phosphorylating), phosphogluco-

XXII-2

150656-38-5

0

1

0

Kinase (phosphorylating), protein (tobacco BY-2 cell isoenzyme ZmPK1 reduced)

XXII-2

9001-59-6

0

1

0

Kinase (phosphorylating), pyruvate

XXII-2

9027-40-1

0

1

0

Kinase (phosphorylating), pyruvate-phosphate di-

XXII-2

9030-57-3

0

1

0

Kinase (phosphorylating), ribulo-

XXII-2

9031-51-0

0

1

0

Kinase (phosphorylating), shikimate

XXII-2

63-42-3

0

1

0

Lactose

79-62-9

0

1

0

Lanost-8-en-3-ol, (3E)-

II.B-2

6890-88-6

0

1

0

Lanost-8-en-3-ol, 24-methylene-, (3E)-

II.B-2 II.B-2

II.A-5, VIII-3

26409-08-5

0

1

0

Lanost-9(11)-en-3-ol, 24,25-epoxy-, (3E)-

79-63-0

0

1

0

Lanosta-8,24-dien-3-ol, (3E)-

{lanosterol}

CH3 CH3

H3C

CH3 CH3

HO H3C

CH3

II.B-2 67493-77-0

0

1

0

II.B-2, V-3

70898-27-0

0

1

0

Lanostane-3,7-diol, (3E,7E)-

7439-91-0

1

1

1

Lanthanum

La

XX-5

13981-28-7

1

1

1

Lanthanum, isotope of mass 140

140

XX-5

7439-92-1

1

1

1

Lead

Pb

XX-5

14255-04-0

1

1

1

Lead, isotope of mass 210

210

XX-5 XX-5

Lanostane-3,7,11-triol, 3,7-diacetate, (3E,7E,11E)-

II.B-2 La Pb

15092-94-1

0

1

0

Lead, isotope of mass 212

212

15067-28-4

0

1

0

Lead, isotope of mass 214

214

XX-5

218

XX-5

Pb Pb

0

1

0

Lead, isotope of mass 218

0

1

0

Lecithins

Pb

7005-03-0

1

1

1

Leucine

61-90-5

0

1

0

L-Leucine

IV.A-3, IV.B-7, XII-2

139681-65-5

0

1

0

L-Leucine, N-[N-[N-[N-[N-[N-[N-(N-L-methionyl-Lphenylalanyl)-L-seryl]-L-leucyl]-L-leucyl]-Lmethionyl]-L-valyl]-L-valyl]-

IV.A-3, IV.B-7, XII-2

9005-53-2

0

1

0

Lignin

XII-2 (H3C)2=CH-CH2-CH(NH2)-COOH IV.A-3, IV.B-7, XII-2

VIII-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1651

11/24/08 1:56:42 PM

1652

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

8068-04-0

0

1

0

Lignin, Klason

VIII-3

8068-00-6

0

1

0

Lignin, milled wood

VIII-3

9001-62-1

Name (per CA Collective Index)

Selected structures

Chapter Table

0

1

0

Lipase, triacylglycerol

XXII-2

0

1

0

Lipoxygenase

XXII-2

7439-93-2

1

1

1

Lithium

Li

17341-24-1

0

1

0

Lithium, ion

Li

545-47-1

0

1

0

Lup-20(29)-en-3-ol, (3E)-

XX-5 +1

XX-5

HO

7439-94-3

1

1

1

Lutecium

9045-78-7

0

1

0

Lyase, isocitrate

9015-75-2

0

1

0

Lyase, pectate

6899-06-5

0

1

0

Lysine

28902-93-4

0

1

0

Lysine, hydroxy-

56-87-1

0

1

0

L-Lysine

1114-34-7

0

1

0

Lyxose

II.B-2

Lu

XX-5 XXII-2 XXII-2

H2N-(CH2)4-CH(NH2)-COOH IV.A-3, IV.B-7, XII-2 IV.A-3, IV.B-7, XII-2 H2N-(CH2)4-CH(NH2)-COOH IV.A-3, IV.B-7 O OH OH

II.A-5, X-2

OH

HO

90803-60-4

0

1

0

M-1nkh

XXII-2

14428-12-7

0

1

0

Magnesate(1-), [9-ethenyl-14-ethyl-13-formyl-21(methoxycarbonyl)-4,8,18-trimethyl-20-oxo-3phorbinepropanoato(3-)-N23,N24,N25,N26]-, hydrogen, [SP-4-2-[3S-(3D,4E,21E)]]{chlorophyllide b}

XX-6

14897-06-4

0

1

0

Magnesate(1-), [9-ethenyl-14-ethyl-21(methoxycarbonyl)-4,8,13,18-tetramethyl-20-oxo3-phorbinepropanoato(3-)-N23,N24,N25,N26]-, hydrogen, [SP-4-2-[3S-(3D,4E,21E)]]{chlorophyllide a}

XX-6

15611-43-5

0

1

0

Magnesate(3-), [18-carboxy-20-(carboxymethyl)-8ethenyl-13-ethyl-2,3-dihydro-3,7,12, 17tetramethyl-21H,23H-porphine-2-propanoato(5-)N21,N22,N23,N24]-, trihydrogen, [SP-4-2-(2Strans)]{chlorophyllin}

XX-6

7439-95-4

1

1

1

Magnesium

Mg

XX-5 +2

XX-5 XX-6

22537-22-0

0

1

0

Magnesium, ion

Mg

1309-48-4

0

1

0

Magnesium oxide

MgO

479-61-8 42617-16-3

0

1

0

Magnesium, [3,7,11,15-tetramethyl-2-hexadecenyl 9-ethenyl-14-ethyl-21-(methoxycarbonyl)4,8,13,18-tetramethyl-20-oxo-3phorbinepropanoato(2-)-N23,N24,N25,N26]-, [SP4-2-[3S-[3D(2E,7S*,11S*),4E,21E]]]{chlorophyll a}

XX-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1652

11/24/08 1:56:43 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1653

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

519-62-0

0

1

0

Magnesium, [3,7,11,15-tetramethyl-2-hexadecenyl 9-ethenyl-14-ethyl-13-formyl-21(methoxycarbonyl)-4,8,18-trimethyl-20-oxo-3phorbinepropanoato(2-)-N23,N24,N25,N26]-, [SP4-2-[3S-[3D(2E,7S*,11S*),4E,21E]]]{chlorophyll b}

0

1

0

Maltase

0

1

0

Į-Maltose

69-79-4

Name (per CA Collective Index)

Selected structures

Chapter Table XX-6

XXII-2 CH2OH

CH2OH

O

O

OH

OH

II.A-5, VIII-3

OH

O OH OH

0

1

0

ȕ-Maltose

7439-96-5

1

1

1

Manganese

Mn

13446-35-0

0

1

0

Manganese chloride

MnCl4

12427-38-2

0

1

0

Manganese, [[1,2ethanediylbis[carbamodithioato]](2-)]- {Maneb®}

OH

II.A-5 XX-5 XX-6

S-

S-

S

S HN

8018-01-7

0

1

0

Manganese, [[1,2-ethanediylbis[carbamodithioato]](2-)] + zinc, [[1,2-ethanediylbis[carbamodithioato]](2-)] {Mancozeb}

NH

Maneb +

0

1

0

XVIII.A-1, XX-6, XXI-3

Zn2+ S-

S-

S

S HN

16397-91-4

XVIII.A-1, XX-6, XXI-3

Mn2+

NH

+2

Manganese, ion

Mn 56

XX-5

HOCH2-(CHOH)4-CH2OH

II.A-5

14681-52-8

0

1

0

Manganese, isotope of mass 56

69-65-8

1

1

1

D-Mannitol

31103-86-3

1

1

1

Mannose

XX-5

Mn

{cordycepic acid}

II.A-5 VIII-3

CH2OH O OH OH HO

3458-28-4

1

1

1

D-Mannose

14307-02-9

0

1

0

D-Mannose, 2-amino-2-deoxy-

3615-41-6

1

1

1

L-Mannose, 6-deoxy-

OH

{seminose}

II.A-5, VIII-3

{mannosamine}

II.A-5, XII-2

{D-rhamnose}

HO

O

II.A-5, VIII-3

OH

CH3

OH OH

9025-42-7

0

1

0

Mannosidase, D-

XXII-2

8049-97-6

0

1

0

Melanin

XXII-2

585-99-9

0

1

0

Melibiose

OH

CH2OH HO

HO

O OH

II.A-5, VIII-3

OH O OH

O OH

CH2

7439-97-6

1

1

1

Mercury

Hg

XX-5

13982-78-0

0

1

0

Mercury, isotope of mass 203

203

XX-5

9002-91-9

0

1

0

Metaldehyde

{acetaldehyde tetramer}

Hg

XXI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1653

11/24/08 1:56:43 PM

1654

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

74-89-5

1

1

1

Methanamine

{methylamine}

H3C-NH2

XII-2

75-50-3

1

1

1

Methanamine, N,N-dimethyl-

{trimethylamine}

(H3C)3ŁN

XII-2

{dimethylamine}

Name (per CA Collective Index)

Selected structures

124-40-3

1

1

1

Methanamine, N-methyl-

62-75-9

1

1

1

Methanamine, N-methyl-N-nitroso-

107-43-7

0

1

0

Methanaminium, 1-carboxy-N,N,N-trimethyl-, inner salt {betaine}

-

74-82-8

1

0

0

Methane

CH4

74-83-9

1

1

1

Methane, bromo{Brom-o-Gas®, Methogas®, Profume®, Terr-o-Gas®, Zytox®}

H3C-Br

XVIII.B-3, XXI-3

74-87-3

1

0

0

Methane, chloro-

H3C-Cl

XVIII.B-3, XXI-3

75-09-2

1

1

1

Methane, dichloro-

H2C=Cl2

XVIII.B-3, XXI-3

75-71-8

1

0

0

Methane, dichlorodifluoro-

CF2Cl2

XVIII.B-3

H3C-I

XVIII.B-3

{NDMA}

(H3C)2=NH

Chapter Table

+

OOC-CH2-N Ł(CH3)3

74-88-4

1

0

0

Methane, iodo-

1

0

0

Methane, isocyanato-

75-52-5

1

0

0

Methane, nitro-

76-06-2

0

1

0

Methane, nitrotrichloro-

{Chloropicrin®}

Cl 3ŁC-NO2

{dimethyl ether}

H3C-O-CH3

H 3C-N=C=O

0

1

0

Methane, oxybis-

67-68-5

0

1

0

Methane, sulfinylbis-

75-18-3

1

1

1

Methane, thiobis-

67-66-3

1

1

1

Methane, trichloro-

75-69-4

1

1

1

Methane, trichlorofluoro-

37924-13-3

0

1

0

Methanesulfonamide, trifluoro-N-(2-methyl-4(phenylsulfonyl)phenyl){Perfluidone®}

XII-2

V-3

H3C-NO2

115-10-6

XII-2, XV-8

1.A-10

624-83-9

{methyl isocyanate}

XII-2

(H3C)2=N-NO(H3C)2=NH

XVI-1 XVI-1, XXI-3 X-2 XVIII.A-1

{methyl sulfide} {chloroform}

(H3C)2=S

XVIII.A-1

H-CŁCl3

XVIII.B-3, XXI-3

F-CŁCl3

{methyl mercaptan}

XVIII.B-3

O

O

S

NH-S-CF3

O

O

H3C-SH

XXI-3

74-93-1

1

0

0

Methanethiol

XVIII.A-1

475-20-7

0

1

0

1,4-Methanoazulene, decahydro-4,8,8-trimethyl-9methylene-, [1S-(1D,3aE,4D,8aE)]-

I.C-1

469-61-4

0

1

0

1H-3a,7-Methanoazulene, 2,3,4,7,8,8a-hexahydro3,6,8,8-tetramethyl-, [3R-(3D,3aE,7E,8aD)]-

I.C-1

77-53-2

0

1

0

1H-3a,7-Methanoazulen-6-ol, octahydro-3,6,8,8tetramethyl-, [3R-(3D,3aE,6D,7E,8aD)]-

II.A-5

CH3

CH3

OH CH3 CH3

4586-22-5

0

1

0

4,8-Methanoazulen-9-ol, decahydro-2,2,4,8tetramethyl-, stereoisomer

II.A-5

17622-35-4

0

1

0

4,8-Methanoazulen-9-ol, decahydro-2,2,4,8tetramethyl-, acetate, stereoisomer

V-3

1031-07-8

1

1

1

6,9-Methano-2,4,3-benzodioxathiepin, 6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9ahexahydro-, 3,3-dioxide {Thiodan® sulfate; Endosulfan® sulfate}

115-29-7

1

1

1

6,9-Methano-2,4,3-benzodioxathiepin, 6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9ahexahydro-, 3-oxide {Thiodan®; Thiosulfan®; Endosulfan®}

Cl Cl Cl

CCl 2

O O

XVIII.B-3, XXI-3

O S O

Cl Cl Cl Cl

CCl2

O O

S

O

XVIII.B-3, XXI-3

Cl

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1654

11/24/08 1:56:44 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1655

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

33213-65-9

1

1

1

6,9-Methano-2,4,3-benzodioxathiepin, 6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9ahexahydro-, 3-oxide, (3D,5aD,6E,9E,9aD){ȕ-Endosulfan®}

XVIII.B-3, XXI-3

959-98-8

1

1

1

6,9-Methano-2,4,3-benzodioxathiepin, 6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9ahexahydro-, 3-oxide, (3D,5aE,6D,9D,9aE){Į-Endosulfan®}

XVIII.B-3, XXI-3

88125-11-5

0

1

0

7H-2,4a-Methano-1H-cyclobuta[de]naphthalen-7one, 1a,2,3,4,7a,7b-hexahydro-1a,5,7b-trimethyl-, [1aS-(1aD,2E,4aE,7aD,7bD)]-

III-13

105300-09-2

0

1

0

7H-2,4a-Methano-1H-cyclobuta[de]naphthalen-7one, 1a-[(E-Dglucopyranosyloxy)methyl]octahydro-5,7bdimethyl-

III-13

125537-96-4

0

1

0

7H-2,4a-Methano-1H-cyclobuta[de]naphthalen-7one, 3-(E-D-glucopyranosyloxy)octahydro-1a,5,7btrimethyl-, [1aS-(1aD,2E,3E,4aE,5D,7aD,7bD)]-

II.A-5, III-13

125537-95-3

0

1

0

7H-2,4a-Methano-1H-cyclobuta[de]naphthalen-7one, 4-(E-D-glucopyranosyloxy)octahydro-1a,5,7btrimethyl-, [1aS-(1aD,2E,4E,4aE,5D,7aD,7bD)]-

II.A-5, III-13

105300-10-5

0

1

0

7H-2,4a-Methano-1H-cyclobuta[de]naphthalen-7one, 5-[(E-D-glucopyranosyloxy)methyl]octahydro1a,7b-dimethyl-, [1aS-(1aD,2E,4aE,5D,7aD,7bD)]-

II.A-5, III-13

88848-60-6

0

1

0

7H-2,4a-Methano-1H-cyclobuta[de]naphthalen-7one, 6-[(2-O-E-D-glucopyranosyl-E-Dglucopyranosyl)oxy]octahydro-1a,5,7b-trimethyl-, [1aS-(1aD,2E,4aE,5D,6E,7aD,7bD )]-

II.A-5, III-13

68690-84-6

0

1

0

7H-2,4a-Methano-1H-cyclobuta[de]naphthalen-7one, octahydro-1a,5,7b-trimethyl-, [1aS(1aD,2E,4aE,5D,7aD,7bD)]-

76-44-8

1

1

1

4,7-Methano-1H-indene, 1,4,5,6,7,8,8-heptachloro3a,4,7,7a-tetrahydro{Heptachlor®}

5103-71-9

0

1

0

4,7-Methano-1H-indene, 1,2,4,5,6,7,8,8-octachloro2,3,3a,4,7,7a-hexahydro{Į-Chlordane®}

Name (per CA Collective Index)

Selected structures

Chapter Table

III-13

XVIII.B-3, XXI-3

Cl

Cl

Cl Cl

CCl2

XVIII.B-3, XXI-3

Cl Cl

12789-03-6

0

1

0

4,7-Methano-1H-indene, 1,2,4,5,6,7,8,8-octachloro2,3,3a,4,7,7a-hexahydro{Ȗ-Chlordane®}

1024-57-3

1

1

1

2,5-Methano-2H-indeno[1,2-b]oxirene, 2,3,4,5,6,7,7-heptachloro-1a,1b,5,5a,6,6ahexahydro-, (1aD,1bE,2D,5D,5aE,6E,6aD){Heptachlor® epoxide}

Cl

XVIII.B-3, XXI-3 XVIII.B-3, XXI-3

Cl

Cl CCl2 O

Cl Cl

297-78-9

1

1

1

4,7-Methanoisobenzofuran, 1,3,4,5,6,7,8,8octachloro-1,3,3a,4,7,7a-hexahydro{Isobenzan®; Telodrin®}

Cl

Cl

Cl CCl2

XVIII.B-3, XXI-3

O

Cl Cl

Cl

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1655

11/24/08 1:56:45 PM

1656

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

113-48-4

0

1

0

4,7-Methano-1H-isoindole-1,3(2H)-dione, 2-(2ethylhexyl)-3a,4,7,7a-tetrahydro-

Name (per CA Collective Index)

67-56-1

1

1

1

Methanol

5293-97-0

1

1

1

Methanone, bis(2-chlorophenyl)-

90-98-2

1

0

0

Methanone, bis(4-chlorophenyl)-

Chapter Table

Selected structures

XIV-1, XXI-3

H3C-OH

II.A-5 III-13, XVIII.B-3, XXI-3 III-13, XVIII.B-3, XXI-3 O C

Cl

24966-13-0

1

0

0

Cl

Methanone, cyclopropyl-3-pyridinyl-

119-61-9

1

1

1

Methanone, diphenyl-

5162-03-8

0

1

0

Methanone, (2-chlorophenyl)phenyl-

{benzophenone}

2385-85-5

0

1

0

1,3,4-Metheno-1H-cyclobuta[cd])pentalene, 1,1a,2,2,3,3a,4,5,5,5a,5b,6dodecachlorooctahydro{Mirex®}

III-13 C6H5-CO-C6H5

III-13 III-13, XVIII.B-3 XXI-3

7005-18-7

0

1

0

Methionine

63-68-3

0

1

0

L-Methionine

20236-97-9

0

1

0

D-Methionine, N-(carboxyacetyl)-

2143-68-2

1

0

0

Methoxy radical

CH3O

XXVII-1

2229-07-4

1

0

0

Methyl radical

CH3

XXVII-1

55285-14-8

0

1

0

Methylcarbamic acid, 2,3-dihydro-2,2-dimethyl-7benzofuranyl [(di-N-butylamino)thio] ester {Carbosulfan®}

2032-59-9

0

1

0

Methylcarbamic acid, 4-(dimethylamino)-3methylphenyl ester {Aminocarb®}

2032-65-7

0

1

0

Methylcarbamic acid, 3,5-dimethyl-4(methylthio)phenyl ester {Methiocarb®}

XVIII.A-1 H3C-S-(CH2)2-CH(NH2)-COOH

XVIII.A-1 XVIII.A-1

(CH2)3-CH3

XXI-3

OOC-N(CH3)-S-N (CH2)3-CH3

O

(H3C)2N

OOC-NH-CH3

XXI-3

CH3

XXI-3

H3C-NH-COO

S

XXI-3

29973-13-5

0

1

0

Methylcarbamic acid, 2-((ethylthio)methyl)phenyl ester {Ethiofencarb®}

1822-74-8

1

0

0

Methyl ethenyl sulfide

50936-45-3

0

1

0

Methyltransferase, caffeate

XXII-2

H3C-NH-COO

H3C-S-CH=CH2-

S

XVIII.A-1

9012-25-3

0

1

0

Methyltransferase, catechol

XXII-2

152288-82-9

0

1

0

Methyltransferase, catechol (tobacco clone OMT3.4 isoenzyme II reduced)

XXII-2

9012-40-2

0

1

0

Methyltransferase, homocysteine

XXII-2

9027-77-4

0

1

0

Methyltransferase, methionine S-

XXII-2

9055-07-6

0

1

0

Methyltransferase, protein (arginine)

XXII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1656

11/24/08 1:56:46 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1657

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

9075-39-2

0

1

0

Methyltransferase, putrescine

7439-98-7

1

1

1

Molybdenum

Name (per CA Collective Index)

Selected structures

Chapter Table XXII-2

Mo

16065-87-5

0

1

0

Molybdenum, ion

110-91-8

0

1

0

Morpholine

Mo

110488-70-5

0

1

0

Morpholine, 3-(3-(4-chlorophenyl)-3-(3,4dimethoxyphenyl)-1-oxo-2-propenyl){Dimethomorph®; Acrobat®}

XX-5

+6

XX-5 X-2, XVII.D-2

147688-58-2

0

1

0

Morpholine, 2,2-dimethyl-

59-89-2

1

1

1

Morpholine, 4-nitroso-

70699-77-3

0

1

0

3-Morpholinepropanamide, 2-oxo-6-(1,2,3,4tetrahydroxybutyl)-, [3S-[3D,6D(1R*,2S*,3S*)]]-

X-2, XVII.D-2, XVIII.B-3, XXI-3

X-2, XVII.D-2 {NMOR}

X-2, XV-8, XVII.D-2

X-2, XVII.D-2

9047-56-7

0

1

0

Mutase

92-24-0

1

0

0

Naphthacene

XXII-2 I.E-6

5385-22-8

1

0

0

Naphth[1,2-e]acephenanthrylene {dibenzo[b,j]fluoranthene}

I.E-6

28258-64-2

1

0

0

Naphthalenamine, N-phenyl-

XII-2

134-32-7

1

0

0

1-Naphthalenamine {naphthalene, 1-amino-; Į-naphthylamine}

XII-2

2246-44-8

1

0

0

1-Naphthalenamine, 2-methyl-

XII-2

91-59-8

1

0

0

2-Naphthalenamine {naphthalene, 2-amino-; ȕ-naphthylamine}

XII-2

10546-24-4

1

0

0

2-Naphthalenamine, 3-methyl-

135-88-6

1

0

0

2-Naphthalenamine, N-phenyl-

91-20-3

1

1

1

Naphthalene

XII-2 NH-C6H5

1

8

2

7

4

5

91-17-8

0

0

Naphthalene, alkyl-

1

0

0

Naphthalene, decahydro-

I.E-6 8 8a 4a 5

0

1

0

Naphthalene, decahydro-1,6-dimethyl-4-(1methylethyl){cadinene}

1

7 6

29350-73-0

I.E-6

3

6

1

XII-2

2

I.C-1

3 4

I.C-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1657

11/24/08 1:56:47 PM

1658

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

3242-05-5

0

1

0

Naphthalene, decahydro-1,8a-dimethyl-7-(1methylethyl)-, [1S- (1D,4aD,7D,8aD)]-

3738-00-9

0

1

0

Naphthalene, decahydro-1-ethoxido-2,5,5,8atetramethyl{ambroxan}

31831-35-3

0

1

0

Naphthalene, diethyl-

29828-28-2

1

0

0

Naphthalene, dihydro-

I.E-6

72692-88-7

1

0

0

Naphthalene, dihydrodimethyl{at least 4 isomers in MSS}

I.E-6

39292-53-0

1

0

0

Naphthalene, dihydromethyl{at least 3 isomers in MSS}

I.E-6

2717-44-4

1

0

0

Naphthalene, 1,2-dihydro-3-methyl-

I.E-6

4373-13-1

1

0

0

Naphthalene, 1,2-dihydro-4-methyl-

I.E-6

67494-22-8

0

1

0

Naphthalene, 1,2-dihydro-5-methyl-3-(1methylethenyl)-

I.E-6

1

1

1

Naphthalene, dihydrotrimethyl{at least 2 isomers in MSS}

I.E-6

30364-38-6

1

1

1

Naphthalene, 1,2-dihydro-1,1,6-trimethyl-

I.E-6

4506-36-9

1

1

1

Naphthalene, 1,2-dihydro-1,5,8-trimethyl-

I.E-6

28804-88-8

1

1

1

Naphthalene, dimethyl-

I.E-6

573-98-8

1

1

1

Naphthalene, 1,2-dimethyl-

I.E-6

575-41-7

1

1

1

Naphthalene, 1,3-dimethyl-

I.E-6

571-58-4

1

1

1

Naphthalene, 1,4-dimethyl-

I.E-6

571-61-9

1

1

1

Naphthalene, 1,5-dimethyl-

I.E-6

575-43-9

1

1

1

Naphthalene, 1,6-dimethyl-

I.E-6

575-37-1

1

1

1

Naphthalene, 1,7-dimethyl-

I.E-6

569-41-5

1

1

1

Naphthalene, 1,8-dimethyl-

I.E-6

581-40-8

1

1

1

Naphthalene, 2,3-dimethyl-

I.E-6

581-42-0

1

1

1

Naphthalene, 2,6-dimethyl-

I.E-6

582-16-1

1

1

1

Naphthalene, 2,7-dimethyl-

I.E-6

Name (per CA Collective Index)

Selected structures

Chapter Table I.C-1

O-

X-2

I.E-6

71630-68-7

1

0

0

Naphthalene, dimethyl-2-ethenyl-

I.E-6

65319-44-0

1

0

0

Naphthalene, dimethylethyl-

I.E-6

71607-89-1

1

0

0

Naphthalene, 1,4-dimethyl-2-ethyl-

I.E-6

66309-90-8

1

0

0

Naphthalene, 1,4-dimethyl- 5-ethyl-

I.E-6

483-76-1

0

1

0

Naphthalene, 4,7-dimethyl-1,2,3,5,6,8a-hexahydro1-(1-methylethyl)-, (1S-cis)-

I.C-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1658

11/24/08 1:56:47 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1659

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

31983-22-9

0

1

0

Naphthalene, 4,7-dimethyl-1,2,4a,5,6,8ahexahydro-1-(1-methylethyl){Į-muurolene}

I.C-1

483-77-2

0

1

0

Naphthalene, 1,6-dimethyl-4-(1-methylethyl)1,2,3,4-tetrahydro-, (1S-Z)-

I.E-6

4630-07-3

0

1

0

Naphthalene, 1,8a-dimethyl-7-(1-methylethenyl)1,2,3,5,6,7,8,8a-octahydro- [1R 1Į,7ȕ,8a Į] {valencene}

I.C-1

Name (per CA Collective Index)

Selected structures

CH2 CH3

10219-75-7

0

1

0

CH3

CH3

I.C-1

Naphthalene, 1,8a-dimethyl-7-(1-methylethenyl)1,2,3,5,6,7,8,8a-octahydro- [1R 1Į,7 Į,8a Į] {eremophilene}

CH2 CH3

71607-60-8

Chapter Table

CH3

CH3

1

0

0

Naphthalene, dimethyl-2-phenyl-

I.E-6

1

0

0

Naphthalene, dimethyltetrahydro{at least 3 isomers in MSS}

I.E-6

51855-29-9 65338-07-0

1

0

0

Naphthalene, dimethyl-1,2,3,4-tetrahydro{at least 5 isomers in MSS}

I.E-6

826-74-4

1

0

0

Naphthalene, 1-ethenyl-

I.E-6

827-54-3

1

0

0

Naphthalene, 2-ethenyl-

I.E-6

64031-89-6

1

0

0

Naphthalene, 2-ethenylmethyl{at least 2 isomers in MSS}

I.E-6

35737-86-1

1

0

0

Naphthalene, 2-ethenyl-1-methyl-

I.E-6

93-18-5

0

1

0

Naphthalene, 2-ethoxy-

X-2

27138-19-8

1

0

0

Naphthalene, ethyl-

I.E-6

1127-76-0

1

1

1

Naphthalene, 1-ethyl-

I.E-6

939-27-5

1

1

1

Naphthalene, 2-ethyl-

I.E-6

31391-42-1

1

0

0

Naphthalene, ethylmethyl-

I.E-6

17057-94-2

1

1

1

Naphthalene, 1-ethyl-3-methyl-

I.E-6

17057-92-0

1

1

1

Naphthalene, 1-ethyl-5-methyl-

I.E-6

31032-91-4

1

1

1

Naphthalene, 1-ethyl-6-methyl-

I.E-6

31032-92-5

1

1

1

Naphthalene, 1-ethyl-7-methyl-

I.E-6

61886-71-3

1

1

1

Naphthalene, 1-ethyl-8-methyl-

I.E-6

31032-94-7

1

1

1

Naphthalene, 2-ethyl-3-methyl-

I.E-6

17179-41-8

1

1

1

Naphthalene, 2-ethyl-4-methyl{naphthalene, 3-ethyl-1-methyl-}

I.E-6

17059-53-9

1

1

1

Naphthalene, 2-ethyl-5-methyl{naphthalene, 6-ethyl-1-methyl-}

I.E-6

7372-86-3

1

1

1

Naphthalene, 2-ethyl-6-methyl-

I.E-6

17059-55-1

1

1

1

Naphthalene, 2-ethyl-7-methyl-

I.E-6

{E-naphthyl ethyl ether}

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1659

11/24/08 1:56:47 PM

1660

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

77242-78-5

1

0

0

Naphthalene, hexamethyl-

I.E-6

93-04-9

0

1

0

Naphthalene, 2-methoxy-

X-2

1321-94-4

1

1

1

Naphthalene, methyl-

I.E-6

90-12-0

1

1

1

Naphthalene, 1-methyl-

I.E-6

91-57-6

1

1

1

Naphthalene, 2-methyl-

I.E-6

29253-36-9

1

1

1

Naphthalene, (1-methylethyl)-

I.E-6

0

1

0

Naphthalene, 2 (1-methylethyl)-

I.E-6

0

1

0

Naphthalene, 7-methyl-4-methylene-1-(1methylethyl)- 1,2,3,4,4a,5,6,8a-octahydro-, (1D,4aE,8aD){Ȗ-cadinene}

I.C-1

1

0

0

Naphthalene, methylphenyl-

I.E-6

71607-61-9

1

0

0

Naphthalene, methyl-2-phenyl-

I.E-6

34540-66-4

0

1

0

Naphthalene, methylpropyl-

I.E-6

39029-41-9

1680-58-6

1

1

1

Naphthalene, 1-(1-methylpropyl)-

I.E-6

16727-91-6

1

1

1

Naphthalene, 1-(2-methylpropyl)-

I.E-6

71607-57-3

1

1

1

Naphthalene, methyltetrahydro{at least 3 isomers in MSS}

I.E-6

31291-71-1

1

1

1

Naphthalene, methyl-1,2,3,4-tetrahydro-

I.E-6

1

1

1

Naphthalene, 1-methyl-1,2,3,4-tetrahydro-

I.E-6

3877-19-8

1

1

1

Naphthalene, 2-methyl-1,2,3,4-tetrahydro-

I.E-6

2809-64-5

0

1

0

Naphthalene, 5-methyl-1,2,3,4-tetrahydro-

I.E-6

1680-51-9

1

1

1

Naphthalene, 6-methyl-1,2,3,4-tetrahydro{naphthalene, 2-methyl-5,6,7,8-tetrahydro-}

I.E-6

86-57-7

1

1

1

Naphthalene, 1-nitro-

XVI-1

56908-81-7

1

1

1

Naphthalene, pentamethyl-

I.E-6

605-02-7

1

1

1

Naphthalene, 1-phenyl-

I.E-6

612-94-2

1

1

1

Naphthalene, 2-phenyl-

I.E-6

71697-04-6

1

0

0

Naphthalene, phenyl-, monomethyl derivative

I.E-6

27378-74-1

0

1

0

Naphthalene, propyl-

I.E-6

2765-18-6

1

0

0

Naphthalene, 1-propyl-

I.E-6

2027-19-2

1

0

0

Naphthalene, 2-propyl-

I.E-6

119-64-2

1

1

1

Naphthalene, 1,2,3,4-tetrahydro-

{tetralin}

I.E-6

121214-18-4

1

0

0

Naphthalene, tetrahydrotrimethyl{at least 3 isomers in MSS}

I.E-6

72843-02-8

1

0

0

Naphthalene, 1,2,3,4-tetrahydrotrimethyl{at least 3 isomers in MSS}

I.E-6

475-03-6

1

1

1

Naphthalene, 1,2,3,4-tetrahydro-1,1,6-trimethyl{Į-ionene}

I.E-6

21693-51-6

0

1

0

Naphthalene, 1,2,3,4-tetrahydro-1,5,8-trimethyl-

I.E-6

30316-36-0

0

1

0

Naphthalene, 1,2,3,4-tetrahydro-1,6,8-trimethyl-

I.E-6

28652-74-6

1

1

1

Naphthalene, tetramethyl{at least 4 isomers in MSS}

I.E-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1660

11/24/08 1:56:48 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1661

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

28652-77-9

1

1

1

Naphthalene, trimethyl{at least 10 isomers in MSS}

I.E-6

2717-42-2

1

1

1

Naphthalene, 1,2,4-trimethyl-

I.E-6

3031-05-8

1

1

1

Naphthalene, 1,2,6-trimethyl-

I.E-6

486-34-0

1

1

1

Naphthalene, 1,2,7-trimethyl-

I.E-6

2131-39-7

1

1

1

Naphthalene, 1,3,5-trimethyl-

I.E-6

3031-08-1

1

1

1

Naphthalene, 1,3,6-trimethyl-

I.E-6

2131-41-1

1

0

0

Naphthalene, 1,4,5-trimethyl-

I.E-6

2131-42-2

1

1

1

Naphthalene, 1,4,6-trimethyl-

I.E-6

2245-38-7

1

1

1

Naphthalene, 1,6,7-trimethyl{naphthalene, 2,3,5-trimethyl-}

I.E-6

Name (per CA Collective Index)

829-26-5

1

1

1

Naphthalene, 2,3,6-trimethyl-

68985-11-5

0

1

0

1-Naphthaleneacetaldehyde, 3,4,4a,5,6,7,8,8aoctahydro-2,5,5,8a-tetramethyl-, (4aS-trans)-

3243-36-5

0

1

0

1-Naphthaleneacetaldehyde, decahydro-5,5,8atrimethyl-2-methylene-, [1S-(1D,4aE,8aD)]-

68982-27-4

0

1

0

Selected structures

Chapter Table

I.E-6 III-12

CHO

III-12

CHO CH2

1-Naphthaleneacetaldehyde, decahydro-5,5,8atrimethyl-2-oxo-, [1R-(1D,4aE,8aD)]-

III-12, III-13

86-87-3

0

1

0

1-Naphthaleneacetic acid

IV.A-3, XXI-3

132-75-2

1

0

0

1-Naphthaleneacetonitrile

XI-2

25551-35-3

1

0

0

Naphthalenecarbonitrile

XI-2

1

0

0

Naphthalenecarbonitrile, alkyl-

XI-2

1

0

0

Naphthalenecarbonitrile, methyl-

86-53-3

1

0

0

1-Naphthalenecarbonitrile

23245-64-9

1

0

0

1-Naphthalenecarbonitrile, 5-nitro-

XI-2

613-46-7

1

0

0

2-Naphthalenecarbonitrile

XI-2

68985-10-4

0

1

0

1-Naphthalenecarboxaldehyde, 3,4,4a,5,6,7,8,8aoctahydro-2,5,5,8a-tetramethyl-, (4aS-trans)-

31519-22-9

0

1

0

2-Naphthalenecarboxylic acid, 1,4-dihydroxy-

79886-54-7

0

1

0

1,2-Naphthalenediol, decahydro-2,5,5,8atetramethyl-, [1R-(1D,2E,4aE,8aD)]-

37208-05-2

0

1

0

1,3-Naphthalenediol, 1,2,3,4,4a,5,6,7-octahydro4,4a-dimethyl-6-(1-methylethenyl)-, [1R(1D,3E,4E,4aD,6D)]-

XI-2

{2 isomers)

XI-2

IV.A-3 II.A-5

CH2 CH3

0

1

0

1,3-Naphthalenediol, 1,2,3,4,4a,5,6,7-octahydro4,4a-dimethyl-6-(1-methylethenyl)-, 3-acetate, [1R(1D,3E,4.

II.A-5

OH

HO

114393-99-6

III-12

CHO

CH3

CH3

II.A-5, V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1661

11/24/08 1:56:48 PM

1662

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

65513-74-8

0

1

0

1,3-Naphthalenediol, 1,2,3,4,4a,5,6,7-octahydro-6[1-(hydroxymethyl)ethenyl]-4,4a-dimethyl-, (1D,3E,4E,4aD,6D)-

Name (per CA Collective Index)

Selected structures

Chapter Table II.A-5

92-44-4

1

0

0

2,3-Naphthalenediol

27656-76-4

0

1

0

IX.A-22

2,3-Naphthalenediol, 1,2D,3E,4,5,6,7,8-octahydro7D-isopropenyl-1D-methyl-

II.A-5

18178-54-6

1

1

1

2,3-Naphthalenediol, 1,2,3,4,5,6,7,8-octahydro-1methyl-7-(1-methylethenyl)-, [1S-(1D,2E,3D,7E)]{rishitin}

II.A-5

73496-12-5

0

1

0

2,3-Naphthalenediol, decahydro-2,5,5,8atetramethyl-1-(3-methyl-2,4-pentadienyl)-, [1S[1D(E),2D,3E,4aE,8aD]]-

1

0

0

1,2-Naphthalenedione

CH3 CH2 OH

H3C

524-42-5

II.A-5

CH3 CH3

OH

CH3

{1,2-naphthoquinone}

IX.B-2

O O

117769-22-9

0

1

0

2,3-Naphthalenedione, 4,4a,5,6,7,8-hexahydro1,4a-dimethyl-7-(1-methylethenyl)-

III-13

CH3

CH3

O

H2C

O CH3

88125-12-6

0

1

0

2,3-Naphthalenedione, 4,4a,5,6,7,8-hexahydro1,4a-dimethyl-7-(1-methylethenyl)-, (4aS-cis)-

130-15-4

1

0

0

1,4-Naphthalenedione

{1,4-naphthoquinone}

III-13 O

IX.B-2

O

IX.B-2, XVIII.B-3, XXI-3

117-80-6

0

1

0

1,4-Naphthalenedione, 2,3-dichloro- {Diclone®}

73850-17-6

1

0

0

1,4-Naphthalenedione, dimethyl-

IX.B-2

2197-57-1

1

0

0

1,4-Naphthalenedione, 2,3-dimethyl-

IX.B-2

482-70-2

1

0

0

1,4-Naphthalenedione, 2,7-dimethyl-

IX.B-2

68860-42-4

1

1

1

1,4-Naphthalenedione, 2,3-dimethyl-6-(4,8,12trimethyltridecyl)-, (R*,R*)-

IX.B-2

481-39-0

0

1

0

1,4-Naphthalenedione, 5-hydroxy-

IX.B-2

1

0

0

1,4-Naphthalenedione, methyl-

58-27-5

1

0

0

1,4-Naphthalenedione, 2-methyl-

IX.B-2

84-80-0

0

1

0

1,4-Naphthalenedione, 2-methyl-3-(3,7,11,15tetramethyl-2-hexadecenyl)-, [R-[R*,R*-(E)]]{Vitamin K1}

IX.B-2

73850-15-4

{juglone}

IX.B-2

1

0

0

1,4-Naphthalenedione, tetramethyl-

IX.B-2

1

0

0

1,4-Naphthalenedione, trimethyl-

IX.B-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1662

11/24/08 1:56:49 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1663

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

20490-42-0

1

1

1

1,4-Naphthalenedione, 2,3,6-trimethyl-

IX.B-2

59832-90-5

1

0

0

1,4-Naphthalenedione, 2,6,7-trimethyl-

IX.B-2

102977-87-7

0

1

0

2-Naphthaleneethanol, 3,4-dihydro-1,5,6-trimethyl-

II.A-5

52617-99-9

0

1

0

1-Naphthalenemethanol, decahydro-2-hydroxy2,5,5,8a-tetramethyl-, [1S-(1D,2E,4aE,8aD)]-

II.A-5

29484-46-6

0

1

0

2-Naphthalenemethanol, 1,2,3,4,4a,8a-hexahydroD,D,4a,8-tetramethyl-, [2S-(2D,4aE,8aE)]-

II.A-5

473-17-6

0

1

0

2-Naphthalenemethanol, 1,2,3,4,4a,8a-hexahydroD,D,4a,8-tetramethyl-, [2R-(2D,4aE,8aE)]-

II.A-5

87797-89-5

0

1

0

2-Naphthalenemethanol, 1,2,3,4-tetrahydro-D,D,5,6tetramethyl-, (R)-

II.A-5

5986-36-7

0

1

0

2-Naphthalenemethanol, 1,2,3,4-tetrahydro-D,D,5,8tetramethyl-, (R)-

II.A-5

61263-48-7

0

1

0

2-Naphthalenemethanol, 1,2,3,4-tetrahydro-D,D,5,8tetramethyl-, acetate, (R)-

II.A-5

87797-88-4

0

1

0

2-Naphthalenemethanol, 1,2,3,4-tetrahydro-D,D,7,8tetramethyl-, (R)-

II.A-5

121269-01-0

0

1

0

2-Naphthalenemethanol, 3,4-dihydro-1,5,6trimethyl-

II.A-5

10267-21-7

0

1

0

1-Naphthalenepentanol, decahydro-2-hydroxyJ,2,5,5,8a-pentamethyl-, [1R-[1D(S*),2E,4aE,8aD]]

II.A-5

0

1

0

1-Naphthalene-2-pentenol, decahydro-J,2,5,5,8apentamethyl-

II.A-5

0

1

0

1-Naphthalene-2-pentenol, 3,4,4a,5,6,7,8,8aoctahydro-J,2,5,5,8a-pentamethyl-

II.A-5

596-85-0

0

1

0

1-Naphthalenepropanol, D-ethenyldecahydroD,5,5,8a-tetramethyl-2-methylene-, [1S[1D(S*),4aE,8aD]]{manool}

4630-08-4

0

1

0

1-Naphthalenepropanol, D-ethenyldecahydro-2hydroxy-D,2,5,5,8a-pentamethyl-, [1R[1D(S*),2E,4aE,8aD]]{episclareol}

II.A-5

515-03-7

0

1

0

1-Naphthalenepropanol, D-ethenyldecahydro-2hydroxy-D,2,5,5,8a-pentamethyl-, [1R[1D(R*),2E,4aE,8aD]]{sclareol}

II.A-5

57567-06-3

0

1

0

1-Naphthalenepropanol, D-ethenyldecahydro-7hydroxy-D,5,5,8a- tetramethyl-2-methylene-

II.A-5

121198-51-4

0

1

0

Naphthalenol, 6,8-dimethyl-

Name (per CA Collective Index)

121198-52-5

0

1

0

Naphthalenol, 7,8-dimethyl-

90-15-3

1

0

0

1-Naphthalenol

Selected structures

Chapter Table

II.A-5

OH

IX.A-22 IX.A-22

{1-naphthol = D-naphthol}

IX.A-22

OH 8 2

7 6

3 5

40529-54-2 59534-35-9

1

0

0

1-Naphthalenol, dimethyl-

4

IX.A-22

1

0

0

1-Naphthalenol, methyl-

IX.A-22

1

0

0

1-Naphthalenol, methyl-nitro-

IX.A-22

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1663

11/24/08 1:56:49 PM

1664

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

7469-77-4

1

0

0

1-Naphthalenol, 2-methyl-

63-25-2

1

1

1

1-Naphthalenol, methylcarbamate {Sevin®; Carbaryl®}

IX.A-22

529-33-9

1

0

0

1-Naphthalenol, 1,2,3,4-tetrahydro-

55591-08-7

0

1

0

1-Naphthalenol, 1,2,3,4-tetrahydro-2,5,8-trimethyl-

II.A-5

30316-22-4

1

0

0

1-Naphthalenol, 1,2,3,4-tetrahydro-3,5,8-trimethyl-

II.A-5

66324-66-1

0

1

0

1-Naphthalenol, 1,2,3,4-tetrahydro-4,5,8-trimethyl-

II.A-5

67494-23-9

0

1

0

1-Naphthalenol, 1,2,3,4-tetrahydro-8-methyl-2-(1methylethenyl)-, (Z)-(r)

II.A-5

135-19-3

1

0

0

2-Naphthalenol

31149-06-1

0

1

0

2-Naphthalenol, 1-[5-(acetyloxy)-3-methyl-3pentenyl]decahydro-2,5,5,8a-tetramethyl-, [1R[1D(E),2E,4aE,8aD]]-

0

1

0

II.A-5

OH

{2-naphthol = E-naphthol}

IX.A-22, XXI-3

OH

CH3 CH3

II.A-5, V-3

CH3 CH2O-COCH3 OH

H3C

66890-73-1

V-3, XXI-3

OOC-NH-CH3

CH3

2-Naphthalenol, decahydro-1-(3-hydroxy-3-methyl1,4-pentadienyl)-2,5,5,8a-tetramethyl-, [1R[1D(1E,3S*),2E,4aE,8aD]]-

II.A-5

OH

H3C

CH2 CH3

CH3

OH H3C

66966-02-7

0

1

0

CH3

2-Naphthalenol, decahydro-1-(3-hydroxy-3-methyl1,4-pentadienyl)-2,5,5,8a-tetramethyl-, [1R[1D(1E,3R*),2E,4aE,8aD]]-

II.A-5

OH

H3C

CH2 CH3

CH3

OH H3C

10267-31-9

0

1

0

CH3

2-Naphthalenol, decahydro-1-(5-hydroxy-3-methyl3-pentenyl)-2,5,5,8a-tetramethyl-, [1R[1D(E),2E,4aE,8aD]]-

CH3 CH3

II.A-5

CH3 CH2OH OH

H3C

CH3

22343-28-8

0

1

0

2-Naphthalenol, decahydro-1-(5-hydroxy-3-methyl3-pentenyl)-2,5,5,8a-tetramethyl-, [1R(1D,2E,4aE,8aD)]-

II.A-5

53163-43-2

0

1

0

2-Naphthalenol, decahydro-1,2,5,5,8a-pentamethyl, [1R-(1D,2E,4aE,8aD)]-

II.A-5

36211-21-9

0

1

0

2-Naphthalenol, decahydro-2,5,5,8a-tetramethyl7 6

H3C

5

8a 4a

II.A-5

CH3

CH3 8

1 4

2 3

OH

CH3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1664

11/24/08 1:56:50 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1665

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

49749-17-9

0

1

0

2-Naphthalenol, decahydro-2,5,5,8a-tetramethyl-, (2D,4aD,8aE)-(±)-

II.A-5

42569-63-1

1

0

0

2-Naphthalenol, decahydro-2,5,5,8a-tetramethyl-1(3-methyl-1,3-pentadienyl)-, [1R[1D(1E,3E),2E,4aE,8aD]]-

II.A-5

1616-86-0

0

1

0

2-Naphthalenol, decahydro-2,5,5,8a-tetramethyl-1(3-methyl-2,4-pentadienyl)-, [1R-(1D,2E,4aE,8aD)]{Z-abienol}

Name (per CA Collective Index)

Selected structures

CH3 CH3

8 7

8a

6

0

1

0

2-Naphthalenol, decahydro-2,5,5,8a-tetramethyl-1(3-methyl-2,4-pentadienyl)-, [1R[1D(E),2E,4aE,8aD]]-

5

1

0

2-Naphthalenol, decahydro-2,5,5,8a-tetramethyl-1(3-methyl-2,4-pentadienyl)-, [1R[1D(Z),2E,4aE,8aD]]-

62121-32-8

0

1

0

2-Naphthalenol, decahydro-2,5,5,8a-tetramethyl-1[(3-methyl-2-furanyl)methyl]-, [1R(1D,2E,4aE,8aD)]-

2

CH2

OH

4

CH3

8 7

8a

II.A-5

CH3 1

CH3

2

OH 3

5

4 CH3

H3C

0

1

CH3

6

17990-16-8

II.A-5, XXI-3

CH3

3

H3C

17990-15-7

Chapter Table

II.A-5

II.A-5

O

CH3

CH3

CH3 OH

H3C

CH3

82451-46-5

0

1

0

2-Naphthalenol, decahydro-4a,8,8-trimethyl-3methylene-4-(3-methyl-2,4-pentadienyl)-, [2S[2D,4D(E),4aD,8aE]]-

II.A-5

82458-63-7

0

1

0

2-Naphthalenol, decahydro-4a,8,8-trimethyl-3methylene-4-(3-methylene-4-pentenyl)-, [2S(2D,4D,4aD,8aE)]-

II.A-5

58239-50-2

0

1

0

2-Naphthalenol, decahydro-5,5,8a-trimethyl-, [2R(2D,4aD,8aE)]-

II.A-5

1

0

0

2-Naphthalenol, dimethyl-

IX.A-22

54703-51-4

1

0

0

2-Naphthalenol, 1,8-dimethyl-

IX.A-22

59534-36-0

1

0

0

2-Naphthalenol, methyl-

IX.A-22 IX.A-22

1076-26-2

1

0

0

2-Naphthalenol, 1-methyl-

71369-76-1

1

0

0

2-Naphthalenol, tetrahydro-

530-91-6

1

0

0

2-Naphthalenol, 1,2,3,4-tetrahydro-

1125-78-6

IX.A-22 II.A-5

OH

1

0

0

2-Naphthalenol, 5,6,7,8-tetrahydro-

IX.A-22

1

0

0

2-Naphthalenol, 5,6,7,8-tetramethyl-

IX.A-22

73850-18-7

1

0

0

2-Naphthalenol, trimethyl-

IX.A-22

30889-50-0

1

0

0

2-Naphthalenol, 3,5,8-trimethyl-

17910-08-6

0

1

0

4a(2H)-Naphthalenol, 1,5,6,7,8,8a-hexahydro-4,7dimethyl-1-(1-methylethyl)-, [1S-(1D,4aE,7D,8aD)]-

IX.A-22 5 6

4a 7

H3C

OH

4 1

8

H3C

II.A-5

CH3 3 2

CH3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1665

11/24/08 1:56:50 PM

1666

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

529-34-0

1

0

0

1(2H)-Naphthalenone, 3,4-dihydro-

117210-52-3

0

1

0

1(2H)-Naphthalenone, 3,4-dihydro-5-methyl-3-(1methylethenyl)-

III-13

1

0

0

1(2H)-Naphthalenone, 3,4-dihydro-4,5,6-trimethyl-

III-13

27410-97-5

1

0

0

1(2H)-Naphthalenone, 3,4-dihydro-4,5,7-trimethyl-

III-13

41720-93-8

0

1

0

1(2H)-Naphthalenone, 3,4,4a,5,6,7-hexahydro-3hydroxy-4,4a-dimethyl-6-(1-methylethenyl)-, [3R(3D,4D,4aE,6E)]-

III-13

52811-60-6

0

1

0

1(2H)-Naphthalenone, octahydro-2-hydroxy2,5,5,8a-tetramethyl-

Name (per CA Collective Index)

Selected structures

{1-tetralone}

III-13

O

O

H3C

Chapter Table

II.A-5, III-13

OH CH3

H3C

55497-93-3

0

1

0

1(2H)-Naphthalenone, octahydro-2-hydroxy2,5,5,8a-tetramethyl-, [2R- (2D,4aD,8aE)]-

25487-94-9

0

1

0

1(4H)-Naphthalenone, 4a,5,6,7,8,8a-hexahydro2,5,5,8a-tetramethyl-, (4aS-trans)-

CH3

II.A-5, III-13 H3C

H3C

III-13

O CH3

CH3

57601-69-1

0

1

0

1(4H)-Naphthalenone, 2-hydroxy-4,4,7-trimethyl-

117472-47-6

0

1

0

1(4H)-Naphthalenone, 5,6,7,8-tetrahydro-8-methyl5-(1-methylethenyl)-

III-13

29210-91-1

1

0

0

2(1H)-Naphthalenone, 3,4-dihydro-4,4,7-trimethyl-

III-13

55733-01-2

0

1

0

2(1H)-Naphthalenone, 4a,5,6,7,8,8a-hexahydro3,4,4a,8,8-pentamethyl-, (4aS-trans)-

III-13

76739-26-9

0

1

0

2(1H)-Naphthalenone, 4a,5,6,7,8,8a-hexahydro3,4,4a,8,8-pentamethyl-

III-13

0

1

0

2(1H)-Naphthalenone, 4a,5,6,7,8,8a-hexahydro-3hydroxy-3,4a,8,8-tetramethyl{2 isomers reported}

0

1

0

2(1H)-Naphthalenone, 4a,5,6,7,8,8a-hexahydro3,4a,8,8-tetramethyl-, (4aR-trans){isonordimenone}

51020-10-1

III-13, IX.A-22

II.A-5, III-13

H3C

H3C

CH3

III-13

CH3

O

72446-33-4

0

1

0

2(1H)-Naphthalenone, 4a,5,6,7,8,8a-hexahydro3,4a,8,8-tetramethyl-4-(3-oxobutyl)-, (4aS-trans)-

III-13

14506-68-4

0

1

0

2(1H)-Naphthalenone, 1-(3-hydroxy-3-methyl-4pentenyl)-octahydro-5,5,8a-trimethyl-, [1R[1D(R*),4aE,8aD]]-

II.A-5, III-13

57567-07-4

0

1

0

2(1H)-Naphthalenone, 8-(3-hydroxy-3-methyl-4pentenyl)-octahydro-4,4,8a- trimethyl-7methylene-

II.A-5, III-13

473-08-5

1

1

1

2(3H)-Naphthalenone, 4,4a,5,6,7,8-hexahydro-1,4adimethyl-7-(1-methylethenyl)-, (4aS-cis){bicyclo[4.4.0]dec-1-en-3-one, 2,6-dimethyl-9isopropenyl-}

60026-22-4

1

0

0

2(3H)-Naphthalenone, 4,4a,5,6,7,8-hexahydro-1,4adimethyl-7-(1-methylethenyl)- {6-epicyperone-1}

O

III-13

III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1666

11/24/08 1:56:51 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1667

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

55051-94-0

0

1

0

Name (per CA Collective Index) 2(3H)-Naphthalenone, 4,4a,5,6,7,8-hexahydro-3hydroxy-4-methyl-6-(1-methylethenyl)-, [3R(3D,4E,4aE,6D)]-

Selected structures

II.A-5, III-13

CH2

CH3 HO

Chapter Table

CH3

O

4674-50-4

0

1

0

2(3H)-Naphthalenone, 4,4a,5,6,7,8-hexahydro-4,4adimethyl-6-(1-methylethenyl)-, [4R-(4D,4aD,6E)]{bicyclo[4.4.0]dec-1-en-3-one, 5,6-dimethyl-8isopropenyl-} {nootkatone}

102977-86-6

0

1

0

2(3H)-Naphthalenone, 4,4a,5,6,7,8-hexahydro-4a,8dimethyl-7-(1-methylethenyl)-

38044-00-7

0

1

0

2(3H)-Naphthalenone, 4,4a,5,6,7,8-hexahydro-4hydroxy-1,4a-dimethyl-7-(1-methylethenyl)-

39815-74-2

0

1

0

2(3H)-Naphthalenone, 4,6,7,8-tetrahydro-4,4,7trimethyl-

CH3

III-13

CH2

CH3

CH3 O

III-13 II.A-5, III-13

3

4

III-13

5

6 7

2

O

68420-60-0

0

1

0

2(4aH)-Naphthalenone, 5,6,7,8-tetrahydro-3hydroxy-1,4a-dimethyl-7-(1-methylethenyl)-, (4aScis)-

II.A-5, III-13

CH3

HO

CH2

O CH3

CH3

38043-97-9

1

1

1

2(4aH)-Naphthalenone, 5,6,7,8-tetrahydro-4hydroxy-1,4a-dimethyl-7-(1-methylethenyl)-, (4aRcis){1-keto-Į-cyperone}

OH

II.A-5, III-13

CH3

CH2

O CH3

CH3

0

1

0

2(6H)-Naphthalenone, 3,4,7,8-tetrahydro-4,4,7trimethyl-

3 2

4

5

III-13 6 7

O

1338-24-5

0

1

0

Naphthenic acids

IV.A-3

192-65-4

1

0

0

Naphtho[1,2,3,4-def]chrysene {dibenzo[a,e]pyrene}

I.E-6

190-99-8

1

0

0

1H-Naphtho[3,2,1,8-defg]chrysene {1,2,5,6-dibenzopyrene}

I.E-6

11141-17-6

0

1

0

1H,7H-Naphtho[1,8a,8-bc:4,4a-c’]difuran-3,7a1 dicarboxylic acid, (3S,3aR,4S, 5S,5aR, 5a R 7aS,8R,10S,10aS)-8-acetoxy1 3,3a,4,5a,5a ,7a,8,9,10-decahydro-3,5-dihydroxy4-{(1S,3S,7S,8R,9S,11R)-7-hydroxy-9-methyl3,7 9,11 2,4,10-trioxatetracyclo[6.3.1.0 .0 ]dodeca-5-en11-yl}-4-methyl-10[(E)-2-methylbut-2-enoyloxy]-, dimethyl ester {Azadirachtin® A and B, Neem®}

XXI-3

1

0

0

Naphthofuran

X-2

1

0

0

Naphthofuran, dimethyl-

X-2

© 2009 by Taylor & Francis Group, LLC

78836_C030.indd 1667

11/24/08 1:56:53 PM

1668

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

Naphthofuran, methyl-

X-2

234-03-7

1

0

0

Naphtho[1,2-b]furan

X-2

71607-62-0

1

0

0

Naphtho[1,2-b]furan, dimethyl-

X-2

25826-63-5

1

0

0

Naphtho[1,2-b]furan, 2-methyl-

232-95-1

1

0

0

Naphtho[2,1-b]furan

X-2 X-2 O

65588-69-4 6790-58-5

0

1

0

Naphtho[2,1-b]furan, dodecahydro-3a,6,6,9atetramethyl-, [3aR-(3aD,5aE,9aD,9bE)]{ambroxide; ambroxyl}

52811-62-8

0

1

0

Naphtho[2,1-b]furan-2-ol, dodecahydro-3a,6,6,9atetramethyl{sclaral}

X-2

O

H3C

II.A-5, X-2

CH3

CH3 CH3

O OH

30450-17-0

0

1

0

Naphtho[2,1-b]furan-2(1H)-one, decahydro3a,6,6,9a-tetramethyl-, [3aS- (3aD,5aD,9aE,9bD)]-

564-20-5

1

1

1

Naphtho[2,1-b]furan-2(1H)-one, decahydro3a,6,6,9a-tetramethyl-, [3aR-(3aD,5aE,9aD,9bE)]{1,5,5,9-tetramethyl-13oxatricyclo[8,3,0,0(4,9)]tridecane} {sclareolide}

52811-59-3

1

1

1

Naphtho[2,1-b]furan-2(1H)-one, decahydro3a,6,6,9a-tetramethyl-, [3aR-(3aD,5aE,9aD,9bE)]{1,5,5,9-tetramethyl-1314 oxatricyclo[8,3,0,0(4,9)]tridecane}, labeled with C 14 {sclareolide- C}

0

1

0

Naphtho[2,1-b]furan-2(3aH)-one, 4,5,5a,6,7,8,9,9aoctahydro-3a,6,6,9a-tetramethyl-, [3aR(3aD,5aE,9aD)]-

X-2 H3C

VI-3

CH3 CH3 CH3

O

O

XXV-29

H 3C

VI-3

CH3

CH 3 O

CH3

O

56682-25-8

0

1

0

Naphtho[2,1-b]furan-2-methanol, Dethenyldodecahydro-D,3a,6,6,9a-pentamethyl-, [2R-[2D(R*),3aE,5aD,9aE,9bD]]-

II.A-5, X-2

OH H2C CH3

CH3 O CH3

H3C

56711-38-7

0

1

0

Naphtho[2,1-b]furan-2-methanol, Dethenyldodecahydro-D,3a,6,6,9a-pentamethyl-, [2R-[2D(S*),3aE,5aD,9aE,9bD]]-

CH3

OH H2C CH3

II.A-5, X-2

CH3 O CH3

H3C

CH3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1668

11/24/08 1:56:53 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1669

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

56711-39-8

0

1

0

Name (per CA Collective Index)

Selected structures

Naphtho[2,1-b]furan-2-methanol, Dethenyldodecahydro-D,3a,6,6,9a-pentamethyl-, [2S-[2D(S*),3aD,5aE,9aD,9bE]]-

II.A-5, X-2

OH H2C

Chapter Table

CH3

CH3

O CH3

H3C

56711-40-1

0

1

0

Naphtho[2,1-b]furan-2-methanol, Dethenyldodecahydro-D,3a,6,6,9a-pentamethyl-, [2S-[2D(R*),3aD,5aE,9aD,9bE]]-

CH3

II.A-5, X-2

OH H2C

CH3

CH3

O CH3

H3C

196-42-9

1

0

0

Naphtho[2,1,8-qra]naphthacene

52811-58-2

0

1

0

3H-Naphtho[2,1-b]pyran-3-one, 4a,5,6,6a,7,8,9,10,10a,10b-decahydro-4a,7,7,10atetramethyl-, [4aR-(4aD,6aE,10aD,10bE)]{dehydroambreinolide}

CH3

I.E-6

H3C

VI-3

CH3 CH3 O

CH3

O

468-84-8

0

1

0

3H-Naphtho[2,1-b]pyran-3-one, dodecahydro4a,7,7,10a-tetramethyl-, [4aR(4aD,6aE,10aD,10bE)]{ambreinolide}

VI-3

5153-92-4

0

1

0

1H-Naphtho[2,1-b]pyran, 4a,5,6,6a,7,8,9,10,10a,10b-decahydro3,4a,7,7,10a-pentamethyl-, [4aR(4aD,6aE,10aD,10bE)]-

X-2

6252-26-2

0

1

0

1H-Naphtho[2,1-b]pyran, dodecahydro3,4a,7,7,10a-pentamethyl-

X-2

596-84-9

0

1

0

1H-Naphtho[2,1-b]pyran, 3-ethenyldodecahydro3,4a,7,7,10a-pentamethyl-, [3R(3D,4aE,6aD,10aE,10bD)]-

X-2

59170-14-8

1

1

1

1H-Naphtho[2,1-b]pyran-2-ol, 3ethenyldodecahydro-3,4a,7,7,10a-pentamethyl-, [2S-(2D,3E,4aE,6aD,10aE,10bD)]{labd-14-ene, 8,13-epoxy-12Į-hydroxy-} {12Į-hydroxy-13-epimanoyl oxide}

OH

0

1

0

CH2

CH3 O CH3 H3C

64681-69-2

II.A-5, X-2

CH3

1H-Naphtho[2,1-b]pyran-2-ol, 3ethenyldodecahydro-3,4a,7,7,10a-pentamethyl-, [2R-(2D,3D,4aD,6aE,10aD,10bE)]-

CH3

OH

II.A-5, X-2

CH3 CH2

CH3 O CH3 H3C

CH3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1669

11/24/08 1:56:54 PM

1670

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

64681-70-5

0

1

0

Name (per CA Collective Index)

Selected structures

1H-Naphtho[2,1-b]pyran-2-ol, 3ethenyldodecahydro-3,4a,7,7,10a-pentamethyl-, [2S-(2D,3D,4aE,6aD,10aE,10bD)]-

OH

Chapter Table II.A-5, X-2

CH3 CH2

CH3 O CH3 H3C

67528-84-1

0

1

0

CH3

1H-Naphtho[2,1-b]pyran-2-ol, 3ethenyldodecahydro-3,4a,7,7,10a-pentamethyl-, [2R-(2D,3E,4aD,6aE,10aD,10bE)]-

OH

II.A-5, X-2

CH3 CH2

CH3 O CH3 H3C

37551-73-8

0

1

0

CH3

1H-Naphtho[2,1-b]pyran-2(3H)-one, 3ethenyldecahydro-3,4a,7,7,10a-pentamethyl-, [3S(3D,4aE,6aD,10aE,10bD)]-

O

III-13, X-2

CH3 CH2

CH3 O CH3 H3C

37551-74-9

0

1

0

CH3

1H-Naphtho[2,1-b]pyran-2(3H)-one, 3ethenyldecahydro-3,4a,7,7,10a-pentamethyl-, [3R(3D,4aD,6aE,10aD,10bE)]-

O

III-13, X-2

CH3 CH2

CH3 O CH3 H3C

CH3

68985-12-6

0

1

0

1H-Naphtho[2,1-b]pyran-2(3H)-one, 3ethenyldecahydro-3,4a,7,7,10a-pentamethyl-

III-13

313-80-4

1

0

0

Naphtho[2,1,8-def]quinoline

1

0

0

Naphtho[2,1,8-def]quinoline, dimethyl-

XVII.E-6

1

0

0

Naphtho[2,1,8-def]quinoline, methyl-

XVII.E-6 XVII.E-6

XVII.E-6

{1-azapyrene}

1

0

0

Naphtho[2,1,8-def]quinoline, trimethyl-

215-26-9

1

0

0

Naphtho[1,2-b]triphenylene {tribenz[a,c,h]anthracene}

191-37-7

1

0

0

Naphtho[2,1,8,7-klmn]xanthene

I.E-6

X-2

1

11 10

2

3

9 6

8 7

O

4 5

1

0

0

Naphthyridine

XVII.E-6

1

0

0

Naphthyridine, C2-alkyl-

XVII.E-6

1

0

0

Naphthyridine, 3-butyryl-

XVII.E-6

1

0

0

Naphthyridine, 3-methyl-

XVII.E-6

© 2009 by Taylor & Francis Group, LLC

78836_C030.indd 1670

11/24/08 1:56:54 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1671

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

254-79-5

1

0

0

1,5-Naphthyridine {1,5-diazanaphthalene; pyrido[3,2-b]pyridine}

XVII.E-6

18937-71-8

1

0

0

1,5-Naphthyridine, 3-methyl-

XVII.E-6

253-72-5

1

0

0

1,6-Naphthyridine {1,6-diazanaphthalene; pyrido[4,3-b]pyridine}

XVII.E-6

14757-43-8

1

0

0

1,6-Naphthyridine, 3-methyl-

XVII.E-6

253-69-0

1

0

0

1,7-Naphthyridine {1,7-diazanaphthalene; pyrido[3,4-b]pyridine}

XVII.E-6

254-60-4

1

0

0

1,8-Naphthyridine {1,8-diazanaphthalene; pyrido[2,3-b]pyridine}

XVII.E-6

14757-45-0

1

0

0

1,8-Naphthyridine, 2,6-dimethyl-

XVII.E-6

14759-22-9

1

0

0

1,8-Naphthyridine, 3-methyl-

XVII.E-6

40000-89-3

1

0

0

1,8-Naphthyridin-2(1H)-one, 3-methyl-

XVII.E-6

8002-65-1

0

1

0

Neem oil

7440-00-8

1

1

1

Neodymium

Ne

XX-5

7440-02-0

1

1

1

Nickel

Ni

XX-5

Name (per CA Collective Index)

Selected structures

Chapter Table

XXI-3

12612-55-4

1

0

0

Nickel carbonyl

Ni(CO)4

XX-6

7440-03-1

1

0

0

Niobium

Nb

XX-5

NO3

XX-6

14797-55-8

1

1

1

Nitrate

125239-87-4

1

0

0

Nitrate, peroxy-

7697-37-2

1

1

1

Nitric acid

HO-NO2

XX-6

7757-79-1

0

1

0

Nitric acid, potassium salt

KO-NO2

XX-6

XX-6

98-58-3

1

0

0

Nitric acid, methyl ester

H3C-O-NO2

7631-99-4

0

1

0

Nitric acid, sodium salt

NaO-NO2

14797-65-0

1

1

1

Nitrite

O=N-O

XX-6

1

0

0

Nitrite, peroxy-

1

0

0

Nitrite radical

O-N=O

XXVII-1

N2

19059-14-4

-1

XX-6

7727-37-9

1

1

1

Nitrogen

11104-93-1

1

0

0

Nitrogen oxide

10024-97-2

1

1

1

Nitrogen oxide

{nitrous oxide}

10102-43-9

1

1

1

Nitrogen oxide

{nitric oxide} {nitrogen dioxide}

10102-44-0 35576-91-1

V-3 XX-6

XX-5 XIX-5

N2O NO

XIX-5 XXVII-1

1

0

0

Nitrogen oxide

NO2

XIX-5

1

1

1

Nitrogen oxides

N2O + NO + NO2

XIX-5

1

0

0

Nitrosamide

H2N-N=O

XIII-1 XX-6

1

1

1

N-Nitrosamines

7782-77-6

1

0

0

Nitrous acid

{GENERAL DISCUSSION} HO-N=O

XV

109-95-5

1

0

0

Nitrous acid, ethyl ester

H3C-CH2-ON=O

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1671

11/24/08 1:56:55 PM

1672

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

624-91-9

1

1

1

Nitrous acid, methyl ester

H3C-ON=O

630-03-5

1

1

1

Nonacosane

H3C-(CH2)27-CH3

Name (per CA Collective Index)

Selected structures

Chapter Table V-3 I.A-10

1560-75-4

1

1

1

Nonacosane, 2-methyl-

(H3C)2=CH-(CH2)26-CH3

I.A-10

14167-67-0

1

1

1

Nonacosane, 3-methyl-

H3C-CH2-CH(CH3)-(CH2)25-CH3

I.A-10 IV.A-3

4250-38-8

1

0

0

Nonacosanoic acid

H3C-(CH2)27-COOH

121878-05-5

1

1

1

Nonacosanoic acid, docosyl ester

H3C-(CH2)27-COO-(CH2)21-CH3 H3C-(CH2)27-COO-(CH2)19-CH3

121877-94-9

1

1

1

Nonacosanoic acid, eicosyl ester

39815-65-1

0

1

0

Nonacosanoic acid, 4-(2-hydroxyethyl)phenyl ester

629-92-5

646-30-0

V-3 V-3 V-3

0

1

0

1-Nonacosanol

H3C-(CH2)27-CH2OH

II.A-5

1

0

0

1-Nonacosene

H2C=CH-(CH2)26-CH3

I.B-1

1

0

0

1-Nonacosene, 2-methyl-

H2C=C(CH3)-(CH2)26-CH3

I.B-1

1

0

0

2-Nonacoscene, (Z)-

H3C-CH=CH-(CH2)25-CH3

1

0

0

2-Nonacoscene, (E)-

1

0

0

2-Nonacosene, 2-methyl-

H3C-C(CH3)=CH-(CH2)25-CH3

1

0

0

2-Nonacosene, 27-methyl-, (Z)-

H3C-CH=CH-(CH2)23-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Nonacosene, 27-methyl-, (E)-

1

0

0

2-Nonacosene, 28-methyl-, (Z)-

1

0

0

2-Nonacosene, 28-methyl-, (E)-

1

1

1

Nonadecane

1

0

0

Nonadecane, methyl-

0

1

0

Nonadecane, 3-methyl-

H3C-(CH2)15-CH(CH3)-CH2-CH3

I.A-10

1

1

1

Nonadecanoic acid

H3C-(CH2)17-COOH

IV.A-3

I.B-1 I.B-1 I.B-1

I.B-1 H3C-CH=CH-(CH2)24-CH(CH3)2

I.B-1 I.B-1

H3C-(CH2)17-CH3

I.A-10 I.A-10

42232-76-8

1

1

1

Nonadecanoic acid, docosyl ester

H3C-(CH2)17-COO-(CH2)21-CH3

V-3

42232-66-6

1

1

1

Nonadecanoic acid, dodecyl ester

H3C-(CH2)17-COO-(CH2)11-CH3

V-3

36610-54-5

1

1

1

Nonadecanoic acid, eicosyl ester

H3C-(CH2)17-COO-(CH2)19-CH3

V-3

42232-75-7

1

1

1

Nonadecanoic acid, heneicosyl ester

H3C-(CH2)17-COO-(CH2)20-CH3

V-3

36610-51-2 36610-50-1

1

1

1

Nonadecanoic acid, heptacosyl ester

H3C-(CH2)17-COO-(CH2)26-CH3

V-3

1

1

1

Nonadecanoic acid, heptadecyl ester

H3C-(CH2)17-COO-(CH2)16-CH3

V-3

1

1

1

Nonadecanoic acid, hexacosyl ester

H3C-(CH2)17-COO-(CH2)25-CH3

V-3

1

1

1

Nonadecanoic acid, hexadecyl ester

H3C-(CH2)17-COO-(CH2)15-CH3

V-3

1731-94-8

0

1

0

Nonadecanoic acid, methyl ester

H3C-(CH2)17-COO-CH3

V-3

36610-53-4

1

1

1

Nonadecanoic acid, nonadecyl ester

H3C-(CH2)17-COO-(CH2)18-CH3

V-3

36610-52-3

1

1

1

Nonadecanoic acid, octadecyl ester

H3C-(CH2)17-COO-(CH2)17-CH3

V-3

1

1

1

Nonadecanoic acid, pentacosyl ester

H3C-(CH2)17-COO-(CH2)24-CH3

V-3

36610-49-8

1

1

1

Nonadecanoic acid, pentadecyl ester

H3C-(CH2)17-COO-(CH2)14-CH3

V-3

121877-66-5

1

1

1

Nonadecanoic acid, tetracosyl ester

H3C-(CH2)17-COO-(CH2)23-CH3

V-3

36610-48-7

1

1

1

Nonadecanoic acid, tetradecyl ester

H3C-(CH2)17-COO-(CH2)13-CH3

V-3

42232-77-9

1

1

1

Nonadecanoic acid, tricosyl ester

H3C-(CH2)17-COO-(CH2)22-CH3

V-3

36610-47-6

1

1

1

Nonadecanoic acid, tridecyl ester

H3C-(CH2)17-COO-(CH2)12-CH3

V-3

53254-53-8

1

1

1

Nonadecanoic acid, 17-methyl-

H3C-CH2-CH(CH3)-(CH2)15-COOH IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1672

11/24/08 1:56:55 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1673

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

121877-54-1

1

1

1

Nonadecanoic acid, 17-methyl-, heneicosyl ester

H3C-CH2-CH(CH3)-(CH2)15-COO-(CH2)20-CH3 V-3

121877-69-8

1

1

1

Nonadecanoic acid, 17-methyl-, tetracosyl ester

H 3C-CH2-CH(CH3)-(CH2)15-COO-(CH2)23-CH3 V-3

121877-59-6

1

1

1

Nonadecanoic acid, 17-methyl-, tricosyl ester

H3C-CH2-CH(CH3)-(CH2)15-COO-(CH2)22-CH3 V-3 (H3C)2=CH-(CH2)16-COOH

Name (per CA Collective Index)

6250-72-2

1

1

1

Nonadecanoic acid, 18-methyl-

145090-31-9

0

1

0

Nonadecanoic acid, 18-methyl-, 2-(acetyloxy)-1(hydroxymethyl)ethyl ester

1

1

1

Nonadecanoic acid, 18-methyl-, eicosyl ester

Chapter Table

Selected structures

IV.A-3 V-3

(H3C)2=CH-(CH2)16-COO-(CH2)19-CH3 V-3

150643-41-7

0

1

0

Nonadecanoic acid, 18-methyl-, ester with 1,2,3propanetriol monoacetate mono(16methylheptadecanoate)

V-3

121877-51-8

1

1

1

Nonadecanoic acid, 18-methyl-, heneicosyl ester

(H3C)2=CH-(CH2)16-COO-(CH2)20-CH3

121877-37-0

1

1

1

Nonadecanoic acid, 18-methyl-, nonadecyl ester

(H3C)2=CH-(CH2)16-COO-(CH2)18-CH3

V-3 V-3 71607-90-4

1

0

0

Nonadecanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester, [R-[R*,R*-(E)]]-

V-3

52783-43-4

1

0

0

Nonadecanol

II.A-5

1

1

1

1-Nonadecanol

6809-52-5

1

1

1

5,9,13,17-Nonadecatetraen-2-one, 6,10,14,18tetramethyl-

27400-77-7

1

0

0

Nonadecene

H-(CH2)n-CH=CH-(CH2)(17-n)-H

I.B-1

18435-45-5

1

1

1

1-Nonadecene

H2C=CH-(CH2)16-CH3

I.B-1

1

0

0

1-Nonadecene, 2-methyl-

H2C=C(CH3)-(CH2)16-CH3

I.B-1

1

0

0

2-Nonadecene, (Z)-

H3C-CH=CH-(CH2)15-CH3

I.B-1

1

0

0

2-Nonadecene, (E)-

1

0

0

2-Nonadecene, 2-methyl-

H3C-C(CH3)=CH-(CH2)15-CH3

I.B-1

1

0

0

2-Nonadecene, 17-methyl-, (Z)-

H3C-CH=CH-(CH2)13-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Nonadecene, 17-methyl-, (E)-

I.B-1

1

0

0

2-Nonadecene, 18-methyl-, (Z)-

1

0

0

2-Nonadecene, 18-methyl-, (E)-

I.B-1

1

1

1

2,4-Nonadienal, (E,E)-

III-12

0

1

0

2,4-Nonadienal, 6-methyl-

III-12

0

1

0

2,4-Nonadienal, 8-methyl-

III-12

26370-28-5

0

1

0

2,6-Nonadienal

557-48-2

0

1

0

2,6-Nonadienal, (E,Z)-

129777-21-5

0

1

0

2,6-Nonadienal, 2-methyl-5-(1-methylethyl)-8-oxo-, (E,E)-(+)-

0

1

0

Nonadiene

0

1

0

Nonadienoic acid

6750-03-4 5910-87-2

71030-52-9

H3C-(CH2)17-CH2OH

II.A-5 III-13

I.B-1

{leaf aldehyde violet}

H3C-CH=CH-(CH2)14-CH(CH3)2

I.B-1

III-12 III-12 III-12, III-13 I.B-1 IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1673

11/24/08 1:56:56 PM

1674

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

0

1

0

2,4-Nonadienoic acid, 2,3-dimethyl-

IV.A-3

60026-10-0

0

1

0

2,6-Nonadienoic acid

IV.A-3

23605-13-2

0

1

0

2,6-Nonadienoic acid, (E,Z)-

IV.A-3

70898-29-2

0

1

0

2,7-Nonadienoic acid, (E,Z)-

IV.A-3

0

1

0

4,6-Nonadienoic acid

IV.A-3

7786-44-9

0

1

0

2,6-Nonadien-1-ol

II.A-5

28069-72-9

0

1

0

2,6-Nonadien-1-ol, (E,Z)-

II.A-5

56805-23-3

0

1

0

3,6-Nonadien-1-ol

II.A-5

53046-97-2

0

1

0

3,6-Nonadien-1-ol, (Z,Z)-

II.A-5

38713-12-1

0

1

0

3,7-Nonadien-1-ol, 4,8-dimethyl- {homogeraniol}

II.A-5

459-88-1

0

1

0

3,7-Nonadien-1-ol, 4,8-dimethyl-, (E)-

II.A-5

150405-75-7

0

1

0

6,8-Nonadien-2-ol, 8-methyl-5-(3-methylbutyl)-

II.A-5

40525-38-0

1

1

1

6,8-Nonadien-2-ol, 8-methyl-5-(1-methylethyl){solanol} {solanol isomer}

II.A-5

0

1

0

3,7-Nonadien-2-one, 4,8-dimethyl-

III-13

0

1

0

3,8-Nonadien-2-one, 4,8-dimethyl-

III-13

1

0

0

5,7-Nonadien-2-one, 8-hydroxy-5-(1-methylethyl)-, (E,Z)-

III-13

1

1

1

5,7-Nonadien-2-one, 8-methyl-5-(1-methylethyl){isosolanone}

III-13

60714-16-1

0

1

0

6,8-Nonadien-2-one, 6-methyl-5-(1-methylethenyl)-

III-13

2278-53-7

0

1

0

6,8-Nonadien-2-one, 8-methyl-5-(1-methylethyl)-, [R-(E)]-

III-13

1937-54-8

1

1

1

6,8-Nonadien-2-one, 8-methyl-5-(1-methylethyl)-, [S-(E)]{solanone}

64130-24-1

123695-65-8

54868-48-3

0

1

0

6,8-Nonadien-2-one, 8-methyl-5-(1-methylethyl)-, (E)-

124-19-6

1

1

1

Nonanal

111-84-2

1

1

1

Nonane

1

0

0

Nonane, 4-acetyl-2,6,8-trimethyl-

871-83-0

1

0

0

Nonane, 2-methyl-

51655-64-2

1

0

0

Nonane, 3-methylene-

123-99-9

1

1

1

Nonanedioic acid

3937-56-2

0

1

0

1,9-Nonanediol

55023-56-8

{pelargonaldehyde}

III-13 O

III-13 H3C-(CH2)7-CH=O H3C-(CH2)7-CH3

III-12 I.A-10 III-13 I.A-10 I.B-1

{azelaic acid}

HOOC-(CH2)7-COOH HOCH2-(CH2)7-CH2OH

IV.A-3 II.A-5

1

1

1

2,8-Nonanediol, 5-(1-methylethyl)-

II.A-5

0

1

0

2,5-Nonanedione

III-13

0

1

0

2,7-Nonanedione, 8-hydroxy-8-methyl-5-(1methylethyl)-

II.A-5, III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1674

11/24/08 1:56:57 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1675

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

55023-57-9

1

1

1

Name (per CA Collective Index) 2,8-Nonanedione, 5-(1-methylethyl){norsolanadione}

Chapter Table

Selected structures

III-13 O O

38284-28-5

0

1

0

2,5,8-Nonanetrione

112-05-0

1

1

1

Nonanoic acid

123-29-5

0

1

0

Nonanoic acid, ethyl ester

H3C-(CH2)7-COO-C2H5 H3C-(CH2)7-COO-CH3

1731-84-6

0

1

0

Nonanoic acid, methyl ester

41653-89-8

0

1

0

Nonanoic acid, 7-methyl-

6064-52-4

0

1

0

Nonanoic acid, 4-oxo-

143-08-8

1

1

1

1-Nonanol

III-13 {pelargonic acid}

H3C-(CH2)7-COOH

IV.A-3 V-3 V-3 IV.A-3 III-13, IV.A-3

H3C-(CH2)7-CH2OH

II.A-5

1

0

0

4-Nonanol, 2,6,8-trimethyl-

821-55-6

1

1

1

2-Nonanone

58002-07-6

0

1

0

2-Nonanone, 6,7-epoxy-8-hydroxy-5-(1methylethyl)-

III-13

55023-54-6

68-26-8

III-13

0

1

0

2-Nonanone, 8-hydroxy-5-(1-methylethyl)-

III-13

1

0

0

4-Nonanone, 2,6,8-trimethyl

III-13

0

1

0

5-Nonanone, 2,8-dimethyl-7,8-epoxy-

III-13

0

1

0

2,4,6,8-Nonatetraen-1-ol, 3,7-dimethyl-9-(2,6,6trimethyl-1-cyclohexen-1-yl)-, (all-E){retinol}

II.A-5

1

1

1

Nonatriacontane

0

1

0

3,5,7-Nonatrien-2-one

2463-53-8

1

1

1

2-Nonenal

18829-56-6

0

1

0

2-Nonenal, (E)-

0

1

0

2-Nonenal, 2,3-dimethyl-8-oxo-

0

1

0

6-Nonenal, (Z)-

1

0

0

1-Nonene

1

0

0

2-Nonene, 3-methyl-

2277-19-2

II.A-5 H3C-(CH2)6-CO-CH3

H3C-(CH2)37-CH3

I.A-10 III-13

H3C-(CH2)5-CH=CH-CH=O

III-12 III-12 III-12, III-13 III-12

H3C-(CH2)6-CH=CH2

I.B-1 I.B-1

53966-53-3

1

0

0

3-Nonene, 2-methyl-

55023-53-5

1

1

1

3-Nonene-2,8-diol, 5-(1-methylethyl)-

H3C-(CH2)4-CH=CH-CH=(CH3)2

I.B-1

38372-56-4

1

1

1

3-Nonene-2,8-dione

{norsolanadione}

III-13

60619-46-7 35953-21-0

1

1

1

3-Nonene-2,8-dione, 5-(1-methylethyl)-, [S-(E)]{oxysolanone}

III-13

37822-76-7

0

1

0

Nonenoic acid, methyl ester

3760-11-0

0

1

0

2-Nonenoic acid

14812-03-4

0

1

0

2-Nonenoic acid, (E)-

IV.A-3

II.A-5

V-3 H3C-(CH2)5-CH=CH-COOH

IV.A-3

4124-88-3

0

1

0

3-Nonenoic acid

IV.A-3

41653-98-9

0

1

0

3-Nonenoic acid, (Z)-

IV.A-3

41653-99-0

0

1

0

6-Nonenoic acid, (Z)-

IV.A-3

31642-67-8

0

1

0

8-Nonenoic acid

IV.A-3

31502-14-4

0

1

0

2-Nonen-1-ol

10340-23-5

0

1

0

3-Nonen-1-ol, (Z)-

H3C-(CH2)5-CH=CH-CH2OH

II.A-5 II.A-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1675

11/24/08 1:56:57 PM

1676

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Chapter Table

Selected structures

68985-18-2

0

1

0

2-Nonen-4-one, 3-methyl-, (E)-

65017-85-8

0

1

0

2-Nonen-4-one, 8-hydroxy-3-methyl-, (E)-

II.A-5, III-13

III-13

0

1

0

5-Nonen-2-one, 8-hydroxy-8-methyl-5-(1methylethyl)-

II.A-5, III-13

55023-59-1

0

1

0

6-Nonen-2-one, 8-hydroxy-8-methyl-5-(1methylethyl)-

II.A-5, III-13

57934-86-8

0

1

0

6-Nonen-2-one, 8-hydroxy-8-methyl-5-(1methylethyl)-, (E)-(±)-

II.A-5, III-13

55023-52-4

0

1

0

6-Nonen-2-one, 8-hydroxy-5-(1-methylethyl)-

II.A-5, III-13

77288-95-0

0

1

0

6-Nonen-2-one, 8,9-dihydroxy-8-methyl-5-(1methylethyl)-, [R-[R*,S*-(E)]]-

II.A-5, III-13

77288-96-1

0

1

0

6-Nonen-2-one, 8,9-dihydroxy-8-methyl-5-(1methylethyl)-, [S-[R*,R*-(E)]]-

II.A-5, III-13

3452-09-3

1

0

0

1-Nonyne

18444-66-1

0

1

0

19-Norlanosta-1,5,23-triene-3,11,22-trione, 25(acetyloxy)-2,16,20-trihydroxy-9-methyl-, (9E,10D,16D,23E)-

II.A-5, III-13, V-3

17278-28-3

0

1

0

19-Norlanosta-5,23-diene-2,11,22-trione, 25(acetyloxy)-3,16,20-trihydroxy-9-methyl-, (3D,9E,10D,16D,23E)-

II.A-5, III-13, V-3

89647-62-1

0

1

0

19-Norlanosta-5,23-diene-2,11,22-trione, 25(acetyloxy)-3,16,20-trihydroxy-9-methyl-, (3E,9E,10D,16D,23E)-

II.A-5, III-13, V-3

5157-09-5

0

1

0

Norleucine

9026-81-7

0

1

0

Nuclease

XXII-2

9003-98-9

0

1

0

Nuclease, deoxyribo-

XXII-2

9055-11-2

0

1

0

Nuclease, endo-

XXII-2

59977-50-3

0

1

0

Nuclease, mammalian deoxyribonucleate-nicking endo-

XXII-2

9001-99-4

0

1

0

Nuclease, ribo-

XXII-2

9025-44-9

0

1

0

Nucleosidase

XXII-2

9033-33-4

0

1

0

Nucleotidase

XXII-2

9012-90-2

0

1

0

Nucleotidyltransferase, deoxyribonucleate

XXII-2

9068-38-6

0

1

0

Nucleotidyltransferase, deoxyribonucleate, RNAdependent

XXII-2

9014-12-4

0

1

0

Nucleotidyltransferase, polyribonucleotide

XXII-2

9014-24-8

0

1

0

Nucleotidyltransferase, ribonucleate

XXII-2

9026-28-2

0

1

0

Nucleotidyltransferase, ribonucleate, RNAdependent

XXII-2

66328-00-5

1

0

0

2,6,10,14,18,22,26-Octacosaheptaene, 2,6,10,14,18,22,26-heptamethyl-, (all-E)-

HCŁC-(CH2)6-CH3

{2-aminohexanoic acid}

I.B-1

H3C-(CH2)3-CH(NH2)-COOH IV.A-3, IV.B-7, XII-2

I.B-1

630-02-4

1

1

1

Octacosane

H3C-(CH2)26-CH3

I.A-10

1560-98-1

1

1

1

Octacosane, 2-methyl-

(H3C)2=CH-(CH2)25-CH3

I.A-10

65820-58-8

1

1

1

Octacosane, 3-methyl-

H3C-CH2-CH(CH3)-(CH2)24-CH3

I.A-10

506-48-9

1

1

1

Octacosanoic acid

H3C-(CH2)26-COOH

IV.A-3

121878-02-2

1

1

1

Octacosanoic acid, docosyl ester

H3C-(CH2)26-COO-(CH2)21-CH3

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1676

11/24/08 1:56:58 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1677

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

121877-91-6

121877-95-0

80756-16-7 95415-29-5

S

T

S T

1

1

1

Octacosanoic acid, dodecyl ester

H3C-(CH2)26-COO-(CH2)11-CH3

V-3

1

1

1

Octacosanoic acid, eicosyl ester

H3C-(CH2)26-COO-(CH2)19-CH3

V-3

1

1

1

Octacosanoic acid, ester with olean-12-en-3-ol, (3E){ȕ-amyrenyl octacosanoate)

Name (per CA Collective Index)

Selected structures

Chapter Table

V-3

1

1

1

Octacosanoic acid, heneicosyl ester

H3C-(CH2)26-COO-(CH2)20-CH3

V-3

1

1

1

Octacosanoic acid, heptacosyl ester

H3C-(CH2)26-COO-(CH2)26-CH3

V-3

1

1

1

Octacosanoic acid, heptadecyl ester

H3C-(CH2)26-COO-(CH2)16-CH3

V-3

1

1

1

Octacosanoic acid, hexacosyl ester

H3C-(CH2)26-COO-(CH2)25-CH3

V-3

1

1

1

Octacosanoic acid, hexadecyl ester

H3C-(CH2)26-COO-(CH2)15-CH3

V-3

1

1

1

Octacosanoic acid, nonadecyl ester

H3C-(CH2)26-COO-(CH2)18-CH3

V-3

1

1

1

Octacosanoic acid, octadecyl ester

H3C-(CH2)26-COO-(CH2)17-CH3

V-3

1

1

1

Octacosanoic acid, pentacosyl ester

H3C-(CH2)26-COO-(CH2)24-CH3

V-3

1

1

1

Octacosanoic acid, pentadecyl ester

H3C-(CH2)26-COO-(CH2)14-CH3

V-3

80252-40-0

1

1

1

Octacosanoic acid, tetracosyl ester

H3C-(CH2)26-COO-(CH2)23-CH3

V-3

28570-28-7

1

1

1

Octacosanoic acid, tetradecyl ester

H3C-(CH2)26-COO-(CH2)13-CH3

V-3

1

1

1

Octacosanoic acid, tricosyl ester

H3C-(CH2)26-COO-(CH2)22-CH3

V-3

1

1

1

Octacosanoic acid, tridecyl ester

H3C-(CH2)26-COO-(CH2)12-CH3

V-3

121878-04-4

1

1

1

Octacosanoic acid, 26-methyl-, docosyl ester

H3C-CH2-CH(CH3)-(CH2)24-COO-(CH2)21-CH3 V-3

557-61-9

1

1

1

1-Octacosanol

H3C-(CH2)26-CH2OH

0

1

0

1-Octacosanol, 26-methyl-

II.A-5

0

1

0

1-Octacosanol, 27-methyl-

II.A-5

18835-34-2

{montanyl alcohol}

II.A-5

1

0

0

1-Octacosene

H3C-(CH2)25-CH=CH2

I.B-1

1

0

0

1-Octacosene, 2-methyl-

H2C=C(CH3)-(CH2)25-CH3

I.B-1

1

0

0

2-Octacosene, (Z)-

H3C-CH=CH-(CH2)24-CH3

I.B-1

1

0

0

2-Octacosene, (E)-

1

0

0

2-Octacosene, 2-methyl-

H3C-C(CH3)=CH-(CH2)24-CH3

I.B-1

1

0

0

2-Octacosene, 26-methyl-, (Z)-

H3C-CH=CH-(CH2)23-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Octacosene, 26-methyl-, (E)-

I.B-1

1

0

0

2-Octacosene, 27-methyl-, (Z)-

1

0

0

2-Octacosene, 27-methyl-, (E)-

26764-25-0

1

0

0

Octadecadienoic acid

IV.A-3

28984-77-2

0

1

0

Octadecadienoic acid, (Z,Z)-

IV.A-3

97145-16-9

0

1

0

Octadecadienoic acid, 1-[[[(2aminoethoxy)hydroxyphosphinyl]oxy]methyl]-1,2ethanediyl ester, (all-Z)-

V-3

97190-11-9

0

1

0

Octadecadienoic acid, ester with 1,2,3-propanetriol 1-(2-aminoethyl hydrogen phosphate) hexadecanoate

V-3

97190-13-1

0

1

0

Octadecadienoic acid, ester with 1,2,3-propanetriol 1-(2-aminoethyl hydrogen phosphate) octadecanoate, (Z,Z)-

V-3

28061-47-4

0

1

0

Octadecadienoic acid, methyl ester

V-3

I.B-1

H3C-CH=CH-(CH2)23-CH(CH3)2

I.B-1 I.B-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1677

11/24/08 1:56:58 PM

1678

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

97210-24-7

0

1

0

Octadecadienoic acid, monoester with 1,2,3propanetriol 1,1'-(hydrogen phosphate) mono-3hexadecenoate, [R-[R*,S*-(E)]]-

Name (per CA Collective Index)

Chapter Table

Selected structures

V-3

60-33-3

1

1

1

9,12-Octadecadienoic acid, (Z,Z)-

{linoleic acid}

IV.A-3

506-21-8

1

1

1

9,12-Octadecadienoic acid, (E,E)- {linoleic acid}

H3C-(CH2)4-CH=CH-CH2-CH=CH-(CH2)7COOH IV.A-3

26836-35-1

0

1

0

9,12-Octadecadienoic acid (Z,Z)-, ester with 1,2,3propanetriol monohexadecanoate mono[(Z)-9octadecenoate]

544-35-4

0

1

0

9,12-Octadecadienoic acid (Z,Z)-, ethyl ester {ethyl linoleate}

4546-59-2

0

1

0

9,12-Octadecadienoic acid, 18-hydroxy-, (Z,Z)-

2462-85-3

0

1

0

9,12-Octadecadienoic acid, methyl ester

112-63-0

1

1

1

9,12-Octadecadienoic acid (Z,Z)-, methyl ester {methyl linoleate}

H3C-(CH2)4-CH=CH-CH2-CH=CH-(CH2)7COO-CH3 V-3

26836-38-4

0

1

0

9,12-Octadecadienoic acid (Z,Z)-, monoester with 1,2,3-propanetriol monooctadecanoate mono-9octadecenoate, (Z)-

V-3

28880-78-6

0

1

0

9,12-Octadecadienoic acid (Z,Z)-, monoester with 1,2,3-propanetriol bis[(Z)-9-octadecenoate]

V-3

34521-51-2

0

1

0

9,12-Octadecadienoic acid (Z,Z)-, monoester with 1,2,3-propanetriol dioctadecanoate

V-3

70495-60-2

1

1

1

9,12-Octadecadienoic acid (Z,Z)-, 3,7,11,15,19,23,27,31,35-nonamethyl2,6,10,14,18,22,26,30,34-hexa-triacontanonaenyl ester

V-3

53950-59-7

1

0

0

9,12-Octadecadienoic acid (Z,Z)-, 3,7,11,15tetramethyl-2-hexadecenyl ester, [R-[R*,R*-(E)]]-

V-3

506-43-4

0

1

0

9,12-Octadecadien-1-ol, (Z,Z)-

56847-03-1

1

0

0

Octadecadiynoic acid, methyl ester

593-45-3

1

1

1

Octadecane

1560-88-9

V-3

H3C-(CH2)4-CH=CH-CH2-CH=CH-(CH2)7COO-C2H5 V-3 IV.A-3 V-3

II.A-5 V-3 H3C-(CH2)16-CH3

I.A-10

0

1

0

Octadecane, 2-methyl-

H3C-(CH2)15-CH=(CH3)2

I.A-10

0

1

0

Octadecane, 3-methyl-

H3C-(CH2)14-CH(CH3)-CH2-CH3

I.A-10

554-62-1

0

1

0

1,3,4-Octadecanetriol, 2-amino-, [2S(2R*,3R*,4S*)]{stearic acid}

II.A-5, XII-2

57-11-4

1

1

1

Octadecanoic acid

22413-03-2

1

1

1

Octadecanoic acid, docosyl ester

H3C-(CH2)16-COO-(CH2)21-CH3

H3C-(CH2)16-COOH

IV.A-3 V-3

5303-25-3

1

1

1

Octadecanoic acid, dodecyl ester

H3C-(CH2)16-COO-(CH2)11-CH3

V-3

22413-02-1

1

1

1

Octadecanoic acid, eicosyl ester

H3C-(CH2)16-COO-(CH2)19-CH3

V-3

111-61-5

1

1

1

Octadecanoic acid, ethyl ester

H3C-(CH2)16-COO-CH2-CH3

V-3

{ethyl stearate}

42232-59-7

1

1

1

Octadecanoic acid, heneicosyl ester

H3C-(CH2)16-COO-(CH2)20-CH3

V-3

121877-78-9

1

1

1

Octadecanoic acid, heptacosyl ester

H3C-(CH2)16-COO-(CH2)26-CH3

V-3

18299-82-6

1

1

1

Octadecanoic acid, heptadecyl ester

H3C-(CH2)16-COO-(CH2)16-CH3

V-3

58886-94-5

1

1

1

Octadecanoic acid, hexacosyl ester

H3C-(CH2)16-COO-(CH2)25-CH3

V-3

1190-63-2

1

1

1

Octadecanoic acid, hexadecyl ester

H3C-(CH2)16-COO-(CH2)15-CH3

1330-70-7

0

1

0

Octadecanoic acid, hydroxy-

3155-42-8

0

1

0

Octadecanoic acid, 18-hydroxy-

V-3 IV.A-3

HOCH2-(CH2)16-COOH

IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1678

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1679

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

112-61-8

1

1

1

Octadecanoic acid, methyl ester

H3C-(CH2)16-COO-CH3

V-3

121877-86-9

1

1

1

Octadecanoic acid, nonacosyl ester

H3C-(CH2)16-COO-(CH2)28-CH3

V-3

36610-45-4

1

1

1

Octadecanoic acid, nonadecyl ester

H3C-(CH2)16-COO-(CH2)18-CH3

V-3

70495-59-9

1

1

1

Octadecanoic acid, 3,7,11,15,19,23,27,31,35nonamethyl-2,6,10,14,18,22,26,30,34hexatriacontanonaenyl ester

63317-82-8

1

1

1

Octadecanoic acid, octacosyl ester

V-3

H3C-(CH2)16-COO-(CH2)27-CH3

V-3

2778-96-3

1

1

1

Octadecanoic acid, octadecyl ester

H3C-(CH2)16-COO-(CH2)17-CH3

V-3

121877-65-4

1

1

1

Octadecanoic acid, pentacosyl ester

H3C-(CH2)16-COO-(CH2)24-CH3

V-3

18299-80-4

1

1

1

Octadecanoic acid, pentadecyl ester

H3C-(CH2)16-COO-(CH2)14-CH3

V-3

42232-61-1

1

1

1

Octadecanoic acid, tetracosyl ester

H3C-(CH2)16-COO-(CH2)23-CH3

V-3

17661-50-6

1

1

1

Octadecanoic acid, tetradecyl ester

H3C-(CH2)16-COO-(CH2)13-CH3

V-3

63317-83-9

1

1

1

Octadecanoic acid, triacontyl ester

H3C-(CH2)16-COO-(CH2)29-CH3

V-3

42232-60-0

1

1

1

Octadecanoic acid, tricosyl ester

H3C-(CH2)16-COO-(CH2)22-CH3

V-3 V-3

31556-45-3

1

1

1

Octadecanoic acid, tridecyl ester

H3C-(CH2)16-COO-(CH2)12-CH3

17001-28-4

1

1

1

Octadecanoic acid, 16-methyl-

H3C-CH2-CH(CH3)-(CH2)14-COOH IVA-3

121877-53-0

1

1

1

Octadecanoic acid, 16-methyl-, docosyl ester

H3C-CH2-CH(CH3)-(CH2)14-COO-(CH2)21-CH3 V-3

121877-75-6

1

1

1

Octadecanoic acid, 16-methyl-, hexacosyl ester

H 3C-CH2-CH(CH3)-(CH2)14-COO-(CH2)25-CH3 V-3

2724-59-6 62172-54-7

0

1

0

Octadecanoic acid, 17-methyl-

(H3C)2=CH-(CH2)15-COOH

0

1

0

Octadecanoic acid, 17-methyl-, methyl ester

(H 3C)2=CH-(CH2)15-COO-CH3

1

0

0

Octadecanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester, [R-[R*,R*- (E)]]{stearyl alcohol}

H3C-(CH2)16-CH2OH

IV.A-3 V-3 V-3

112-92-5

1

1

1

1-Octadecanol

2490-01-9

0

1

0

1-Octadecanol, 16-methyl-

II.A-5

51592-59-7

0

1

0

3,6,9,12,15-Octadecapentaenoic acid, (all-Z)-

IV.A-3

25448-06-0

0

1

0

Octadecatetraenoic acid

IV.A-3

25448-03-7

0

1

0

Octadecatrienoic acid

IV.A-3

27213-43-0

0

1

0

Octadecatrienoic acid, (Z,Z,Z)-

IV.A-3

97190-08-4

0

1

0

Octadecatrienoic acid, ester with 1,2,3-propanetriol 1-(2-aminoethyl hydrogen phosphate) octadecadienoate, (all-Z)-

V-3

97229-62-4

0

1

0

Octadecatrienoic acid, ester with 1,2,3-propanetriol 1-(2-aminoethyl hydrogen phosphate) 2(or 3)hexadecanoate, (Z,Z,Z)-

V-3

97229-63-5

0

1

0

Octadecatrienoic acid, ester with 1,2,3-propanetriol 1,1'-(hydrogen phosphate) 2(or 3)-(3hexadecenoate), [R-(R*,S*)]-

V-3

29565-44-4

0

1

0

Octadecatrienoic acid, methyl ester

V-3

13296-76-9

1

0

0

9,11,13-Octadecatrienoic acid

463-40-1

1

1

1

9,12,15-Octadecatrienoic acid, (Z,Z,Z){linolenic acid}

H3C-(CH2CH=CH)3-(CH2)7-COOH IV.A-3

1

1

1

9,12,15-Octadecatrienoic acid, docosyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)21-CH3 V-3

II.A-5

IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1679

11/24/08 1:57:00 PM

1680

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke S

T

S T

1

1

1

9,12,15-Octadecatrienoic acid, dodecyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)11-CH3 V-3

1

1

1

9,12,15-Octadecatrienoic acid, eicosyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)19-CH3 V-3

0

1

0

9,12,15-Octadecatrienoic acid, ethyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COOC2H5 V-3

1

1

1

9,12,15-Octadecatrienoic acid, heneicosyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)20-CH3 V-3

1

1

1

9,12,15-Octadecatrienoic acid, heptacosyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)26-CH3 V-3

1

1

1

9,12,15-Octadecatrienoic acid, heptadecyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)16-CH3 V-3

1

1

1

9,12,15-Octadecatrienoic acid, hexacosyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)25-CH3 V-3

1

1

1

9,12,15-Octadecatrienoic acid, hexadecyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)15-CH3 V-3

51327-73-2

0

1

0

9,12,15-Octadecatrienoic acid, 18-hydroxy-, (Z,Z,Z)-

HOCH2-(CH2CH=CH)3-(CH2)7-COOH IV.A-3

7361-80-0

1

1

1

9,12,15-Octadecatrienoic acid, methyl ester {methyl linolenate}

H3C-(CH2CH=CH)3-(CH2)7-COOCH3

301-00-8

1

1

1

9,12,15-Octadecatrienoic acid, methyl ester, (Z,Z,Z){methyl linolenate}

H3C-(CH2CH=CH)3-(CH2)7-COO-CH3 V-3

1

1

1

9,12,15-Octadecatrienoic acid, nonadecyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)18-CH3 V-3

28973-74-2

1

1

1

9,12,15-Octadecatrienoic acid, 3,7,11,15,19,23,27,31,35-nonamethyl2,6,10,14,18,22,26,30,34-hexatriacontanonaenyl ester

17673-60-8

1

1

1

9,12,15-Octadecatrienoic acid, octadecyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)17-CH3 V-3

1

1

1

9,12,15-Octadecatrienoic acid, pentacosyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)24-CH3 V-3

1

1

1

9,12,15-Octadecatrienoic acid, pentadecyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)14-CH3 V-3

1

1

1

9,12,15-Octadecatrienoic acid, tetracosyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)23-CH3 V-3

1

1

1

9,12,15-Octadecatrienoic acid, tetradecyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)13-CH3 V-3

1

1

1

9,12,15-Octadecatrienoic acid, tricosyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)22-CH3 V-3

1

1

1

9,12,15-Octadecatrienoic acid, tridecyl ester, (Z,Z,Z)-

H3C-(CH2CH=CH)3-(CH2)7-COO-(CH2)12-CH3 V-3

30452-68-7

1

0

0

9,12,15-Octadecatrienoic acid, 3,7,11,15tetramethyl-2-hexadecenyl ester, [R-[R*,R*(E,Z,Z,Z)]]-

506-44-5

1

0

0

9,12,15-Octadecatrien-1-ol, (Z,Z,Z)-

56554-87-1

0

1

0

16-Octadecenal

27070-58-2

1

0

0

Octadecene

CAS No.

1191-41-9

Name (per CA Collective Index)

Selected structures

Chapter Table

V-3

V-3

V-3

II.A-5 III-12 H-(CH2)n-CH=CH-(CH2)(16-n)-H

I.B-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1680

11/24/08 1:57:00 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1681

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 112-88-9

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

1-Octadecene

H2C=CH-(CH2)15-CH3

I.B-1

1

0

0

1-Octadecene, 2-methyl-

H2C=C(CH3)-(CH2)15-CH3

I.B-1

1

0

0

2-Octadecene, (Z)-

H3C-CH=CH-(CH2)14-CH3

1

0

0

2-Octadecene, (E)-

1

0

0

2-Octadecene, 2-methyl-

H3C-C(CH3)=CH-(CH2)14-CH3

1

0

0

2-Octadecene, 16-methyl-, (Z)-

H3C-CH=CH-(CH2)12-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Octadecene, 16-methyl-, (E)-

1

0

0

2-Octadecene, 17-methyl-, (Z)-

I.B-1 I.B-1 I.B-1

I.B-1 H3C-CH=CH-(CH2)13-CH(CH3)2

1

0

0

2-Octadecene, 17-methyl-, (E)

26764-26-1

1

1

1

Octadecenoic acid

112-79-8

1

1

1

Octadecenoic acid, (E)-

27104-13-8

0

1

0

Octadecenoic acid, (Z)-

93976-10-4

1

1

1

Octadecenoic acid, docosyl ester, (Z)-

I.B-1 I.B-1

{oleic acid}

IV.A-3

{elaidic acid}

IV.A-3 IV.A-3 V-3

1

1

1

Octadecenoic acid, heneicosyl ester, (Z)-

V-3

93976-08-0

1

1

1

Octadecenoic acid, hexacosyl ester, (Z)-

V-3

27234-05-5

0

1

0

Octadecenoic acid, methyl ester

V-3

93976-09-1

1

1

1

Octadecenoic acid, tetracosyl ester, (Z)-

V-3

112-80-1

1

1

1

9-Octadecenoic acid (Z)-

71607-93-7

1

1

1

9-Octadecenoic acid (Z)-, 3,7,11,15,19,23,27,31,35nonamethyl-2,6,10,14,18,22,26,30,34-hexatria contanonaenyl ester

{oleic acid}

H3C-(CH2)7-CH=CH-(CH2)7-COOH IV.A-3 V-3

57840-35-4

1

0

0

9-Octadecenoic acid (Z)-, 3,7,11,15-tetramethyl-2hexadecenyl ester, [R-[R*,R*-(E)]]-

V-3

36078-10-1

1

1

1

9-Octadecenoic acid (Z)-, dodecyl ester

H3C-(CH2)7-CH=CH-(CH2)7-COO-(CH2)11CH3 V-3

22393-88-0

1

1

1

9-Octadecenoic acid (Z)-, eicosyl ester

H3C-(CH2)7-CH=CH-(CH2)7-COO-(CH2)19CH3 V-3

111-62-6

1

1

1

9-Octadecenoic acid (Z)-, ethyl ester {ethyl oleate}

H3C-(CH2)7-CH=CH-(CH2)7-COO-C2H5 V-3

1

1

1

9-Octadecenoic acid (Z)-, heptacosyl ester

H3C-(CH2)7-CH=CH-(CH2)7-COO-(CH2)26CH3 V-3

22393-86-8

1

1

1

9-Octadecenoic acid (Z)-, hexadecyl ester

H3C-(CH2)7-CH=CH-(CH2)7-COO-(CH2)16CH3 V-3

112-62-9

1

1

1

9-Octadecenoic acid (Z)-, methyl ester

H3C-(CH2)7-CH=CH-(CH2)7-COO-CH3 V-3

17673-49-3

69454-18-8

1

1

1

9-Octadecenoic acid (Z)-, nonadecyl ester

H3C-(CH2)7-CH=CH-(CH2)7-COO-(CH2)18CH3 V-3

1

1

1

9-Octadecenoic acid (Z)-, octadecyl ester

H3C-(CH2)7-CH=CH-(CH2)7-COO-(CH2)17CH3 V-3

1

1

1

9-Octadecenoic acid (Z)-, pentacosyl ester

H3C-(CH2)7-CH=CH-(CH2)7-COO-(CH2)24CH3 V-3

1

1

1

9-Octadecenoic acid (Z)-, pentadecyl ester

H3C-(CH2)7-CH=CH-(CH2)7-COO-(CH2)14CH3 V-3

1

1

1

9-Octadecenoic acid (Z)-, tetracosyl ester

H3C-(CH2)7-CH=CH-(CH2)7-COO-(CH2)23CH3 V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1681

11/24/08 1:57:01 PM

1682

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Chapter Table

22393-85-7

1

1

1

9-Octadecenoic acid (Z)-, tetradecyl ester

H3C-(CH2)7-CH=CH-(CH2)7-COO-(CH2)13CH3 V-3

1

1

1

9-Octadecenoic acid (Z)-, tricosyl ester

H3C-(CH2)7-CH=CH-(CH2)7-COO-(CH2)22CH3 V-3

75164-73-7

1

1

1

9-Octadecenoic acid (Z)-, tridecyl ester

H3C-(CH2)7-CH=CH-(CH2)7-COO-(CH2)12CH3 V-3

104077-09-0

0

1

0

9-Octadecenoic acid, 18-[(1-oxo-9octadecenyl)oxy]-, 1-(hydroxymethyl)-2- [(1-oxo-9octadecenyl)oxy]ethyl ester, (Z,Z,Z)-

V-3

104077-10-3

0

1

0

9-Octadecenoic acid, 18-[(1-oxo-9octadecenyl)oxy]-, 1-(hydroxymethyl)-1,2ethanediyl ester, (all-Z)-

V-3

104100-34-7

0

1

0

9-Octadecenoic acid, 18-[(1-oxo-9octadecenyl)oxy]-, 2-hydroxy-1,3-propanediyl ester, (all-Z)-

V-3

104077-06-7

0

1

0

9-Octadecenoic acid, 18-[(1-oxo-9octadecenyl)oxy]-, 2-hydroxy-3-[(1-oxo-9octadecenyl)oxy]propyl ester, (Z,Z,Z)-

V-3

104077-07-8

0

1

0

9-Octadecenoic acid, 18-[[1-oxo-18-[(1-oxo-9octadecenyl)oxy]-9-octadecenyl]oxy]-, 2-hydroxy3-[[1-oxo-18-[(1-oxo-9-octadecenyl)oxy]-9octadecenyl]oxy]propyl ester, (all-Z)-

V-3

104077-11-4

0

1

0

9-Octadecenoic acid, 18-[[1-oxo-18-[(1-oxo-9octadecenyl)oxy]-9-octadecenyl]oxy]-, 1(hydroxymethyl)-2-[[1-oxo-18-[(1-oxo-9octadecenyl)oxy]-9-octadecenyl]oxy]ethyl ester, (all-Z)-

V-3

104077-12-5

0

1

0

9-Octadecenoic acid, 18-[[1-oxo-18-[(1-oxo-9octadecenyl)oxy]-9-octadecenyl]oxy]-, 1(hydroxymethyl)-1,2-ethanediyl ester, (all-Z)-

V-3

104100-35-8

0

1

0

9-Octadecenoic acid, 18-[[1-oxo-18-[(1-oxo-9octadecenyl)oxy]-9-octadecenyl]oxy]-, 2-hydroxy1,3-propanediyl ester, (all-Z)-

V-3

104077-08-9

0

1

0

9-Octadecenoic acid, 18-[[1-oxo-18-[[1-oxo-18-[(1oxo-9-octadecenyl)oxy]-9-octadecenyl]oxy ]-9octadecenyl]oxy]-, 2-hydroxy-3-[[1-oxo-18-[[1-oxo18- [(1-oxo-9-octadecenyl)oxy]-9octadecenyl]oxy]-9-octadecenyl]oxy]propyl ester, (all-Z)-

V-3

104077-13-6

0

1

0

9-Octadecenoic acid, 18-[[1-oxo-18-[[1-oxo-18-[(1oxo-9-octadecenyl)oxy]-9-octadecenyl]oxy ]-9octadecenyl]oxy]-, 1-(hydroxymethyl)-2-[[1-oxo-18[[1-oxo- 18-[(1-oxo-9-octadecenyl)oxy]-9octadecenyl]oxy]-9-octadecenyl]oxy]ethyl ester, (all-Z)-

V-3

24753-52-4

0

1

0

9-Octadecenoic acid, 18-hydroxy-, (Z)-

2462-84-2

0

1

0

9-Octadecenoic acid, methyl ester

593-47-5

0

1

0

9-Octadecen-1-ol

Selected structures

II.A-5, IV.A-3 V-3 II.A-5

71899-42-8

0

1

0

5-Octadecyne

5392-40-5

1

1

1

2,6-Octadienal, 3,7-dimethyl-

H3C-(CH2)3-CŁC-(CH2)11-CH3

71607-91-5

1

0

0

1,6-Octadiene, 4,7-dimethyl{2,5-dimethyl-2,7-octadiene}

{citral}

I.B-1 III-12

H2C=CH-C(CH3)=CH-CH2-CH=C(CH3)2 I.B-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1682

11/24/08 1:57:02 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1683

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

123-35-3

1

1

1

1,6-Octadiene, 7-methyl-3-methylene- {myrcene}

H2C=CH-C(=CH2)-(CH2)2-CH=C(CH3)2 I.B-1

2216-70-8

1

0

0

2,4-Octadiene, 7-methyl-

H3C-CH=CH-CH=CH-CH2-CH(CH3)2 I.B-1 H3C-CH=CH-CH2-CH=CH-CH(CH3)2 I.B-1

71607-92-6

66957-95-7

Name (per CA Collective Index)

Selected structures

1

0

0

2,5-Octadiene, 7-methyl-

1

0

0

2,6-Octadiene, 2,6-dimethyl-

1

0

0

2,7-Octadiene, 2,7-dimethyl-

0

1

0

2,7-Octadiene-1,6-diol, 2,6-dimethyl-, [S-(E)]-

Chapter Table

I.B-1 I.B-1 II.A-5

0

1

0

Octadienoic acid

IV.A-3

459-80-3

0

1

0

2,6-Octadienoic acid, 3,7-dimethyl- {geranic acid}

IV.A-3

4698-08-2

0

1

0

2,6-Octadienoic acid, 3,7-dimethyl-, (E)-

IV.A-3

4613-38-1

0

1

0

2,6-Octadienoic acid, 3,7-dimethyl-, (Z)-

IV.A-3

64090-50-2

0

1

0

5,7-Octadienoic acid, 7-methyl-4-(1-methylethyl)-

IV.A-3

54557-54-9

0

1

0

5,7-Octadienoic acid, 7-methyl-4-(1-methylethyl)-, (E)-

IV.A-3

70687-51-3

0

1

0

5,7-Octadienoic acid, 7-methyl-4-(1-methylethyl)-, methyl ester

V-3

78-70-6

1

1

1

1,6-Octadien-3-ol, 3,7-dimethyl-

1

1

1

1,6-Octadien-3-ol, 3,7-dimethyl-, labeled with C 14 {linalool- C}

XXV-29

115-95-7

0

1

0

1,6-Octadien-3-ol, 3,7-dimethyl-, acetate {linalyl acetate}

V-3

115-99-1

0

1

0

1,6-Octadien-3-ol, 3,7-dimethyl-, formate {linalyl formate}

V-3

106-24-1

1

1

1

2,6-Octadien-1-ol, 3,7-dimethyl-, (E)-

{linalool}

II.A-5 HO

14

{geraniol}

II.A-5 CH2OH

106-25-2

0

1

0

2,6-Octadien-1-ol, 3,7-dimethyl-, (Z)-

38284-27-4

0

1

0

3,5-Octadien-2-one

30086-02-3

0

1

0

3,5-Octadien-2-one, (E,E)-

124-13-0

1

1

1

Octanal

107-75-5

0

1

0

Octanal, 7-hydroxy-3,7-dimethyl{hydroxycitronellal}

111-86-4

1

1

1

1-Octanamine

H3C-(CH2)6-CH2-NH2

111-65-9

1

1

1

Octane

H3C-(CH2)6-CH3

I.A-10

1

0

0

Octane, dimethyl-

C6H12=(CH3)2

I.A-10

1

0

0

Octane, methyl-

C7H15-CH3

I.A-10

61193-19-9

{nerol}

II.A-5 III-13 III-13 H3C-(CH2)6-CH=O

III-12 III-12 XII-2

2216-34-4

0

1

0

Octane, 4-methyl-

71607-64-2

1

0

0

Octane, phenyl-

I.A-10

505-48-6

1

0

0

Octanedioic acid

20653-90-1

0

1

0

2,3-Octanediol

II.A-5

585-25-1

1

1

1

2,3-Octanedione

III-13

65716-44-1

0

1

0

2,7-Octanedione, 3,3-dimethyl-

124-07-2

1

1

1

Octanoic acid

I.A-10, I.D-1 {suberic acid}

IV.A-3

III-13 {caprylic acid}

H3C-(CH2)6-COOH

IV.A-3, XXI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1683

11/24/08 1:57:02 PM

1684

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

14352-59-1

0

1

0

Octanoic acid, 3,3-dimethyl-

106-32-1

1

1

1

Octanoic acid, ethyl ester

Name (per CA Collective Index)

Chapter Table

Selected structures

IV.A-3 {ethyl caprylate}

V-3

111-11-5

0

1

0

Octanoic acid, methyl ester

3004-93-1

0

1

0

Octanoic acid, 2-methyl-

{methyl caprylate}

V-3

16493-80-4

0

1

0

Octanoic acid, 4-ethyl-

IV.A-3

693-19-6

0

1

0

Octanoic acid, 7-methyl-

IV.A-3

70898-30-5

1

1

1

Octanoic acid, 3,7,11,15,19,23,27,31,35nonamethyl-2,6,10,14,18,22,26,30,34hexatriacontanonaenyl ester, (all-E)-

96937-51-8

1

0

0

Octanoic acid, oxo-

IV.A-3

V-3

III-13, IV.A-3

638-25-5

0

1

0

Octanoic acid, pentyl ester

V-3

70898-31-6

0

1

0

Octanoic acid, 3,7,11,15-tetramethyl-2-hexadecenyl ester, [R-[R*,R*-(E)]]-

V-3

111-87-5

123-96-6

1

1

1

1-Octanol

0

1

0

1-Octanol, 3,7-dimethyl-, acetate {tetrahydrogeranyl acetate}

1

0

0

2-Octanol

589-98-0

0

1

0

3-Octanol

78-69-3

0

1

0

3-Octanol, 3,7-dimethyl-

111-13-7

1

1

1

2-Octanone

{caprylic alcohol}

H3C-(CH2)6-CH2OH

II.A-5, XXI-3 V-3

H3C-(CH2)5-CHOH-CH3

II.A-5 II.A-5

{tetrahydrolinalool} {hexyl methyl ketone}

II.A-5 H3C-(CH2)5-CO-CH3

III-13

65716-45-2

0

1

0

2-Octanone, 7-hydroxy-3,3-dimethyl-, (±)-

106-68-3

0

1

0

3-Octanone

II.A-5, III-13

7194-85-6

1

1

1

Octatriacontane

H3C-(CH2)36-CH3

929-20-4

1

0

0

1,3,6-Octatriene

H2C=CH-CH=CH-CH2-CH=CH-CH3 I.B-1

13877-91-3

1

1

1

1,3,6-Octatriene, 3,7-dimethyl-

3779-61-1

0

1

0

1,3,6-Octatriene, 3,7-dimethyl-, (E)-

673-84-7

1

0

0

2,4,6-Octatriene, 2,6-dimethyl-

29414-56-0

1

0

0

1,5,7-Octatrien-3-ol, 2,6-dimethyl-

0

1

0

2-Octenal

III-12

0

1

0

2-Octenal, 4-(1-methylethyl)-

III-12

106-23-0

1

1

1

6-Octenal, 3,7-dimethyl-

71607-54-0

1

0

0

Octene, methyl-

{ethyl amyl ketone}

{ocimene}

III-13 I.A-10

H2C=CH-C(CH3)=CH-CH2-CH=C(CH3)2 I.B-1 I.B-1

{alloöcimene}

(H3C)2=C=CH-CH=CH-C(CH3)=CH-CH3 I.B-1 II.A-5

{citronellal}

(H3C) 2=C=CH-(CH2) 2-CH(CH3)-CH2-CH=O III-12 I.B-1

111-66-0

1

0

0

1-Octene

H2C=CH-(CH2)5-CH3

I.B-1

4588-18-5

1

0

0

1-Octene, 2-methyl-

H2C=C(CH3)-(CH2)5-CH3

I.B-1

111-67-1

1

0

0

2-Octene

H3C-CH=CH-(CH2)4-CH3

I.B-1

H3C-(CH2)2-CH=CH-(CH2)2-CH3

592-99-4

1

0

0

4-Octene

28962-27-8

1

0

0

Octenoic acid

1470-50-4

{caprylene}

I.B-1 IV.A-3

0

1

0

2-Octenoic acid

0

1

0

2-Octenoic acid, 4-(1-methylethyl)-7-oxo-

III-13, IV.A-3

IV.A-3

0

1

0

4-Octenoic acid, 3-hydroxy-3-methyl- 6-(1methylethyl)-

II.A-5, IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1684

11/24/08 1:57:03 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1685

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

0

1

0

Name (per CA Collective Index) 4-Octenoic acid, 3-hydroxy-3-methyl-6-(1methylethyl)-, methyl ester

Selected structures H3C

Chapter Table II.A-5, V-3

CH3 CH3

H3C

OH H3C-OOC

41654-08-4

0

1

0

4-Octenoic acid, 6-ethyl-3-hydroxy-3,7-dimethyl-

II.A-5

63892-00-2

0

1

0

5-Octenoic acid

IV.A-3

41653-97-8

0

1

0

5-Octenoic acid, (Z)-

IV.A-3

502-47-6

0

1

0

6-Octenoic acid, 3,7-dimethyl-

IV.A-3

18719-24-9

0

1

0

7-Octenoic acid

IV.A-3

3391-86-4

0

1

0

1-Octen-3-ol

18409-17-1

0

1

0

2-Octen-1-ol, (E)-

II.A-5 H3C-(CH2)4-CH=CH-CH2OH

II.A-5

106-22-9

1

1

1

6-Octen-1-ol, 3,7-dimethyl-

{dl-citronellol}

II.A-5

6812-78-8 141-25-3

0

1

0

7-Octen-1-ol, 3,7-dimethyl-

{rhodinol}

II.A-5

1669-44-9

0

1

0

3-Octen-2-one

III-13

14129-48-7

0

1

0

4-Octen-3-one

III-13

124354-88-7

0

1

0

Octen-4-one, 2,6-dimethyl-, monoepoxy derivative

111-12-6

0

1

0

2-Octynoic acid, methyl ester

508-02-1

0

1

0

Olean-12-en-28-oic acid, 3-hydroxy-, (3E)-

471-53-4

1

0

0

Olean-12-en-29-oic acid, 3-hydroxy-11-oxo-, (3E,20E)-

559-70-6

1

1

1

Olean-12-en-3-ol, (3E)-

III-13, X-2 H3C-(CH2)4-CŁC-COO-CH3

V-3 II.A-5, IV.A-3

II.A-5, III-13, IV.A-3

{ȕ-amyrin}

H3C

H3C

CH3

CH3

II.A-5, II.B-2

CH3 CH3

HO H3C

7006-33-9

1

1

1

Ornithine

{2,3-diaminopentanoic acid}

CH3

H 2N-(CH2)3-CH(NH2)-COOH IV.A-3, IV.B-7, XII-2

70-26-8

1

1

1

L-Ornithine

IV.A-3, IV.B-7, XII-2

20197-09-5

0

1

0

L-Ornithine, N2-(1-carboxyethyl)-, (R)-

IV.A-3, IV.B-7, XII-2

372-75-8

0

1

0

L-Ornithine, N5-(aminocarbonyl)-

7440-04-2

1

1

1

Osmium

141093-09-6

0

1

0

1-226-Osmotin (Nicotiana tabacum samsun clone pMOG404 reduced)

XXII-2

141093-08-5

0

1

0

Osmotin (Nicotiana tabacum samsun clone pMOG404 reduced)

XXII-2

143638-31-7

0

1

0

Osmotin (Nicotiana tabacum samsun clone pTOL1 precursor reduced)

XXII-2

143638-32-8

0

1

0

Osmotin (Nicotiana tabacum samsun clone pTOL1 reduced)

XXII-2

131553-54-3

0

1

0

Osmotin (Nicotiana tabacum samsun reduced)

XXII-2

142583-50-4

0

1

0

Osmotin (tobacco clone pVK5 precursor reduced)

XXII-2

{citrulline}

H2N-CO-NH-(CH2)3-CH(NH2)-COOH IV.A-3, IV.B-7, XII-2, XIII-1 Os

XX-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1685

11/24/08 1:57:03 PM

1686

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

142583-51-5

0

1

0

Osmotin (tobacco clone pVK5 reduced)

190-26-1

1

0

0

Ovalene

38284-11-6

0

1

0

7-Oxabicyclo[4.1.0]heptane-2,5-dione, 1,3,3trimethyl-

73051-73-7

0

1

0

7-Oxabicyclo[2.2.1]heptan-2-ol, 1-(3-hydroxy-1butenyl)-2,6,6-trimethyl-

Name (per CA Collective Index)

Chapter Table

Selected structures

XXII-2 I.E-6

III-13, X-2 II.A-5, X-2

OH

H3C

CH3 CH3

O

CH3 OH

68573-20-6

0

1

0

7-Oxabicyclo[4.1.0]heptan-3-ol, 6-(3-hydroxy-1butenyl)-1,5,5-trimethyl-

H3C

CH3

O HO

72777-88-9

0

1

0

7-Oxabicyclo[4.1.0]heptan-3-ol, 6-(3-hydroxy-1butenyl)-1,5,5-trimethyl-

470-82-6

1

1

1

2-Oxabicyclo[2.2.2]octane, 1,3,3-trimethyl{eucalyptol; 1.8-cineole}

II.A-5, X-2

OH

CH3

CH3

II.A-5, X-2 X-2

CH3

H3C O

CH3

72693-08-4

1

0

0

6-Oxabicyclo[3.2.1]octan-7-one, 8-hydroxy-1methyl-

640-06-2

1

0

0

6-Oxabicyclo[3.2.1]octan-7-one, 1,3,4-trihydroxy{Cyclohexanecarboxylic acid, 1,3,4,5-tetrahydroxy, Ȗ -lactone; quinic acid lactone; quinide}

II.A-5 II.A-5, VI-3

OH OH

HO

C

O

O

27783-00-2

1

1

1

6-Oxabicyclo[3.2.1]octan-7-one, 1,3,4-trihydroxy-, (exo,exo)-

II.A-5

665-27-0

1

0

0

6-Oxabicyclo[3.2.1]octan-7-one, 1,3,4-trihydroxy-, [1S-(exo,exo)]-

II.A-5, X-2

98064-77-8

0

1

0

15-Oxabicyclo[10.2.1]pentadec-6-en-3-one, 5,11dihydroxy-1,5,11-trimethyl-8-(1-methylethyl)-, [1R(1R*,5S*,6E,8S*,11R*,

II.A-5, III-13, X-2 CH3

H3C OH H3C

8

11

9 1

0

1

0

15-Oxabicyclo[10.2.1]pentadec-6-en-3-one, 5,11dihydroxy-1,5,11-trimethyl-8-(1-methylethyl)-, [1R(1R*,5S*,6E,8S*,11S*,12S*)]-

5

7 2

4

3

CH3

O

98167-33-0

OH

6

10

CH3

O

II.A-5, III-13, X-2 CH3

H3C OH H3C

8

11

9 1

O

OH

6

10

5

7 2

3

4

CH3

CH3 O

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1686

11/24/08 1:57:04 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1687

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

98064-76-7

0

1

0

Name (per CA Collective Index) 15-Oxabicyclo[10.2.1]pentadec-6-en-3-one, 5hydroxy-1,5-dimethyl-11-methylene-8-(1methylethyl)-, [1R-(1R*,5S*,6E,8S*,1

II.A-5, III-13, X-2 CH3

H3C H2C 12

8

9 14

13

1

0

15-Oxabicyclo[10.2.1]pentadec-6-ene-2,3,5-triol, 1,5-dimethyl-11-methylene-8-(1-methylethyl)-, [1R(1R*,2S*,3R*,5S*,6E,8

57760-48-2

1

1

1

15-Oxabicyclo[10.2.1]pentadeca-2,6,10-trien-5-ol, 1,5,11-trimethyl-8-(1-methylethyl)-, [1R(1R*,2E,5S*,6E,8S*,10E,12S*)]-

5

7 2

1

CH3 4

3

CH3

O

0

OH

6

10 11

121927-14-8

Chapter Table

Selected structures

O

II.A-5, X-2

H3C

II.A-5, X-2

CH3

H3C

OH

6

10 8

9

11

5

7

CH3

2

1

4 3

CH3

O

60047-18-9

1

1

1

15-Oxabicyclo[10.2.1]pentadeca-2,6,10-trien-5-ol, 1,5,11-trimethyl-8-(1-methylethyl)-

H3C

II.A-5, X-2

CH3

H3C

OH

6

10 8

9

11

5

7 2

1

CH3 4

3

CH3

O

60026-18-8

1

1

1

15-Oxabicyclo[10.2.1]pentadeca-2,6,10-triene, 1,11-dimethyl-5-methylene-8-(1-methylethyl)-

69010-30-6

1

1

1

15-Oxabicyclo[10.2.1]pentadeca-2,6,10-triene, 1,11-dimethyl-5-methylene-8-(1-methylethyl)-, [1R(1R*,2E,6E,8S*,10Z,12S*)]-

X-2 H3C

6

10

H3C

X-2

CH3

11

8

9

CH2

5

7 2

4

1

CH3

O

1

1

1

15-Oxabicyclo[10.2.1]pentadeca-2,6,10-triene, 1,5,11-trimethyl-8-(1-methylethyl)-

H3C

8

6

11

1

1

15-Oxabicyclo[10.2.1]pentadeca-2,6-dien-5-ol, 1,5dimethyl-11-methylene-8-(1-methylethyl)-, [1R(1R*,2E,5S*,6E,8R*,10S*)]-

4

H3C

II.A-5, X-2

CH3 OH

6

10

H2C

5

CH3

O

1

CH3

2

1

57688-98-9

X-2

CH3

10

H3C

3

11

8

9

5

7 2

CH3

O

57760-47-1

1

1

1

15-Oxabicyclo[10.2.1]pentadeca-2,6-dien-5-ol, 1,5dimethyl-11-methylene-8-(1-methylethyl)-, [1R(1R*,2E,5R*,6E,8S*,12S*)]-

H3C

3

11

OH

6 9

8 1

O

II.A-5, X-2

CH3

10

H2C

CH3 4

1

7

5

2

4

CH3

3

CH3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1687

11/24/08 1:57:04 PM

1688

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

60047-16-7

1

1

1

Name (per CA Collective Index) 15-Oxabicyclo[10.2.1]pentadeca-2,6-dien-5-ol, 1,5dimethyl-11-methylene-8-(1-methylethyl)-

Selected structures

II.A-5, X-2

CH3

H3C

Chapter Table

CH3

H2C

OH

CH3

O

102977-88-8

0

1

0

15-Oxabicyclo[10.2.1]pentadeca-2,6-dien-5-ol, 5methyl-11-methylene-8-(1-methylethyl)-

72693-05-1

1

1

1

15-Oxabicyclo[10.2.1]pentadeca-2,6-diene, 1methyl-5,11-bis(methylene)-8-(1-methylethyl)-

H2C

CH2

CH3

O

58947-96-9

0

1

0

15-Oxabicyclo[10.2.1]pentadeca-6,10-dien-2-one, 8-hydroxy-8,12-dimethyl-5-(1-methylethyl)-

98064-75-6

0

1

0

15-Oxabicyclo[10.2.1]pentadeca-6,10-dien-3-one, 5-hydroxy-1,5,11-trimethyl-8-(1-methylethyl)-, [1R(1R*,5S*,6E,8S*,10E,

II.A-5, III-13, X-2 II.A-5, III-13, X-2 CH3

H3C

9

11 12

14

13

8

1

0

15-Oxabicyclo[10.2.1]pentadeca-6,10-diene-2,8diol, 2,8,12-trimethyl-5-(1-methylethyl)-, [1S(1R*,2S*,5R*,6E,8R*,10E,12S*)]-

CH3 4

3

O

II.A-5, X-2

CH3

3

OH

5

2

H3C

2

CH3

H3 C OH

5

7

1

O

0

OH

6

10

H3C

66890-76-4

X-2

CH3

H3C

4

7

6 10

1

CH3 8

9

CH3

O

66966-04-9

0

1

0

15-Oxabicyclo[10.2.1]pentadeca-6,10-diene-2,8diol, 2,8,12-trimethyl-5-(1-methylethyl)-, [1S(1R*,2R*,5R*,6E,8R*,10E,12S*)]-

H3 C OH

3

OH

5

2

H3C

II.A-5, X-2

CH3

4

7

6 10

1

CH3 8

9

CH3

O

119613-99-9

0

1

0

15-Oxabicyclo[12.1.0]pentadec-9-en-5-one, 11,13dihydroxy-1,11-dimethyl-8-(1-methylethyl)-, [1S(1R*,8R*,9E,11R*,13S*,14S*)]-

98064-73-4

0

1

0

15-Oxabicyclo[12.1.0]pentadeca-4,9-dien-6-one, 8hydroxy-4,8,14-trimethyl-11-(1-methylethyl)-, [1S(1R*,4E,8R*,9E,11R*)]

II.A-5, III-13, X-2

H3C CH3 O

13 14

II.A-5, III-13, X-2

CH3

12 11

10

3

5

9

CH3 8

OH

1 2

4

CH3

6

7

O

152209-53-5

0

1

0

15-Oxabicyclo[12.1.0]pentadeca-4,9-diene-6,8-diol, 11-(1-hydroxy-1-methylethyl)-4,8,14-trimethyl-, [1S-(1R*,4E,6S*,8R*,9E,11S*,14R*)]-

II.A-5, X-2

70969-36-7

0

1

0

15-Oxabicyclo[12.1.0]pentadeca-4,9-diene-6,8-diol, 4,8,14-trimethyl-11-(1-methylethyl)-

II.A-5, X-2

75281-93-5

0

1

0

15-Oxabicyclo[12.1.0]pentadeca-4,9-diene-6,8-diol, 4,8,14-trimethyl-11-(1-methylethyl)-, [1S(1R*,4E,6S*,8S*,9E,11R*,14R*)]-

II.A-5, X-2

75281-99-1

0

1

0

15-Oxabicyclo[12.1.0]pentadeca-4,9-diene-6,8-diol, 4,8,14-trimethyl-11-(1-methylethyl)-, [1S(1R*,4E,6S*,8R*,9E,11R*,14R*)]-

II.A-5, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1688

11/24/08 1:57:05 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1689

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

75282-00-7

0

1

0

15-Oxabicyclo[12.1.0]pentadeca-4,9-diene-6,8-diol, 4,8,14-trimethyl-11-(1-methylethyl)-, [1R(1R*,4E,6R*,8S*,9E,11S*,14R*)]-

62498-80-0

0

1

0

15-Oxabicyclo[9.3.1]pentadeca-2,6-diene-5,12-diol, 1,5,11-trimethyl-8-(1-methylethyl)-, [1R(1R*,2E,5S*,6E,8R*,11S*,12S*)]-

Name (per CA Collective Index)

Selected structures

Chapter Table II.A-5, X-2

OH

6

10

H3C

8

9

11

2

1

HO

5

7

O

12

II.A-5, X-2

CH3

H3C

4

CH3

3

CH3

123-69-3

1

0

0

Oxacycloheptadec-8-en-2-one, (Z)-{ambrettolide}

106-02-5

0

1

0

Oxacyclohexadecan-2-one

(CH2)8

VI-6

O

(CH2)6

{Z-pentadecalactone; exaltolide} 68985-15-9

0

1

0

O

(CH2)6

VI-6

O O

(CH2)6

Oxacyclononadec-10-en-2-one, (E)-

(CH2)8

VI-6

O O

(CH2)7

60918-97-0

0

1

0

1,3,4-Oxadiazol-2-amine, N-(4-bromophenyl)-5-(1naphthalenylmethyl)-

72962-43-7

0

1

0

E-homo-7-Oxaergostan-6-one, 2,3,22,23tetrahydroxy-, (2D,3D,5D,22R,23R,24S)-

80722-28-7

0

1

0

1-Oxaspiro[4.5]deca-2,6-dien-8-one, 2,6,10,10tetramethyl-

XII-2, XVII.D-2, XVIII.B-3 II.A-5, III-13

9 8

O

57893-27-3

0

1

0

1-Oxaspiro[4.5]decane, 6-acetoxy-2,6,10,10tetramethyl{6-acetoxydihydrotheaspirane}

CH3

H3C

H3C

7

III-13, X-2

3

4

2

10

CH3

O

6

CH3

V-3, X-2

CH3 CH3

O CH3 OOC-CH3

65620-50-0

0

1

0

1-Oxaspiro[4.5]decane, 6-hydroxy-2,6,10,10tetramethyl{6-hydroxydihydrotheaspirane}

H3C

II.A-5, X-2

CH3

O

CH3

CH3 OH

0

1

0

1-Oxaspiro[4,5]dec-7-ene, 2,10,10-trimethyl{vitispirane}

H3C

X-2

CH3 CH3

O CH2

38713-26-7

0

1

0

1-Oxaspiro[4.5]dec-2-en-8-one, 2,6,6,10tetramethyl-

H3C

CH3

O

CH3

CH3

O

III-13, X-2 19377-59-4

0

1

0

1-Oxaspiro[4.5]dec-6-en-8-one, 2,6,10,10tetramethyl-

H3C

III-13, X-2

CH3

O O

CH3

CH3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1689

11/24/08 1:57:05 PM

1690

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

5259-88-1

0

1

0

Name (per CA Collective Index)

Selected structures

1,4-Oxathiin-3-carboxamide 4,4-dioxide, 5,6dihydro-2-methyl-N-phenyl{Oxycarboxin®}

XXI-3

O H N O

S

Chapter Table

O

O

1139-30-6

0

1

0

5-Oxatricyclo[8.2.0.04,6]dodecane, 4,12,12trimethyl-9-methylene-, [1R-(1R*,4R*,6R*,10S*)]{E-caryophyllene oxide}

X-2

CH3 11 10

H2C

CH3

12 1

2

9 6

8 7

5O

4

3

CH3

15769-88-7

1

1

1

2H-1,2-Oxazine, tetrahydro-2-methyl-6-(3-pyridinyl), (-)-

XVII.B-2

71607-95-9

1

0

0

2H-1,2-Oxazine, tetrahydro-3-(1-methylethyl)-6-(3pyridinyl)-

XVII.B-2

7208-05-1

1

0

0

Oxazole, 2,4-dimethyl-

XVII.D-2

1

0

0

Oxazole, 2,4-dimethyl-5-butyl-

XVII.D-2

1

0

0

Oxazole, 2,4-dimethyl-5-ethyl-

XVII.D-2

1

0

0

Oxazole, 2,4-dimethyl-5-(2-methylpropyl)-

XVII.D-2

1

0

0

Oxazole, 2,4-dimethyl-5-propyl-

XVII.D-2

1

0

0

Oxazole, 2,5-dimethyl-

XVII.D-2

1

0

0

Oxazole, 2,5-dimethyl-4-ethyl-

XVII.D-2

1

0

0

Oxazole, 2,5-dimethyl-4-(2-methylpropyl)-

XVII.D-2

1

0

0

Oxazole, 4,5-dimethyl-

XVII.D-2

1

0

0

Oxazole, 4,5-dimethyl-2-butyl-

XVII.D-2

1

0

0

Oxazole, 4,5-dimethyl-2-ethyl-

XVII.D-2

1

0

0

Oxazole, 4,5-dimethyl-2-(1-methylpropyl)-

XVII.D-2

1

0

0

Oxazole, 4,5-dimethyl-2-(2-methylpropyl)-

XVII.D-2

1

0

0

Oxazole, 2-ethyl-4-methyl-

XVII.D-2

1

0

0

Oxazole, 2-ethyl-5-methyl-

1

0

0

Oxazole, 2-methyl-

23012-11-5

20654-94-8 20662-83-3

23012-10-4

XVII.D-2 5 1

O

XVII.D-2

4

N3

CH3

1

0

0

Oxazole, 2-(2-methylpropyl)-

XVII.D-2

1

0

0

Oxazole, 2-(3-methylbutyl)-

XVII.D-2

1

0

0

Oxazole, 2-methyl-4-butyl-

XVII.D-2

1

0

0

Oxazole, 2-methyl-5-ethyl-

XVII.D-2

1

0

0

Oxazole, 2-methyl-4-(2-methylpropyl)-

XVII.D-2

1

0

0

Oxazole, 4-(2-methylpropyl)-

XVII.D-2

1

0

0

Oxazole, 4-methyl-2-butyl-

XVII.D-2

1

0

0

Oxazole, 4-methyl-2-(2-methylpropyl)-

XVII.D-2

1

0

0

Oxazole, 4-methyl-5-(2-methylpropyl)-

XVII.D-2

1

0

0

Oxazole, 4-methyl-2-propyl-

XVII.D-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1690

11/24/08 1:57:06 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1691

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

1

0

0

Oxazole, 4-methyl-5-propyl-

XVII.D-2

1

0

0

Oxazole, 4-pentyl-

XVII.D-2

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

Oxazole, 5-methyl-4-ethyl-

XVII.D-2

20662-84-4

0

1

0

Oxazole, trimethyl- = 2,4,5-Trimethyloxazole

XVII.D-2

2346-26-1

1

0

0

2,4-Oxazolidinedione

50471-44-8

0

1

0

2,4-Oxazolidinedione, 3-(3,5-dichlorophenyl)-5ethenyl-5-methyl{Vinclozolin®}

XIV-1, XVII.D-2 XIV-1, XVIII.B-3, XXI-3

Cl O

N Cl

O O

1

0

0

2,4-Oxazolidinedione, 5-ethyl-1-methyl-

XIV-1, XVII.D-2

27770-23-6

1

0

0

2,4-Oxazolidinedione, 5-methyl-

XIV-1, XVII.D-2

9035-73-8

0

1

0

Oxidase

XXII-2

9029-44-1

0

1

0

Oxidase, ascorbate

XXII-2

0

1

0

Oxidase, choline

XXII-2

9076-84-0

0

1

0

Oxidase, coproporphyrinogen

XXII-2

9001-16-5

0

1

0

Oxidase, cytochrome

XXII-2

9001-53-0

0

1

0

Oxidase, diamine

XXII-2

9028-71-1

0

1

0

Oxidase, glycolate

XXII-2

9027-85-4

0

1

0

Oxidase, indoleacetate

XXII-2

55326-39-1

0

1

0

Oxidase, isopentenyladenosine

XXII-2

37259-79-3

0

1

0

Oxidase, methylputrescine

XXII-2

9001-96-1

0

1

0

Oxidase, pyruvate

XXII-2

9032-21-7

0

1

0

Oxidase, reduced nicotinamide adenine dinucleotide

XXII-2

9032-22-8

0

1

0

Oxidase, reduced nicotinamide adenine dinucleotide phosphate

XXII-2

9014-35-1

0

1

0

Oxidase, succinate

XXII-2

69671-26-7

0

1

0

Oxidase, ubiquinol

XXII-2

9002-12-4

0

1

0

Oxidase, urate

XXII-2

9002-17-9

0

1

0

Oxidase, xanthine

75-21-8

1

0

0

Oxirane

106-89-8

0

1

0

Oxirane, (chloromethyl)-

7200-26-2

1

0

0

Oxirane, 2,2-dimethyl-3-(3,7,12,16,20-pentamethyl3,7,11,15,19-heneicosapentaenyl)-, (all-E)-

X-2

75-56-9

1

0

0

Oxirane, methyl-

{propylene oxide}

X-2

96-09-3

0

1

0

Oxirane, phenyl-

{phenylethylene oxide}

X-2

77288-97-2

0

1

0

Oxiranebutanol, 3-(1-hydroxy-1-methylethyl)-Dmethyl-G-(1-methylethyl)-, [2D(DS*,GR*),3D]-

II.A-5, X-2

77288-94-9

0

1

0

Oxiranebutanol, 3-(1-hydroxyethyl)-D-methyl-G-(1methylethyl)-

II.A-5, X-2

0

1

0

Oxiranecarboxylic acid, 3-methyl-3-phenyl-, ethyl ester {ethyl methylphenylglycidate}

0

1

0

2,3-Oxiranedimethanol, monopropanoate

61892-62-4

XXII-2 {ethylene oxide}

X-2 X-2, XVIII.B-3

V-3, X-2 II.A-5, V-3, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1691

11/24/08 1:57:06 PM

1692

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

556-52-5

1

0

0

Name (per CA Collective Index) Oxiranemethanol

Chapter Table

Selected structures

{glycidol}

II.A-5, X-2

O CH2OH

0

1

0

Oxiranemethanol, acetate

{glycidyl acetate}

V-3, X-2

O CH2OOC-CH3

51297-34-8

0

1

0

Oxiranemethanol, 3-(1-ethyl-2-methylpropyl)-D,Ddimethyl-

7782-44-7

1

1

1

Oxygen

7782-44-7

1

1

1

Oxygen (diradical)

II.A-5, X-2 O2

XIX-5, XX-5 XXVII-1

9029-57-6

0

1

0

Oxygenase, 2,5-dihydroxypyridine 5,6-di-

XXII-2

152060-37-2

0

1

0

Oxygenase, benzoate 2-mono-

XXII-2

9077-75-2

0

1

0

Oxygenase, cinnamate 4-mono-

XXII-2

9068-40-0

0

1

0

Oxygenase, p-coumarate 3-mono-

XXII-2

9002-10-2

0

1

0

Oxygenase, monophenol mono-

XXII-2

9028-06-2

0

1

0

Oxygenase, protocollagen proline di-

XXII-2

39335-11-0

0

1

0

Oxygenase, ribulose diphosphate

7440-05-3

1

1

1

Palladium

142193-29-1

0

1

0

Parasiticein

XXII-2 Pd

XXII-2

142193-19-9

0

1

0

Parasiticein (Phytophthora parasitica reduced)

9046-40-6

0

1

0

Pectic acid

0

1

0

Pectic acid, labeled with C

0

1

0

Pectic acid, magnesium salt

65028-58-2 9000-69-5

XX-5 XXII-2 IV.A-3, VIII-3

14

0

1

0

Pectin

0

1

0

Pectin, labeled with C

14

{pectic acid- C}

XXV-29 XX-6 VIII-3

14

14

{pectin- C}

XXV-29

0

1

0

Pectinic acid

135-48-8

1

0

0

Pentacene

629-99-2

1

1

1

Pentacosane

H3C-(CH2)23-CH3

I.A-10

629-87-8

1

0

0

Pentacosane, 2-methyl-

H3C-(CH2)22-CH=(CH3)2

I.A-10

506-38-7

1

1

1

Pentacosane, 3-methyl-

506-38-7

1

1

1

Pentacosanoic acid

121877-88-1 121877-80-3

10482-74-3

IV.A-3, VIII-3 {benzo[b]naphthacene}

I.E-6

I.A-10 H3C-(CH2)23-COOH

IV.A-3

1

1

1

Pentacosanoic acid, docosyl ester

H3C-(CH2)23-COO-(CH2)21-CH3

V-3

1

1

1

Pentacosanoic acid, dodecyl ester

H3C-(CH2)23-COO-(CH2)11-CH3

V-3

1

1

1

Pentacosanoic acid, eicosyl ester

H3C-(CH2)23-COO-(CH2)19-CH3

V-3

1

1

1

Pentacosanoic acid, heneicosyl ester

H3C-(CH2)23-COO-(CH2)20-CH3

V-3

1

1

1

Pentacosanoic acid, heptacosyl ester

H3C-(CH2)23-COO-(CH2)26-CH3

V-3

1

1

1

Pentacosanoic acid, heptadecyl ester

H3C-(CH2)23-COO-(CH2)16-CH3

V-3

1

1

1

Pentacosanoic acid, hexacosyl ester

H3C-(CH2)23-COO-(CH2)25-CH3

V-3

1

1

1

Pentacosanoic acid, hexadecyl ester

H3C-(CH2)23-COO-(CH2)15-CH3

V-3

1

1

1

Pentacosanoic acid, nonadecyl ester

H3C-(CH2)23-COO-(CH2)18-CH3

V-3

1

1

1

Pentacosanoic acid, octadecyl ester

H3C-(CH2)23-COO-(CH2)17-CH3

V-3

1

1

1

Pentacosanoic acid, pentacosyl ester

H3C-(CH2)23-COO-(CH2)24-CH3

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1692

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1693

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke S

T

S T

Selected structures

Chapter Table

1

1

1

1

1

1

Pentacosanoic acid, pentadecyl ester

H3C-(CH2)23-COO-(CH2)14-CH3

V-3

Pentacosanoic acid, tetracosyl ester

H3C-(CH2)23-COO-(CH2)23-CH3

V-3

1

1

1

1

1

1

Pentacosanoic acid, tetradecyl ester

H3C-(CH2)23-COO-(CH2)13-CH3

V-3

Pentacosanoic acid, tricosyl ester

H3C-(CH2)23-COO-(CH2)32-CH3

V-3

1

1

0

1

1

Pentacosanoic acid, tridecyl ester

H3C-(CH2)23-COO-(CH2)12-CH3

V-3

0

Pentacosanoic acid, 23-methyl-

H3C-CH2-CH(CH3)-(CH2)21-COOH IV.A-3

121877-85-8

1

1

1

Pentacosanoic acid, 23-methyl-, heneicosyl ester

H3C-CH2-CH(CH3)-(CH2)21-COO-(CH2)20-CH3 V-3

129074-11-9

1

0

0

Pentacosanol

26040-98-2

0

1

0

1-Pentacosanol

H3C-(CH2)23-CH2OH

II.A-5

63785-24-0

0

1

0

1-Pentacosanol, 24-methyl-

(H3C)2=CH-(CH2)22-CH2OH

II.A-5

30551-31-6

1

0

0

Pentacosene

CAS No.

16980-85-1

Name (per CA Collective Index)

I.B-1

1

0

0

1-Pentacosene

H3C-(CH2)22-CH=CH2

I.B-1

1

0

0

1-Pentacosene, 2-methyl-

H2C=CH-(CH2)22-CH3

I.B-1

1

0

0

2-Pentacosene, (Z)-

H3C-CH=CH-(CH2)21-CH3

1

0

0

2-Pentacosene, (E)-

1

0

0

2-Pentacosene, 2-methyl-

H3C-C(CH3)=CH-(CH2)21-CH3

1

0

0

2-Pentacosene, 23-methyl-, (Z)-

H3C-CH=CH-(CH2)19-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Pentacosene, 23-methyl-, (E)-

1

0

0

2-Pentacosene, 24-methyl-, (Z)-

1

0

0

2-Pentacosene, 24-methyl-, (E)-

102673-27-8

0

1

0

4,9-Pentadecadienal, 6-(acetyloxy)-8-hydroxy-4,8dimethyl-11-(1-methylethyl)-14-oxo-, [6R(4E,6R*,8R*,9E,11S*)]-

95360-16-0

0

1

0

4,9-Pentadecadienal, 6,8-dihydroxy-4,8-dimethyl11-(1-methylethyl)-14-oxo-, [6R(4E,6R*,8S*,9E,11S*)]-

1

0

0

Pentadecadiene, 2,6,10,14-tetramethyl-

1

0

0

4,9-Pentadecadienoic acid, 6,8-dihydroxy-4,8dimethyl-11-(1-methylethyl)-14-oxo-

70898-33-8

II.A-5

I.B-1 I.B-1 I.B-1

I.B-1 H3C-CH=CH-(CH2)20-CH(CH3)2

I.B-1 I.B-1

II.A-5, V-3, III-12

II.A-5, III-12

I.B-1 II.A-5, IV.A-3, III-13 CH3

H3C

CH3

H3C

OH

O HOOC

CH3

OH

102734-50-9

0

1

0

4,9-Pentadecadienoic acid, 6,8-dihydroxy-4,8dimethyl-11-(1-methylethyl)-14-oxo-, methyl ester, [6R-(4E,6R*,8S*,9E,11S*)]-

II.A-5, V-3, III-13

102734-51-0

0

1

0

4,9-Pentadecadienoic acid, 6,8-dihydroxy-4,8dimethyl-11-(1-methylethyl)-14-oxo-, methyl ester, [6R-(4E,6R*,8R*,9E,11S*)]-

II.A-5, V-3, III-13

152209-55-7

0

1

0

6,11-Pentadecadien-2-one, 8,10,15-trihydroxy-8,12dimethyl-5-(1-methylethyl)-, [5S(5R*,6E,8R*,10S*,11E)]-

2765-11-9

0

1

0

Pentadecanal

68982-28-5

0

1

0

Pentadecanal, 2-ethylidene-6,10,14-trimethyl- H-

II.A-5, III-13

H3C-(CH2)13-CH=O

III-12 III-12

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1693

11/24/08 1:57:07 PM

1694

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 629-62-9

S

T

S T

Name (per CA Collective Index)

Selected structures H3C-(CH2)13-CH3

Chapter Table

1

1

1

Pentadecane

0

1

0

Pentadecane, 4-acetoxy-

I.A-10

1560-93-6

1

1

1

Pentadecane, 2-methyl-

H3C-(CH2)12-CH=(CH3)2

I.A-10

2882-96-4

1

1

1

Pentadecane, 3-methyl-

H3C-(CH2)11-CH(CH3)-CH2-CH3

I.A-10

1921-70-6

1

0

0

Pentadecane, 2,6,10,14-tetramethyl-

I.A-10

3892-00-0

1

0

0

Pentadecane, 2,6,10-trimethyl-

I.A-10

1460-18-0

1

0

0

Pentadecanedioic acid

HOOC-(CH2)13-COOH

IV.A-3

1002-84-2

1

1

1

Pentadecanoic acid

H3C-(CH2)13-COOH

IV.A-3

V-3

42232-23-5

1

1

1

Pentadecanoic acid, docosyl ester

H3C-(CH2)13-COO-(CH2)21-CH3

V-3

42232-14-4

1

1

1

Pentadecanoic acid, dodecyl ester

H3C-(CH2)13-COO-(CH2)11-CH3

V-3

36617-37-5

1

1

1

Pentadecanoic acid, eicosyl ester

H3C-(CH2)13-COO-(CH2)19-CH3

V-3

41114-00-5

0

1

0

Pentadecanoic acid, ethyl ester

H3C-(CH2)13-COO-CH2-CH3

V-3

42232-22-4

1

1

1

Pentadecanoic acid, heneicosyl ester

H3C-(CH2)13-COO-(CH2)20-CH3

V-3

1

1

1

Pentadecanoic acid, heptacosyl ester

H3C-(CH2)13-COO-(CH2)26-CH3

V-3

1

1

1

Pentadecanoic acid, heptadecyl ester

H3C-(CH2)13-COO-(CH2)16-CH3

V-3

36617-34-2

1

1

1

Pentadecanoic acid, hexacosyl ester

H3C-(CH2)13-COO-(CH2)25-CH3

V-3

36617-33-1

1

1

1

Pentadecanoic acid, hexadecyl ester

H3C-(CH2)13-COO-(CH2)15-CH3

V-3

7132-64-1

1

1

1

Pentadecanoic acid, methyl ester

H3C-(CH2)13-COO-CH3

V-3

36617-36-4

1

1

1

Pentadecanoic acid, nonadecyl ester

H3C-(CH2)13-COO-(CH2)18-CH3

V-3

36617-35-3

1

1

1

Pentadecanoic acid, octadecyl ester

H3C-(CH2)13-COO-(CH2)17-CH3

V-3

1

1

1

Pentadecanoic acid, pentacosyl ester

H3C-(CH2)13-COO-(CH2)24-CH3

V-3

1

1

1

Pentadecanoic acid, pentadecyl ester

H3C-(CH2)13-COO-(CH2)14-CH3

V-3

36617-32-0 121877-44-9

1

1

1

Pentadecanoic acid, tetracosyl ester

H3C-(CH2)13-COO-(CH2)23-CH3

V-3

36617-31-9

1

1

1

Pentadecanoic acid, tetradecyl ester

H3C-(CH2)13-COO-(CH2)13-CH3

V-3

42232-24-6

1

1

1

Pentadecanoic acid, tricosyl ester

H3C-(CH2)13-COO-(CH2)22-CH3

V-3

36617-30-8

1

1

1

Pentadecanoic acid, tridecyl ester

H3C-(CH2)13-COO-(CH2)12-CH3

V-3 V-3

1

1

1

Pentadecanoic acid, 13-methyl-

H3C-CH2-CH(CH3)-(CH2)11-COOH

121877-18-7

1

1

1

Pentadecanoic acid, 13-methyl-, heptadecyl ester

H 3C-CH2-CH(CH3)-(CH2)11-COO-(CH2)16-CH3 V-3

121877-55-2

1

1

1

Pentadecanoic acid, 13-methyl-, pentacosyl ester

H3C-CH2-CH(CH3)-(CH2)11-COO-(CH2)24-CH3 V-3

121877-43-8

1

1

1

Pentadecanoic acid, 13-methyl-, tricosyl ester

H3C-CH2-CH(CH3)-(CH2)11-COO-(CH2)32-CH3 V-3

4669-02-7

1

1

1

Pentadecanoic acid, 14-methyl-

(H3C)2=CH-(CH2)12-COOH

121877-31-4

1

1

1

Pentadecanoic acid, 14-methyl-, docosyl ester

(H3C)2=CH-(CH2)12-COO-(CH2)21-CH3 V-3

IV.A-3

121877-27-8

1

1

1

Pentadecanoic acid, 14-methyl-, eicosyl ester

(H3C)2=CH-(CH2)12-COO-(CH2)19-CH3 V-3

121877-13-2

1

1

1

Pentadecanoic acid, 14-methyl-, heptadecyl ester

(H 3C)2=CH-(CH2)12-COO-(CH2)16-CH3 V-3

121877-20-1

1

1

1

Pentadecanoic acid, 14-methyl-, octadecyl ester

(H 3C)2=CH-(CH2)12-COO-(CH2)17-CH3 V-3

121877-47-2

1

1

1

Pentadecanoic acid, 14-methyl-, tetracosyl ester

(H 3C)2=CH-(CH2)12-COO-(CH2)23-CH3 V-3

121877-38-1

1

1

1

Pentadecanoic acid, 14-methyl-, tricosyl ester

(H3C)2=CH-(CH2)12-COO-(CH2)22-CH3 V-3

0

1

0

Pentadecanoic acid, 3,7,11,15,19,23,27,31,35nonamethyl-2,6,10,14,18,22,26,30,34hexatriacontanonaenyl ester

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1694

11/24/08 1:57:08 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1695

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

71607-96-0

1

0

0

Pentadecanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester, [R-[R*,R*- (E)]]-

629-76-5

1

1

1

1-Pentadecanol

H3C-(CH2)13-CH2OH

II.A-5

20194-48-3

0

1

0

1-Pentadecanol, 14-methyl-

(H3C)2=CH-(CH2)12-CH2OH

II.A-5

2345-28-0

0

1

0

2-Pentadecanone

H3C-(CH2)12-CO-CH3

III-13

502-69-2

1

1

1

2-Pentadecanone, 6,10,14-trimethyl{phytone; hexahydrofarnesyl acetone}

H-[CH2-CH(CH3)-CH2-CH2]3-CH2-CO-CH3 III-13

16825-16-4

0

1

0

2-Pentadecanone, 6,10,14-trimethyl-, [R-(R*,R*)]-

81345-07-5

1

0

0

3,8,12,14-Pentadecatetraen-2-one, 8,12-dimethyl-5(1-methylethyl)-, (E,E,E)-

Name (per CA Collective Index)

Selected structures

Chapter Table V-3

III-13 III-13

CH3

H3 C H3 C

CH3 O CH2

CH3

81345-08-6

1

0

0

3,8,12,14-Pentadecatetraen-2-one, 8,12-dimethyl-5(1-methylethyl)-, (E,Z,E)-

III-13

CH3

H3C H3C

CH3 CH3

O CH2

41429-55-4

0

1

0

3,7,12-Pentadecatriene-2,14-dione, 4,8-dimethyl11-(1-methylethyl)-, (E,Z,E)-

III-13 8

10 5

7 6

57760-50-6

0

1

0

3,7,12-Pentadecatriene-2,14-dione, 4,8-dimethyl11-(1-methylethyl)-, [S-(E,E,E)]-

762-29-8

1

1

1

5,9,13-Pentadecatrien-2-one, 6,10,14-trimethyl{farnesyl acetone} {3 isomers}

13

9

11

4

12 3

2

14

O O

III-13 III-13

CH3 CH3

O

CH3 H3C

CH3

1117-52-8

1

1

1

5,9,13-Pentadecatrien-2-one, 6,10,14-trimethyl-, (E,E)-

III-13

27251-68-9

1

1

1

Pentadecene

H-(CH2)n-CH=CH-(CH2)(13-n)-H

I.B-1

13360-61-7

1

1

1

1-Pentadecene

H3C-(CH2)12-CH=CH2

I.B-1

1

1

1

1-Pentadecene, 2-methyl-

H2C=C(CH3)-(CH2)11-CH3

I.B-1

1

1

1

2-Pentadecene, (Z)-

H3C-CH=CH-(CH2)11-CH3

1

1

1

2-Pentadecene, (E)-

1

1

1

2-Pentadecene, 2-methyl-

H2C=C(CH3)-(CH2)12-CH3

1

1

1

2-Pentadecene, 13-methyl-, (Z)-

H3C-CH=CH-(CH2)9-CH(CH3)-CH2-CH3 I.B-1

1

1

1

2-Pentadecene, 13-methyl-, (E)-

1

1

1

2-Pentadecene, 14-methyl-, (Z)-

1

1

1

2-Pentadecene, 14-methyl-, (E)-

I.B-1 I.B-1 I.B-1

I.B-1 H3C-CH=CH-(CH2)10-CH(CH3)2

I.B-1 I.B-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1695

11/24/08 1:57:09 PM

1696

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

2140-82-1 60976-73-0

1

1

1

1-Pentadecene, 2,6,10,14-tetramethyl{norphytene}

H2C=C(CH3)-CH2-{(CH2)2-CH(CH3)-CH2}3-H I.B-1

36232-37-8

1

0

0

6-Pentadecene, 2,6,10,14-tetramethyl-

(H3C)2CH-(CH2)3-C(CH3)=CH2-{(CH2)2CH(CH3)-CH2}2-H I.B-1

26444-04-2

1

1

1

Pentadecenoic acid

31422-28-3

0

1

0

Pentadecenoic acid, methyl ester

17351-34-7

0

1

0

14-Pentadecenoic acid

764-40-9

1

1

1

2,4-Pentadienal

41050-31-1

1

1

1

Pentadiene

1

1

1

Pentadiene, methyl-

1

1

1

1,2-Pentadiene

{ethylallene}

H3C-CH2-CH=C=CH2

{piperylene}

H3C-CH=CH-CH=CH2

591-95-7

Name (per CA Collective Index)

Selected structures

Chapter Table

IV.A-3 V-3 IV.A-3 H2C=CH-CH=CH-CH=O

III-12 I.B-1 I.B-1 I.B-1

504-60-9

1

1

1

1,3-Pentadiene

2004-70-8

1

1

1

1,3-Pentadiene, (E)-

I.B-1

1574-41-0

1

1

1

1,3-Pentadiene, (Z)-

1118-58-7

1

1

1

1,3-Pentadiene, 2-methyl-

H3C-CH=CH-C(CH3)=CH2

926-56-7

0

1

0

1,3-Pentadiene, 4-methyl-

H3C-C(CH3)=CH-CH=CH2

I.B-1

591-93-5

1

0

0

1,4-Pentadiene

H2C=CH-CH2-CH=CH2

I.B-1

21293-29-8 14375-45-2

0

1

0

2,4-Pentadienoic acid, 5-(1-hydroxy-2,6,6-trimethyl4-oxo-2-cyclohexen-1-yl)-3-methyl-, [S-(Z,E)]{abscisic acid}

I.B-1 I.B-1 I.B-1

II.A-5, III-13, IV.A-3 H3C

CH3

CH3

COOH OH

O

4949-20-6

1

0

0

2,4-Pentadien-1-ol

110-62-3

1

1

1

Pentanal

{valeraldehyde}

CH3

H2C=CH-CH=CH-CH2OH

II.A-5

H3C-(CH2)3-CH=O

III-12

1

0

0

Pentanal, methyl-

123-15-9

1

0

0

Pentanal, 2-methyl-

III-12

15877-57-3

1

0

0

Pentanal, 3-methyl-

1119-16-0

1

0

0

Pentanal, 4-methyl-

H3C-CH(CH3)-(CH2)2-CH=O

7332-93-6

1

0

0

Pentanal, 2-oxo-

H3C-(CH2)2-CO-CH=O

III-12, III-13

626-96-0

1

0

0

Pentanal, 4-oxo-

H3C-CO-(CH2)2-CH=O

III-12, III-13

626-97-1

1

0

0

Pentanamide

61892-69-1

1

0

0

Pentanamide, 3-methyl-

XIII-1

1119-29-5

1

0

0

Pentanamide, 4-methyl-

XIII-1

54007-33-9

1

0

0

Pentanamide, N-ethyl-

H3C-(CH2)3-CO-NH-C2H5

XIII-1

110-58-7

1

1

1

1-Pentanamine

H3C-(CH2)4-NH2

XII-2

688-31-3

1

0

0

1-Pentanamine, 2-ethyl-N,N-dimethyl-

H3C-(CH2)2-CH(C2H5)-CH2-N(CH3)2 XII-2

625-30-9

1

1

1

2-Pentanamine

H3C-(CH2)2-CH(NH2)-CH3

616-24-0

1

0

0

3-Pentanamine

(H3C-CH2)2=CH-NH2

109-66-0

1

1

1

Pentane

H3C-(CH2)3-CH3

1067-20-5

1

0

0

Pentane, 3,3-diethyl-

I.A-10

H3C-(CH2)2-CH(CH3)-CH=O

III-12 III-12

{valeramide}

H3C-(CH2)3-CO-NH2

III-12

XIII-1

XII-2 XII-2 I.A-10

108-08-7

1

0

0

Pentane, 2,4-dimethyl-

I.A-10

43133-95-5

1

0

0

Pentane, methyl-

I.A-10

107-83-5

1

1

1

Pentane, 2-methyl-

H3C-(CH2)2-CH=(CH3)2

I.A-10

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1696

11/24/08 1:57:10 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1697

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

96-14-0

1

1

1

Pentane, 3-methyl-

760-21-4

1

0

0

Pentane, 3-methylene-

Name (per CA Collective Index)

Chapter Table

Selected structures (H3C-CH2)2=CH-CH3

{2-ethyl-1-butene}

I.A-10

(H3C-CH2)2=C=CH2

I.B-1

628-05-7

1

0

0

Pentane, 1-nitro-

H3C-(CH2)3-CH2-NO2

XVI-1

4609-89-6

1

0

0

Pentane, 2-nitro-

H3C-(CH2)2-CH(NO2)-CH3

XVI-1

0

1

0

1,5-Pentanediamide, 2-amino- {glutamine amide}

H2N-OC-(CH2)2-CH(NH2)-CO-NH2 XII-2, XIII-1

0

1

0

1,5-Pentanediamine

H2N-(CH2)5-NH2

462-94-2

{cadaverine}

110-94-1

1

1

1

Pentanedioic acid

63892-02-4

0

1

0

Pentanedioic acid, 2-(1-methylethyl)-, (S)-

HOOC-(CH2)2-CH[CH(CH3)2]-COOH IV.A-3

617-62-9

0

1

0

Pentanedioic acid, 2-methyl-

HOOC-(CH2)2-CH(CH3)-COOH

328-50-7

1

1

1

Pentanedioic acid, 2-oxo-

626-51-7

1

0

0

Pentanedioic acid, 3-methyl-

HOOC-CH2-CH(CH3)-CH2-COOH IV.A-3

0

1

0

Pentanedioic acid, 2,3,4-trihydroxy-

HOOC-(CHOH)3-COOH

1

0

0

1,3-Pentanediol

II.A-5

1

0

0

1,4-Pentanediol, 3-[2-(2-hydroxyethyl)-1,3,3trimethylcyclohexyl]-

II.A-5

107-41-5

1

1

1

2,4-Pentanediol, 2-methyl-

II.A-5

52786-29-5

1

0

0

1,4-Pentanedione, 1-(2-furanyl)-

III-13

3174-67-2

{glutaric acid}

XII-2

{D-ketoglutaric acid}

HOOC-(CH2)3-COOH

HOOC-(CH2)2-CO-COOH

IV.A-3

IV.A-3

III-13, IV.A-3 II.A-5, IV.A-3

600-14-6

1

1

1

2,3-Pentanedione

H3C-CH2-CO-CO-CH3

III-13

7493-58-5

1

0

0

2,3-Pentanedione, 4-methyl-

H3C-CH(CH3)-CO-CO-CH3

III-13

H3C-CO-CH2-CO-CH3

III-13

123-54-6

0

1

0

2,4-Pentanedione

110-59-8

1

0

0

Pentanenitrile

69975-94-6

6339-13-5

{valeronitrile}

H3C-(CH2)3-CN

XI-2

1

0

0

Pentanenitrile, 2,4-dimethyl-

1

0

0

Pentanenitrile, 2-hydroxy-

H3C-CH(CH3)-CH2-CH(CH3)-CN

XI-2

1

0

0

Pentanenitrile, 3-hydroxy-4-methyl-

XI-2

1

0

0

Pentanenitrile, methyl-

XI-2

1

0

0

Pentanenitrile, 2-methyl-

XI-2

H3C-(CH2)2-CH(CH3)-CN

XI-2

1

0

0

Pentanenitrile, 3-methyl-

542-54-1

1

0

0

Pentanenitrile, 4-methyl-

(H3C)2=CH(CH2)2-CN

XI-2

927-56-0

1

0

0

Pentanenitrile, 4-oxo-

H3C-CO-(CH2)2-CN

III-1, XI-2

110-66-7

1

0

0

1-Pentanethiol

H3C-(CH2)4-SH

XVIII.A-1

XI-2

1

0

0

1,2,5-Pentanetriol, 3-methyl-

109-52-4

1

1

1

Pentanoic acid

II.A-5

591-68-4

0

1

0

Pentanoic acid, butyl ester

539-82-2

1

1

1

Pentanoic acid, ethyl ester

96937-52-9

1

0

0

Pentanoic acid, hydroxy-methyl-

27936-41-0

0

1

0

Pentanoic acid, methyl-

624-24-8

0

1

0

Pentanoic acid, methyl ester

96937-54-1

1

0

0

Pentanoic acid, methyloxo-

III-13, IV.A-3

96937-53-0

1

0

0

Pentanoic acid, oxo-

III-13, IV.A-3

10361-39-4

0

1

0

Pentanoic acid, phenylmethyl ester

{valeric acid}

H3C-(CH2)3-COOH

IV.A-3 V-3

{ethyl valerate}

H 3C-(CH2)3-COO-C2H5

V-3 II.A-5, IV.A-3 IV.A-3

{methyl valerate}

H 3C-(CH2)3-COO-CH3

V-3

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1697

11/24/08 1:57:10 PM

1698

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1185-39-3

0

1

0

Pentanoic acid, 2,2-dimethyl-

IV.A-3

20225-24-5

0

1

0

Pentanoic acid, 2-ethyl-

IV.A-3

617-31-2

0

1

0

Pentanoic acid, 2-hydroxy-

II.A-5, IV.A-3

488-15-3

0

1

0

Pentanoic acid, 2-hydroxy-3-methyl-

II.A-5, IV.A-3

498-36-2

0

1

0

Pentanoic acid, 2-hydroxy-4-methyl-

II.A-5, IV.A-3

54031-97-9

0

1

0

Pentanoic acid, 2-hydroxy-4-oxo-

II.A-5, IV.A-3

97-61-0

1

1

1

Pentanoic acid, 2-methyl-

6641-83-4

1

0

0

Pentanoic acid, 2-methyl-4-oxo-

{2-methylvaleric acid}

IV.A-3

70340-00-0

0

1

0

Pentanoic acid, 2-methylphenyl ester

V-3

6376-59-6

1

0

0

Pentanoic acid, 2-oxo-, methyl ester

V-3

1

1

1

Pentanoic acid, 2,5-di-(methylnitrosoamino)-

III-13, IV.A-3

R-(CH2)3-CH(R)-COOH where R = H3C-N(NO)IV.A-3, XII-2, XV-8

150-96-9

0

1

0

Pentanoic acid, 3-hydroxy-3-methyl-

II.A-5, IV.A-3

5980-21-2

0

1

0

Pentanoic acid, 3-hydroxy-4-methyl-

II.A-5, IV.A-3

105-43-1

1

1

1

Pentanoic acid, 3-methyl{ȕ-methylvaleric acid; 3-methylpentanoic acid}

5870-68-8

1

1

1

Pentanoic acid, 3-methyl-, ethyl ester

2177-78-8

1

0

0

Pentanoic acid, 3-methyl-, methyl ester

6628-79-1

1

0

0

Pentanoic acid, 3-methyl-4-oxo-

III-13, IV.A-3

10191-25-0

0

1

0

Pentanoic acid, 3-oxo-

III-13, IV.A-3

150-97-0

0

1

0

Pentanoic acid, 3,5-dihydroxy-5-methyl{mevalonic acid}

II.A-5, IV.A-3

41654-03-9

0

1

0

Pentanoic acid, 4-hydroxy-3-methyl-

II.A-5, IV.A-3

646-07-1

1

1

1

Pentanoic acid, 4-methyl-

2412-80-8

1

0

0

Pentanoic acid, 4-methyl-, methyl ester

IV.A-3 V-3 V-3

{isocaproic acid}

V-3

123-76-2

1

1

1

Pentanoic acid, 4-oxo-

539-88-8

1

1

1

Pentanoic acid, 4-oxo-, ethyl ester {ethyl levulinate}

H3C-CO-(CH2) 2-COO-CH2-CH3 III-13, V-3

624-45-3

1

1

1

Pentanoic acid, 4-oxo-, methyl ester {methyl levulinate}

H3C-CO-(CH2) 2-COO-CH3

67920-51-8

0

1

0

Pentanoic acid, 5-(acetylamino)-2-hydroxy-, (±)-

II.A-5, IV.A-3, XII-2

63316-30-3

0

1

0

Pentanoic acid, 5-(acetylamino)-2-hydroxy-, (R)-

II.A-5, IV.A-3, XII-2

16814-81-6

0

1

0

Pentanoic acid, 5-amino-2-hydroxy-, (S)-

II.A-5, IV.A-3, XII-2

63316-28-9

0

1

0

Pentanoic acid, 5-amino-3-hydroxy-

106-60-5

0

1

0

Pentanoic acid, 5-amino-4-oxo-

0

1

0

Pentanoic acid, 5-hydroxy-3-(1-methylethyl)-

1

0

0

Pentanoic acid, 5-hydroxy-4-oxo-, methyl ester

1

0

0

Pentanoic acid, 2,3,4,5-tetrahydroxy-

HOCH2-(CHOH)3-COOH

71-41-0

1

1

1

1-Pentanol

H3C-(CH2)3-CH2OH

6570-87-2

0

1

0

1-Pentanol, 3,4-dimethyl-

II.A-5

0

1

0

1-Pentanol, 2-methyl-

II.A-5

0

1

0

1-Pentanol, 3-methyl-

II.A-5

66274-27-9

589-35-5

{levulinic acid}

IV.A-3 H3C-CO-(CH2) 2-COOH

III-13, IV.A-3

III-13, V-3

II.A-5, IV.A-3, XII-2 H2N-CH2-CO-(CH2)2-COOH III-13, IV.A-3, XII-2

{amyl alcohol}

II.A-5, IV.A-3 II.A-5, III-13, V-3 II.A-5, IV.A-3 II.A-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1698

11/24/08 1:57:11 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1699

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

626-89-1

0

1

0

1-Pentanol, 4-methyl-

II.A-5

590-36-3

0

1

0

2-Pentanol, 2-methyl-

II.A-5

108-11-2

1

1

1

2-Pentanol, 4-methyl-

584-02-1

0

1

0

3-Pentanol

77-74-7

1

0

0

3-Pentanol, 3-methyl-

II.A-5

1

0

0

3-Pentanol, 1-phenyl-

II.A-5

27154-67-2

1

0

0

Pentanone

III-13

63072-44-6

0

1

0

Pentanone, methyl-

III-13

1009-14-9

1

0

0

1-Pentanone, 1-phenyl-

H3C-(CH2)3-CO-C6H5

III-13

107-87-9

1

1

1

2-Pentanone

H3C-(CH2)2-CO-CH3

III-13

1

0

0

2-Pentanone, 1-hydroxy-

H3C-(CH2)2-CO-CH2OH

II.A-5, III-13

4161-60-8

1

1

1

2-Pentanone, 4-hydroxy-

H3C-CHOH-CH2-CO-CH3

II.A-5, III-13

123-42-2

1

1

1

2-Pentanone, 4-hydroxy-4-methyl{diacetone alcohol}

(H3C)2=C(OH)-CH2-CO-CH3 II.A-5, III-13

565-61-7

1

0

0

2-Pentanone, 3-methyl-

H3C-CH2-CH(CH3)-CO-CH3 (H3C)2=CH-CH2-CO-CH3

Name (per CA Collective Index)

Chapter Table

Selected structures

II.A-5 (H3C-CH2)2=CHOH

II.A-5

III-13

108-10-1

1

1

1

2-Pentanone, 4-methyl-

5349-62-2

0

1

0

2-Pentanone, 4-methyl-1-phenyl-

5185-97-7

0

1

0

2-Pentanone, 5-(acetyloxy)-

H3C-COO-(CH2)3-CO-CH3

1567-93-7

1

0

0

2-Pentanone, 5-hydroxy-3-methyl-

HOCH2-CH2-CH(CH3)-CO-CH3 II.A-5, III-13

66309-84-0

1

0

0

2-Pentanone, 5-hydroxy-4-methyl-

HOCH2-CH(CH3)-CH2-CO-CH3 II.A-5, III-13

96-22-0

1

1

1

3-Pentanone

H3C-CH2-CO-CH2-CH3 (H3C)2= CH-CO-CH=(CH3)2

565-80-0

III-13 III-13 III-13, V-3

III-13

1

0

0

3-Pentanone, 2,4-dimethyl-

1

0

0

3-Pentanone, 1-(methylthio)-

565-69-5

1

1

1

3-Pentanone, 2-methyl-

222-93-5

1

0

0

Pentaphene {dibenzo[b,j]phenanthrene; 2,3,6,7dibenzophenanethrene}

488-31-3

0

1

0

Pentaric acid

IV.A-3

320-77-4

0

1

0

Pentaric acid, 3-carboxy-2,3-dideoxy-

IV.A-3

630-07-9

III-13

III-13, XVIII.A-1 (H3C)2= CH-CO-CH2-CH3

III-13 I.E-6

1

1

1

Pentatriacontane

H3C-(CH2)33-CH3

I.A-10

0

1

0

Pentatriacontane, 2-methyl-

H3C-CH(CH3)-(CH2)32-CH3

I.A-10

78692-70-3

0

1

0

Pentatriacontane, 3-methyl-

H3C-CH2-CH(CH3)-(CH2)31-CH3

I.A-10

21978-49-4

1

1

1

5,9,13,17,21,25,29,33-Pentatriacontaoctaen-2-one, 6,10,14,18,22,26,30,34-octamethyl-, (all-E)-

III-13

34786-54-4

0

1

0

1,5,9,13,17,21,25,29,33-Pentatriacontanonaene, 2,6,10,14,18,22, 26,30,34-nonamethyl{norsolanesene}

I.B-1

31424-04-1

1

0

0

Pentenal

764-39-6

0

1

0

2-Pentenal

1

0

0

2-Pentenal, 2,3-dimethyl-

III-12 H3C-CH2-CH=CH-CH=O

III-12 III-12

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1699

11/24/08 1:57:11 PM

1700

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

623-36-9 5604-55-7

S

T

S T

1

0

0

2-Pentenal, 2,4-dimethyl-

III-12

1

0

0

2-Pentenal, 2-methyl-

III-12

1

1

1

2-Pentenal, 4-methyl-

III-12

0

1

0

3-Pentenal

III-12

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

4-Pentenal, 2-methyl-

III-12

3973-43-1

1

0

0

4-Pentenal, 4-methyl-

III-12

15856-96-9

1

0

0

2-Pentenamide

61892-67-9

1

0

0

2-Pentenamide, N-methyl-

70265-05-3

1

0

0

3-Pentenamide, 4-methyl-

22537-07-1

1

0

0

4-Penten-1-amine

1

0

0

Pentene

H3C-CH2-CH=CH-CO-NH2

XIII-1 XIII-1 XIII-1

H2C=CH-(CH2)3-NH2

XII-2 I.B-1

1

0

0

Pentene, methyl-

109-67-1

1

0

0

1-Pentene

H3C-(CH2)2-CH=CH2

I.B-1

3404-73-7

1

0

0

1-Pentene, 3,3-dimethyl-

H3C-CH2-C(CH3)2-CH=CH2

I.B-1

763-29-1

1

0

0

1-Pentene, 2-methyl-

H3C-(CH2)2-C(CH3)=CH2

I.B-1

760-20-3

1

0

0

1-Pentene, 3-methyl-

H3C-CH2-CH(CH3)-CH=CH2

I.B-1

691-37-2

1

0

0

1-Pentene, 4-methyl-

(H3C)2=CH-CH2-CH=CH2

I.B-1

109-68-2

1

1

1

2-Pentene

H3C-CH2-CH=CH-CH3

646-04-8

1

0

0

2-Pentene, (E)-

I.B-1

627-20-3

1

0

0

2-Pentene, (Z)-

I.B-1

625-27-4

1

0

0

2-Pentene, 2-methyl-

H3C-CH2-CH=C=(CH3)2

I.B-1

922-61-2

1

0

0

2-Pentene, 3-methyl- (Z)

H3C-CH2-C(CH3)=CH-CH3

I.B-1

I.B-1

I.B-1

616-12-6

1

0

0

2-Pentene, 3-methyl-, (E)-

4461-48-7

1

0

0

2-Pentene, 4-methyl-

I.B-1

674-76-0

1

0

0

2-Pentene, 4-methyl-, (E)-

I.B-1

691-38-3

1

0

0

2-Pentene, 4-methyl-, (Z)-

I.B-1

H3C-CH(CH3)-CH=CH-CH3

1724-02-3

0

1

0

2-Pentenedioic acid

5164-76-1

0

1

0

2-Pentenedioic acid, dimethyl ester

101758-45-6

0

1

0

2-Pentene-1,4-diol, 5-(decahydro-2-hydroxy2,5,5,8a-tetramethyl-1- naphthalenyl)-3-methyl-, [1D(3E,4S*),2E,4a

II.A-5

91238-45-8

1

0

0

4-Pentene-2,3-dione

III-13

592-51-8

1

0

0

4-Pentenenitrile

27516-53-6

1

0

0

Pentenoic acid

{glutaconic acid}

HOOC-CH2-CH=CH-COOH

I.B-1

IV.A-3 V-3

XI-2 IV.A-3

626-98-2

1

1

1

2-Pentenoic acid

H3C-CH2-CH=CH-COOH

IV.A-3

3142-72-1

1

1

1

2-Pentenoic acid, 2-methyl-

H3C-CH2-CH=C(CH3)-COOH

IV.A-3

3675-21-6

0

1

0

2-Pentenoic acid, 3-methyl-

H3C-CH2-C(CH3)=CH-COOH

IV.A-3

0

1

0

2-Pentenoic acid, 3-methyl-5-(2,6,6-trimethyl-1cyclohexenyl)-

10321-71-8

0

1

0

2-Pentenoic acid, 4-methyl-

1617-32-9

1

0

0

3-Pentenoic acid, (E)-

33698-87-2

1

0

0

3-Pentenoic acid, (Z)-

IV.A-3 H3C-CH(CH3)-CH=CH-COOH

IV.A-3 IV.A-3 IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1700

11/24/08 1:57:12 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1701

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

16313-37-4

0

1

0

3-Pentenoic acid, 3-methyl-

IV.A-3

41653-93-4

0

1

0

3-Pentenoic acid, 3-methyl-, (E)-

IV.A-3

504-85-8

0

1

0

3-Pentenoic acid, 4-methyl-

591-80-0

1

1

1

4-Pentenoic acid

16386-93-9

0

1

0

4-Pentenoic acid, 2,2-dimethyl-

1575-74-2

0

1

0

4-Pentenoic acid, 2-methyl-

Name (per CA Collective Index)

Selected structures

Chapter Table

IV.A-3 H2C=CH-(CH2)2-COOH

IV.A-3 IV.A-3 II.A-5

616-25-1

1

1

1

1-Penten-3-ol

II.A-5

2088-07-5

1

1

1

1-Penten-3-ol, 2-methyl-

II.A-5

0

1

0

2-Penten-1-ol, (Z)

87563-33-5

0

1

0

2-Penten-1-ol, 3-methyl-5-(1,4,4a,5,6,7,8,8aoctahydro-2,5,5,8a-tetramethyl-1-naphthalenyl)-, [1S-[1D(E),4aE,8aD]]-

H3C-CH2-CH=CH-CH2OH

II.A-5

87585-55-5

0

1

0

2-Penten-1-ol, 3-methyl-5-(3,4,4a,5,6,7,8,8aoctahydro-2,5,5,8a-tetramethyl-1-naphthalenyl)-, [4aS-[1(E),4aD,8aE]]-

II.A-5

0

1

0

3-Penten-1-ol, 4-methyl-

II.A-5

4325-82-0

1

0

0

3-Penten-2-ol, 4-methyl-

60026-13-3

0

1

0

4-Penten-2-ol, 5-(tetrahydro-2-methyl-2-furanyl)-

1629-58-9

1

1

1

1-Penten-3-one

3712-68-8

0

1

0

1-Penten-3-one, 2,4-dimethyl-

0

1

0

1-Penten-3-one, 1-(4-methoxyphenyl)-

1

0

0

1-Penten-3-one, 2-methyl-

H3C-CH2-CO-C(CH3)=CH2

25044-01-3

II.A-5

II.A-5 II.A-5, X-2 H3C-CH2-CO-CH=CH2

III-13 III-13 III-13, X-2 III-13

1

0

0

2-Penten-4-one, 2,3-dimethyl-

(H3C)2=C=C(CH3)-CO-CH3

III-13

625-33-2

1

1

1

3-Penten-2-one

H3C-CH=CH-CO-CH3

III-13

3102-33-8

0

1

0

3-Penten-2-one, (E)

1118-66-7

1

0

0

3-Penten-2-one, 4-amino-

H3C-C(NH2)=CH-CO-CH3

III-13, XII-2

565-62-8

1

0

0

3-Penten-2-one, 3-methyl-

H3C-CH=C(CH3)-CO-CH3

III-13

(H3C)2=C=CH-CO-CH3

III-13

H2C=CH-CH2-CO-CH3

III-13

III-13

141-79-7

1

1

1

3-Penten-2-one, 4-methyl-

13891-87-7

1

0

0

4-Penten-2-one

{mesityl oxide}

127-42-4

0

1

0

4-Penten-3-one, 5-(2,6,6-trimethyl-2-cyclohexen-1yl){methyl-D-ionone}

III-13

72692-98-9

1

0

0

Pentitol, 2,3-dideoxy-3-methyl-

II.A-5

61989-60-4

1

0

0

Pentonic acid, 2,3-anhydro-, J-lactone

491-14-5

1

0

0

Pentonic acid, 5-C-[3,5-bis(1-methylpropyl)-1cyclopenten-1-yl]-4-deoxy-

9473-19-9

1

1

1

D-erythro-Pentonic acid, 3-deoxy-, J-lactone

5803-57-6

1

0

0

Pentonic acid, 5-deoxy-, J-lactone

533-67-5

0

1

0

D-erythro-Pentose, 2-deoxy-

VI-3 II.A-5, VI-3 VI-3 VI-3

{deoxyribose}

II.A-5

OH OH HO

1

0

0

Pentoxyl radical

488-84-6

0

1

0

D-erythro-2-Pentulose = D-Ribulose

24218-00-6

0

1

0

D-erythro-2-Pentulose, 1,5-bis(dihydrogen phosphate)

O

OC5CH11 {xylulose}

HOCH2-CO-(CHOH)2-CH2OH

XXVII-1 II.A-5 II.A-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1701

11/24/08 1:57:12 PM

1702

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

627-21-4

1

0

0

2-Pentyne

9031-96-3

0

1

0

Peptidase

H3C-CŁC-CH2-CH3 XXII-2

9003-99-0

0

1

0

Peroxidase

XXII-2

72906-87-7

0

1

0

Peroxidase, ascorbate

XXII-2

0

1

0

Peroxidase, glutathione

XXII-2

1

0

0

Perylene

I.E-6

1

0

0

Perylene, alkyl-

I.E-6

64760-19-6

1

0

0

Perylene, dimethyl-

64031-91-0

1

0

0

Perylene, methyl-

24471-47-4

1

0

0

Perylene, 3-methyl-

518-85-4

1

0

0

1H-Phenalen-1-one, 2,3-dihydro-

4176-53-8

1

0

0

1-Phenanthrenamine

198-55-0

I.E-6 {at least 2 isomers in MSS}

I.E-6 I.E-6 O 1

2

III-13

3

9

10

NH2

8

XII-2

1

7

2 6

5

4

3

3366-65-2

1

0

0

2-Phenanthrenamine

XII-2

1892-54-2

1

0

0

3-Phenanthrenamine

XII-2

17423-48-2

1

0

0

4-Phenanthrenamine

XII-2

947-73-9

1

0

0

9-Phenanthrenamine

XII-2

85-01-8

1

0

0

Phenanthrene

I.E-6

1

0

0

Phenanthrene, alkyl-

1

0

0

Phenanthrene, 3,6-dichloro-

20851-90-5

I.E-6 XVIII.B-3

1

0

0

Phenanthrene, dihydro-

I.E-6

776-35-2

1

0

0

Phenanthrene, 9,10-dihydro-

I.E-6

71607-56-2

1

0

0

Phenanthrene, dihydrobis(methylene)-

I.E-6

29062-98-4

1

0

0

Phenanthrene, dimethyl-

I.E-6

20291-72-9

1

0

0

Phenanthrene, 1,2-dimethyl-

I.E-6

22349-59-3

1

0

0

Phenanthrene, 1,4-dimethyl-

I.E-6

20291-74-1

1

0

0

Phenanthrene, 1,6-dimethyl-

I.E-6

483-87-4

1

0

0

Phenanthrene, 1,7-dimethyl-

I.E-6

7372-87-4

1

0

0

Phenanthrene, 1,8-dimethyl-

I.E-6

3674-66-6

1

0

0

Phenanthrene, 2,5-dimethyl-

I.E-6

17980-16-4

1

0

0

Phenanthrene, 2,6-dimethyl-

I.E-6

1576-69-8

1

0

0

Phenanthrene, 2,7-dimethyl-

I.E-6

1576-67-6

1

0

0

Phenanthrene, 3,6-dimethyl-

I.E-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1702

11/24/08 1:57:13 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1703

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 3674-69-9

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

Phenanthrene, 4,5-dimethyl-

I.E-6

1

0

0

Phenanthrene, dimethylene-

I.E-6

71607-65-3

1

0

0

Phenanthrene, dimethylethyl-

I.E-6

30997-38-7

1

0

0

Phenanthrene, ethyl-

I.E-6

71607-66-4

1

0

0

Phenanthrene, ethylmethyl-

I.E-6

71607-67-5

1

0

0

Phenanthrene, hexamethyl-

I.E-6

61128-87-8

1

0

0

Phenanthrene, methoxy-

X-2

31711-53-2

1

1

1

Phenanthrene, methyl-

I.E-6

832-69-9

1

0

0

Phenanthrene, 1-methyl-

I.E-6

2531-84-2

1

0

0

Phenanthrene, 2-methyl-

I.E-6

832-71-3

1

0

0

Phenanthrene, 3-methyl-

I.E-6

832-64-4

1

0

0

Phenanthrene, 4-methyl-

I.E-6

883-20-5

1

0

0

Phenanthrene, 9-methyl-

I.E-6

1

0

0

Phenanthrene, 1-methyl-5-(1-methylethyl)-

I.E-6

71607-68-6

1

0

0

Phenanthrene, pentamethyl-

I.E-6

71607-69-7

1

0

0

Phenanthrene, propyl-

I.E-6

71607-70-0

1

0

0

Phenanthrene, tetramethyl{at least 5 isomers in MSS}

I.E-6

30232-26-9

1

0

0

Phenanthrene, trimethyl{at least 3 isomers in MSS}

I.E-6

84-11-7

1

0

0

9,10-Phenanthrenedione {phenanthrenequinone; phenanthraquinone}

IX.B-2

O O

111924-41-5

0

1

0

1,2,8-Phenanthrenetriol, tetradecahydro-8,10adimethyl-4-methylene-5-(1-methylethyl)-

H3C 9

H3C HO

4

8 7

6

5

II.A-5

OH 1

10

2

OH

3

CH2 CH3

H3C

229-87-8

1

1

1

Phenanthridine

XVII.E-6 N

108-95-2

1

1

1

Phenol

IX.A-22

OH 6

2

5

3 4

1

0

0

Phenol, C2-alkyl-

IX.A-22

1

0

0

Phenol, C3-alkyl-

IX.A-22

1

0

0

Phenol, C4-alkyl-

IX.A-22

1

0

0

Phenol, C5-alkyl-

IX.A-22

1

0

0

Phenol, C2-alkyl-ethenyl-

1

0

0

Phenol, C4-alkyl-ethenyl-

IX.A-22

1

0

0

Phenol, C5-alkyl-ethenyl-

IX.A-22

{2 isomers}

IX.A-22

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1703

11/24/08 1:57:13 PM

1704

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

1300-71-6

50984-45-7

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

Phenol, alkyl-dimethoxy-

1

0

0

Phenol, diethyl-

IX.A-22, X-2

1

0

0

Phenol, dimethoxy-

IX.A-22, X-2

1

0

0

Phenol, dimethoxy-4-ethenyl-

IX.A-22, X-2

IX.A-22

1

1

1

Phenol, dimethyl-

1

0

0

Phenol, dimethyl-ethenyl-

{xylenol}

IX.A-22 IX.A-22

1

0

0

Phenol, dimethyl-4-ethenyl-

IX.A-22

1

0

0

Phenol, dimethyl-ethenyl-ethyl-

IX.A-22

1

0

0

Phenol, dimethyl-ethenyl-2-methoxy-

27178-34-3

1

0

0

Phenol, (1,1-dimethylethyl)-

1329-97-1

1

0

0

Phenol, dimethyl-methoxy-

IX.A-22, X-2

1

0

0

Phenol, dimethyl-2-methoxy-

IX.A-22, X-2

1

0

0

Phenol, dimethyl-4-methoxy-

IX.A-22, X-2

1

0

0

Phenol, dimethyl-2-nitro-

1

0

0

Phenol, ethenyl-

31257-96-2 50851-69-9

IX.A-22, X-2 IX.A-22

IX.A-22, XVI-1 IX.A-22

1

0

0

Phenol, ethenyl-ethyl-

IX.A-22

1

0

0

Phenol, ethenyl-ethyl-methyl-

IX.A-22

1

0

0

Phenol, ethenyl-2-methoxy-trimethyl-

IX.A-22

73850-05-2

1

0

0

Phenol, ethenyl-methyl-

IX.A-22

73850-13-2

1

0

0

Phenol, ethenyl-trimethyl-

IX.A-22

25429-37-2

1

0

0

Phenol, ethyl-

80652-16-0

1

0

0

Phenol, ethyl-methoxy-

IX.A-22, X-2

1

0

0

Phenol, ethyl-2-methoxy-

IX.A-22, X-2

1

0

0

Phenol, ethyl-methyl-

1

0

0

Phenol, ethyl-methyl-nitro-

IX.A-22, XVI-1

1

0

0

Phenol, ethyl-nitro-

IX.A-22, XVI-1

26638-03-9

1

0

0

Phenol, methoxy-

IX.A-22, X-2

32391-38-1

1

0

0

Phenol, methoxy-methyl-

IX.A-22, X-2

30230-52-5

IX.A-22

IX.A-22

1319-77-3

1

1

1

Phenol, methyl-

12167-20-3

1

0

0

Phenol, methyl-nitro-

{cresol}

IX.A-22

1

0

0

Phenol, methylpropylenyl-

1

0

0

Phenol, methyl-propyl-

IX.A-22

1

0

0

Phenol, propenyl-

IX.A-22

IX.A-22, XVI-1 IX.A-22

1

0

0

Phenol, propyl-

IX.A-22

66586-93-4

1

0

0

Phenol, tetramethyl-

IX.A-22

26998-80-1

1

0

0

Phenol, trimethyl-

IX.A-22

3180-09-4

1

0

0

Phenol, 2-butyl-

IX.A-22

95-57-8

1

0

0

Phenol, 2-chloro-

3743-22-4

1

0

0

Phenol, 2-(dimethylamino)-

IX.A-22, XVIII.B-3

88-18-6

1

0

0

Phenol, 2-(1,1-dimethylethyl)-

IX.A-22

695-84-1

1

0

0

Phenol, 2-ethenyl-

IX.A-22

IX.A-22, XII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1704

11/24/08 1:57:13 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1705

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

120550-69-8

1

0

0

Phenol, 2-ethenyl-6-methoxy-

135295-09-9

1

0

0

Phenol, 2-ethenyl-6-methyl-

94-86-0

0

1

0

Phenol, 2-ethoxy-5-propenyl{5-propenylguaethol}

90-00-6

1

0

0

Phenol, 2-ethyl-

Selected structures

Chapter Table IX.A-22, X-2 IX.A-22 IX.A-22, X-2 IX.A-22

1

0

0

Phenol, 2-ethyl-4-methoxy-

IX.A-22, X-2

90534-46-6

1

0

0

Phenol, 2-ethyl-6-methoxy-

IX.A-22, X-2

6161-62-2

1

0

0

Phenol, 2-ethyl-3-methyl-

IX.A-22

3855-26-3

1

0

0

Phenol, 2-ethyl-4-methyl-

IX.A-22

1687-61-2

1

0

0

Phenol, 2-ethyl-5-methyl-

IX.A-22

1687-64-5

1

0

0

Phenol, 2-ethyl-6-methyl-

IX.A-22

71607-97-1

1

0

0

Phenol, 2-ethyl-3-nitro-

1

0

0

Phenol, 2-ethyl-4-nitro-

90-05-1

1

1

1

Phenol, 2-methoxy-

60825-46-9

IX.A-22, XVI-1 IX.A-22, XVI-1 {guaiacol}

14

IX.A-22, X-2

14

1

0

0

Phenol- C6, 2-methoxy-, labeled with C

IX.A-22, X-2

1

0

0

Phenol, 2-methoxy-methyl-

IX.A-22, X-2

18102-31-3

1

0

0

Phenol, 2-methoxy-3-methyl-

IX.A-22, X-2

53587-16-9

1

0

0

Phenol, 2-methoxy-4-(1-methylethyl)-

IX.A-22, X-2

97-54-1

1

1

1

Phenol, 2-methoxy-4-(1-propenyl)-

{isoeugenol}

IX.A-22, X-2

5932-68-3

1

1

1

Phenol, 2-methoxy-4-(1-propenyl)-, (E){trans-isoeugenol}

IX.A-22, X-2

5912-86-7

1

1

1

Phenol, 2-methoxy-4-(1-propenyl)-, (Z){cis-isoeugenol}

IX.A-22, X-2

97-53-0

1

1

1

Phenol, 2-methoxy-4-(2-propenyl)-

{eugenol}

IX.A-22, X-2

93-15-2

1

0

0

Phenol, 2-methoxy-methyl-4-(2-propenyl){eugenol, methyl-}

IX.A-22, X-2

2896-66-4

1

0

0

Phenol, 2-methoxy-4,6-dimethyl-

IX.A-22, X-2

93-51-6

1

1

1

Phenol, 2-methoxy-4-methyl- {4-methylguaiacol}

IX.A-22, X-2

2785-87-7

1

1

1

Phenol, 2-methoxy-4-propyl-

IX.A-22, X-2

19784-98-6

1

0

0

Phenol, 2-methoxy-5-(1-propenyl)-, (E)-

IX.A-22, X-2

1195-09-1

1

1

1

Phenol, 2-methoxy-5-methyl-

IX.A-22, X-2

58539-27-8

1

0

0

Phenol, 2-methoxy-5-propyl-

IX.A-22, X-2

29275-83-0

1

0

0

Phenol, 2-methoxy-6-(1-propenyl)-, (E)-

IX.A-22, X-2

29275-82-9

1

0

0

Phenol, 2-methoxy-6-(1-propenyl)-, (Z)-

IX.A-22, X-2

2896-67-5

1

0

0

Phenol, 2-methoxy-6-methyl-

IX.A-22, X-2

32073-24-8

1

0

0

Phenol, 2-methoxy-propyl-

IX.A-22, X-2

1

0

0

Phenol, 2-methoxy-trimethyl-

95-48-7

1

1

1

Phenol, 2-methyl-

70-30-4

1

0

0

Phenol, 2,2'-methylenebis[3,4,6-trichloro-

114-26-1

0

1

0

Phenol, 2-(1-methylethoxy)-, methylcarbamate {Undene®; Propoxur®}

IX.A-22, X-2 {o-cresol}

IX.A-22 IX.A-22, XVIII.B-3 OOC-NH-CH3

V-3, X-2, XXI-3

O-CH(CH3)2

88-69-7

1

1

1

Phenol, 2-(1-methylethyl)-

{2-isopropylphenol}

IX.A-22

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1705

11/24/08 1:57:14 PM

1706

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

1740-97-2

1

0

0

Phenol, 2-methyl-4-(1-methylethyl)-

499-75-2

1

1

1

Phenol, 2-methyl-5-(1-methylethyl)-

1

0

0

Phenol, 2-methyl-(2-methylpropyl)-

99-53-6

1

0

0

Phenol, 2-methyl-4-nitro-

Selected structures

Chapter Table IX.A-22

{carvacrol}

IX.A-22 IX.A-22 IX.A-22, XVI-1

3520-52-3

1

0

0

Phenol, 2-methyl-6-propyl-

IX.A-22

89-72-5

1

0

0

Phenol, 2-(1-methylpropyl)-

IX.A-22

1

0

0

Phenol, 2-(1-propenyl)-

IX.A-22

1

0

0

Phenol, 2-(2-propenyl)-

IX.A-22

1745-81-9 4167-75-3

1

0

0

Phenol, 2-(2-methylpropyl)-

88-75-5

1

0

0

Phenol, 2-nitro-

IX.A-22

1

0

0

Phenol, 2-phenoxy-

IX.A-22, X-2

IX.A-22, XVI-1

1

0

0

Phenol, 2-propenyl-

IX.A-22

644-35-9

1

0

0

Phenol, 2-propyl-

IX.A-22

591-27-5

1

0

0

Phenol, 3-amino-

IX.A-22, X-2

108-43-0

1

0

0

Phenol, 3-chloro-

IX.A-22, XVIII.B-3

585-34-2

1

0

0

Phenol, 3-(1,1-dimethylethyl)-

88-32-4

1

0

0

Phenol, 3-(1,1-dimethyethyl)-4-methoxy-

IX.A-22 IX.A-22, X-2

618-45-1

1

0

0

Phenol, 3-(1-methylethyl)-

IX.A-22

79755-53-6

1

0

0

Phenol, 3-(1-propenyl)-

IX.A-22

620-18-8

1

0

0

Phenol, 3-ethenyl-

IX.A-22

1

0

0

Phenol, 3-ethenyl-methyl-

IX.A-22

66164-30-5

1

0

0

Phenol, 3-ethenyl-4-methyl-

IX.A-22

621-34-1

1

0

0

Phenol, 3-ethoxy-

620-17-7

1

1

1

Phenol, 3-ethyl-

IX.A-22

1123-73-5

1

0

0

Phenol, 3-ethyl-2-methyl-

IX.A-22

6161-67-7

1

0

0

Phenol, 3-ethyl-4-methyl-

IX.A-22

IX.A-22, X-2

698-71-5

1

1

1

Phenol, 3-ethyl-5-methyl-

150-19-6

1

1

1

Phenol, 3-methoxy-

IX.A-22

5451-83-2

1

0

0

Phenol, 3-methoxy-, acetate

108-39-4

1

0

0

Phenol, 3-methyl-

4920-77-8

1

0

0

Phenol, 3-methyl-2-nitro-

2581-34-2

1

0

0

Phenol, 3-methyl-4-nitro-

IX.A-22, XVI-1

554-84-7

1

0

0

Phenol, 3-nitro-

IX.A-22, XVI-1

713-68-8

1

0

0

Phenol, 3-phenoxy-

621-27-2

1

0

0

Phenol, 3-propyl-

IX.A-22

98-54-4

1

1

1

Phenol, 4-(1,1-dimethylethyl)-

IX.A-22

99-89-8

1

1

1

Phenol, 4-(1-methylethyl)-

IX.A-22

99-71-8

1

0

0

Phenol, 4-(1-methylpropyl)-

51-67-2

1

1

1

Phenol, 4-(2-aminoethyl)-

501-92-8

1

0

0

Phenol, 4-(2-propenyl)-

0

1

0

Phenol, 4-(3-hydroxy-1-propenyl){coumaryl alcohol}

IX.A-22, X-2 V-3, X-2 {m-cresol}

IX.A-22 IX.A-22, XVI-1

IX.A-22, X-2

IX.A-22 {tyramine}

IX.A-22, X-2 IX.A-22 II.A-5, IX.A-22

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1706

11/24/08 1:57:14 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1707

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

537-33-7

0

1

0

Phenol, 4-(3-hydroxy-1-propenyl)-2,6-dimethoxy{sinapyl alcohol}

IX.A-22, X-2

458-35-5

1

1

1

Phenol, 4-(3-hydroxy-1-propenyl)-2-methoxy{coniferyl alcohol}

IX.A-22, X-2

32811-40-8

0

1

0

Phenol, 4-(3-hydroxy-1-propenyl)-2-methoxy-, (E)-

IX.A-22, X-2

69056-21-9

0

1

0

Phenol, 4-(3-hydroxy-1-propenyl)-2-methoxy-, (Z)-

IX.A-22, X-2

101-53-1

1

0

0

Phenol, 4-(phenylmethyl)-

59832-96-1

1

0

0

Phenol, 4-butyl-2-methoxy-

2628-17-3

1

1

1

Phenol, 4-ethenyl-

IX.A-22

1

0

0

Phenol, 4-ethenyl-2-ethyl-

IX.A-22

Name (per CA Collective Index)

7786-61-0

1

1

1

Phenol, 4-ethenyl-2-methoxy-

45803-83-6

1

0

0

Phenol, 4-ethenyl-2-methyl-

Selected structures

Chapter Table

IX.A-22 IX.A-22, X-2

{4-vinylguaiacol}

IX.A-22, X-2 IX.A-22

123-07-9

1

1

1

Phenol, 4-ethyl-

2785-89-9

1

1

1

Phenol, 4-ethyl-2-methoxy-

{p-ethylphenol}

IX.A-22

{ethyguaiacol}

IX.A-22, X-2

120550-71-2

1

0

0

Phenol, 4-ethyl-2-methoxy-5-methyl-

IX.A-22, X-2

120550-70-1

1

0

0

Phenol, 4-ethyl-2-methoxy-6-methyl-

IX.A-22, X-2

2219-73-0

1

0

0

Phenol, 4-ethyl-2-methyl-

IX.A-22

1123-94-0

1

0

0

Phenol, 4-ethyl-3-methyl-

IX.A-22

71607-98-2

1

0

0

Phenol, 4-ethyl-3-nitro-

150-76-5

1

1

1

Phenol, 4-methoxy-

106-44-5

1

1

1

Phenol, 4-methyl-

IX.A-22, XVI-1 IX.A-22, X-2 {p-cresol}

IX.A-22

4427-56-9

1

0

0

Phenol, 4-methyl-2-(1-methylethyl)-

119-33-5

1

0

0

Phenol, 4-methyl-2-nitro-

IX.A-22, XVI-1

2042-14-0

1

0

0

Phenol, 4-methyl-3-nitro-

IX.A-22, XVI-1

4074-46-8

1

0

0

Phenol, 4-methyl-2-propyl-

100-02-7 1988-89-2 6380-21-8

1

0

0

Phenol, 4-nitro-

1

0

0

Phenol, 4-phenoxy-

IX.A-22

IX.A-22 IX.A-22, XVI-1 IX.A-22, X-2

0

1

0

Phenol, 4-(1phenylethyl)-

IX.A-22

1

0

0

Phenol, 4-phenylmethyl-

IX.A-22

1

0

0

Phenol, 4-propenyl-

IX.A-22

645-56-7

1

0

0

Phenol, 4-propyl-

2785-88-8

1

0

0

Phenol, 5-ethyl-2-methoxy-

IX.A-22

71278-12-1

1

0

0

Phenol, 5-ethyl-2-methyl-4-nitro{phenol, 3-ethyl-6-methyl-4-nitro-}

89-83-8

1

0

0

Phenol, 5-methyl-2-(1-methylethyl)-

IX.A-22, X-2

{thymol}

IX.A-22, XVI-1 IX.A-22

5150-42-5

1

0

0

Phenol, 2,3-dimethoxy-

IX.A-22, X-2

20578-97-6

1

1

1

Phenol, 2,3-dimethoxy-4-ethyl-

IX.A-22, X-2

526-75-0

1

1

1

Phenol, 2,3-dimethyl-

18441-55-9

1

0

0

Phenol, 2,3-dimethyl-6-ethyl-

{2,3-xylenol}

34883-01-7

1

1

1

Phenol, 2,3-dimethyl-5-methoxy-

6665-95-8

1

0

0

Phenol, 2,3-dimethyl-6-nitro{phenol, 5,6-dimethyl-2-nitro-}

IX.A-22 IX.A-22 IX.A-22, X-2 IX.A-22, XVI-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1707

11/24/08 1:57:15 PM

1708

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 105-67-9

S

T

S T

Name (per CA Collective Index)

Chapter Table

1

1

1

Phenol, 2,4-dimethyl-

1

0

0

Phenol, 2,4-dimethyl-6-ethyl-

1

1

1

Phenol, 2,5-dimethyl-

1

0

0

Phenol, 2,5-dimethyl-6-nitro-

1006-59-3

1

0

0

Phenol, 2,6-diethyl-

IX.A-22

4130-42-1

1

1

1

Phenol, 2,6-bis(1,1-dimethylethyl)-4-ethyl-

IX.A-22

95-87-4

{2,4-xylenol}

Selected structures

IX.A-22 IX.A-22

{2,5-xylenol}

IX.A-22 IX.A-22, XVI-1

128-37-0

1

1

1

Phenol, 2,6-bis(1,1-dimethylethyl)-4-methyl- {BHT}

91-10-1

1

1

1

Phenol, 2,6-dimethoxy-

{syringol}

IX.A-22 IX.A-22, X-2

1

0

0

Phenol, 2,6-dimethoxy-ethenyl-

IX.A-22, X-2

28343-22-8

1

1

1

Phenol, 2,6-dimethoxy-4-ethenyl-

IX.A-22, X-2

14059-92-8

1

1

1

Phenol, 2,6-dimethoxy-4-ethyl-

IX.A-22, X-2

6638-05-7

1

1

1

Phenol, 2,6-dimethoxy-4-methyl-

IX.A-22, X-2

20675-95-0

1

1

1

Phenol, 2,6-dimethoxy-4-(1-propenyl)-, (E)-

IX.A-22, X-2

26624-13-5

1

1

1

Phenol, 2,6-dimethoxy-4-(1-propenyl)-, (Z)-

IX.A-22, X-2

6627-88-9

1

1

1

Phenol, 2,6-dimethoxy-4-(2-propenyl)-

IX.A-22, X-2

576-26-1

1

1

1

Phenol, 2,6-dimethyl-

71526-64-2

1

0

0

Phenol, 2,6-dimethyl-4-ethenyl-

IX.A-22

10570-69-1

{2,6-xylenol}

IX.A-22

1

0

0

Phenol, 2,6-dimethyl-4-ethyl-

IX.A-22

0

1

0

Phenol, 2,6-dimethyl-4-(2-propenyl)-

IX.A-22

2033-89-8

1

0

0

Phenol, 3,4-dimethoxy-

95-65-8

1

1

1

Phenol, 3,4-dimethyl-

500-99-2

1

1

1

Phenol, 3,5-dimethoxy-

IX.A-22, X-2 {3,4-xylenol}

IX.A-22 IX.A-22, X-2

108-68-9

1

1

1

Phenol, 3,5-dimethyl-

2785-85-5

1

0

0

Phenol, 3,5-dimethyl-2-methoxy-

{3,5-xylenol}

IX.A-22

71608-10-1

1

0

0

Phenol, 3,6-dimethyl-2-nitro{phenol, 2,5-dimethyl-6-nitro-}

72312-07-3

0

1

0

Phenol, 4,5-dimethoxy-2-methyl-

IX.A-22, X-2

7771-25-7

1

0

0

Phenol, 4,5-dimethyl-2-methoxy-

IX.A-22, X-2

2219-79-6

1

0

0

Phenol, 4,6-dimethyl-2-ethyl-

IX.A-22, X-2 IX.A-22, XVI-1

IX.A-22

2896-66-4

1

0

0

Phenol, 4,6-dimethyl-2-methoxy-

IX.A-22, X-2

123844-48-4

1

0

0

Phenol, 5,6-dimethyl-2-methoxy-

IX.A-22, X-2

3238-38-8

1

0

0

Phenol, 2,3,4,6-tetramethyl-

527-35-5

1

1

1

Phenol, 2,3,5,6-tetramethyl-

526-85-2

1

1

1

Phenol, 2,3,4-trimethyl-

697-82-5

1

0

0

Phenol, 2,3,5-trimethyl-

2416-94-6

1

0

0

Phenol, 2,3,6-trimethyl-

IX.A-22 {durenol}

IX.A-22 IX.A-22

{isopseudocumenol}

IX.A-22 IX.A-22

496-78-6

1

0

0

Phenol, 2,4,5-trimethyl-

118-79-6

0

1

0

Phenol, 2,4,6-tribromo-

{pseudocumenol}

IX.A-22

527-60-6

1

1

1

Phenol, 2,4,6-trimethyl-

527-54-8

1

0

0

Phenol, 3,4,5-trimethyl-

IX.A-22

732-26-3

1

1

1

Phenol, 2,4,6-tris(1,1-dimethylethyl)-

IX.A-22

IX.A-22, XVIII.B-3, XXI-3 {mesitol}

IX.A-22

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1708

11/24/08 1:57:15 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1709

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

63-91-2

1

1

1

L-Phenylalanine

31105-03-0

0

1

0

L-Phenylalanine, N-(1-deoxy-D-fructos-1-yl)-

51064-37-0

0

1

0

Phenylalanine, ar,ar-dihydroxy-

21609-90-5

0

1

0

Phenylphosphonothioic acid, O-(4-bromo-2,5dichlorophenyl)-, O-methyl ester {Phosvel®}

Name (per CA Collective Index)

Selected structures

Chapter Table

C6H5-CH2-CH(NH2)-COOH IV.A-3, IV.B-7, XII-2 II.A-5, IV.A-3, IV.B-7, XII-2 IV.A-3, IV.B-7, XII-2, IX.A-22 XVIII.A-1, XVIII.B-3, XXI-3 H3CO

Cl

S P

Br

O

Cl

24861-47-0

0

1

0

Phorbine

20239-99-0

0

1

0

3-Phorbinepropanoic acid, 9-ethenyl-14-ethyl-13formyl-21-(methoxycarbonyl)-4,8,18-trimethyl-20oxo-, [3S- (3D,4E,21E)]-

IV.A-3, XVII.A-4

XVII.A-4

3147-18-0

0

1

0

3-Phorbinepropanoic acid, 9-ethenyl-14-ethyl-13formyl-21-(methoxycarbonyl)-4,8,18-trimethyl-20oxo-, 3,7,11,15-tetramethyl-2-hexadecenyl ester, [3S-[3D(2E,7S*,11S*),4E,21E]]-

V-3, XVII.A-4

15664-29-6

0

1

0

3-Phorbinepropanoic acid, 9-ethenyl-14-ethyl-21(methoxycarbonyl)-4,8,13,18-tetramethyl-20-oxo-, [3S-(3D,4E,21E)]-

IV.A-3, XVII.A-4

603-17-8

0

1

0

3-Phorbinepropanoic acid, 9-ethenyl-14-ethyl-21(methoxycarbonyl)-4,8,13,18-tetramethyl-20-oxo-, 3,7,11,15-tetramethyl-2-hexadecenyl ester, [3S[3D(2E,7S*,11S*),4E,21E]]-

V-3, XVII.A-4

9013-05-2

0

1

0

Phosphatase

122319-88-4

0

1

0

Phosphatase, 2-carboxyarabinitol 1-

XXII-2

9001-77-8

0

1

0

Phosphatase, acid

XXII-2

XXII-2

9000-83-3

0

1

0

Phosphatase, adenosine tri-

XXII-2

134632-85-2

0

1

0

Phosphatase, adenosine tri- (Petunia hybrida strain 3704 mitochondria subunit 9)

XXII-2

9001-78-9

0

1

0

Phosphatase, alkaline

XXII-2

9001-52-9

0

1

0

Phosphatase, fructose di-

XXII-2

9001-39-2

0

1

0

Phosphatase, glucose 6-

XXII-2

69669-68-7

0

1

0

Phosphatase, glucose di-

XXII-2

9027-69-4

0

1

0

Phosphatase, nucleoside di-

XXII-2

9075-51-8

0

1

0

Phosphatase, nucleoside tri-

XXII-2

9055-30-5

0

1

0

Phosphatase, phosphoglycerate

XXII-2

9025-76-7

0

1

0

Phosphatase, phosphoglycolate

XXII-2

52227-92-6

0

1

0

Phosphatase, phosphorylcholine

XXII-2

37341-58-5

0

1

0

Phosphatase, phytate

XXII-2

9059-33-0

0

1

0

Phosphatase, sucrose

14265-44-2

1

1

1

Phosphate

300-76-5

0

1

0

Phosphate, 1,2-dibromo-2,2-dichloroethyl dimethyl {Naled®}

14066-20-7

0

1

0

Phosphate, dihydrogen

H2PO4

XX-5

Phosphate, monohydrogen

-2 HPO4

XX-5

0

1

0

XXII-2 -3

PO4

XX-5 XVIII.B-3, XXI-3 -1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1709

11/24/08 1:57:16 PM

1710

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

20859-73-8

0

1

0

Phosphide, aluminum

AlŁP

XX-6, XXI-3

12057-74-8

0

1

0

Phosphide, magnesium

Mg3P2

XX-6, XXI-3

7803-51-2

1

1

1

Phosphine

PH3

115-26-4

0

1

0

Phosphine oxide, bis(dimethylamino)fluoro{Dimefox®}

Name (per CA Collective Index)

Selected structures

Chapter Table

XX-6, XXI-3 XVIII.B-3, XXI-3 N(CH3)2

F

P

O

N(CH3)2

9036-21-9

0

1

0

Phosphodiesterase, adenosine cyclic 3',5'phosphate

XXII-2

39434-01-0

0

1

0

Phosphodiesterase, nucleotide

XXII-2

12712-31-1

0

1

0

Phosphodoxin

XXII-2

9001-81-4

0

1

0

Phosphomutase, glucose

XXII-2

16672-87-0

0

1

0

Phosphonic acid, 2-chloroethyl{Ethephon®; Ethrel®}

52-68-6

0

1

0

Phosphonic acid, 2,2,2-trichloromethyl-1hydroxyethyl-, dimethyl ester {Trichlorphon®; Dylox®, Dipterex®}

98886-44-3

0

1

0

Phosphonodithioic acid, O-ethyl S-(1-methylpropyl) (2-oxo-3-thiazolidinyl){Fosthiazate®}

944-22-9

0

1

0

Phosphonodithioic acid, ethyl-, O-ethyl S-phenyl ester {Fonofos®}

XVIII.B-3, XXI-3

OH Cl-(CH2)2-P

O OH

H3CO

H3CO

O

V-3, XVIII.B-3, XXI-3

OH

CH P

CCl3

XVIII.A-1, XXI-3 XVIII.A-1, XXI-3

OC2H5

H5C2 P

S-C6H5

S

22224-92-6

0

1

0

Phosphoramidic acid, (1-methylethyl)-, ethyl 3methyl-4-(methylthio)phenyl ester {Fenamiphos®; Nemacur®}

V-3, XVIII.A-1, XXI-3

30560-19-1

0

1

0

Phosphoramidothioic acid, N-acetyl-, O,S-dimethyl ester {Orthene®; Acephate®}

V-3, XVIII.A-1, XXI-3

10265-92-6

0

1

0

Phosphoramidothioic acid O,S-dimethyl ester {Methamidophos®}

V-3, XVIII.A-1, XXI-3

25311-71-1

0

1

0

Phosphoramidothioic acid, O-ethyl O-2-(1methylethyl)carbonylphenyl-, (1-methylethyl) ester {Isofenphos®}

9030-26-6

0

1

0

Phosphoribosyltransferase, nicotinate

7664-38-2

0

1

0

Phosphoric acid

7757-93-9

0

1

0

Phosphoric acid, calcium salt (1:1)

470-90-6

0

1

0

Phosphoric acid, 2-chloro-1-(2dichlorophenyl)ethenyl-, diethyl ester {Chlorfenvivphos®; Birlane®}

XXI-3

XXII-2 XX-6 XX-6 V-3, XVIII.B-3, XXI-3 CHCl H5C2O

O P

H5C2O

O

Cl

Cl

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1710

11/24/08 1:57:17 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1711

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

13171-21-6

0

1

0

Name (per CA Collective Index) Phosphoric acid, 2-chloro-3-(diethylamino-1-methyl3-oxo-1-propenyl)-, dimethyl ester {Phosphamidon®}

Selected structures

V-3, XVIII.B-3, XXI-3 CH3 H3CO

C

H3CO

0

1

0

O

V-3, XVIII.B-3, XXI-3

H3CO

1

0

Phosphoric acid, diammonium salt

62-73-7

0

1

0

Phosphoric acid, 2,2,-dichloroethenyl-, dimethyl ester {DDVP; Dichlorvos®}

OC2H5

Cl

H3CO

0

Cl

Cl

O CHCl

P

O

XX-6 V-3, XVIII.B-3, XXI-3 H3CO

Cl

CH=C

O

Cl

P H3CO

141-66-2

0

1

0

OC2H5

N

Cl

Phosphoric acid, 2-chloro-1-(2,4,5trichlrophenyl)ethenyl-, dimethyl ester {DDVP; Tetrachlorvinphos®}

7783-28-0

O

O P

22248-79-9

Chapter Table

O

Phosphoric acid, 3-(dimethylamino-1-methyl-3-oxo1-propenyl)-, dimethyl ester {Dicrotophos®}

V-3, XXI-3 CH3 H3CO

O

O

C

CH

P H3CO

N=(CH3)2

O

7757-86-0

0

1

0

Phosphoric acid, magnesium salt

XX-6

7778-53-2

0

1

0

Phosphoric acid, tripotassium salt

XX-6

1754-58-1

1

1

1

Phosphorodiamidic acid, N,N'-dimethyl-, phenyl ester {Diamidafos®}

V-3, XXI-3 O C6H5-O-P

NH-CH3

NH-CH3

13194-48-4

0

1

0

Phosphorodithioic acid, O-ethyl-S,S, dipropyl ester {Mocap®, Ethoprop®, Prophos®, Rovokil®, Ethoprophos®}

2497-06-5

0

1

0

Phosphorodithioic acid, O,O-diethyl S-[2(ethylsulfonyl)ethyl] ester (Thiodemeton sulfone®)

298-04-4

1

1

1

Phosphorodithioic acid, O,O-diethyl S-[2(ethylthio)ethyl] ester {Disulfoton®}

V-3, XVIII.A-1, XXI-3 S

O

(CH2)2-CH3

P S

H3C-CH2-O

(CH2)2-CH3

V-3, XVIII.A-1, XXI-3

V-3, XVIII.A-1, XXI-3 S S H3CO

P

CH3

S

CH3O

298-02-2

0

1

0

Phosphorodithioic acid, O,O-diethyl S-[2(ethylthio)methyl] ester {Phorate®}

V-3, XVIII.A-1, XXI-3 S H3CO

P

S

S

CH3

CH3O

301-12-2

0

1

0

Phosphorodithioic acid, O,O-dimethyl S-[2(ethylsulfinyl)ethyl] ester {Oxydemeton methyl®}

XXI-3 O H3C-CH2-S

O

OCH3 P

(CH2)2-S

OCH3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1711

11/24/08 1:57:18 PM

1712

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

640-15-3

0

1

0

Phosphorodithioic acid, O,O-dimethyl S-[2(ethylthio)ethyl] ester {Thiometon®}

950-37-8

0

1

0

Phosphorodithioic acid, O,O-dimethyl-S-2,3dihydro-5-methoxy-2-oxo-1,3,4-thiadiazol-3ylmethyl ester {Supracide®; Methidathion®}

Name (per CA Collective Index)

Selected structures

XVIII.A-1, XXI-3 V-3, XVIII.A-1, XXI-3 O OCH3 S

0

1

0

Phosphorodithioic acid, O,O-dimethyl- S-(Įethoxycarbonylbenzyl) ester {Fenthoate®; Phenthoate®}

N

S

N H3C

2597-03-7

Chapter Table

S

P

OCH3

O

V-3, XVIII.A-1, XXI-3 COOC2H5 H3CO

CH

S P S

H3CO

60-51-5

0

1

0

Phosphorodithioic acid, O,O-dimethyl-S-[2methylamino)-2-oxoethyl] ester {Dimethoate®}

V-3, XVIII.A-1, XXI-3 S H3CO

H N

P

2642-71-9

0

1

0

Phosphorodithioic acid, O,O-diethyl S-[(4-oxo-1,2,3benzotriazin-3(4H)-yl)methyl] ester {Azinphos Ethyl®}

86-50-0

1

1

1

Phosphorodithioic acid, O,O-dimethyl S-[(4-oxo1,2,3-benzotriazin-3(4H)-yl)methyl] ester {Guthion®; Azinphos-Methyl®}

CH3

S O

CH3O

V-3, XVIII.A-1, XXI-3

V-3, XVIII.A-1, XXI-3 S

O

CH2-S-P-OCH3

N

OCH3

N

N

298-04-4

0

1

0

Phosphorodithioic acid, O,O-diethyl S-(2(ethylthio)ethyl) ester {Disulfoton®}

V-3, XVIII.A-1, XXI-3

2310-17-0

0

1

0

Phosphorodithioic acid, S-[(6-chloro-2-oxo-3(2H)benzoxazolyl)methyl] O,O-diethyl ester {Phosalone®}

V-3, XVIII.A-1, XVIII.B-3, XXI-3 Cl

O O N H5C2O

S P

H5C2O

2540-82-1

0

1

0

S

Phosphorodithioic acid, S-[2-formylmethylamino)-2oxoethyl] O,O-dimethyl ester {Formothion®}

V-3, XVIII.A-1, XXI-3 CH3 H3CO

S-CH2-CO-N-CH=O P S

H3CO

41198-08-7

0

1

0

Phosphorothioic acid, O-(4-bromo-2-chlorophenyl)O-ethyl-S-propyl ester {Profenophos®}

14816-18-3

0

1

0

Phosphorothioic acid, O,O-diethyl O-(Įcyanobenzylideneamino){Phoxim®}

V-3, XVIII.A-1, XXVIII.B-3, XXI-3 V-3, XI-2, XVIII.A-1, XXI-3 CN S N

P (O-C2H5)2

2921-88-2

1

1

1

Phosphorothioic acid, O,O-diethyl O-(3,5,6-trichloro2-pyridinyl) ester {Chlorpyriphos®; Dursban®}

V-3, XVII.B-2, XVIII.A-1, XXVIII.B-3, XXI-3 H3CO

Cl

S P

H3CO

N Cl

O

Cl

13071-79-9

0

1

0

Phosphorodithioic acid, O,O-diethyl S-[(1,1dimethylethyl)thio]methyl ester {Terbuphos®}

V-3, XVIII.A-1, XXI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1712

11/24/08 1:57:18 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1713

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

115-90-2

0

1

0

Phosphorothioic acid, O,O-diethyl O-[4(methylsulfinyl)phenyl] ester {Fensulfothion®}

56-38-2

0

1

0

Phosphorothioic acid, O,O-diethyl O-(4-nitrophenyl) ester {Parathion®}

Name (per CA Collective Index)

Selected structures

Chapter Table

V-3, XVIII.A-1, XXI-3 V-3, XVI-1, XVIII.A-1, XXI-3 H5C2O

S P

H5C2O

297-97-2

0

1

0

Phosphorothioic acid, O,O-diethyl O-pyrazinyl ester {Thionazine®, Zinophos®}

O

NO2

V-3, XVII.B-2, XVIII.A-1, XXI-3 N

O

P

(OC2H5)2

N

298-00-0

0

1

0

Phosphorothioic acid, O,O-dimethyl O-(4nitrophenyl) ester {Parathion-methyl®}

S

V-3, XVI-1, XVIII.A-1, XXI-3 H3CO

S P

299-84-3

0

1

0

Phosphorothioic acid, O,O-dimethyl O-(2,4,5trichlorophenyl) ester {Fenchlorphos®; Phenchlorphos®}

H3CO

O

H3CO

S

NO2

V-3, XVIII.A-1, XXI-3 Cl

P H3CO

Cl

O

Cl

2104-96-3

0

1

0

Phosphorothioic acid, O,O-dimethyl O-(4-bromo2,5-dichlorophenyl) ester {Bromophos®}

V-3, XVIII.A-1, XXI-3 H3CO

Cl

S P

H3CO

Br

O

Cl

333-41-5

0

1

0

Phosphorothioic acid, O,O-diethyl O-[6-methyl-2-(1methylethyl)-4-pyrimidinyl] ester {Diazinon®}

V-3, XVII.B-2, XVIII.A-1, XXI-3

24017-47-8

0

1

0

Phosphorothioic acid, O,O-diethyl O-(1-phenyl-1H1,2,4-triazol-3-yl) ester {Triazophos®}

V-3, XVIII.A-1, XXI-3

919-86-8

0

1

0

Phosphorothioic acid, O,O-dimethyl S-[2(ethylthio)ethyl] ester {Demeton-S-methyl®}

V-3, XVIII.A-1, XXI-3

961-22-8

0

1

0

Phosphorothioic acid, O,O-dimethyl S-[(4-oxo-1,2,3benzotriazin-3(4H)-yl) methyl] ester

V-3, XVIII.A-1, XXI-3 O

O N N

N

CH2-S-P-OCH3 OCH3

20300-00-9

0

1

0

Phosphorothioic acid, O,O-dimethyl S-[2-[[1-methyl2-(methylamino)-2-oxoethyl]sulfinyl]ethyl] ester

V-3, XVIII.A-1, XXI-3

2275-23-2

0

1

0

Phosphorothioic acid, O,O-dimethyl S-[2-[[1-methyl2-(methylamino)-2-oxoethyl]thio]ethyl] ester {Vamidothion®}

V-3, XVIII.A-1, XXI-3

70898-34-9

0

1

0

Phosphorothioic acid, O,O dimethyl S-[2-[[1-methyl2-(methylamino)-2-oxoethyl]sulfonyl]ethyl] ester

V-3, XVIII.A-1, XXI-3

122-14-5

0

1

0

Phosphorothioic acid, O,O-dimethyl O-(3-methyl-4nitrophenyl) ester {Fenitrothion®}

V-3, XVI-1, XVIII.A-1, XXI-3

55-38-9

0

1

0

Phosphorothioic acid O,O-dimethyl O-(4methylthio)-3-methylphenyl ester {Fenthion®}

V-3, XVIII.A-1, XXI-3

29232-93-7

0

1

0

Phosphorothioic acid, O-[2-(diethylamino)-6-methyl4-pyrimidinyl] O,O-dimethyl ester {Pirimiphos-methyl®}

7723-14-0

1

1

1

Phosphorus

V-3, XVII.B-2, XVIII.A-1, XXI-3

P

XX-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1713

11/24/08 1:57:19 PM

1714

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1314-56-3

0

1

0

Phosphorus oxide

P2O5

XX-6

14596-37-3

0

1

0

Phosphorus, isotope of mass 32

32

XX-5

9035-74-9

0

1

0

Phosphorylase

XXII-2

9032-10-4

0

1

0

Phosphorylase a

XXII-2

0

1

0

Phosphorylase, guanosine

XXII-2

0

1

0

Phosphorylase, polynucleotide

XXII-2

9030-28-8 71010-49-6 37297-20-4

P

1

1

1

Phytadiene C

I.B-1

0

1

0

Phytodienes

I.B-1

0

1

0

Phytoalexins

0

1

0

Phytuberin

213-46-7

1

0

0

Picene

30283-95-5

0

1

0

Picene, methyl-

106-58-1

1

0

0

Piperazine, 1,4-dimethyl-

XXII-2 V-3, XXII-2

I.E-6

{benzo[a]chrysene}

I.E-6 XVII.B-2

106-55-8

1

0

0

Piperazine, 2,5-dimethyl-

XVII.B-2

109-01-3

1

0

0

Piperazine, 1-methyl-

XVII.B-2

109-07-9

1

0

0

Piperazine, 2-methyl-

XVII.B-2

106-57-0

1

0

0

2,5-Piperazinedione

XVII.B-2

14771-77-8

1

0

0

2,5-Piperazinedione, 3-(1-methylethyl)-

XVII.B-2, XVII.C-1

61892-78-2

1

0

0

2,5-Piperazinedione, 3-(2-propenyl)-

XVII.B-2, XVII.C-1

5625-46-7

1

0

0

2,5-Piperazinedione, 3,6-dimethyl-

XVII.B-2, XVII.C-1

5625-53-6

1

0

0

2,5-Piperazinedione, 3-methyl-

XVII.B-2, XVII.C-1

4526-77-6

1

0

0

2,5-Piperazinedione, 3-methyl-, (S)-

110-89-4

1

1

1

Piperidine

3350-86-5

XVII.B-2, XVII.C-1

{azacyclohexane}

XVII.B-2

H N

0

1

0

Piperidine, 1-acetyl-2-(3-pyridinyl)-, (S)-

XVII.B-6

1

0

0

Piperidine, C2-alkyl-

XVII.B-2

1

0

0

Piperidine, C3-alkyl-

XVII.B-2

1

0

0

Piperidine, C4-alkyl)-

XVII.B-2

23513-39-5

1

0

0

Piperidine, 2,3-dimethyl-, cis-

XVII.B-2

19683-91-1

1

0

0

Piperidine, 2,4-dimethyl-, cis-

XVII.B-2

504-03-0

1

0

0

Piperidine, 2,6-dimethyl-

XVII.B-2

17721-95-8

1

0

0

Piperidine, 2.6-dimethyl-1-nitroso-

0

1

0

Piperidine, 2,4-di(3-pyridinyl)-

XV-8, XVII.B-2 {anatalline}

XVII.B-6

HN N

N

1484-80-6

1

0

0

Piperidine, 2-ethyl-

XVII.B-2

© 2009 by Taylor & Francis Group, LLC

78836_C030.indd 1714

11/24/08 1:57:19 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1715

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

626-67-5

S T

S

T

Name (per CA Collective Index)

1

0

0

Piperidine, 2-ethyl-1-nitroso-

0

1

0

Piperidine, 1-methyl-

Selected structures

Chapter Table XV-8, XVII.B-2 XVII.B-2

626-56-2

1

0

0

Piperidine, 3-methyl-

13603-07-1

1

0

0

Piperidine, 3-methyl-1-nitroso-

XV-8, XVII.B-2

XVII.B-2 XV-8, XVII.B-2

1

0

0

Piperidine, 4-methyl-1-nitroso-

71607-72-2

1

0

0

Piperidine, (1-methylethyl)-

100-75-4

1

1

1

Piperidine, 1-nitroso-

96552-69-1

1

0

0

Piperidine, 1-(1-oxooctyl)-2-(3-pyridinyl)-, (S)-

XVII.B-6

XVII.B-2 XV-8, XVII.B-2

{NPIP}

62783-95-3

1

0

0

Piperidine, 1-(1-oxopentyl)-2-(3-pyridinyl)-, (S)-

XVII.B-6

77-10-1

1

0

0

Piperidine, 1-(1-phenylcyclohexyl)-

XVII.B-2

1

0

0

Piperidine, 1-(3-pyridinemethyl)-2-cyano-4,5didehydro-

XVII.B-6

1

0

0

Piperidine, 1-(3-pyridinemethyl)-2-cyano-

71635-28-4

0

1

0

1-Piperidinecarboxaldehyde, 2-(3-pyridinyl)-, (S)-

III-12, XVII.B-6

XVII.B-6

13406-98-9

0

1

0

1-Piperidinecarboxylic acid

IV.A-3, XVII.B-2

56078-09-2

1

0

0

1-Piperidinecarboxylic acid, 2-(3-pyridinyl)-, methyl ester, (S)-

V-3, XVII.B-6

N COO-CH3

N

0

1

0

2-Piperidineacetic acid, 1-nitroso-

{NPIPAC}

IV.A-3, XV-8, XVII.B-2

535-75-1

0

1

0

2-Piperidinecarboxylic acid

{pipecolic acid}

IV.A-3, XVII.B-2

4515-18-8

1

1

1

2-Piperidinecarboxylic acid, 1-nitroso{N-nitrosopipecolic acid: NPIC}

IV.A-3, XV-8, XVII.B-2

65445-62-7

0

1

0

3-Piperidinecarboxylic acid, 1-nitroso-

IV.A-3, XV-8, XVII.B-2

6238-69-3

0

1

0

4-Piperidinecarboxylic acid, 1-nitroso-

1121-89-7

1

0

0

2,6-Piperidinedione

IV.A-3, XV-8, XVII.B-2

{glutarimide}

4

O

1

XIV-1, XVII.B-2

3 2

N H

0

1

0

0

2,6-Piperidinedione, methoxy-

X-2, XIV-1, XVII.B-2

61892-70-4

1

0

0

2,6-Piperidinedione, 4-methoxy-

X-2, XIV-1, XVII.B-2

72692-70-7

1

0

0

2,6-Piperidinedione, methyl-

XIV-1, XVII.B-2

29553-51-3

1

0

0

2,6-Piperidinedione, 3-methyl-

XIV-1, XVII.B-2

25077-26-3

1

0

0

2,6-Piperidinedione, 4-methyl-

XIV-1, XVII.B-2

27154-43-4

1

0

0

Piperidinone

XIV-1, XVII.B-2

675-20-7

1

1

1

2-Piperidinone

{5-pentanelactam}

XVII.B-2, XVII.C-1

NH O

61891-65-4

1

0

0

2-Piperidinone, methyl-

XVII.B-2, XVII.C-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1715

11/24/08 1:57:20 PM

1716

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Chapter Table

Selected structures

931-20-4

1

1

1

2-Piperidinone, 1-methyl-

XVII.B-2, XVII.C-1

4775-98-8

1

0

0

2-Piperidinone, 6-methyl-

XVII.B-2, XVII.C-1

13200-35-6

1

0

0

4-Piperidinone, 2,6-dimethyl-, cis-

III-13, XVII.B-2

CH3 O

NH

CH3

69135-98-4

1

0

0

4-Piperidinone, 2,6-dimethyl-, trans-

III-13, XVII.B-2

3311-23-7

1

0

0

4-Piperidinone, 2,2,6-trimethyl-, (R)-

III-13, XVII.B-2

0

1

0

Plastochromenol

0

1

0

Plastoquinol

IX.B-2

11005-16-6

0

1

0

Plastoquinone C

IX.B-2

12778-15-3

0

1

0

Plastoquinone D

IX.B-2

4299-57-4

0

1

0

Plastoquinone 9

{solanachromene isomer}

IX.A-22

IX.B-2 CH3

O H3C

CH3 [

CH3 ]7

CH3

H3C O

7440-06-4

0

1

0

Platinum

Pt

XX-5 XX-5 XX-5

13981-16-3

0

1

0

Plutonium, isotope of mass 238

238

15117-48-3

1

1

1

Plutonium, isotope of mass 239

239

XX-5

Pu Pu

14119-33-6

1

1

1

Plutonium, isotope of mass 240

240

7440-08-6

1

1

1

Polonium

Po

XX-5

13981-52-7

1

1

1

Polonium, isotope of mass 210

210

XX-5

25322-68-3

0

1

0

Poly(oxy-1,2-ethanediyl), D-hydro-Z-hydroxy-

II.A-5

9032-75-1

0

1

0

Polygalacturonase

XXII-2

152415-56-0

0

1

0

Polygalacturonase (tobacco clone G27.1/G27.2 gene Npg1 precursor reduced)

XXII-2

0

1

0

Polymerase, nucleic acid deoxyribo

XXII-2

0

1

0

Polyphenoloxidase

XXII-2

Pu Po

0

1

0

Poly(U)polymerase

XXII-2

159965-71-6

0

1

0

Polyubiquitin (Nicotiana tabacum clone Ubi.U4 gene Ubi.U4)

XXII-2

101-60-0

1

1

1

21H,23H-Porphine

XVII.A-4

{porphyrin} N H N

N H N

644-00-8

1

0

0

21H,23H-Porphine-2-propanoic acid, 8,13-diethyl3,7,12,17-tetramethyl-

IV.A-3, XVII.A-4

1976-85-8

0

1

0

21H,23H-Porphine-2,7,12,18-tetrapropanoic acid, 3,8,13,17-tetrakis(carboxymethyl)5,10,15,20,22,24-hexahydro-

IV.A-3, XVII.A-4

9055-40-7

0

1

0

Porphobilinogenase

7440-09-7

1

1

1

Potassium

K

13966-00-2

1

1

1

Potassium, isotope of mass 40

40

XXII-2 XX-5 K

XX-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1716

11/24/08 1:57:20 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1717

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

14378-21-3

0

1

0

Potassium, isotope of mass 42

42

K

XX-5

7447-40-7

1

1

1

Potassium chloride

KCl

XX-6

12136-45-7

0

1

0

Potassium oxide

K2O

XX-6

24203-36-9

1

0

0

Potassium, ion

K

+1

XX-5

Pr

Name (per CA Collective Index)

Selected structures

7440-10-0

1

1

1

Praseodymium

57-83-0

0

1

0

Pregn-4-ene-3,20-dione

145-13-1

0

1

0

Pregn-5-en-20-one, 3-hydroxy-, (3E)-

32378-60-2

0

1

0

Pregnan-20-one, 3-[(1-oxohexadecyl)oxy]-, (3E,5D)-

147-85-3

1

1

1

L-Proline

Chapter Table

XX-5 III-13 II.A-5, III-13 III-13 IV.A-3, IV.B-7, XVII.A-4

N H

COOH

147427-29-0

0

1

0

L-Proline, 1-[1-[1-(1-L-seryl-L-prolyl)-L-prolyl]-Lprolyl]-

IV.A-3, IV.B-7, XVII.A-4

18610-59-8

0

1

0

L-Proline, 1-hydroxy-

IV.A-3, IV.B-7, XVII.A-4

7519-36-0

1

1

1

L-Proline, 1-nitroso-

{NPRO}

IV.A-3, IV.B-7, XV-8, XVII.A-4

N

COOH

NO

1

1

1

L-Proline, 1-nitroso-, methyl ester

V-3, XV-8, XVII.A-4

N

COO-CH3

NO

62137-28-4

0

1

0

L-Proline, 4-[(O-E-L-arabinofuranosyl-(1o2)-O-E-Larabinofuranosyl-(1o2)-E-L-arabinofuranosyl)oxy], trans-

II.A-5, IV.A-3, IV.B-7, XVII.A-4

62137-29-5

0

1

0

L-Proline, 4-[(O-E-L-arabinofuranosyl-(1o3)-O-E-Larabinofuranosyl-(1o2)-O-E-L-arabinofuranosyl(1o2)-E-L-arabinofuranosyl)oxy]-, trans-

II.A-5, IV.A-3, IV.B-7, XVII.A-4

51-35-4

0

1

0

L-Proline, 4-hydroxy-, trans-

30310-80-6

0

1

0

L-Proline, 4-hydroxy-1-nitroso-, trans-

II.A-5, XVII.A-4

463-49-0

1

0

0

1,2-Propadiene

123-38-6

1

1

1

Propanal

630-19-3

1

0

0

367-47-5

1

1

1

{NHPRO} {allene}

II.A-5, XV-8, XVII.A-4 H2C=C=CH2

I.B-1

{propionaldehyde}

H3C-CH2-CH=O

III-12

Propanal, 2,2-dimethyl-

{pivalaldehyde}

(H3C)3ŁC-CH=O

Propanal, 2,3-dihydroxy-

{glyceraldehyde}

142-10-9

0

1

0

Propanal, 2,3-dihydroxy-, 3-phosphate

78-84-2

1

1

1

Propanal, 2-methyl-

1646-87-3

0

1

0

Propanal, 2-methyl-2-(methylsulfinyl)-, O[(methylamino)carbonyl]oxime {Aldicarb Sulfoxide®}

{isobutyraldehyde}

III-12

HOCH2-CH2OH-CH=O

II.A-5, III-12 II.A-5, III-12

(H3C)2=CH-CH=O

III-12 III-12, XVIII.A-1, XXI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1717

11/24/08 1:57:21 PM

1718

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

1646-88-4

0

1

0

Name (per CA Collective Index) Propanal, 2-methyl-2-(methylsulfonyl)-, O[(methylamino)carbonyl]oxime {Aldoxycarb®}

III-12, XVIII.A-1, XXI-3 O

O

116-06-3

0

1

0

Chapter Table

Selected structures

Propanal, 2-methyl-2-(methylthio)-, O[(methylamino)carbonyl]oxime {Aldicarb®}

S

N O

O

N H

III-12, XVIII.A-1, XXI-3 H N

O

S

N

O

0

1

0

Propanal, 3-(nitrosomethylamino)-

1

1

1

Propanal, 2-oxo-

0

1

0

Propanal, 2-oxo-3-hydroxy-

{reductone}

3268-49-3

1

1

1

Propanal, 3-(methylthio)-

{methional}

78-98-8

H3C-N(NO)-(CH2)2-CHO

{pyruvaldehyde; methylglyoxal}

III-12, XV-8

H3C-CO-CH=O HOCH2-CO-CH=O

III-12, III-13 II.A-5, III-12, III-13 III-12, XVIII.A-1

79-05-0

1

0

0

Propanamide

H3C-CH2-CO-NH2

7324-05-2

0

1

0

Propanamide, 2-amino-, (S)-

H3C-CH(NH2)-CO-NH2

563-83-7

1

0

0

Propanamide, 2-methyl-

631-66-3

1

0

0

Propanamide, 2-oxo-

61892-68-0

1

0

0

Propanamide, 3-cyano-

15299-99-7

0

1

0

Propanamide, diethyl-2-(1-naphthyloxy){Devrinol®; (Napropamide®}

XIII-1 XII-2, XIII-1

(H3C)2=CH-CO-NH2 {pyruvamide}

XIII-1

H3C-CO-CO-NH2

III-3, XIII-1

NC-CH2-CH2-CO-NH2

2675-88-9

1

0

0

Propanamide, N,2-dimethyl-

35256-85-0

0

1

0

Propanamide, dimethyl-N-(1-methylethyl)-N(phenylmethyl) {Butam®}

XI-2, XIII-1 XIII-1, XXI-3

O-CH(CH3)-CO-N=(C2H5)2

H3C-CH(CH3)-CO-NH-CH3

XIII-1 XIII-1, XXI-3

N

CH(CH3)2

O=C-C(CH3)3

5129-72-6

1

0

0

Propanamide, N-ethyl-

H3C-CH2-CO-NH-CH2-CH3

XIII-1

H3C-CH2-CO-NH-CH3

XIII-1

1187-58-2

1

0

0

Propanamide, N-methyl-

25457-49-2

1

0

0

Propanamide, N-methyl-N-(1-oxopropyl)-

XIII-1

107-10-8

1

1

1

1-Propanamine

H3C-(CH2)2-NH2

XII-2

5813-64-9

1

0

0

1-Propanamine, 2,2-dimethyl-

H3C-C(CH3)2CH2-NH2

XII-2

625-43-4

1

1

1

1-Propanamine, N,2-dimethyl-

H3C-CH(CH3)CH2-NH-CH3

34419-76-6 2504-18-9

1

0

0

1-Propanamine, N,2-dimethyl-N-nitroso-

H3C-CH(CH3)CH2-N(NO)-CH3

XII-2

71607-99-3

1

1

1

1-Propanamine, N-ethyl-2-methyl-N-nitroso-

H3C-CH(CH3)CH2-N(NO)-CH2CH3

XV-8

25413-61-0

1

1

1

1-Propanamine, N-ethyl-N-nitroso-

H3C-(CH2)2-N(NO)-CH2CH3

XV-8

XII-2, XV-8

627-35-0

1

1

1

1-Propanamine, N-methyl-

H3C-(CH2)2-NH-CH3

XII-2

78-81-9

1

1

1

1-Propanamine, 2-methyl-

(H3C)2=CH-CH2-NH2

XII-2

1

0

0

1-Propanamine, 2-methyl-, N-butyl-

(H3C)2=CH-CH2-NH-(CH2)3-CH3

XII-2

1

0

0

1-Propanamine, 2-methyl-, N-(2-methylpropyl)-Nnitroso-

21968-17-2

1

1

1

1-Propanamine, N-(1-methylethyl)-

H3C-(CH2)2-NH-CH=(CH3)2

XII-2

22023-64-9

1

0

0

1-Propanamine, N-(1-methylethylidene)-

H3C-(CH2)2-NH-C(CH3)=CH2

XII-2

924-46-9

1

1

1

1-Propanamine, N-methyl-N-nitroso-

{NMPA}

XV-8

H3C-(CH2)2-N(NO)-CH3

XV-8

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1718

11/24/08 1:57:21 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1719

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

3405-42-3

1

0

0

1-Propanamine, N-methyl-N-propyl-

621-64-7

1

1

1

1-Propanamine, N-nitroso-N-propyl-

Name (per CA Collective Index)

Chapter Table

Selected structures

{NDPA}

(H3C-CH2CH2)2=N-CH3

XII-2

(H3C-CH2CH2)2=N-NO

XV-8

142-84-7

1

1

1

1-Propanamine, N-propyl-

(H3C-CH2CH2)2=NH

XII-2

7239-24-9

0

1

0

1-Propanamine, N,N,2-trimethyl-

(H3C)2=CH-CH2-N=(CH3)2

XII-2

75-31-0

1

1

1

2-Propanamine

(H3C)2=CH-NH2

XII-2

75-64-9

1

1

1

2-Propanamine, 2-methyl-

(H3C)3ŁC-NH2

XII-2

7515-80-2

1

0

0

2-Propanamine, 2-methyl-N-(1-methylethyl)-

(H3C)3ŁC-NH-CH(CH3)2

XII-2

3376-24-7

1

0

0

2-Propanamine, 2-methyl-N-(phenylmethylene)-, Noxide

XII-2

1

0

0

2-Propanamine, N-(2,2-dimethylethyl)-

XII-2

4747-21-1

1

1

1

2-Propanamine, N-methyl-

(H3C)2=CH-NH-CH3

XII-2

108-18-9

1

0

0

2-Propanamine, N-(1-methylethyl)-

(H3C)2=CH-NH-CH=(CH3)2

XII-2

[(H3C)2=CH]2-N-NO

XV-8

601-77-4

1

0

0

2-Propanamine, N-(1-methylethyl)-N-nitroso

3332-08-9

1

0

0

2-Propanamine, N-(1-methylethylidene)-

XII-2

1

0

0

2-Propanamine, N-(2-methylpropyl)-

XII-2

1

1

1

2-Propanamine, N-propyl-

74-98-6

1

0

0

Propane

96-12-8

0

1

0

Propane, 1,2-dibromo-3-chloro-

78-87-5

0

1

0

Propane, 1,2-dichloro-

XII-2 H3C-CH2-CH3 {DBCP®}

I.A-10 XVIII.B-3, XXI-3 XVIII.B-3, XXI-3

142-28-9

0

1

0

Propane, 1,3-dichloro-

4110-50-3

1

0

0

Propane, 1-(ethylthio)-

H3C-(CH2)2-S-CH2-CH3

XVIII.B-3, XXI-3 XVIII.A-1

3877-15-4

1

0

0

Propane, 1-(methylthio)-

H3C-(CH2)2-S-CH3

XVIII.A-1

505-84-0

1

0

0

Propane, 1,1'-[methylenebis(oxy)]bis-

76-19-7

0

1

0

Propane, octafluoro{Freon® 218; Perfluoropropane}

CF3CF2CF3

111-43-3

1

0

0

Propane, 1,1'-oxybis-

{dipropyl ether}

[H3C-(CH2)2]2=O

X-2

111-47-7

1

0

0

Propane, 1,1'-thiobis-

{dipropyl sulfide}

[H3C-(CH2)2]2=S

XVIII.A-1

592-65-4

1

0

0

Propane, 1,1'-thiobis[2-methyl- {diisobutyl sulfide}

[(H 3C)2=CH)2]2=S

XVIII.A-1

108-03-2

1

0

0

Propane, 1-nitro-

H3C-(CH2)2-NO2

XVI-1

75-28-5

1

0

0

Propane, 2-methyl-

(H3C)2=CH-CH3

I.A-10

79-46-9

1

0

0

Propane, 2-nitro-

(H3C)2=CH-NO2

XVI-1

X-2

{isobutane}

XVIII.B-3

542-78-9

1

0

0

Propanedial

H2C=(CHO)2

4464-20-4

1

0

0

Propanedial, dihydroxy-

(HO)2=C=(CH=O)2

II.A-5, III-12

O=C=(CHO)2

III-12, III-13

497-16-5

1

0

0

Propanedial, oxo-

56-18-8

1

0

0

1,3-Propanediamine, N-3-aminopropyl){norspermidine}

141-82-2

1

1

1

Propanedioic acid

{malonic acid}

III-12

XII-2 H2C=(COOH)2

IV.A-3

108-59-8

0

1

0

Propanedioic acid, dimethyl ester

H2C=(COO-CH3)2

V-3

80-69-3

1

1

1

Propanedioic acid, hydroxy-

HO-CH=(COOH)2

II.A-5, IV.A-3

516-05-2

0

1

0

Propanedioic acid, methyl-

H3C-CH=(COOH)2

IV.A-3

607-81-8

1

0

0

Propanedioic acid, (phenylmethyl)-, diethyl ester

57-55-6

1

1

1

1,2-Propanediol

{propylene glycol}

V-3 H3C-CHOH-CH2OH

II.A5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1719

11/24/08 1:57:22 PM

1720

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Chapter Table

Selected structures

627-69-0

1

1

1

1,2-Propanediol, 1-acetate

H3C-CHOH-CH2-OOC-CH3

II.A5, V-3

6214-01-3

1

1

1

1,2-Propanediol, 2-acetate

H3C-CH(OOC-CH3)-CH2OH

II.A5, V-3

Cl-CH2-CHOH-CH2OH

96-24-2

1

0

0

1,2-Propanediol, 3-chloro-

10602-14-9

0

1

0

1,2-Propanediol, 1-(dihydrogen phosphate)

II.A5, XVIII.B-3 II.A-5

20390-21-0

1

0

0

1,2-Propanediol, 3-(furfuryloxy)-

115888-33-0

0

1

0

1,2-Propanediol, 2-(1,2,3,5,6,7,8,8a-octahydro8,8a-dimethyl-2-naphthalenyl)-, [2S[2D(S*),8D,8aE]]-

II. A-5, X-2 II.A-5

99694-82-3

0

1

0

1,2-Propanediol, 2-(1,2,3,5,6,7,8,8a-octahydro8,8a-dimethyl-2-naphthalenyl)-, [2R[2D(S*),8E,8aD]]-

II.A-5

115788-21-1

0

1

0

1,2-Propanediol, 2-(1,2,3,5,6,7,8,8a-octahydro-3hydroxy-8,8a-dimethyl-2-naphthalenyl)-, [2S[2D(S*),3D,8E,8aD]]-

II.A-5

115788-20-0

0

1

0

1,2-Propanediol, 2-(1,2,3,5,6,7,8,8a-octahydro-5hydroxy-8,8a-dimethyl-2-naphthalenyl)-, [2R[2D(R*),5D,8.

II.A-5

54541-18-3

1

0

0

1,2-Propanediol, 2-propanoate

504-63-2

1

1

1

1,3-Propanediol

II.A-5, V-3 {trimethylene glycol}

HOCH2-CH2-CH2OH

II.A-5

126-30-7

1

0

0

1,3-Propanediol, 2,2-dimethyl-

II.A-5

1438-92-2

1

1

1

1,2-Propanedione, 1-(2-furanyl)-

III-13

2034-60-8

0

1

0

1,2-Propanedione, 1-(4-hydroxy-3-methoxyphenyl)-

1197-20-2

1

1

1

1,2-Propanedione, 1-(5-methyl-2-furanyl)-

III-13, X-2 III-13

579-07-7

1

0

0

1,2-Propanedione, 1-phenyl-

107-12-0

1

0

0

Propanenitrile

III-13

78-97-7

1

0

0

Propanenitrile, 2-hydroxy-

H3C-CHOH-CN

II.A-5, XI-2

75-86-5

1

0

0

Propanenitrile, 2-hydroxy-2-methyl-

(H3C)2=COH-CN

II.A-5, XI-2

78-82-0

1

1

1

Propanenitrile, 2-methyl-

(H3C)2=CH-CN

78-67-1

0

1

0

Propanenitrile, 2-methyl-, 2,2’-azobis{Porofor-57®}

631-57-2

1

0

0

Propanenitrile, 2-oxo-

H3C-CH2-CN

{isobutyronitrile}

60153-49-3

1

1

1

Propanenitrile, 3-(methylnitrosamino)-

1738-25-6

1

0

0

Propanenitrile, 3-(dimethylamino)-

{MNPN}

111-97-7

1

0

0

Propanenitrile, 3,3'-thiobis-

107-03-9

1

0

0

1-Propanethiol

513-44-0

1

0

0

1-Propanethiol, 2-methyl-

75-33-2

1

0

0

2-Propanethiol

30810-51-6

0

1

0

1,2,3-Propanetricarboxylic acid, 1-hydroxy{isocitric acid}

XI-2

XI-2 XI-2

H3C-CO-CN

III-13, XI-2

H3C-N(NO)-(CH2)2-CN

XI-2, XV-8 XI-2, XII-2 XI-2, XVIII.A-1

{propyl mercaptan}

XVIII.A-1

{isobutyl mercaptan}

XVIII.A-1

{isopropyl mercaptan}

XVIII.A-1 HO-CH-COOH

II.A-5, IV.A-3

H-C-COOH H2C-COOH

77-92-9

1

1

1

1,2,3-Propanetricarboxylic acid, 2-hydroxy{citric acid}

H2C-COOH

II.A-5, IV.A-3

HO-C-COOH H2C-COOH

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1720

11/24/08 1:57:22 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1721

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

58308-53-5

0

1

0

1,2,3-Propanetricarboxylic-1,5- C2 acid, 2-hydroxy-, 14 14 labeled with C {citric acid- C}

3609-96-9

0

1

0

1,2,3-Propanetricarboxylic acid, 2-hydroxy-, dipotassium salt

II.A-5, XX-6

1

0

0

1,2,3-Propanetricarboxylic acid, 2-hydroxy-, monomethyl ester

II.A-5, V-3

18996-35-5

0

1

0

1,2,3-Propanetricarboxylic acid, 2-hydroxy-, monosodium salt

II.A-5, XX-6

866-84-2

0

1

0

1,2,3-Propanetricarboxylic acid, 2-hydroxy-, potassium salt

II.A-5, XX-6

68-04-2

0

1

0

1,2,3-Propanetricarboxylic acid, 2-hydroxy-, sodium salt

II.A-5, XX-6

77-93-0

0

1

0

1,2,3-Propanetricarboxylic acid, 2-hydroxy-, triethyl ester {triethyl citrate}

II.A-5, V-3

56-81-5

1

1

1

1,2,3-Propanetriol

1

1

1

Name (per CA Collective Index)

Chapter Table

Selected structures

14

1,2,3-Propanetriol, labeled with

{glycerol} 14

XXV-29

HOCH2-CHOH-CH2OH

II.A-5

C

XXV-29 14

{glycerol- C} 61892-59-9

1

0

0

1,2,3-Propanetriol, 1-acetate 2-formate

25395-31-7

1

1

1

1,2,3-Propanetriol, diacetate

II.A-5, V-3 {diacetin}

II.A-5, V-3

57-03-4

0

1

0

1,2,3-Propanetriol, 1-(dihydrogen phosphate)

II.A-5

927-20-8

0

1

0

1,2,3-Propanetriol, 1-(dihydrogen phosphate), magnesium salt (1:1)

II.A-5, XX-6

17603-42-8

0

1

0

1,2,3-Propanetriol, 1-(dihydrogen phosphate), sodium salt

II.A-5, XX-6

1335-34-8

0

1

0

1,2,3-Propanetriol, mono(dihydrogen phosphate), potassium salt

II.A-5, XX-6

26446-35-5

1

1

1

1,2,3-Propanetriol, monoacetate

72692-68-3

1

0

0

1,2,3-Propanetriol, monoformate

0

1

0

1,2,3-Propanetriol, phosphatidyl-

1

0

0

1,2,3-Propanetriol, 1-propanoate, (R)-

62244-24-0 102-76-1

{monoacetin}

II.A-5, V-3 II.A-5, V-3 II.A-5 II.A-5, V-3

1

1

1

1,2,3-Propanetriol, triacetate

0

1

0

1,2,3-Propanetriol, tri-9,12octadecadienatepropanoate

{triacetin}

V-3

V-3

139-45-7

1

0

0

1,2,3-Propanetriol, tripropanoate

V-3

555-45-3

0

1

0

1,2,3-Propanetriol, tritetradecanoate

79-09-4

1

1

1

Propanoic acid

590-01-2

0

1

0

Propanoic acid, butyl ester

76578-14-8

0

1

0

Propanoic acid, 2-[4-[(6-chloro-2quinoxalinyl)oxy]phenoxy]-, ethyl ester {Quizalofop-Et®}

{trimyristin}

{propionic acid}

V-3 H3C-CH2-COOH

V-3 XVIII.B-3, XXI-3 C 2H 5 N

Cl

75-98-9

0

1

0

IV.A-3

Propanoic acid, 2,2-dimethyl-

{pivalic acid} {glyceric acid}

473-81-4

1

1

1

Propanoic acid, 2,3-dihydroxy-

6000-40-4

0

1

0

Propanoic acid, 2,3-dihydroxy-, (R)-

82546-67-6

1

0

0

Propanoic acid, 3-(ethoxycarbonyl)-3-(1cyclohexenenyl)-

O

N

(H3C)3ŁC-COOH HOCH2-CHOH-COOH

O

O

O

IV.A-3 II.A-5, IV.A-3 II.A-5, IV.A-3 IV.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1721

11/24/08 1:57:23 PM

1722

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

50-21-5 598-82-3 97-73-4

1

1

1

Propanoic acid, 2-hydroxy-

0

1

0

Propanoic acid, 2-hydroxy-, anhydride

97-64-3

1

1

1

Propanoic acid, 2-hydroxy-, ethyl ester {ethyl lactate}

H3C-CHOH-COO-C2H5

Name (per CA Collective Index) {lactic acid}

Chapter Table

Selected structures H3C-CHOH-COOH

II.A-5, IV.A-3 VII-1 II.A-5, V-3

547-64-8

1

0

0

Propanoic acid, 2-hydroxy-, methyl ester

H3C-CHOH-COO-CH3

16595-31-6

0

1

0

Propanoic acid, 2-hydroxy-, sodium salt

H3C-CHOH-COO-Na

594-61-6

0

1

0

Propanoic acid, 2-hydroxy-2-methyl-

(H3C)2=COH-COOH

820-11-1

0

1

0

Propanoic acid, 2-hydroxy-3-(phosphonooxy)-

79-31-2

1

1

1

Propanoic acid, 2-methyl-

97-89-2

0

1

0

Propanoic acid, 2-methyl-, 3,7-dimethyl-6-octenyl ester

97-62-1

0

1

0

Propanoic acid, 2-methyl-, ethyl ester

V-3

37704-28-2

0

1

0

Propanoic acid, 2-methyl-, 3,5,5-trimethyl-4-(3-oxo1-butenyl)-3-cyclohexen-1-yl ester

V-3

547-63-7

{isobutyric acid}

0

1

0

Propanoic acid, 2-methyl-, methyl ester

0

1

0

Propanoic acid, 2-methyl-, 2-methylbutyl ester

II.A-5, V-3 II.A-5, XX-6 IV.A-3 II.A-5, IV.A-3

(H 3C)2=CH-COOH

IV.A-3 V-3

(H3C)2=CH-COO-CH3

V-3 V-3

0

1

0

Propanoic acid, 2-methyl-, 3-methylbutyl ester

V-3

65416-14-0

0

1

0

Propanoic acid, 2-methyl-, 2-methyl-4-oxo-4Hpyran-3-yl ester

V-3, X-2

103-93-5

0

1

0

Propanoic acid, 2-methyl-, 4-methylphenyl ester {p-tolyl isobutyrate}

109-15-9

0

1

0

Propanoic acid, 2-methyl-, octyl ester

V-3

103-48-0

0

1

0

Propanoic acid, 2-methyl-, phenylethyl ester

V-3

103-28-6

0

1

0

Propanoic acid, 2-methyl-, phenylmethyl ester

V-3

103-59-3

0

1

0

Propanoic acid, 2-methyl-, 3-phenyl-2-propen-1-yl ester

V-3

0

1

0

Propanoic acid, 2-methylbutyl ester

V-3

127-17-3

0

1

0

Propanoic acid, 2-oxo-

617-35-6

1

0

0

Propanoic acid, 2-oxo-, ethyl ester

H3C-CO-COO-C2H5 H3C-CO-COO-CH3

{pyruvic acid}

600-22-6

1

0

0

Propanoic acid, 2-oxo-, methyl ester

3913-50-6

0

1

0

Propanoic acid, 2-oxo-3-(phosphonooxy)-

69806-50-4

0

1

0

Propanoic acid, 2-(4-(5-trifluoromethyl-2pyridyloxy)phenoxy)-, butyl ester {Fluazifop-butyl®}

V-3

H3C-CO-COOH

1

0

0

III-13, V-3 III-13, V-3 III-13, IV.A-3 X-2, XVIII.B-3, XXI-3

F3C

O

N

4272-12-2

III-13, IV.A-5

O

O

O-(CH2)3-CH3

Propanoic acid, 3-(acetyloxy)-

H3C-COO-(CH2)2-COOH

IV.A-3, V-3

503-66-2

1

1

1

Propanoic acid, 3-hydroxy-

HO-(CH2)2-COOH

II.A-5, IV.A-3

4835-90-9

0

1

0

Propanoic acid, 3-hydroxy-,2,2-dimethyl{hydroxypivalic acid}

HOH2C-C(CH3)2-COOH

II.A-5, IV.A-3

1

0

0

Propanoic acid, 3-hydroxyphenyl-

935-13-7 1456-08-2

1

0

0

Propanoic acid, 3-(2-furanyl)-

1

0

0

Propanoic acid, 3-(4-hydroxyphenyl)-, methyl ester-

1

0

0

Propanoic acid, 3-(5-methyl-2-furanyl)-

IV.A-3, IX.A-22 IV.A-3, X-2 V-3, IX.A-22 IV.A-3, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1722

11/24/08 1:57:23 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1723

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke S

T

S T

1

0

0

Propanoic acid, 3-hydroxy-, 2-methylamino-, propyl ester

2553-59-5

0

1

0

Propanoic acid, 3-hydroxy-2-(phosphonooxy)-

1113-60-6

0

1

0

Propanoic acid, 3-hydroxy-2-oxo-

2544-06-1

0

1

0

Propanoic acid, 3-methoxy-

105-68-0

0

1

0

Propanoic acid, 3-methylbutyl ester

CAS No.

Name (per CA Collective Index)

Selected structures

Chapter Table II.A-5, V-3, XII-2 II.A-5, IV.A-3

II.A-5, III-13, IV.A-3 IV.A-3, X-2 V-3

0

1

0

Propanoic acid, 3-(methylnitrosoamino)-

13532-18-8

0

1

0

Propanoic acid, 3-(methylthio)-, methyl ester H3C-(CH2)2-COO-CH3

{NMPA}

H3C-N(NO)-(CH2)2-COOH

IV.A-3, XV-8

103-56-0

0

1

0

Propanoic acid, 3-phenyl-2-propenyl ester {cinnamyl propionate}

0

1

0

Propanoic acid, 4-hydroxyphenyl-

105-38-4

0

1

0

Propanoic acid, ethenyl ester

105-37-3

1

1

1

Propanoic acid, ethyl ester

554-12-1

1

1

1

Propanoic acid, methyl ester

122-63-4

0

1

0

Propanoic acid, phenylmethyl ester {benzyl propionate}

71-23-8

1

1

1

1-Propanol

78-83-1

1

1

1

1-Propanol, 2-methyl-

108-61-2

1

0

0

1-Propanol, 2,2'-oxybis-

II.A-5, X-2 II.A-5, X-2

V-3, XVIII.A-1 V-3 IV.A-3, IX.A-22 H3C-CH2-COO-CH=CH2

{ethyl propionate}

H 3C-CH2-COO-C2H5

V-3

H3C-CH2-COO-CH3

V-3 V-3

H3C-CH2-CH2OH {isobutyl alcohol}

2396-61-4

1

0

0

1-Propanol, 3,3'-oxybis-

67-63-0

1

1

1

2-Propanol

110-98-5

1

0

0

2-Propanol, 1,1'-oxybis-

127-00-4

1

0

0

2-Propanol, 1-chloro-

0

1

0

2-Propanol, 2-(2-ethyl-1,3-dimethylcyclopenten-2yl)-

V-3

(H3C)2=CH-CH2OH

II.A-5 II.A-5

II.A-5 II.A-5, X-2 II.A-5, XVIII.B-3 II.A-5

107-98-2

0

1

0

2-Propanol, 1-methoxy-

75-65-0

1

0

0

2-Propanol, 2-methyl-

II.A-5, X-2

1

0

0

1-Propanone, 1-(dimethylhydroxyphenyl)-

III-13, IX.A-22

1

0

0

1-Propanone, 1-(3,5-dimethyl-4-hydroxyphenyl)-

III-13, IX.A-22

1

0

0

1-Propanone, 1-(2-furanyl)-

1

0

0

1-Propanone, 1-(3-furanyl)-

1

0

0

1-Propanone, 1-(2-hydroxyphenyl)-

III-13, IX.A-22

1

0

0

1-Propanone, 1-(3-hydroxyphenyl)-

III-13, IX.A-22

1

0

0

1-Propanone, 1-(2-methylphenyl)-

{tert-butanol}

(H3C)3ŁC-OH

II.A-5

III-13, X-2 III-13, X-2

III-13

51772-30-6

1

0

0

1-Propanone, 1-(3-methylphenyl)-

93-55-0

1

1

1

1-Propanone, 1-phenyl-

1

0

0

1-Propanone, 1-phenyl-3-hydroxy-

1

0

0

1-Propanone, 1-(2-pyridinyl)-

III-13, XVII.B-2

1

0

0

1-Propanone, 1-(2-pyridinyl)-2-methyl-

III-13, XVII.B-2

1

1

1

1-Propanone, 1-(3-pyridinyl)- {pyridyl ethyl ketone}

III-13, XVII.B-2

1

0

0

1-Propanone, 1-(4-methyl-2-pyridinyl)-

III-13, XVII.B-2

1

0

0

1-Propanone, 1-(4-pyridinyl)-

III-13, XVII.B-2

{propiophenone}

III-13 C6H5-CO-CH2-CH3

III-13 II.A-5, III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1723

11/24/08 1:57:24 PM

1724

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1

1

1

1-Propanone, 1-(1H-pyrrol-2-yl)-

III-13, XVII.A-4

80933-75-1

0

1

0

1-Propanone, 1-[2-(3,4,5,6-tetrahydropyridinyl)]-

III-13, XVII.B-2

67-64-1

1

1

1

2-Propanone

592-20-1

1

0

0

2-Propanone, 1-(acetyloxy)-

{acetone}

H3C-CO-CH3

III-13

H3C-CO-CH2-OOC-CH3

298-08-8

1

0

0

2-Propanone, 1-amino-

H3C-CO-CH2-NH2

78-95-5

1

0

0

2-Propanone, 1-chloro-

H3C-CO-CH2-Cl

10258-70-5

0

1

0

2-Propanone, 1-(formyloxy)-

116-09-6

1

1

1

2-Propanone, 1-hydroxy-

1

0

0

2-Propanone, 1-hydroxy-, 2-furoyl ester

III-13, XII-2 III-13, XVIII.B-3

H3C-CO-CH2-OOC-H {acetol}

H3C-CO-CH2-OH

0

1

0

2-Propanone, 1-hydroxy-3-(phosphonooxy)-

122-84-9

0

1

0

2-Propanone, 1-(4-methoxyphenyl)-

496-49-1

0

1

0

2-Propanone, 1-(1-methyl-2-pyrrolidinyl)-

103-79-7

1

1

1

2-Propanone, 1-phenyl-

20194-70-1

1

1

1

2-Propanone, 1-(tetrahydro-4-methyl-2H-pyran-2yl)-

0

1

0

2-Propanone, 1-[tetrahydro-(2-methyl-5methylethyl)-2-furanyl]-

III-13, V-3 II.A-5, III-13 III-13, V-3, X-2

COOCH2-CO-CH3

O

57-04-5

III-13, V-3

II.A-5, III-13 III-13 III-13, XVII.A-4 III-13 III-13, X-2 H3C

O CH3 O

III-13, X-2

CH3

CH3

38713-24-5

0

1

0

2-Propanone, 1-[tetrahydro-3-(1-methylethyl)-2furanyl]-, trans-

III-13, X-2

H3C

H3C

CH3 O O

39815-69-5

0

1

0

2-Propanone, 1-[tetrahydro-4-(1-methylethyl)-2furanyl]-

39815-68-4

0

1

0

2-Propanone, 1-[tetrahydro-6-methyl-3-(1methylethyl)-2H-pyran-2-yl]- {2 isomers reported}

III-13, X-2

CH3 H3C

6975-60-6

13100-05-5 5211-62-1

III-13, X-2

CH3

O

CH2-CO-CH3

0

1

0

2-Propanone, 1-[tetrahydro-6-methyl-4-(1methylethyl)-2H-pyran-2-yl]-

III-13, X-2

1

1

1

2-Propanone, 1-(2-furanyl)-

III-13, X-2

0

1

0

2-Propanone, 1-[2-hydroxy-5-(1-methylethyl)-2methyl-1-cyclopentyl]-

1

0

0

2-Propanone, 1-(2-hydroxyphenyl)-

III-13, IX.A-22

II.A-5, III-13

1

0

0

2-Propanone, 1-(2-methoxyphenyl)-

III-13

1

0

0

2-Propanone, 1-(2-tetrahydrofuranyl)-

III-13

1

1

1

2-Propanone, 1-(3-hydroxyphenyl)-

18826-61-4

1

0

0

2-Propanone, 1-(3-methylphenyl)-

6302-03-0

1

1

1

2-Propanone, 1-(3-pyridinyl)-

III-13, IX.A-22 III-13 III-13, XVII.B-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1724

11/24/08 1:57:24 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1725

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

96-26-4

S

T

S T

0

1

0

2-Propanone, 1-(1,5-dimethyl-6,8dioxabicyclo[3.2.1)oct-7-yl)-

1

0

0

2-Propanone, 1,3-dihydroxy-

Name (per CA Collective Index)

Selected structures

Chapter Table III-13, X-2 II.A-5, III-13

0

1

0

2-Propanone, 1-(3,4-dihydro-6-methylpyran-2-yl)-

19037-58-2

1

0

0

2-Propanone, 1-(3,5-dimethoxy-4-hydroxyphenyl)-

16695-72-0

1

1

1

2-Propanone, 1-(3,5,5-trimethyl-2-cyclohexen-1ylidene)-, (E)-

III-13

16695-73-1

1

1

1

2-Propanone, 1-(3,5,5-trimethyl-2-cyclohexen-1ylidene)-, (Z)-

III-13

2503-46-0

1

1

1

2-Propanone, 1-(4-hydroxy-3-methoxyphenyl)-

III-13, IX.A-22

770-39-8

1

0

0

2-Propanone, 1-(4-hydroxyphenyl)-

III-13, IX.A-22 III-13, XVII.B-2

6304-16-1

1

0

0

2-Propanone, 1-(4-pyridinyl)-

13678-74-5

1

1

1

2-Propanone, 1-(5-methyl-2-furanyl)-

III-13, X-2 III-13, IX.A-22, X-2

III-13, X-2

50672-03-2

1

0

0

2-Propanone, 1-[5-(hydroxymethyl)-2-furanyl]-

107-02-8

1

1

1

2-Propenal

636-38-4

0

1

0

2-Propenal, 2,3-dihydroxy-

78-85-3

1

1

1

2-Propenal, 2-methyl-

31704-79-7

1

0

0

2-Propenal, 2-methyl-3-(5-methyl-2-furanyl)-

{acrolein}

II.A-5, III-13, X-2 H2C=CH-CH=O

III-12 II.A-5, III-12

{methacrolein}

H2C=C(CH3)-CH=O

III-12 III-12, X-2

101-39-3

0

1

0

2-Propenal, 2-methyl-3-phenyl-

79407-66-2

0

1

0

2-Propenal, 3-(2,4-dihydroxyphenyl)-

III-12

874-66-8

1

0

0

2-Propenal, 3-(2-furanyl)-2-methyl-

104-55-2

1

1

1

2-Propenal, 3-phenyl-

{cinnamaldehyde}

III-12

14371-10-9

0

1

0

2-Propenal, 3-phenyl-, (E){trans-cinnamaldehyde}

III-12

122-40-7

0

1

0

2-Propenal, 3-phenyl-, Į-pentyl-

III-12

79-06-1

1

0

0

2-Propenamide

79-39-0

1

0

0

2-Propenamide, 2-methyl-

1202-41-1

0

1

0

2-Propenamide, 3-(3,4-dihydroxyphenyl)-

59001-33-1

0

1

0

2-Propenamide, 3-(3,4-dihydroxyphenyl)-N-[3-[[4[[3-(3,4-dihydroxyphenyl)-1-oxo-2propenyl]amino]butyl]amino]propyl]{dicaffeoylspermidine}

59576-98-6

0

1

0

2-Propenamide, 3-(4-hydroxyphenyl)-

621-79-4

1

0

0

2-Propenamide, 3-phenyl-

61892-63-5

1

0

0

2-Propenamide, N-(1-oxopropyl)-

29554-26-5

0

1

0

2-Propenamide, N-(4-aminobutyl)-3-(3,4dihydroxyphenyl){caffeoylputrescine}

IX.A-22, XII-2, XIII-1

501-13-3

0

1

0

2-Propenamide, N-(4-aminobutyl)-3-(4-hydroxy-3methoxyphenyl)-

IX.A-22, XII-2, XIII-1

34136-53-3

0

1

0

2-Propenamide, N-(4-aminobutyl)-3-(4hydroxyphenyl)-

IX.A-22, XII-2, XIII-1

42369-86-8

0

1

0

2-Propenamide, N,N'-1,4-butanediylbis[3-(4hydroxy-3-methoxyphenyl)-

III-12, IX.A-22 III-12, X-2

{acrylamide}

H2C=CH-CONH2

XIII-1

{methacrylamide}

XIII-1 XIII-1 IX.A-22, XII-2, XIII-1

IX.A-22, XIII-1 C6H5-CH=CH-CONH2

107-11-9

1

0

0

2-Propen-1-amine

2878-14-0

1

0

0

2-Propen-1-amine, 2-methyl-

{allyl amine; acrylamine}

XIII-1 XIII-1

X-2, IX.A-22, XIII-1 H2C=CH-CH2-NH2

XII-2

H2C=C(CH3)-CH2-NH2

XII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1725

11/24/08 1:57:25 PM

1726

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

115-07-1

1

0

0

1-Propene

115-11-7

1

0

0

1-Propene, 2-methyl-

26952-23-8

0

1

0

1-Propene, 1,2-dichloro-

{Telone®}

542-75-6

0

1

0

1-Propene, 1,3-dichloro-

{1,3-D}

2157-98-4

0

1

0

1-Propene, 1-methyl-3-(methylamino)-3-oxo-, dimethyl phosphate {Monocrotophos®}

Name (per CA Collective Index)

Chapter Table

Selected structures

{isobutylene}

H3C-CH=CH2

I.B-1

H3C-C(CH3)=CH2

I.B-1 XVIII.B-3, XXI-3 XVIII.B-3, XXI-3 V-3, XXI-3

OCH3 H3C-NH-CO-CH=C(CH3)-P=O OCH3

557-31-3

1

1

1

1-Propene, 3-ethoxy-

10152-76-8

1

0

0

1-Propene, 3-(methylthio)-

{allyl ethyl ether}

X-2

27817-67-0

1

0

0

1-Propene, 3-(propylthio)-

XVIII.A-1

592-88-1

1

0

0

1-Propene, 3,3'-thiobis-

XVIII.A-1

XVIII.A-1

107-13-1

1

0

0

2-Propenenitrile

126-98-7

1

0

0

2-Propenenitrile, 2-methyl-

{methacrylonitrile}

{acrylonitrile}

H2C=CH-CN

XI-2

H 2C=C(CH3)-CN

XI-2

4360-47-8

1

0

0

2-Propenenitrile, 3-phenyl-

{cinnamonitrile}

54356-27-3

1

0

0

2-Propenenitrile, 3-(3-pyridinyl)-, (E)-

XI-2, XVII.B-2

54356-28-4

1

0

0

2-Propenenitrile, 3-(3-pyridinyl)-, (Z)-

XI-2, XVII.B-2

870-23-5

1

0

0

2-Propene-1-thiol

499-12-7

1

1

1

1-Propene-1,2,3-tricarboxylic acid {aconitic acid}

79-10-7

1

0

0

2-Propenoic acid

138-08-9

0

1

0

2-Propenoic acid, 2-(phosphonooxy)-

IV.A-3 IV.A-3

XI-2

XVIII.A-1 {acrylic acid}

79-41-4

1

0

0

2-Propenoic acid, 2-methyl-

80-62-6

0

1

0

2-Propenoic acid, 2-methyl-, methyl ester

31082-90-3

1

0

0

2-Propenoic acid, 3-(2,3-dihydroxyphenyl)-

331-39-5

1

1

1

2-Propenoic acid, 3-(3,4-dihydroxyphenyl){caffeic acid}

IV.A-3 H2C=CH-COOH

IV.A-3

{methacrylic acid}

V.A-3 IV.A-3, IX.A-22 IV.A-3, IX.A-22, XXI-3 HO

COOH

HO

501-16-6

1

1

1

2-Propenoic acid, 3-(3,4-dihydroxyphenyl)-, (E){trans-caffeic acid}

IV.A-3, IX.A-22

4361-87-9

1

1

1

2-Propenoic acid, 3-(3,4-dihydroxyphenyl)-, (Z){cis-caffeic acid}

IV.A-3, IX.A-22

58994-15-3

0

1

0

2-Propenoic acid, 3-(3,4-dihydroxyphenyl)-, monoamide with N-(3-aminopropyl)-1,4butanediamine {caffeoylspermidine}

IX.A-22, XIII-1

2316-26-9

0

1

0

2-Propenoic acid, 3-(3,4-dimethoxyphenyl)-

17093-82-2

0

1

0

2-Propenoic acid, 3-[4-(E-D-glucopyranosyloxy)-3hydroxyphenyl]{1-O-caffeoylglucose}

IV.A-3, X-2 IV.A-3, IX.A-22 HO

COOH

Glucose-O

14364-12-6

0

1

0

2-Propenoic acid, 3-[4-(E-D-glucopyranosyloxy)-3methoxyphenyl]{1-O-feruloylglucose}

II.A-5, IV.A-3, X-2 H3CO

COOH

Glucose-O

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1726

11/24/08 1:57:25 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1727

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

14364-05-7

0

1

0

2-Propenoic acid, 3-[4-(E-Dglucopyranosyloxy)phenyl]-

7362-37-0

1

1

1

2-Propenoic acid, 3-(3,5-dimethoxy-4hydroxyphenyl)-, (E){trans-sinapic acid}

Name (per CA Collective Index)

Chapter Table

Selected structures

II.A-5, IV.A-3 IV.A-3, IX.A-22, X-2 H3CO

COOH

HO OCH3

7361-90-2

1

1

1

2-Propenoic acid, 3-(3,5-dimethoxy-4hydroxyphenyl)-, (Z){cis-sinapic acid}

IV.A-3, IX.A-22, X-2

537-73-5

1

0

0

2-Propenoic acid, 3-(3-hydroxy-4-methoxyphenyl)-

IV.A-3, IX.A-22, X-2

25522-33-2

1

0

0

2-Propenoic acid, 3-(3-hydroxy-4-methoxyphenyl)-, (E)-

IV.A-3, IX.A-22, X-2

0

1

0

2-Propenoic acid, 3-(4,5-dihydroxy-3methoxyphenyl){5-hydroxyferulic acid}

IV.A-3, IX.A-22, X-2

1

1

1

2-Propenoic acid, 3-(4-hydroxy-3-methoxyphenyl)-, (E){trans-ferulic acid}

537-98-4

IV.A-3, X-2, IX.A-22, XXI-3 H3CO

COOH

HO

1014-83-1

1

1

1

2-Propenoic acid, 3-(4-hydroxy-3-methoxyphenyl)-, (Z){cis-ferulic acid}

2309-07-1

1

0

0

2-Propenoic acid, 3-(4-hydroxy-3-methoxyphenyl)-, methyl ester {ferulic acid, methyl ester}

25429-38-3

1

0

0

2-Propenoic acid, 3-(hydroxyphenyl)-

539-47-9

1

0

0

2-Propenoic acid, 3-(2-furanyl)-

583-17-5 614-60-8

1

0

0

2-Propenoic acid, 3-(2-hydroxyphenyl){o-coumaric acid}

IV.A-3, IX.A-22, X-2, XXI-3 V-3, IX.A-22, X-2 IV.A-3, IX.A-22 IV.A-3, X-2 IV.A-3, IX.A-22

588-30-7

0

1

0

2-Propenoic acid, 3-(3-hydroxyphenyl)-

IV.A-3, IX.A-22

14755-02-3

0

1

0

2-Propenoic acid, 3-(3-hydroxyphenyl)-, (E)-

IV.A-3, IX.A-22

7400-08-0

1

1

1

2-Propenoic acid, 3-(4-hydroxyphenyl){coumaric acid}

IV.A-3, IX.A-22, XXI-3

501-98-4

1

1

1

2-Propenoic acid, 3-(4-hydroxyphenyl)-, (E){trans-coumaric acid}

IV.A-3, IX.A-22

4501-31-9

1

1

1

2-Propenoic acid, 3-(4-hydroxyphenyl)-, (Z){cis-coumaric acid}

IV.A-3, IX.A-22

14779-25-0

1

0

0

2-Propenoic acid, 3-(5-methyl-2-furanyl)-

IV.A-3, X-2

17570-26-2

1

1

1

2-Propenoic acid, 3-(3-methoxyphenyl)-, (E)-

IV.A-3, X-2

621-82-9

1

1

1

2-Propenoic acid, 3-phenyl-

140-10-3

1

1

1

2-Propenoic acid, 3-phenyl-, (E){trans-cinnamic acid}

{cinnamic acid}

C6H5-CH=CH-COOH

IV.A-3

IV.A-3

102-94-3

1

1

1

2-Propenoic acid, 3-phenyl-, (Z){cis-cinnamic acid}

IV.A-3

47018-25-7

1

0

0

2-Propenoic acid, 3-phenyl-, 2-phenylethenyl ester

V.A-3

122-69-0

1

1

1

2-Propenoic acid, 3-phenyl-, 3-phenyl-2-propenyl ester {cinnamyl cinnamate}

V.A-3

103-36-6

1

1

1

2-Propenoic acid, 3-phenyl-, ethyl ester {ethyl cinnamate}

V.A-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1727

11/24/08 1:57:26 PM

1728

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

103-26-4

1

1

1

2-Propenoic acid, 3-phenyl-, methyl ester {methyl cinnamate}

7779-65-9

1

1

1

2-Propenoic acid, 3-phenyl-, 3-methylbutyl ester

V.A-3

Name (per CA Collective Index)

Selected structures C6H5-CH=CH-COO-CH3

Chapter Table V.A-3

122-67-8

0

1

0

2-Propenoic acid, 3-phenyl-, 2-methylpropyl ester

V.A-3

103-53-7

0

1

0

2-Propenoic acid, 3-phenyl-, phenylethyl ester;

V.A-3

103-41-3

1

1

1

2-Propenoic acid, 3-phenyl-, phenylmethyl ester {benzyl cinnamate}

V.A-3

122-68-9

0

1

0

2-Propenoic acid, 3-phenyl-, 3-phenylpropyl ester {3-phenylpropyl cinnamate}

V.A-3

96-33-3

1

1

1

2-Propenoic acid, methyl ester

90-50-6

0

1

0

2-Propenoic acid, 3-(3,4,5-trimethoxyphenyl)-

107-18-6

1

1

1

2-Propen-1-ol

104-54-1

1

1

1

2-Propen-1-ol, 3-phenyl-

H2C=CH-COO-CH3 {allyl alcohol}

4407-36-7

0

1

0

2-Propen-1-ol, 3-phenyl-, (E)-

0

1

0

2-Propen-1-ol, 3-phenyl-, acetate, (E)-

2983-65-5

1

0

0

2-Propen-1-one, 1-(4-hydroxy-3-methoxyphenyl)-

94-41-7

1

0

0

2-Propen-1-one, 1,3-diphenyl-

145917-24-4

0

1

0

2-Propen-1-one, 1,3-di-3-pyridinyl-, (E)-

10152-76-8

H2C=CH-CH2OH

{cinnamyl alcohol}

21040-45-9

V.A-3 IV.A-3 II.A-5, XXI-3 II.A-5 II.A-5 V.A-3 III-13, IX.A-22, X-2

{chalcone}

III-13 III-13, XVII.B-2

1

0

0

1-Propenylmethyl sulfide

H3C-S-CH2-CH=CH2

1

0

0

Propoxyl radical

OC3H5

1

0

0

1-Propyne

H3C-CŁCH

0

1

0

Protease

XXII-2

0

1

0

Protease, serine

XXII-2

0

1

0

Protease, sulfhydryl

XXII-2

144419-45-4

0

1

0

Protein (Arabidopsis thaliana clone G9.1 gene A9 11.6-kilodalton reduced)

XXII-2

132966-19-9

0

1

0

Protein (tobacco 27.4-kilodalton RNA-binding precursor reduced)

XXII-2

132966-16-6

0

1

0

Protein (tobacco 27.4-kilodalton RNA-binding)

XXII-2

137801-72-0

0

1

0

Protein (tobacco chloroplast clone pTB24 gene psbK)

XXII-2

139874-83-2

0

1

0

Protein (tobacco clone .lambda.18C gene RB7 reduced)

XXII-2

139874-82-1

0

1

0

Protein (tobacco clone .lambda.5A gene RB7 reduced)

XXII-2

162572-20-5

0

1

0

Protein (tobacco clone lambda T-FLO 4 gene NFL2)

XXII-2

147445-75-8

0

1

0

Protein (tobacco clone pMG15 extensin-like precursor reduced)

XXII-2

146591-93-7

0

1

0

Protein (tobacco clone PRP3g12 gene PRP3 pistilspecific proline-rich precursor)

XXII-2

162572-19-2

0

1

0

Protein (tobacco clone pTGF220 gene NFL1)

XXII-2

145895-79-0

0

1

0

Protein (tobacco flower-associated reduced)

XXII-2

155077-18-2

0

1

0

Protein (tobacco gene MST1 hydrogen ionmonosaccharide-cotransporting reduced)

XXII-2

160936-45-8

0

1

0

Protein (tobacco leaf curl virus coat)

XXII-2

74-99-7

XVIII.A-1 XXVII-1 I.B-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1728

11/24/08 1:57:26 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1729

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

155663-14-2

0

1

0

Protein CPB 20 (tobacco clone cpb20-44 antifungal reduced)

XXII-2

155663-12-0

0

1

0

Protein CPB 20 (tobacco clone cpb20-52 antifungal reduced)

XXII-2

155663-10-8

0

1

0

Protein CPB 20, prepro- (tobacco clone cpb20-52 antifungal reduced)

XXII-2

155663-13-1

0

1

0

Protein CPB 20, pro- (tobacco clone cpb20-44 antifungal reduced)

XXII-2

155663-11-9

0

1

0

Protein CPB 20, pro- (tobacco clone cpb20-52 antifungal reduced)

XXII-2

144997-83-1

0

1

0

Protein D 2 (Nicotiana sylvestris clone yaDC12/yaDC17 gene psaDa precursor)

XXII-2

144997-84-2

0

1

0

Protein D 2 (Nicotiana sylvestris clone yaDC12/yaDC17 gene psaDa)

XXII-2

146150-25-6

0

1

0

Protein formation initiation factor eIF 4A (Nicotiana plumbaginifolia clone NeIF-4A2 isoform reduced)

XXII-2

146150-27-8

0

1

0

Protein formation initiation factor eIF 4A (Nicotiana plumbaginifolia clone NeIF-4A3 isoform reduced)

XXII-2

162572-22-7

0

1

0

Protein formation initiation factor eIF 4A (Nicotiana tabacum clone NeIF-4A9)

XXII-2

162572-23-8

0

1

0

Protein formation initiation factor eIF 4A (Nicotiana tabacum clone NeIF-4A11)

XXII-2

162572-24-9

0

1

0

Protein formation initiation factor eIF 4A (Nicotiana tabacum clone NeIF-4A7)

XXII-2

162572-25-0

0

1

0

Protein formation initiation factor eIF 4A (Nicotiana tabacum clone NeIF-4A15)

XXII-2

162572-26-1

0

1

0

Protein formation initiation factor eIF 4A (Nicotiana tabacum clone NeIF-4A6)

XXII-2

162572-27-2

0

1

0

Protein formation initiation factor eIF 4A (Nicotiana tabacum clone NeIF-4A13)

XXII-2

162572-28-3

0

1

0

Protein formation initiation factor eIF 4A (Nicotiana tabacum clone NeIF-4A14)

XXII-2

143514-66-3

0

1

0

Protein formation initiation factor eIF 5A (Nicotiana plumbaginifolia clone NeIF-5A1 isoform C-terminal fragment reduced)

XXII-2

143514-67-4

0

1

0

Protein formation initiation factor eIF 5A (Nicotiana plumbaginifolia clone NeIF-5A2 isoform reduced)

XXII-2

143514-68-5

0

1

0

Protein formation initiation factor eIF 5A (Nicotiana tabacum samsun clone NeIF-5A3 isoform reduced)

XXII-2

152745-97-6

0

1

0

Protein L 17 (tobacco clone TSC81 ribosome reduced)

XXII-2

142978-88-9

0

1

0

Protein L 27 (tobacco chloroplast clone L27-1 ribosome precursor reduced)

XXII-2

142978-89-0

0

1

0

Protein L 27 (tobacco chloroplast clone L27-1 ribosome reduced)

XXII-2

160082-04-2

0

1

0

Protein LTP (tobacco)

XXII-2

143513-70-6

0

1

0

Protein OEE 2 (tobacco strain NK326 precursor reduced)

XXII-2

9001-92-7

0

1

0

Proteinase

XXII-2

Name (per CA Collective Index)

Selected structures

Chapter Table

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1729

11/24/08 1:57:27 PM

1730

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

37205-61-1

0

1

0

Proteinase inhibitor

XXII-2

145090-32-0

0

1

0

Proteinase inhibitor, PI-1

XXII-2

150474-41-2

0

1

0

Proteinase inhibitor, prepro-TIMPa (Nicotiana tabacum samsun reduced)

XXII-2

150474-40-1

0

1

0

Proteinase inhibitor, prepro-TIMPb (Nicotiana tabacum samsun reduced)

XXII-2

150474-44-5

0

1

0

Proteinase inhibitor, pro-TIMPa (Nicotiana tabacum samsun reduced)

XXII-2

150474-42-3

0

1

0

Proteinase inhibitor, pro-TIMPb (Nicotiana tabacum samsun reduced)

XXII-2

150474-45-6

0

1

0

Proteinase inhibitor, TIMPa (Nicotiana tabacum samsun reduced)

XXII-2

150474-43-4

0

1

0

Proteinase inhibitor, TIMPb (Nicotiana tabacum samsun reduced)

XXII-2

551-68-8

0

1

0

D-Psicose

73-24-5

0

1

0

1H-Purin-6-amine

HOCH2-CO-(CHOH)3-CH2OH III-13, II.A-5 {adenine}

XVII.E-8

NH2 N

N

N H

N

525-79-1

0

1

0

1H-Purin-6-amine, N-(2-furanylmethyl)-

XVII.E-8

2365-40-4

0

1

0

1H-Purin-6-amine, N-(3-methyl-2-butenyl)-

XVII.E-8

1214-39-7

0

1

0

1H-Purin-6-amine, N-(phenylmethyl)-

XVII.E-8

56159-42-3

0

1

0

7H-Purin-6-amine, 7-E-D-glucopyranosyl-N(phenylmethyl)-

38477-23-5

0

1

0

7H-Purin-6-amine, 7-D-glucofuranosyl-N(phenylmethyl)-

54538-20-4

0

1

0

7H-Purin-6-amine, 7-D-glucosyl-N-(phenylmethyl)-

20-73-0

0

1

0

1H-Purine

II.A-5, XVII.E-8 II.A-5, XVII.E-8 II.A-5, XVII.E-8 N

N

N

69-89-6

0

1

0

1H-Purine-2,6-dione, 3,7-dihydro-

83-67-0

1

1

1

1H-Purine-2,6-dione, 3,7-dihydro-3,7-dimethyl{theobromine}

XIV-1, XVII.E-8 N 7

1

0

0

1H-Purine-2,6-dione, 3,9-dihydro-1,9-dimethyl-

58-08-2

1

1

1

1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl{caffeine}

4 5

6

O

N

6H-Purine-2,6-dione, 1,7-dihydro-

4 5

{xanthine}

0

6H-Purine-2,6-dione, 1,7-dihydro-, C3-alkyl-

2

N CH3

XIV-1, XVII.E-8

O

O

0

6

O

N

HN

1

XIV-1, XVII.E-8 O

N

3

CH3

0

NH

XIV-1, XVII.E-8

7

1

2

CH3

N

0

O

N

3

CH3

33073-01-7

XIV-1, XVII.E-8

CH3

N

69-89-6

XVII.E-6

H N

N H

N H

XIV-1, XVII.E-8

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1730

11/24/08 1:57:27 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1731

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

73-40-5

0

1

0

Name (per CA Collective Index)

Selected structures

6H-Purin-6-one, 2-amino-1,7-dihydro- {guanine}

Chapter Table

XII-2, XVII.C-1, XVII.E-8 O N

HN H2N

68-94-0

0

1

0

6H-Purin-6-one, 1,7-dihydro-

N H

N

{hypoxanthine}

XII-2, XVII.C-1, XVII.E-8 O N

HN

N H

25512-65-6

1

1

1

2H-Pyran, dihydro-

110-87-2

1

0

0

2H-Pyran, 3,4-dihydro-

X-2 X-2

1

6

O

2 3

5 4

10141-72-7

0

1

0

2H-Pyran, 2-methyltetrahydro-

142-68-7

1

1

1

2H-Pyran, tetrahydro-

X-2 X-2

1

6

O

2 3

5 4

16409-43-1

0

1

0

Pyran, tetrahydro-4-methyl-2-(2-methylpropen-1-yl){rose oxide}

100-73-2

1

1

1

2H-Pyran-2-carboxaldehyde, 3,4-dihydro{acrolein dimer}

70898-35-0

1

0

0

2H-Pyran-2-carboxaldehyde, 3,4-dihydro-6-hydroxy3-oxo-

112468-46-9

1

0

0

2H-Pyran-2,5(6H)-dione

1

0

0

2H-Pyran-4-methanol, 3,4-dihydro-2-hydroxy-

X-2 III-12, X-2 II.A-5, III-12, III-13, X-2 III-13, VI-3 1

6 5

O

OH

II.A-5, X-2

2 3

4

CH2OH

61892-96-4

1

0

0

2H-Pyran-6-methanol, 3,4-dihydro-3-hydroxy-

II.A-5, X-2 II.A-5, X-2

19752-84-2

1

0

0

2H-Pyran-3-ol, tetrahydro-

121198-47-8

1

0

0

Pyranone, dimethyl-

504-31-4

1

0

0

2H-Pyran-2-one

III-13, X-2 6

O

O 2

VI-3

3

5 4

1

0

0

2H-Pyran-2-one, 6-chloro-

VI-3, XVIII.B-3

0

1

0

2H-Pyran-2-one, 5,6-dihydro-

VI-3

1

0

0

2H-Pyran-2-one, 5,6-dihydro-4,5-dimethyl-

VI-3

1

0

0

2H-Pyran-2-one, 4,5-dihydro-3-hydroxy-

VI-3

55100-07-7

0

1

0

2H-Pyran-2-one, 5,6-dihydro-4-hydroxy-

II.A-5, VI-3

54657-94-2

1

0

0

2H-Pyran-2-one, 3,4-dihydro-5-methyl-

VI-3

2381-87-5

1

1

1

2H-Pyran-2-one, 5,6-dihydro-4-methyl-

VI-3

21722-33-8

1

1

1

2H-Pyran-2-one, 5,6-dihydro-4-(1-methylethyl)-

VI-3

6400-69-4

1

0

0

2H-Pyran-2-one, 5,6-dihydro-6-propyl-

VI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1731

11/24/08 1:57:28 PM

1732

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

73692-69-0

S

T

S T

1

0

0

2H-Pyran-2-one, hydroxyethyl-

II.A-5, VI-3

1

0

0

2H-Pyran-2-one, hydroxy-methyl-

II.A-5,VI-3

1

1

1

2H-Pyran-2-one, 3-hydroxy-

II.A-5,VI-3

0

1

0

2H-Pyran-2-one, 3-hydroxy-6-methyl-

II.A-5, VI-3

Name (per CA Collective Index)

Selected structures

Chapter Table

1

1

1

2H-Pyran-2-one, 4-(1-methylethyl)-

VI-3

27593-23-3

0

1

0

2H-Pyran-2-one, 6-pentyl-

VI-3

542-28-9

1

1

1

2H-Pyran-2-one, tetrahydro-

{6-amyl-Į-pyrone}

VI-3 {į-valerolactone}

1 5058-01-5

0

0

2H-Pyran-2-one, tetrahydro-3,4-epoxy-5-hydroxy-

II.A-5, VI-3, X-2

1

0

0

2H-Pyran-2-one, tetrahydro-3-hydroxy-

1

0

0

2H-Pyran-2-one, tetrahydro-methoxy-

II.A-5, VI-3

1

0

0

2H-Pyran-2-one, tetrahydro-methyl-

32821-70-8

0

1

0

2H-Pyran-2-one, tetrahydro-3-(1-methylethyl)-

VI-3

78094-66-3

1

0

0

2H-Pyran-2-one, tetrahydro-4,5-dimethyl-, cis-(±)-

VI-3

VI-3, X-2 VI-3

1

1

1

2H-Pyran-2-one, tetrahydro-4,6-dimethyl-

VI-3

710-04-3

0

1

0

2H-Pyran-2-one, tetrahydro-6-hexyl{G-undecalactone}

VI-3

61892-56-6

1

0

0

2H-Pyran-2-one, tetrahydro-4-hydroxy-

II.A-5, VI-3 II.A-5, VI-3

503-48-0

0

1

0

2H-Pyran-2-one, tetrahydro-4-hydroxy-4-methyl-

1121-84-2

1

1

1

2H-Pyran-2-one, tetrahydro-4-methyl-

VI-3

96168-15-9

1

0

0

2H-Pyran-2-one, tetrahydro-4-methyl-6-(3,7,11trimethyldodecyl)-

VI-3

56947-55-8

1

1

1

2H-Pyran-2-one, tetrahydro-4-(1-methylethyl)-

VI-3

21754-22-3

0

1

0

2H-Pyran-2-one, tetrahydro-4-(1-methylethyl)-, (±)-

VI-3

10413-18-0 24405-16-1

0

1

0

2H-Pyran-2-one, tetrahydro-5,6-dimethyl-

VI-3

33691-73-5

1

0

0

2H-Pyran-2-one, tetrahydro-5-hydroxy-

3301-94-8

0

1

0

2H-Pyran-2-one, tetrahydro-6-butyl{G-nonalactone}

2610-95-9

0

1

0

2H-Pyran-2-one, tetrahydro-6,6-dimethyl-

VI-3

713-95-1

0

1

0

2H-Pyran-2-one, tetrahydro-6-heptyl{G-dodecalactone}

VI-3

90-80-2

1

0

0

2H-Pyran-2-one, tetrahydro-6-hydroxymethyl, 3,4,5trihydroxygluconic acid, G-lactone}

823-22-3

1

1

1

2H-Pyran-2-one, tetrahydro-6-methyl-

II.A-5, VI-3 VI-3

II.A-5, VI-3 VI-3

{G-hexalactone; į -caprolactone} 21722-34-9

0

1

0

2H-Pyran-2-one, tetrahydro-6-methyl-3-(1methylethyl){2 isomers indicated}

VI-3

0

1

0

2H-Pyran-2-one, tetrahydro-6-methyl-4-(1methylethyl)-

VI-3

2721-22-4

0

1

0

2H-Pyran-2-one, tetrahydro-6-nonyl{tetradecalactone}

VI-3

705-86-2

0

1

0

2H-Pyran-2-one, tetrahydro-6-pentyl{G-decalactone}

VI-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1732

11/24/08 1:57:28 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1733

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

698-76-0

0

1

0

2H-Pyran-2-one, tetrahydro-6-propyl{G-octalactone}

28743-04-6

1

0

0

2H-Pyran-3(4H)-one

Name (per CA Collective Index)

Selected structures

VI-3 6

O

III-13, X-2

2

5

O

4

1 121197-11-3

0

0

2H-Pyran-3(4H)-one, dihydro-

III-13, X-2

1

0

0

2H-Pyran-3(4H)-one, dihydro-4-(hydroxymethyl)-

1

0

0

2H-Pyran-3(4H)-one, dihydro-6-methoxy-

43152-89-2

1

0

0

2H-Pyran-3(4H)-one, dihydro-6-methyl-

98166-23-5

1

0

0

2H-Pyran-3(6H)-one

II.A-5, III-13, X-2 III-13, X-2 III-13, X-2 6

O

III-13, X-2

2

5

O

4

108-97-4

1

0

0

Chapter Table

4H-Pyran-4-one

6 5

O

III-13, X-2

2 3

4 O

84302-42-1

1

0

0

4H-Pyran-4-one, 2,3-dihydro-

28564-83-2

1

1

1

4H-Pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6methyl-

III-13, X-2 H3C

O

6 1 5

HO

4

II.A-5, III-13, X-2

2

3 OH

O

6380-97-8

1

1

1

4H-Pyran-4-one, 2,3-dihydro-5-hydroxy-2(hydroxymethyl)-

II.A-5, III-13, X-2

38877-21-3

1

0

0

4H-Pyran-4-one, 2,3-dihydro-5-hydroxy-6-methyl-

II.A-5, III-13, X-2

131524-09-9

1

0

0

4H-Pyran-4-one, 2,6-diethyl-3-hydroxy-

II.A-5, III-13, X-2

1004-36-0

1

0

0

4H-Pyran-4-one, 2,6-dimethyl-

III-13, X-2

4940-17-4

1

0

0

4H-Pyran-4-one, 2-butyl-3-hydroxy-

II.A-5, III-13, X-2

131524-16-8

1

0

0

4H-Pyran-4-one, 2-butyl-3-hydroxy-6-methyl-

II.A-5, III-13, X-2 II.A-5, III-13, X-2

4940-11-8

1

1

1

4H-Pyran-4-one, 2-ethyl-3-hydroxy-

131524-08-8

1

0

0

4H-Pyran-4-one, 2-ethyl-3-hydroxy-5,6-dimethyl-

II.A-5, III-13, X-2

131524-04-4

1

0

0

4H-Pyran-4-one, 2-ethyl-3-hydroxy-5-methyl-

II.A-5, III-13, X-2

22639-24-3

1

0

0

4H-Pyran-4-one, 2-ethyl-3-hydroxy-6-methyl-

II.A-5, III-13, X-2

61892-88-4

1

0

0

4H-Pyran-4-one, 2-hydroxy-3-methyl-

II.A-5, III-13, X-2

61892-87-3

488-18-6

{ethylmaltol}

1

0

0

4H-Pyran-4-one, 2-hydroxy-5-methyl-

II.A-5, III-13, X-2

1

0

0

4H-Pyran-4-one, 2-hydroxymethyl-3,5,6-trihydroxy-

II.A-5, III-13, X-2

1

0

0

4H-Pyran-4-one, 2-methyl-3,5,6-trihydroxy-

II.A-5, III-13, X-2

1

0

0

4H-Pyran-4-one, 3,5-dihydroxy-

II.A-5, III-13, X-2

1

0

0

4H-Pyran-4-one, 2,5-dihydroxy-3-methyl-

II.A-5, III-13, X-2

61892-86-2

1

0

0

4H-Pyran-4-one, 3,5-dihydroxy-2,6-dimethyl-

II.A-5, III-13, X-2

1073-96-7

1

1

1

4H-Pyran-4-one, 3,5-dihydroxy-2-methyl{5-hydroxymaltol}

II.A-5, III-13, X-2

1

0

0

4H-Pyran-4-one, 3,5-dihydroxymethyl-2,6-dimethyl-

II.A-5, III-13, X-2

496-63-9

1

0

0

4H-Pyran-4-one, 3-hydroxy-

II.A-5, III-13, X-2

40311-00-0

1

0

0

4H-Pyran-4-one, 3-hydroxy-2-(1-methylethyl)-

II.A-5, III-13, X-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1733

11/24/08 1:57:29 PM

1734

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

4940-18-5

1

0

0

4H-Pyran-4-one, 3-hydroxy-2-(1-methylpropyl)-

II.A-5, III-13, X-2

131524-11-3

1

0

0

4H-Pyran-4-one, 3-hydroxy-2-(2-methylbutyl)-

II.A-5, III-13, X-2

76015-10-6

1

0

0

4H-Pyran-4-one, 3-hydroxy-2-(2-methylpropyl)-

II.A-5, III-13, X-2

131524-12-4

1

0

0

4H-Pyran-4-one, 3-hydroxy-2-(3-methylbutyl)-

II.A-5, III-13, X-2

131524-05-5

1

0

0

4H-Pyran-4-one, 3-hydroxy-2,5,6-trimethyl-

II.A-5, III-13, X-2

131524-02-2

1

0

0

4H-Pyran-4-one, 3-hydroxy-2,5-dimethyl-

II.A-5, III-13, X-2

2298-99-9

1

0

0

4H-Pyran-4-one, 3-hydroxy-2,6-dimethyl-

II.A-5, III-13, X-2

1

0

0

4H-Pyran-4-one, 3-hydroxy-methyl-

II.A-5, III-13, X-2

118-71-8

1

1

1

4H-Pyran-4-one, 3-hydroxy-2-methyl-

131524-10-2

1

0

0

4H-Pyran-4-one, 3-hydroxy-2-methyl-6-propyl-

{maltol}

II.A-5, III-13, X-2 II.A-5, III-13, X-2

131524-13-5

1

0

0

4H-Pyran-4-one, 3-hydroxy-2-pentyl-

II.A-5, III-13, X-2

4940-16-3

1

0

0

4H-Pyran-4-one, 3-hydroxy-2-propyl-

II.A-5, III-13, X-2

131524-07-7

1

0

0

4H-Pyran-4-one, 3-hydroxy-6-methyl-2-(1methylethyl)-

II.A-5, III-13, X-2

131524-14-6

1

0

0

4H-Pyran-4-one, 3-hydroxy-6-methyl-2-(1methylpropyl)-

II.A-5, III-13, X-2

131524-15-7

1

0

0

4H-Pyran-4-one, 3-hydroxy-6-methyl-2-(2methylpropyl)-

II.A-5, III-13, X-2

40861-87-8

1

0

0

4H-Pyran-4-one, 3-hydroxy-6-methyl-2-propyl-

II.A-5, III-13, X-2

50671-50-6

1

0

0

4H-Pyran-4-one, 3-methyl-

644-46-2

1

0

0

4H-Pyran-4-one, 5-hydroxy-2-methyl- = 4H-Pyran4-one, 3-hydroxy-6-methyl{allomaltol}

II.A-5, III-13, X-2

131524-06-6

1

0

0

4H-Pyran-4-one, 6-ethyl-3-hydroxy-2-methyl-

II.A-5, III-13, X-2

131524-17-9

1

0

0

4H-Pyran-4-one, 6-ethyl-3-hydroxy-2-propyl-

II.A-5, III-13, X-2

1

0

0

4H-Pyran-4-one-2-carboxylic acid, 5-hydroxy-

1

0

0

4H-Pyran-4-one-2-carboxylic acid, 5-hydroxy-, (1methylethyl) ester

III-13, X-2

II.A-5, III-13, IV.A-5, X-2 II.A-5, III-13, V-3, X-2 O

COO-CH(CH3)2

HO O

290-37-9

1

1

1

Pyrazine

6 5

N

N

2

XVII.B-2

3

1

1

1

Pyrazine, alkyl-

XVII.B-2

66288-42-4

1

1

1

Pyrazine, butenyl-

XVII.B-2

78210-56-7

1

1

1

Pyrazine, 3-butenyl- = Pyrazine, 2-butenyl-

XVII.B-2

29460-91-1

1

0

0

Pyrazine, butyl-

XVII.B-2

32184-51-3

1

1

1

Pyrazine, 2-cyclopentyl-6-methyl-

XVII.B-2

15707-24-1

1

1

1

Pyrazine, 2,3-diethyl-

XVII.B-2

13238-84-1

1

1

1

Pyrazine, 2,5-diethyl-

XVII.B-2

13067-27-1

1

1

1

Pyrazine, 2,6-diethyl-

XVII.B-2

18138-05-1

1

0

0

Pyrazine, 3,5-diethyl-2-methyl- = Pyrazine, 2,6diethyl-3-methyl-

XVII.B-2

25704-73-8

1

1

1

Pyrazine, dimethyl-

XVII.B-2

5910-89-4

1

1

1

Pyrazine, 2,3-dimethyl-

XVII.B-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1734

11/24/08 1:57:29 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1735

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke S

T

S T

1

0

0

Pyrazine, 2,3-dimethyl-6-propyl-

XVII.B-2

1

1

1

Pyrazine, 2,5-dimethyl-

XVII.B-2

0

1

0

Pyrazine, 2,5-dimethyl-3-(1-methylethyl)- = Pyrazine, 3,6-dimethyl-2(1-methylethyl)-

XVII.B-2

1

0

0

Pyrazine, 2,5-dimethyl-6-propyl-

XVII.B-2

108-50-9

1

1

1

Pyrazine, 2,6-dimethyl-

XVII.B-2

71607-73-3

1

1

1

Pyrazine, dimethyethyl-

XVII.B-2

4177-16-6

1

1

1

Pyrazine, ethenyl-

XVII.B-2

13925-08-1

1

1

1

Pyrazine, 2-ethenyl-5-methyl-

XVII.B-2

13925-09-2

1

1

1

Pyrazine, 2-ethenyl-6-methyl-

XVII.B-2

13925-00-3

1

1

1

Pyrazine, ethyl- = Pyrazine, 2-ethyl-

XVII.B-2

33504-66-4

1

0

0

Pyrazine, ethylmethyl-

XVII.B-2

0

1

0

Pyrazine, 2-ethyl-5-ethylene-

XVII.B-2

25680-58-4

0

1

0

Pyrazine, 2-ethyl-3-methoxy-

X-2, XVII.B-2

0

1

0

Pyrazine, 2-ethyl-5-methoxy-

X-2, XVII.B-2 X-2, XVII.B-2

CAS No.

123-32-0

Name (per CA Collective Index)

Selected structures

Chapter Table

0

1

0

Pyrazine, 2-ethyl-6-methoxy-

15707-23-0

1

1

1

Pyrazine, 2-ethyl-3-methyl-

XVII.B-2

13360-64-0

1

1

1

Pyrazine, 2-ethyl-5-methyl-

XVII.B-2

13925-03-6

1

1

1

Pyrazine, 2-ethyl-6-methyl- = Pyrazine, 6-ethyl-2methyl-

XVII.B-2

0

1

0

Pyrazine, 2-ethyl-3,5,6-trimethyl-

XVII.B-2

13360-65-1

1

1

1

Pyrazine, 2-ethyl-3,6-dimethyl- = Pyrazine, 6-ethyl2,5-dimethyl-

XVII.B-2

13925-07-0

1

1

1

Pyrazine, 2-ethyl-3,5-dimethyl- = Pyrazine, 3-ethyl2,6-dimethyl-

XVII.B-2

15707-34-3

1

1

1

Pyrazine, 2-ethyl-5,6-dimethyl- = Pyrazine, 5-ethyl2,3-dimethyl-

XVII.B-2

32736-95-1

1

1

1

Pyrazine, 2-furanyl-

29460-98-8

1

1

1

Pyrazine, 3-furanyl-

X-2, XVII.B-2

36238-34-3

1

1

1

Pyrazine, 5-(2-furanyl)-2,3-dimethyl- = Pyrazine, 2(2-furanyl)-5,6-dimethyl-

X-2, XVII.B-2

27610-38-4

1

1

1

Pyrazine, 2-(2-furanyl)-5-methyl-

X-2, XVII.B-2

32737-03-4

1

1

1

Pyrazine, 2-(2-furanyl)-6-methyl-

X-2, XVII.B-2

29461-10-7

1

0

0

Pyrazine, 2-(3-furanyl)-5-methyl-

X-2, XVII.B-2

3149-28-8

0

1

0

Pyrazine, methoxy-

X-2, XVII.B-2

2847-30-5

0

1

0

Pyrazine, 3-methoxy-2-methyl-

X-2, XVII.B-2

2882-22-6

0

1

0

Pyrazine, 5-methoxy-2-methyl-

X-2, XVII.B-2

2882-21-5

0

1

0

Pyrazine, 6-methoxy-2-methyl-

X-2, XVII.B-2

X-2, XVII.B-2

109-08-0

1

1

1

Pyrazine, methyl- = Pyrazine, 2-methyl-

XVII.B-2

38713-41-6

1

1

1

Pyrazine, (1-methylethenyl)-

XVII.B-2

29460-90-0

0

1

0

Pyrazine, (1-methylethyl)-

XVII.B-2

34514-52-8

1

0

0

Pyrazine, methyl(1-methylethyl)-

XVII.B-2

1

0

0

Pyrazine, 2-methyl-3-butyl-

XVII.B-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1735

11/24/08 1:57:30 PM

1736

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

13925-06-9

S

T

S T

1

0

0

Pyrazine, 2-methyl-3-(2-methylbutyl)-

XVII.B-2

1

0

0

Pyrazine, 2-methyl-3-(3-methylbutyl)-

XVII.B-2

0

1

0

Pyrazine, 2-methyl-3-(1-methylethyl)-

XVII.B-2

1

0

0

Pyrazine, 2-methyl-3-(2-methylpropyl)-

XVII.B-2

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

Pyrazine, 2-methyl-5-(1-methylethyl)-

XVII.B-2

58861-90-8

1

0

0

Pyrazine, 2-methyl-5-phenyl-

XVII.B-2

55138-67-5

0

1

0

Pyrazine, 2-methyl-6-(1-propenyl)-

XVII.B-2

36541-30-7

1

0

0

Pyrazine, methylpropyl-

XVII.B-2

29461-03-8 6303-75-9

1

0

0

Pyrazine, 2-methyl-5-propyl-

XVII.B-2

1

0

0

Pyrazine, 2-methyl-6-propyl-

XVII.B-2

1

0

0

Pyrazine, pentyl-

XVII.B-2

29460-97-7

1

1

1

Pyrazine, phenyl-

XVII.B-2

18138-03-9

1

0

0

Pyrazine, propyl-

XVII.B-2

1

0

0

Pyrazine, 2-(1-propenyl)-

XVII.B-2

1124-11-4

1

1

1

Pyrazine, tetramethyl-

XVII.B-2

14667-55-1

1

1

1

Pyrazine, trimethyl-

61892-91-9

1

0

0

Pyrazinebutanol, 3-methyl-

5780-66-5

XVII.B-2 II.A-5, XVII.B-2

1

0

0

Pyrazinecarboxaldehyde

0

1

0

Pyrazinecarboxaldehyde, 5-(2-furanyl)-3-methyl-

III-12, XVII.B-2

6705-31-3

1

1

1

Pyrazineethanol

II.A-5, XVII.B-2

61892-92-0

1

1

1

Pyrazineethanol, 3-methyl-

II.A-5, XVII.B-2

61892-93-1

1

1

1

Pyrazineethanol, 6-methyl-

II.A-5, XVII.B-2

III-12, X-2, XVII.B-2

6705-33-5

1

0

0

Pyrazinemethanol

II.A-5, XVII.B-2

61892-95-3

1

1

1

Pyrazinemethanol, 5-methyl- = Pyrazinemethanol, 3-methyl-

II.A-5, XVII.B-2

0

1

0

Pyrazinepentanol

II.A-5, XVII.B-2 II.A-5, XVII.B-2

1

1

1

Pyrazinol, 3-methyl-

78210-68-1

1

0

0

2(1H)-Pyrazinone, 1-methyl-3-(1-methylethyl)-

XVII.B-2

19838-07-4

1

0

0

2(1H)-Pyrazinone, 3-methyl-

XVII.B-2

20721-17-9

1

0

0

2(1H)-Pyrazinone, 5-methyl-

XVII.B-2

20721-18-0

1

0

0

2(1H)-Pyrazinone, 6-methyl-

288-13-1

1

1

1

1H-Pyrazole

67771-72-6

XVII.B-2 H N

XVII.A-4 N

1

0

0

1H-Pyrazole, C2-alkyl-

XVII.A-4

1

0

0

1H-Pyrazole, dimethyl-

XVII.A-4

2820-37-3

1

0

0

1H-Pyrazole, 3,4-dimethyl-

XVII.A-4

67-51-6

1

0

0

1H-Pyrazole, 3,5-dimethyl-

XVII.A-4

1131-16-4

1

0

0

1H-Pyrazole, 3,5-dimethyl-1-phenyl-

XVII.A-4

66719-08-2

1

0

0

1H-Pyrazole, methyl-

XVII.A-4

1453-58-3

1

0

0

1H-Pyrazole, 3-methyl-

XVII.A-4

3347-62-4

0

1

0

1H-Pyrazole, 3-methyl-5-phenyl-

XVII.A-4

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1736

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1737

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

1072-91-9

1

0

0

1H-Pyrazole, 1,3,5-trimethyl-

XVII.A-4

5519-42-6

1

0

0

1H-Pyrazole, 3,4,5-trimethyl-

XVII.A-4

61892-79-3

1

0

0

1H,7H-Pyrazolo[1,2-a]pyrazole-1,7-dione, tetrahydro-

Name (per CA Collective Index)

Selected structures

O

O

Chapter Table

XVII.E-8

N N

33986-27-5

0

1

0

1H-Pyrazolo[4,3-d]pyrimidin-7-amine, 3-methyl-N(3-methyl-2-butenyl)-

XII-2, XVII.E-8

33698-49-6

0

1

0

1H-Pyrazolo[4,3-d]pyrimidin-7-amine, 3-methyl-N(3-methylbutyl)-

XII-2, XVII.E-8

34232-31-0

0

1

0

1H-Pyrazolo[4,3-d]pyrimidin-7-amine, N-(3-methyl2-butenyl)-

XII-2, XVII.E-8

33986-28-6

0

1

0

1H-Pyrazolo[4,3-d]pyrimidin-7-amine, N-(3methylbutyl)-

XII-2, XVII.E-8

64990-23-4

1

0

0

Pyrenamine

XII-2

64828-53-1

1

0

0

Pyrenamine, N-methyl-

XII-2

1606-67-3

1

0

0

1-Pyreneamine

XII-2

129-00-0

1

1

1

Pyrene

1

0

0

Pyrene, alkyl-

I.E-6

1

0

0

Pyrene, 1-butyl-

I.E-6

35980-18-8

{benzo[def]phenanthrene}

I.E-6

55682-90-1

1

0

0

Pyrene, 1-decyl-

I.E-6

28779-32-0

1

0

0

Pyrene, dihydro-

I.E-6

30582-03-7

1

0

0

Pyrene, dimethyl- {at least three isomers in MSS}

I.E-6

64401-21-4

1

0

0

Pyrene, 1,3-dimethyl-

I.E-6

1

0

0

Pyrene, dimethyl-3,4-dimethylene-

I.E-6

1

0

0

Pyrene, 3,4-dimethylene-

I.E-6

1

0

0

Pyrene, 3,4-dimethylenemethyl-

I.E-6

1

0

0

Pyrene, 1,6-dinitro-

XVI-1

1

0

0

Pyrene, 1,8-dinitro-

XVI-1

1

0

0

Pyrene, ethyl-

I.E-6

56142-12-2

1

0

0

Pyrene, 1-ethyl-

I.E-6

71607-74-4

1

0

0

Pyrene, ethylmethyl-

I.E-6

71607-75-5

1

0

0

Pyrene, hexamethyl-

I.E-6

72692-89-8

1

0

0

Pyrene, 1-hexyl-

27577-90-8

1

0

0

Pyrene, methyl-

2381-21-7

1

0

0

Pyrene, 1-methyl-

I.E-6

3442-78-2

1

0

0

Pyrene, 2-methyl-

I.E-6

25732-74-5

I.E-6 {several isomers in MSS}

I.E-6

3353-12-6

1

0

0

Pyrene, 4-methyl-

5522-43-0

1

0

0

Pyrene, 1-nitro-

XVI-1

1

0

0

Pyrene, 4-nitro-

XVI-1

1

0

0

Pyrene, 1-octyl-

I.E-6

71608-00-9

I.E-6

© 2009 by Taylor & Francis Group, LLC

78836_C030.indd 1737

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1738

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

71607-76-6

1

0

0

Pyrene, pentamethyl{at least three isomers in MSS}

I.E-6

56142-09-7

1

0

0

Pyrene, propyl-

I.E-6

71630-71-2

1

0

0

Pyrene, 1-tetradecyl-

I.E-6

66161-17-9

1

0

0

Pyrene, tetrahydro-

I.E-6

60826-75-7

1

0

0

Pyrene, tetramethyl- {at least four isomers in MSS}

I.E-6

41637-88-1

1

0

0

Pyrene, trimethyl- {at least three isomers in MSS}

I.E-6

121-21-1, 4466-14-2, 25402-06-6, 121-21-9, 1171-63-0, 121-29-9, 121-20-0

0

1

0

Pyrethrins (natural)

123-33-1

1

Name (per CA Collective Index)

Selected structures

Chapter Table

V-3, XXI-3 O O O

1

1

3,6-Pyridazinedione, 1,2-dihydro{maleic hydrazide; MH; MH-30®}

H N

O

XVII.B-2, XVII.C-1, XXI-3

H N O

O

5716-15-4

0

1

0

3,6-Pyridazinedione, 1,2-dihydro-, diethanolamine salt

XVII.B-2, XVII.C-1

51542-52-0

0

1

0

3,6-Pyridazinedione, 1,2-dihydro-, potassium salt

XVII.B-2, XVII.C-1

26445-05-6

1

0

0

Pyridinamine

XII-2, XVII.B-2

71607-77-7

1

0

0

Pyridinamine, N-methyl-

XII-2, XVII.B-2

504-29-0

1

1

1

2-Pyridinamine

XII-2, XVII.B-2

1603-40-3

1

0

0

2-Pyridinamine, 3-methyl-

695-34-1

1

0

0

2-Pyridinamine, 4-methyl-

1603-41-4

1

0

0

2-Pyridinamine, 5-methyl-

XII-2, XVII.B-2

1824-81-3

1

0

0

2-Pyridinamine, 6-methyl-

XII-2, XVII.B-2

30315-34-5

1

0

0

2-Pyridinamine, 5-(1-methyl-2-pyrrolidinyl)-, (S)-

XII-2, XVII.B-4

1202-34-2

1

0

0

2-Pyridinamine, N-2-pyridinyl-

XII-2, XVII.B-6

XII-2, XVII.B-2 {2-amino-4-picoline}

XII-2, XVII.B-2

462-08-8

1

0

0

3-Pyridinamine

61771-67-3

1

0

0

3-Pyridinamine, 6-methoxy-N-methyl-

XII-2, XVII.B-2

3430-10-2

1

0

0

3-Pyridinamine, 2-methyl-

XII-2, XVII.B-2

3430-27-1

1

0

0

3-Pyridinamine, 4-methyl-

XII-2, XVII.B-2

18364-47-1

1

0

0

3-Pyridinamine, N-methyl-

XII-2, XVII.B-2

504-24-5

1

0

0

4-Pyridinamine

110-86-1

1

1

1

Pyridine

X-2, XII-2, XVII.B-2

XII-2, XVII.B-2 5 6

27175-64-0

1

0

0

Pyridine, alkyl-

1

0

0

Pyridine, C3-alkyl-

1

0

0

Pyridine, (C3-alkylphenyl)-

1

0

0

Pyridine, butenyl-

1

1

1

Pyridine, dimethyl-

XVII.B-2

4 3 N

2

XVII.B-2 XVII.B-2 {2 isomers detected}

XVII.B-2

{3 isomers}

XVII.B-2

{lutidine}

XVII.B-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1738

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1739

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 29011-62-9

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

Pyridine, dimethylethenyl-

0

1

0

Pyridine, dimethylethyl-

1

0

0

Pyridine, dimethyl-2-(1-methylethyl)-

XVII.B-2

1

0

0

Pyridine, dimethylphenyl-

XVII.B-2

56842-43-4

1

0

0

Pyridine, diphenyl-

XVII.B-2

1337-81-1

1

0

0

Pyridine, ethenyl-

XVII.B-2

25638-00-0

XVII.B-2 {2 isomers detected}

XVII.B-2

1

0

0

Pyridine, ethenylmethyl-

XVII.B-2

1

0

0

Pyridine, ethenyltrimethyl-

XVII.B-2

28631-77-8

1

0

0

Pyridine, ethyl-

27987-10-6

1

1

1

Pyridine, ethylmethyl-

64849-96-3

1

0

0

Pyridine, ethylphenyl-

1333-41-1

1

1

1

Pyridine, methyl-

64828-54-2

1

0

0

Pyridine, methylphenyl-

64828-55-3

XVII.B-2 XVII.B-2

{picoline}

XVII.B-2 XVII.B-2

1

0

0

Pyridine, phenylpropyl-

XVII.B-2

1

0

0

Pyridine, phenyltrimethyl-

XVII.B-2

1

0

0

Pyridine, propenyl-

XVII.B-2

1

0

0

Pyridine, propyl-

XVII.B-2

1

0

0

Pyridine, tetramethyl-

29611-84-5

1

0

0

Pyridine, trimethyl-

6972-40-3

1

0

0

Pyridine, 1-ethyl-1,2,3,6-tetrahydro-

694-05-3

XVII.B-2 {4 isomers}

1

1

1

Pyridine, 1,2,3,6-tetrahydro-

XVII.B-2 {collidine}

XVII.B-2 XVII.B-2

3

{¨ -piperidine}

XVII.B-2

3 2

1

6

N H

0

1

0

Pyridine, 1-methyl-6-(2-pyridinyl)-1,2,5,6-tetrahydro-

XVII.B-6

1

0

0

Pyridine, 2-(C3-alkylphenyl)- {2 isomers detected}

XVII.B-2

5058-19-5

1

0

0

Pyridine, 2-butyl-

1929-82-4

0

1

0

Pyridine, 2-chloro-6-(trichloromethyl){Nitrapyrin®}

100-69-6

1

0

0

Pyridine, 2-ethenyl-

XVII.B-2

22382-94-1

1

0

0

Pyridine, 2-ethenyl-3-methyl-

XVII.B-2

1122-70-9

1

0

0

Pyridine, 2-ethenyl-6-methyl-

XVII.B-2

XVII.B-2 Cl

N

CCl3

XVII.B-2, XVIII.B-3, XXI-3

100-71-0

1

1

1

Pyridine, 2-ethyl-

XVII.B-2

1123-96-2

1

0

0

Pyridine, 2-ethyl-3,5-dimethyl- = Pyridine, 2,4dimethyl-6-ethyl-

XVII.B-2

1124-35-2

1

0

0

Pyridine, 2-ethyl-4,6-dimethyl-

XVII.B-2

2150-18-7

1

0

0

Pyridine, 2-ethyl-4-methyl-

XVII.B-2

18113-81-0

1

0

0

Pyridine, 2-ethyl-5-methyl-

XVII.B-2

1122-69-6

1

0

0

Pyridine, 2-ethyl-6-methyl-

1628-89-3

1

0

0

Pyridine, 2-methoxy-

109-06-8

XVII.B-2 X-2, XVII.B-2

1

1

1

Pyridine, 2-methyl-

{2-picoline}

XVII.B-2

1

1

1

Pyridine, 2-methyl-3-(1-methyl-2-pyrrolidinyl){2-methylnicotine}

XVII.B-4

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1739

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1740

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

78210-48-7

S

T

S T

1

0

0

Pyridine, 2-(2-methylbutyl)-

XVII.B-2

1

0

0

Pyridine, 2-(3-methylbutyl)-

XVII.B-2

1

0

0

Pyridine, 2-(1-methylethenyl)-

XVII.B-2

1

0

0

Pyridine, 2-(1-methylethyl)-

XVII.B-2

1

0

0

Pyridine, 2-methyl-3-(1-methylethyl)-

XVII.B-2

1

0

0

Pyridine, 2-methyl-3-(1-propenyl)-

XVII.B-2

Name (per CA Collective Index)

Selected structures

Chapter Table

15032-21-0

1

0

0

Pyridine, 2-methyl-4-phenyl-

XVII.B-2

56057-93-3

1

1

1

Pyridine, 2-methyl-5-(1-methylethenyl)-

XVII.B-2

20194-71-2

1

1

1

Pyridine, 2-methyl-5-(1-methylethyl)-

XVII.B-2

56057-96-6

1

0

0

Pyridine, 2-methyl-5-(1-propenyl)-

XVII.B-2

1

0

0

Pyridine, 2-methyl-6-(3-methylbutyl)-

XVII.B-2

2294-76-0

1

1

1

Pyridine, 2-pentyl-

XVII.B-2

1008-89-5

1

0

0

Pyridine, 2-phenyl-

XVII.B-2

1

0

0

Pyridine, 2-propenyl-

XVII.B-2

1

0

0

Pyridine, 2-propyl-

XVII.B-2

622-39-9 101-82-6

1

0

0

Pyridine, 2-(phenylmethyl)-

XVII.B-2

64389-08-8

1

0

0

Pyridine, 2-(1,5-dimethyl-1H-pyrrol-2-yl)-

XVII.B-4

7399-50-0

1

0

0

Pyridine, 2-(1-ethylpropyl)-

XVII.B-2

59409-91-5

1

0

0

Pyridine, 2-(1-methyl-3-butenyl)-

XVII.B-2

525-75-7

1

0

0

Pyridine, 2-(1-methyl-1H-pyrrol-2-yl){D-nicotyrine}

XVII.B-4

17618-94-9

1

0

0

Pyridine, 2-(1-propenyl)-

XVII.B-2

78210-51-2

1

0

0

Pyridine, 2-(1H-pyrrol-1-ylmethyl)-

XVII.B-4

21606-61-1

1

0

0

Pyridine, 2-(2-butenyl)-

XVII.B-2

6304-24-1

1

0

0

Pyridine, 2-(2-methylpropyl)-

583-61-9

1

1

1

Pyridine, 2,3-dimethyl-

78210-40-9

1

0

0

Pyridine, 2-(3-ethylphenyl)-

68258-35-5

0

1

0

Pyridine-2- C-3- C, 3-fluoro-5-(2-piperidinyl)-, (±)-, 13 14 labeled with C and C

XVII.B-6

2233-29-6

1

0

0

Pyridine, 2,3,4-trimethyl-

XVII.B-2

13

XVII.B-2 {2,3-lutidine}

XVII.B-2 XVII.B-2

14

{2,3,4-collidine}

695-98-7

1

1

1

Pyridine, 2,3,5-trimethyl-

{2,3,5-collidine}

XVII.B-2

1462-84-6

0

1

0

Pyridine, 2,3,6-trimethyl-

{2,3,6-collidine}

XVII.B-2

{2,4-lutidine}

XVII.B-2

108-47-4

1

1

1

Pyridine, 2,4-dimethyl-

36238-36-5

1

0

0

Pyridine, 2,4-dimethyl-5-(1-methylethyl)-

XVII.B-2

1122-39-0

1

0

0

Pyridine, 2,4,5-trimethyl-

{2,4,5-collidine}

XVII.B-2

108-75-8

1

0

0

Pyridine, 2,4,6-trimethyl-

{2,4,6-collidine}

XVII.B-2

589-93-5

1

1

1

Pyridine, 2,5-dimethyl-

{2,5-lutidine}

XVII.B-2

15827-72-2

0

1

0

Pyridine, 2,5-diphenyl-

108-48-5

1

1

1

Pyridine, 2,6-dimethyl-

{2,6-lutidine}

XVII.B-2

1463-03-2

1

0

0

Pyridine, 2,6-dimethyl-3-phenyl-

XVII.B-2

3558-69-8

1

0

0

Pyridine, 2,6-diphenyl-

XVII.B-2

1

0

0

Pyridine, (C5-alkenyl)-

XVII.B-2

XVII.B-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1740

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1741

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

539-32-2

1

1

1

Pyridine, 3-butyl-

XVII.B-2

6760-12-9

1

0

0

Pyridine, 3-butyl-2,6-dimethyl-

XVII.B-2

1121-55-7

1

1

1

Pyridine, 3-ethenyl-

XVII.B-2

51961-51-4

1

0

0

Pyridine, 3-ethenyl-5-methyl-

XVII.B-2

536-78-7

1

1

1

Pyridine, 3-ethyl-

XVII.B-2

23580-52-1

0

1

0

Pyridine, 3-ethyl-2,6-dimethyl-

XVII.B-2

529-21-5

1

0

0

Pyridine, 3-ethyl-4-methyl-

XVII.B-2

3999-78-8

1

0

0

Pyridine, 3-ethyl-5-methyl-

XVII.B-2

7295-76-3

1

1

1

Pyridine, 3-methoxy-

XVII.B-2

78210-42-1

1

0

0

Pyridine, 3-methoxy-5-methyl-

XVII.B-2

108-99-6

1

1

1

Pyridine, 3-methyl-

1

0

0

Pyridine, 3-(1-methylethyl)-

XVII.B-2

1

0

0

Pyridine, 3-methyl-2-(2-methylbutyl)-

XVII.B-2

{3-picoline}

XVII.B-2

1

0

0

Pyridine, 3-methyl-2-(3-methylbutyl)-

XVII.B-2

72693-04-0

1

0

0

Pyridine, 3-methyl-2-(1-methylethyl)-

XVII.B-2

18368-73-5

1

0

0

Pyridine, 3-methyl-2-nitro-

10477-94-8

1

0

0

Pyridine, 3-methyl-5-phenyl-

XVII.B-2

1802-20-6

1

1

1

Pyridine, 3-pentyl-

XVII.B-2

1008-88-4

1

0

0

Pyridine, 3-phenyl-

XVII.B-2

4673-31-8

1

0

0

Pyridine, 3-propyl-

XVII.B-2

XVI-1, XVII.B-2

1

1

1

Pyridine, 3-propenyl-

XVII.B-2

8210-50-1

1

0

0

Pyridine, 3-(tetrahydro-2-furanyl)-

XVII.B-2

78210-38-5

1

0

0

Pyridine, 3-(1,3-dimethyl-1H-pyrrol-2-yl)-

XVII.B-4

27293-93-2

0

1

0

Pyridine, 3-(1,3-dimethyl-2-pyrrolidinyl)-

XVII.B-4

1

0

0

Pyridine, 3-(1,5-dimethyl-1H-pyrrol-2-yl)-

1

0

0

Pyridine, 3-[1-(5-ethyl-2-furanyl)-1H-pyrrol-2-yl]-

78210-88-5

XVII.B-4 X-2, XVII.B-4

68245-76-1

0

1

0

Pyridine, 3-(1-ethyl-2-piperidinyl)-, (S)-

XVII.B-6

5979-92-0

1

0

0

Pyridine, 3-(1-ethyl-2-pyrrolidinyl)-, (S)-

XVII.B-4

78210-87-4

1

0

0

Pyridine, 3-[1-[2-(2-furanyl)ethyl]-2-pyrrolidinyl]-, (S)-

X-2, XVII.B-4

78210-85-2

1

0

0

Pyridine, 3-[1-(2-furanylmethyl)-2-pyrrolidinyl]-, (S)-

123676-95-9

0

1

0

Pyridine, 3-[1-[(hydroxy-1-oxooctyl)oxy]-2pyrrolidinyl]-

1

0

0

Pyridine, 3-(1-methyl-3-butenyl)-

72461-69-9

0

1

0

Pyridine, 3-[1-(1-methylethyl)-2-pyrrolidinyl]-, (S)-

XVII.B-4

15825-89-5

1

0

0

Pyridine, 3-(1-methylethenyl)-

XVII.B-2

1

0

0

Pyridine, 3-(1-methylethyl)-

78210-86-3

1

0

0

Pyridine, 3-[1-[(5-methyl-2-furanyl)methyl]-2pyrrolidinyl]-, (S)-

8210-84-1

1

0

0

Pyridine, 3-[1-methyl-2-(1-methylethyl)-1H-imidazol5-yl]-

X-2, XVII.B-4 II.A-5, XVII.B-4 XVII.B-2

XVII.B-2 X-2, XVII.B-4 XVII.B-4

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1741

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1742

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

24380-92-5 19730-04-2

1

1

1

Name (per CA Collective Index)

Selected structures

Pyridine, 3-(1-methyl-2-piperidinyl)-, (S){N-methylanabasine}

Chapter Table XVII.B-6

N N

CH 3

22083-74-5

0

1

0

Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (r)-

XVII.B-4

25162-00-9

1

0

0

Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (R){d-nicotine}

XVII.B-4

54-11-5

1

1

1

Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (S){l-nicotine}

XVII.B-4, XXI-3 N N

CH3

65-30-5

0

1

0

Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (S)-, sulfate (2:1) {Black Leaf 40®}

XVII.B-4, XXI-3

6505-86-8

0

1

0

Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (S)-, sulfate

XVII.B-4, XXI-3

2820-55-5

1

1

1

Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, 1-oxide, (S){nicotine N-oxide}

XVII.B-4

2820-51-1

0

1

0

Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, hydrochloride, (S)-

XVII.B-4, XVIII.B-3

16586-18-8

0

1

0

Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (S)-, labeled 14 with C,

XVII.B-4

25429-24-7

1

1

1

Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, monohydroxy derivative, (S)-

XVII.B-4

0

1

0

Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, 6-hydroxy

XVII.B-4

2055-29-0

0

1

0

Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, N,1-dioxide, (S)-

XVII.B-4

491-26-9

1

0

0

Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, N-oxide, (2S)-

XVII.B-4

1

1

1

Pyridine, 3-(1-methyl-2-pyrrolinyl){2,3-dehydronicotine}

XVII.B-4 N N

487-19-4

CH3

0

1

0

Pyridine, 3-(1-methyl-2-pyrrolinyl)-6-methyl-

XVII.B-4

1

1

1

Pyridine, 3-(1-methyl-1H-pyrrol-2-yl)- {nicotyrine}

XVII.B-4 N N

CH3

1133-64-8 37620-20-5

1

1

1

Pyridine, 3-(1-nitroso-2-piperidinyl)-, (S)-

{NAB}

XV-8, XVII.B-6

16543-55-8

1

1

1

Pyridine, 3-(1-nitroso-2-pyrrolidinyl)-, (S)-

{NNN}

XV-8, XVII.B-4

53844-45-4

1

1

1

Pyridine, 3-(1-nitroso-2-pyrrolidinyl-2- C)-, (S)-, 14 labeled with C

15376-62-2

14

XVII.B-4

1

0

0

Pyridine, 3-(1-pentyl-2-piperidinyl)-,

XVII.B-6

1

0

0

Pyridine, 3-(1-pentyl-2-pyrrolidinyl)-

XVII.B-4

1

1

1

Pyridine, 3-(1-propenyl)-

XVII.B-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1742

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1743

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

78210-89-6

1

0

0

Pyridine, 3-[1-(5-propyl-2-furanyl)-1H-pyrrol-2-yl]-

XVII.B-4

72692-99-0

1

0

0

Pyridine, 3-(1H-pyrrol-1-yl)-

XVII.B-4

494-98-4

1

1

1

Pyridine, 3-(1H-pyrrol-2-yl)-

Name (per CA Collective Index)

Selected structures

Chapter Table

XVII.B-4

{nornicotyrine} N H N

78210-90-9

1

0

0

Pyridine, 3-(2-butenyl)-

XVII.B-2

78210-49-8

1

0

0

Pyridine, 3-(2-methyl-1H-pyrrol-1-yl)-

XVII.B-4

6312-09-0 494-52-0

1

0

0

Pyridine, 3-(2-phenylethyl)-

1

0

0

Pyridine, 3-(2-piperidinyl)-, (R)-

{d-anabasine}

XVII.B-6

XVII.B-2

1

1

1

Pyridine, 3-(2-piperidinyl)-, (S)-

{l-anabasine}

XVII.B-6 N H N

7300-28-9 494-97-3

1

0

0

Pyridine, 3-(2-propenyl)-

XVII.B-2

1

0

0

Pyridine, 3-(2-pyrrolidinyl)-, (R)-

{d-nornicotine}

XVII.B-4

1

1

1

Pyridine, 3-(2-pyrrolidinyl)-, (S)-

{l-nornicotine}

XVII.B-4 N H N

53844-44-3 71532-24-6

532-12-7

1

1

1

14

Pyridine, 3-(2-pyrrolidinyl-2- C)-, (S)-, labeled with 14 C

XVII.B-4

1

0

0

Pyridine, 3-(3-butenyl)-

XVII.B-2

1

0

0

Pyridine, 3-(3,4-dihydro-2H-pyrrol-5-yl){d-myosmine}

XVII.B-4

1

1

1

Pyridine, 3-(3,4-dihydro-2H-pyrrol-5-yl){l-myosmine}

XVII.B-4 N N

N H N

78249-81-7

0

1

0

Pyridine, 3-(3,4-dihydro-1-methyl-2H-pyrrol-5-yl){N-methylmyosmine}

XVII.B-4

1

0

0

Pyridine, 3-(3,4-dihydro-2H-pyrrol-5-yl)-, monomethyl derivative

XVII.B-4

78210-37-4

1

0

0

Pyridine, 3-(3,4-dihydro-3-methyl-2H-pyrrol-5-yl)-

XVII.B-4

24950-44-5

1

0

0

Pyridine, 3,3'-(1,2-ethenediyl)bis-

XVII.B-2

78210-39-6

1

0

0

Pyridine, 3-(3-ethyl-3,4-dihydro-2H-pyrrol-5-yl)-

XVII.B-4

18793-19-6

1

1

1

Pyridine, 3,3'-(2,4-piperidinediyl)bis-

XVII.B-6

78210-43-2 4385-67-5

1

0

0

Pyridine, 3,3'-methylenebis-

XVII.B-2

1

0

0

Pyridine, 3,4’-methylenebis

XVII.B-2

1

0

0

Pyridine, 3-(3-methylphenyl)-

XVII.B-2

525-74-6

1

0

0

Pyridine, 3-(4,5-dihydro-1-methyl-1H-pyrrol-2-yl)-

XVII.B-4

583-58-4

1

1

1

Pyridine, 3,4-dimethyl-

XVII.B-2

{3,4-lutidine}

1

0

0

Pyridine, 3-(4-butenyl)-

XVII.B-2

78210-41-0

1

0

0

Pyridine, 3-(4-ethylphenyl)-

XVII.B-2

2057-39-8

1

0

0

Pyridine, 3-(4-methyl-3-pentenyl)-

XVII.B-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1743

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1744

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

72692-97-8

1

0

0

Pyridine, 3-(4-methylpentyl)-

XVII.B-2

78210-44-3

1

0

0

Pyridine, 3-(4-pyridinylmethyl)-

XVII.B-6

78210-45-4

1

0

0

Pyridine, 3-[2,5-dihydro-1-[(5-methyl-2furanyl)methyl]-1H-pyrrol-2-yl]-

XVII.B-4

591-22-0

1

1

1

Pyridine, 3,5-dimethyl-

XVII.B-2

78210-46-5

1

0

0

Pyridine, 3-[(5-methyl-2-furanyl)methyl]-

5335-75-1

1

0

0

Pyridine, 4-butyl-

XVII.B-2

100-43-6

1

1

1

Pyridine, 4-ethenyl-

XVII.B-2

536-75-4

1

1

1

Pyridine, 4-ethyl-

70199-60-9

1

0

0

Pyridine, 4-(methoxymethyl)-

108-89-4 78210-47-6

Name (per CA Collective Index)

{3,5-lutidine}

Selected structures

Chapter Table

X-2, XVII.B-2

XVII.B-2 X-2, XVII.B-2

1

1

1

Pyridine, 4-methyl-

1

0

0

Pyridine, 4-methyl-2-(2-methylbutyl)-

{4-picoline}

XVII.B-2 XVII.B-2

1

0

0

Pyridine, 4-methyl-2-(3-methylbutyl)-

XVII.B-2

1

0

0

Pyridine, 4-methyl-2-(2-methylpropyl)-

XVII.B-2

84625-54-7

1

0

0

Pyridine, 4-methyl-2-pentyl-

XVII.B-2

30256-45-2

1

0

0

Pyridine, 4-methyl-2-propyl-

XVII.B-2

75835-01-7

1

0

0

Pyridine, 4-methyl-2-(2-phenylethyl)-

XVII.B-2

19352-29-5

1

1

1

Pyridine, 4-methyl-3-phenyl-

XVII.B-2

939-23-1

1

1

1

Pyridine, 4-phenyl-

XVII.B-2

2116-65-6

0

1

0

Pyridine, 4-(phenylmethyl)-

XVII.B-2

78210-91-0

1

0

0

Pyridine, 4-(1-butenyl)-

XVII.B-2

3978-81-2

1

1

1

Pyridine, 4-(1,1-dimethylethyl)-

22241-38-9

1

0

0

Pyridine, 4-(4-methylpentyl)-

XVII.B-2

17618-95-0

1

0

0

Pyridine, 4-(1-propenyl)-

XVII.B-2

{4-tert-butylpyridine}

XVII.B-2

140-76-1

1

0

0

Pyridine, 5-ethenyl-2-methyl-

XVII.B-2

104-90-5

1

1

1

Pyridine, 5-ethyl-2-methyl-

XVII.B-2

34137-26-3

0

1

0

Pyridine, 5-fluoro-3-(1-methyl-2-pyrrolidinyl)-, (S)-

55270-47-8

1

0

0

Pyridine, 5-methoxy-2-methyl-

1

0

0

Pyridine, 5-methyl-2-(2-methylbutyl)-

6343-58-4

XVII.B-4, XVIII.B-3 X-2, XVII.B-2 XVII.B-2

1

0

0

Pyridine, 5-methyl-2-(1-methylethyl)-

XVII.B-2

1

0

0

Pyridine, 5-methyl-2-(2-methylpropyl)-

XVII.B-2

1

0

0

Pyridine, 5-methyl-2-pentyl-

XVII.B-2

1

0

0

Pyridine, 5-methyl-2-propyl-

XVII.B-2

1

0

0

Pyridinecarbonitrile, dimethyl-

XI-2, XVII.B-2

1

0

0

Pyridinecarbonitrile, methyl-

XI-2, XVII.B-2

55738-21-1

1

0

0

Pyridinedicarbonitrile

17945-79-8

1

0

0

2-Pyridinebutanol

XI-2, XVII.B-2 II.A-5, XVII.B-2

100-70-9

1

0

0

2-Pyridinecarbonitrile

XI-2, XVII.B-2

20970-75-6

1

0

0

2-Pyridinecarbonitrile, 3-methyl-

XI-2, XVII.B-2

1620-76-4

1

0

0

2-Pyridinecarbonitrile, 4-methyl-

XI-2, XVII.B-2

1452-77-3

1

0

0

2-Pyridinecarboxamide

XIII-1, XVII.B-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1744

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1745

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

72693-02-8

1

0

0

2-Pyridinecarboxamide, 4,6-dimethyl-

XIII-1, XVII.B-2

32743-35-4

1

0

0

2-Pyridinecarboxamide, 4-ethyl-

XIII-1, XVII.B-2

13509-17-6

1

0

0

2-Pyridinecarboxamide, 5-ethyl-

XIII-1, XVII.B-2

78210-61-4

1

0

0

2-Pyridinecarboxamide, 6-ethyl-

XIII-1, XVII.B-2

20970-77-8

1

0

0

2-Pyridinecarboxamide, 5-methyl-

XIII-1, XVII.B-2

63668-37-1

1

0

0

2-Pyridinecarboxamide, 6-methyl-

XIII-1, XVII.B-2

1918-02-1

0

1

0

2-Pyridinecarboxylic acid, 4-amino-3,5,6-trichloro{Picloram®}

Name (per CA Collective Index)

Selected structures

Chapter Table

XII-2, XVII.B-2, XVIII.B-3, XXI-3 H2N

Cl

Cl

COOH N Cl

40222-77-3

1

0

0

2-Pyridinemethanol, 5-hydroxy-

35549-47-4

1

0

0

2-Pyridinepropanenitrile

42545-63-1

1

0

0

3-Pyridineacetaldehyde

70898-37-2

0

1

0

3-Pyridinebutanal, J-(methylamino)-

64091-90-3

1

1

1

3-Pyridinebutanal, J-(methylnitrosoamino)-

64142-45-6

1

1

1

3-Pyridinebutanal, J-(methylnitrosoamino)-, (Z)-

III-12, XV-8, XVII.B-2

76014-80-7

0

1

0

3-Pyridinebutanal, J-oxo-

III-12, III-13, XVII.B-2

1

0

0

3-Pyridinebutanamide, N-methyl-

1

1

1

3-Pyridinebutanamine, N-methyl{dihydrometanicotine}

3000-74-6

II.A-5, XVII.B-2 XI-2, XVII.B-2 III-12, XVII.B-2 III-12, XII-2, XVII.B-2 III-12, XV-8, XVII.B-2

{NNA}

III-12, XVII.B-2 XII-2, XVII.B-2 NH-CH3

N

17270-48-3

0

1

0

3-Pyridinebutanoic acid, J-(methylamino)-, (±)-

IV.A-3, XII-2, XVII.B-2

152720-16-6

0

1

0

3-Pyridinebutanoic acid, J-(methylnitroamino)-

IV.A-3, XII-2, XVI-1, XVII.B-2

124128-84-0 133201-36-2

1

1

1

3-Pyridinebutanoic acid, J-(methylnitrosoamino){iso-NNAC}

4192-31-8

0

1

0

3-Pyridinebutanoic acid, J-oxo-

IV.A-3, XV-8, XVII.B-2

III-13, IV.A-3, XVII.B-2 CO-(CH2)2-COOH

N

15873-27-5

1

1

1

III-13, IV.A-3, XVII.B-2

3-Pyridinebutanoic acid, 1,6-dihydro-J,6-dioxo-

CO-(CH2)2-COOH

O

N H

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1745

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1746

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

59578-66-4

1

1

1

Name (per CA Collective Index) 3-Pyridinebutanol, G-(methylnitrosoamino)-

Selected structures

Chapter Table

II.A-5, XV-8, XVII.B-2

{NNAL}

{1-butanol, 4-(N-methylnitrosamino)-1-(3pyridinyl)-} 133201-37-3

1

1

1

3-Pyridinebutanol, G-(methylnitrosoamino){iso-NNAL} {1-butanol, 4-(N-methylnitrosamino)-4-(3pyridinyl)-}

II.A-5, XV-8, XVII.B-2

70898-36-1

0

1

0

3-Pyridinebutanol, G-amino-

II.A-5, XII-2, XVII.B-2

100-54-9

1

1

1

3-Pyridinecarbonitrile

38076-78-7

1

0

0

3-Pyridinecarbonitrile, 2-amino-5-methyl-

XI-2, XVII.B-2

71607-63-1

1

0

0

3-Pyridinecarbonitrile, dimethyl-

XI-2, XVII.B-2

61391-07-9

1

0

0

3-Pyridinecarbonitrile, 5-ethyl-

XI-2, XVII.B-2

3222-52-4 32214-82-7

1

0

0

3-Pyridinecarbonitrile, 6-ethyl-

XI-2, XVII.B-2

5444-01-9

1

0

0

3-Pyridinecarbonitrile, 4-methyl-

XI-2, XVII.B-2

42885-14-3

1

0

0

3-Pyridinecarbonitrile, 5-methyl-

500-22-1

1

1

1

3-Pyridinecarboxaldehyde {nicotinaldehyde; 3-formylpyridine}

{nicotinonitrile}

XI-2, XVII.B-2

XI-2, XVII.B-2 CH=O

III-12, XVII.B-2

CO-NH2

XIII-1, XVII.B-2

N

98-92-0

1

1

1

3-Pyridinecarboxamide

{nicotinamide} N

72692-96-7

1

0

0

3-Pyridinecarboxamide, 2,4-dimethyl-

XIII-1, XVII.B-2

10131-48-3

1

0

0

3-Pyridinecarboxamide, 2,6-dimethyl-

XIII-1, XVII.B-2

58539-65-4

1

0

0

3-Pyridinecarboxamide, 2-methyl-

XIII-1, XVII.B-2

78210-59-0

1

0

0

3-Pyridinecarboxamide, 4-ethyl-

XIII-1, XVII.B-2

78210-60-3

1

0

0

3-Pyridinecarboxamide, 6-ethyl-

XIII-1, XVII.B-2

6960-22-1

1

0

0

3-Pyridinecarboxamide, 6-methyl-

XIII-1, XVII.B-2

4314-66-3

1

0

0

3-Pyridinecarboxamide, N-ethyl-

XIII-1, XVII.B-2

114-33-0

1

1

1

3-Pyridinecarboxamide, N-methyl-

XIII-1, XVII.B-2

1453-82-3

0

1

0

4-Pyridinecarboxamide

59-67-6

1

1

1

3-Pyridinecarboxylic acid

{isonicotinamide}

XIII-1, XVII.B-2

{nicotinic acid}

IV.A-3, XVII.B-2

5006-66-6

0

1

0

3-Pyridinecarboxylic acid, 1,6-dihydro-6-oxo-

93-60-7

1

1

1

3-Pyridinecarboxylic acid, methyl ester {methyl nicotinate}

89-00-9

0

1

0

2,3-Pyridinedicarboxylic acid

58-56-0

0

1

0

3,4-Pyridinedimethanol, 5-hydroxy-6-methyl-, hydrochloride

13121-99-8

1

0

0

4-Pyridineacetonitrile

5264-15-3

1

0

0

4-Pyridinebutanol

100-48-1

1

0

0

4-Pyridinecarbonitrile

{quinolinic acid}

III-13, IV.A-3, XVII.B-2 V-3, XVII.B-2 IV.A-3, XVII.B-2 II.A-5, XVII.B-2, XVIII.B-3 XI-2, XVII.B-2 II.A-5, XVII.B-2 XI-2, XVII.B-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1746

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1747

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

5154-01-8

0

1

0

2,5-Pyridinediol

II.A-5, XVII.B-2

626-06-2

0

1

0

2,6-Pyridinediol

II.A-5, XVII.B-2

70898-25-8

1

0

0

2,6(1H,3H)-Pyridinedione, 3,5-dimethyl-

72692-95-6

1

0

0

2,6(1H,3H)-Pyridinedione, 4-methyl-

Name (per CA Collective Index)

Selected structures

XIV-1, XVII.B-2

O

1

0

0

2,6(1H,3H)-Pyridinedione, 5-methyl-

XIV-1, XVII.B-2

CH3 4

72692-94-5

Chapter Table

1

N H

3 2

O

XIV-1, XVII.B-2

1

0

0

3-Pyridinemethanamine, ethyl-

XII-2, XVII.B-2

3000-75-7

1

0

0

3-Pyridinemethanamine, N-ethyl-

XII-2, XVII.B-2

3-Pyridinemethanol

100-55-0

0

1

0

76014-81-8

0

1

0

3-Pyridinemethanol, D-[3(methylnitrosoamino)propyl]-

II.A-5, XV-8, XVII.B-2

II.A-5, XVII.B-2

85352-99-4

0

1

0

3-Pyridinemethanol, D-[3(methylnitrosoamino)propyl]-, 1-oxide

II.A-5, XV-8, XVII.B-2

71608-01-0

0

1

0

3-Pyridinepentanoic acid, 1,6-dihydro-G,6-dioxo-

III-13, IV.A-3, XVII.B-2, XVII.C-1 CO-(CH2)3-COOH

O

N H

39954-19-3

0

1

0

2,3,6-Pyridinetriol {see 2(1H)-pyridinone, 3,6-dihydroxy-}

II.A-5, XVII.B-2

60655-87-0

0

1

0

Pyridinium, 1-D-L-arabinopyranosyl-3-carboxy-

II.A-5, XVII.B-2

35323-45-6

0

1

0

Pyridinium, 3-carboxy-1-E-D-glucopyranosyl-, hydroxide {trigonelline}

II.A-5, XVII.B-2

535-83-1

0

1

0

Pyridinium, 3-carboxy-1-methyl-, hydroxide, inner salt

II.A-5, XVII.B-2

27341-45-3

1

0

0

Pyridinol

II.A-5, XVII.B-2

1

1

1

Pyridinol, methyl-

II.A-5, XVII.B-2

1

0

0

Pyridinol, dimethyl-

II.A-5, XVII.B-2

51025-25-3 72762-00-6

3279-76-3

1

0

0

2-Pyridinol

1

0

0

2-Pyridinol, 3,4-dimeth {2(1H)-pyridinone, 3,4-dimethyl-}

{2(1H)-pyridinone}

II.A-5, XVII.B-2

1

0

0

2-Pyridinol, 3,5-dimethyl-

II.A-5, XVII.B-2

1

0

0

2-Pyridinol, 3,6-dimethyl-

II.A-5, XVII.B-2

1

0

0

2-Pyridinol, 4,6-dimethyl-

II.A-5, XVII.B-2

1

0

0

2-Pyridinol, 6-ethyl-

II.A-5, XVII.B-2

1

0

0

2-Pyridinol, 3-methyl-

II.A-5, XVII.B-2

1

0

0

2-Pyridinol, 5-methyl-

II.A-5, XVII.B-2

1

0

0

2-Pyridinol, 6-methyl-

1

1

1

2-Pyridinol, 4-phenyl-

{2(1H)-pyridinone, 6-methyl-}

II.A-5, XVII.B-2

II.A-5, XVII.B-2 II.A-5, XVII.B-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1747

11/24/08 1:57:35 PM

1748

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

0

1

0

2-Pyridinol, 5-(2,3,4,5-tetrahydropyridinyl)-

Chapter Table

Selected structures

II.A-5, XVII.B-6

N HO

0

1

0

N

2-Pyridinol-5-butanoic acid, Ȗ-oxo-

III-13, IV.A-3, XVII.B-2 CO-(CH2)2-COOH

N

HO

0

1

0

2-Pyridinol-5-pentanoic acid, į-oxo-

109-00-2

1

0

0

3-Pyridinol

17747-43-2

1

0

0

3-Pyridinol, acetate (ester)

27296-76-0

III-13, IV.A-3, XVII.B-2 II.A-5, XVII.B-2 V-3, XVII.B-2

1

0

0

3-Pyridinol, alkyl-

II.A-5, XVII.B-2

1

0

0

3-Pyridinol, 2,4-dimethyl-

II.A-5, XVII.B-2

1122-43-6

1

0

0

3-Pyridinol, 2,6-dimethyl-

II.A-5, XVII.B-2

27296-77-1

1

0

0

3-Pyridinol, 4,6-dimethyl-

II.A-5, XVII.B-2

61893-00-3

1

0

0

3-Pyridinol, 5,6-dimethyl-

II.A-5, XVII.B-2

61893-02-5

1

1

1

3-Pyridinol, 2-ethyl-

II.A-5, XVII.B-2

62003-48-9 42451-07-0 61893-01-4

1

0

0

3-Pyridinol, 5-ethyl-

II.A-5, XVII.B-2

1

0

0

3-Pyridinol, 6-ethyl-

II.A-5, XVII.B-2

1

0

0

3-Pyridinol, 6-ethyl-2-methyl-

II.A-5, XVII.B-2

1

0

0

3-Pyridinol, 6-ethyl-4-methyl-

II.A-5, XVII.B-2

1

0

0

3-Pyridinol, 6-hydroxymethyl-

II.A-5, XVII.B-2

91491-14-4

1

0

0

3-Pyridinol, methyl-

II.A-5, XVII.B-2

1121-25-1

1

1

1

3-Pyridinol, 2-methyl-

II.A-5, XVII.B-2

1121-19-3

1

0

0

3-Pyridinol, 4-methyl-

II.A-5, XVII.B-2

42732-49-0

1

0

0

3-Pyridinol, 5-methyl-

II.A-5, XVII.B-2

1121-78-4

1

0

0

3-Pyridinol, 6-methyl-

II.A-5, XVII.B-2

14159-68-3

1

0

0

3-Pyridinol, 2-propyl-

II.A-5, XVII.B-2

61893-03-6

1

0

0

3-Pyridinol, 4-propyl-

II.A-5, XVII.B-2

61893-04-7

1

0

0

3-Pyridinol, 5-propyl-

II.A-5, XVII.B-2

626-64-2

1

0

0

4-Pyridinol

II.A-5, XVII.B-2

142-08-5

1

1

1

2(1H)-Pyridinone

XVII.B-2, XVII.C-1

N H

O

N

O

N

OH

61892-76-0

1

0

0

2(1H)-Pyridinone, 5-acetyl-3,4-dihydro-

XVII.B-2, XVII.C-1

57147-25-8

1

0

0

2(1H)-Pyridinone, 3,4-dihydro-

XVII.B-2, XVII.C-1

61892-77-1

1

0

0

2(1H)-Pyridinone, 3,6-dihydro-

XVII.B-2, XVII.C-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1748

11/24/08 1:57:36 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1749

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

6052-73-9

1

1

1

Name (per CA Collective Index)

Selected structures

2(1H)-Pyridinone, 5,6-dihydro{2-piperidone, 3,4-dehydro-}

XVII.B-2, XVII.C-1

4 3

5 6

Chapter Table

2

1

N H

O

0

1

0

2(1H)-Pyridinone, 5,6-dihydro-3,6,6-trimethyl-

XVII.B-2, XVII.C-1

70969-38-9

0

1

0

2(1H)-Pyridinone, 5-(3,4-dihydro-2H-pyrrol-5-yl)-

XVII.B-2, XVII.C-1

39954-19-3

0

1

0

2(1H)-Pyridinone, 3,6-dihydroxy{see 2,3,6-pyridinetriol}

XVII.B-2, XVII.C-1

72692-83-2

1

0

0

2(1H)-Pyridinone, dimethyl-

XVII.B-2, XVII.C-1

6456-92-4

1

0

0

2(1H)-Pyridinone, 1,3-dimethyl-

XVII.B-2, XVII.C-1

36330-90-2

1

0

0

2(1H)-Pyridinone, 3,4-dimethyl-

XVII.B-2, XVII.C-1

3718-67-0

1

0

0

2(1H)-Pyridinone, 3,5-dimethyl-

XVII.B-2, XVII.C-1

53428-02-7

1

0

0

2(1H)-Pyridinone, 3,6-dimethyl-

XVII.B-2, XVII.C-1

16115-08-5

1

0

0

2(1H)-Pyridinone, 4,6-dimethyl-

XVII.B-2, XVII.C-1

61892-99-7

1

0

0

2(1H)-Pyridinone, 6-ethyl-

XVII.B-2, XVII.C-1

5154-01-8

0

1

0

2(1H)-Pyridinone, 5-hydroxy-

626-06-2

0

1

0

2(1H)-Pyridinone, 6-hydroxy-

694-85-9

1

1

1

2(1H)-Pyridinone, 1-methyl-

II.A-5, XVII.B-2, XVII.C-1 II.A-5, XVII.B-2, XVII.C-1 XVII.B-2, XVII.C-1

4 3

5 6

1 N

2 O

CH3

1003-56-1

1

0

0

2(1H)-Pyridinone, 3-methyl-

XVII.B-2, XVII.C-1

1003-68-5

1

0

0

2(1H)-Pyridinone, 5-methyl-

XVII.B-2, XVII.C-1

3279-76-3

1

0

0

2(1H)-Pyridinone, 6-methyl-

XVII.B-2, XVII.C-1

40316-88-9

1

0

0

2(1H)-Pyridinone, 3-(1-methyl-2-pyrrolidinyl)-, (S){nicotone}

XVII.B-4, XVII.C-1

10516-09-3

0

1

0

2(1H)-Pyridinone, 5-(1-methyl-2-pyrrolidinyl)-, (S)-

XVII.B-4, XVII.C-1

19006-81-6

1

0

0

2(1H)-Pyridinone, 4-phenyl-

XVII.B-2, XVII.C-1

58064-43-0

1

1

1

3-Pyridinone

III-13, XVII.B-2

108-96-3

1

0

0

4(1H)-Pyridinone

III-13, XVII.B-2

1

0

0

Pyridoindole

XVII.E-6

1

0

0

Pyridoindole, butyl-

XVII.E-6

1

0

0

Pyridoindole, C3-alkyl-

XVII.E-6

1

0

0

Pyridoindole, N-methyl-

1

0

0

1H-Pyrido[2,3-b]indol-2-amine

26148-68-5

XVII.E-6 XII-2, XVII.F-8

{ADC}

N H

68006-83-7

1

0

0

N

1H-Pyrido[2,3-b]indol -2-amine, 3-methyl{MeADC}

NH2

XII-2, XVII.F-8 CH3

N H

N

NH2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1749

11/24/08 1:57:36 PM

1750

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

244-76-8

1

0

0

Name (per CA Collective Index)

Selected structures

1H-Pyrido[2,3-b]indole

4

Chapter Table XVII.E-6

3 2

N

N H

72693-00-6 61893-11-6

1

0

0

1

1H-Pyrido[2,3-b]indole, 1-butyl-

XVII.E-6

1

0

0

1H-Pyrido[2,3-b]indole, 2-ethyl-

XVII.E-6

1

0

0

1H-Pyrido[2,3-b]indole, 2-methyl-

XVII.E-6

1

0

0

1H-Pyrido[2,3-b]indole, 3-methyl-

XVII.E-6

78210-53-4

1

0

0

1H-Pyrido[2,3-b]indole, 2-(2-methylpropyl)-

XVII.E-6

78210-54-5

1

0

0

1H-Pyrido[2,3-b]indole, 2-pentyl-

XVII.E-6

42438-90-4

1

0

0

1H-Pyrido[3,4-b]indole-3-carboxylic acid, 2,3,4,9tetrahydro-, (S)-

IV.A-3, XVII.E-8

40678-46-4

1

0

0

1H-Pyrido[3,4-b]indole-3-carboxylic acid, 2,3,4,9tetrahydro-1-methyl-, (1S-cis)-

IV.A-3, XVII.E-8

83177-17-7

0

1

0

3H-Pyrido[3,4-b]indol-7-ol; 1,2-dihydro{1,2-dihydro-1-demethylharmalol}

XVII.E-8 H N HO

62450-06-0

1

0

0

NH

5H-Pyrido[4,3-b]indol-3-amine, 1,4-dimethyl{Trp-P-1}

XII-2, XVII.F-8 CH3 N NH2 N H

62450-07-1

1

0

0

5H-Pyrido[4,3-b]indol-3-amine, 1-methyl{Trp-P-2}

CH3

XII-2, XVII.F-8 CH3 N NH2 N H

17276-85-6

1

0

0

9H-Pyrido[2,3-b]indole, 2-methyl-

244-63-3

1

1

1

9H-Pyrido[3,4-b]indole

XVII.E-6 XVII.E-6 N

{norharman = E-carboline = 2-azacarbazole} N H

10371-85-4 20127-61-1

486-84-0

1

0

0

9H-Pyrido[3,4-b]indole, 1-butyl-

XVII.E-6

1

0

0

9H-Pyrido[3,4-b]indole, 1-ethyl-

XVII.E-6

1

0

0

9H-Pyrido[3,4-b]indole, methyl{methylnorharman}

XVII.E-6

1

1

1

9H-Pyrido[3,4-b]indole, 1-methyl-

{harman}

XVII.E-6 N N H

78210-55-6

1

0

0

9H-Pyrido[3,4-b]indole, 1-(1-propenyl)-

78538-74-6

1

0

0

9H-Pyrido[3,4-b]indole-3-carboxamide, N-methyl-

CH3

XVII.E-6 XIII-1, XVII.E-8

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1750

11/24/08 1:57:37 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1751

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

50609-61-5

1

0

0

4H-Pyrido[1,2-a]pyrimidine-3-acetic acid, 9-hydroxy4-oxo-, ethyl ester

3303-26-2

0

1

0

Pyrido[3,2-d]pyrimidin-4-ol, 2-methyl-

289-95-2

0

1

0

Pyrimidine

Name (per CA Collective Index)

Selected structures

Chapter Table

II.A-5, V-3, XVII.E-8 II.A-5, XVII.E-8

{1,3-diazine}

XVII.B-2

N N

5221-53-4

0

1

0

Pyrimidine, 5-butyl-2-dimethylamino-4-hydroxy-6methyl{Dimetherimol®}

II.A-5, XVII.B-2, XXI-3

(CH2)3-CH3 HO

CH3 N

N N (CH3)2

72692-81-0

1

0

0

Pyrimidine, dimethyl-

XVII.B-2

14331-54-5

1

0

0

Pyrimidine, 2,4-dimethyl-

XVII.B-2

1

0

0

Pyrimidine, 2,5-dimethyl-6-hydroxy-

XVII.B-2

1

0

0

Pyrimidine, 4,6-dimethyl-

XVII.B-2

1558-17-4 88070-43-3 66-22-8

1

0

0

Pyrimidine, 5-hydroxy-4-phenyl-

1

0

0

Pyrimidine, methylethyl- {2 isomers}

0

1

0

2,4(1H,3H)-Pyrimidinedione

II.A-5, XVII.B-2 XVII.B-2 {uracil}

XVII.B-2

O HN O

N H

4160-77-4

1

0

0

2,4(1H,3H)-Pyrimidinedione, 3,5-dimethyl-

XVII.B-2

61893-13-8

1

0

0

2,4(1H,3H)-Pyrimidinedione, 3-ethyldihydro-5methyl-

XVII.B-2

65-71-4

1

1

1

2,4(1H,3H)-Pyrimidinedione, 5-methyl-

XVII.B-2

71-30-7

0

1

0

2(1H)-Pyrimidinone, 4-amino-

{thymine} {cytosine}

XVII. B-2, XVII.C-1

H2N N

NH O

34939-17-8

1

0

0

2(1H)-Pyrimidinone, 4,5-dimethyl-= 2- Pyrimidinol, 4,5-dimethyl-

XVII.B-2, XVII.C-1

3059-71-0

1

0

0

4(1H)-Pyrimidinone, 2,5-dimethyl- = 6-Pyrimidinol, 2,5-dimethyl-

XVII.B-2, XVII.C-1

6622-92-0

1

0

0

4(1H)-Pyrimidinone, 2,6-dimethyl- = 6-Pyrimidinol, 2,4-dimethyl-

XVII.B-2, XVII.C-1

34916-78-4

1

0

0

4(1H)-Pyrimidinone, 5,6-dimethyl- = 6-Pyrimidinol, 4,5-dimethyl-

XVII.B-2, XVII.C-1

16858-16-5

1

0

0

4(1H)-Pyrimidinone, 6-methyl-2-propyl- = 6Pyrimidinol, 4-methyl-2-propyl-

XVII.B-2, XVII.C-1

533-37-9

1

0

0

5H-1-Pyrindine, 6,7-dihydro-

55713-43-4

0

1

0

7H-2-Pyrindin-7-one, 5,6-dihydro-3,6,6-trimethyl-

XVII.E-8 CH3

5

3

H3C O

III-13

4

6 7

1

CH3

N2

9033-44-7

0

1

0

Pyrophosphatase

XXII-2

9024-82-2

0

1

0

Pyrophosphatase, inorganic

XXII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1751

11/24/08 1:57:37 PM

1752

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

37289-33-1

0

1

0

Pyrophosphatase, nicotinamide adenine dinucleotide

XXII-2

9032-64-8

0

1

0

Pyrophosphatase, nucleotide

XXII-2

Name (per CA Collective Index)

Selected structures

Chapter Table

9038-53-3

0

1

0

Pyrophosphatase, thiamin

XXII-2

68858-66-2

0

1

0

Pyrophosphorylase

XXII-2

37277-74-0

0

1

0

Pyrophosphorylase, nicotinate mononucleotide (carboxylating)

XXII-2

106398-69-0

1

0

0

Pyrrole, butyl-

XVII.A-4

71607-59-5

1

0

0

Pyrrole, dihydromethyl-

XVII.A-4

1

0

0

Pyrrole, hydroxymethyl-

1

1

1

1H-Pyrrole

109-97-7

II.A-5, XVII.A-4 {azole}

4 5

XVII.A-4

3 2

N H

609-41-6

1

0

0

1H-Pyrrole, 1-acetyl-

XVII.A-4

23105-58-0

1

0

0

1H-Pyrrole, 1-acetyl-2,3-dihydro-

XVII.A-4

38207-11-3

0

1

0

1H-Pyrrole, 1-acetyl-2-methyl-

XVII.A-4

0

1

0

1H-Pyrrole, 1-acetyl-3-methyl-

XVII.A-4

589-33-3

1

0

0

1H-Pyrrole, 1-butyl-

XVII.A-4

62672-96-2

1

0

0

1H-Pyrrole, 1-(1-cyclohexen-1-yl)-

XVII.A-4

28350-87-0

1

0

0

1H-Pyrrole, dihydro-

109-96-6

1

1

1

1H-Pyrrole, 2,5-dihydro-

XVII.A-4 {3-pyrroline} 5

554-15-4

XVII.A-4

3

4 1 N H

2

0

1

0

1H-Pyrrole, 2,5-dihydro-1-methyl-

XVII.A-4

1

0

0

1H-Pyrrole, 2,3-dimethyl-

XVII.A-4

625-82-1

1

1

1

1H-Pyrrole, 2,4-dimethyl-

XVII.A-4

625-84-3

1

1

1

1H-Pyrrole, 2,5-dimethyl-

XVII.A-4

1

0

0

1H-Pyrrole, 3,4-dimethyl-

XVII.A-4

0

1

0

1H-Pyrrole, 2-ethenyl-

XVII.A-4

2433-66-1 617-92-5

1

1

1

1H-Pyrrole, 1-ethyl-

XVII.A-4

1

0

0

1H-Pyrrole, 3-ethyl-1-phenyl-

XVII.A-4

1

0

0

1H-Pyrrole, 1-(2-furanyl)-

XVII.A-4

1438-94-4

1

1

1

1H-Pyrrole, 1-(2-furanylmethyl)-

XVII.A-4

27417-39-6

1

0

0

1H-Pyrrole, methyl-

XVII.A-4

96-54-8

1

1

1

1H-Pyrrole, 1-methyl-

XVII.A-4

636-41-9

1

0

0

1H-Pyrrole, 2-methyl-

XVII.A-4

1

0

0

1H-Pyrrole, 2-methyl-1-phenyl-

XVII.A-4

1

0

0

1H-Pyrrole, 3-methyl-

XVII.A-4

0

1

0

1H-Pyrrole, 3-methyl-4-ethyl-

XVII.A-4

1

0

0

1H-Pyrrole, 3-methyl-1-phenyl-

XVII.A-4

13679-79-3

1

1

1

1H-Pyrrole, 1-(3-methylbutyl)-

XVII.A-4

66309-87-3

1

0

0

1H-Pyrrole, 1-(2-methyl-1-cyclohexen-1-yl)-

XVII.A-4

616-43-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1752

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1753

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

7057-97-8

1

0

0

1H-Pyrrole, 1-(1-methylethyl)-

XVII.A-4

13678-52-9

1

0

0

1H-Pyrrole, 1-[(5-methyl-2-furanyl)methyl]-

XVII.A-4

78075-83-9

1

0

0

1H-Pyrrole, 2-methyl-1-(phenylmethyl)-

XVII.A-4

20884-13-3

1

0

0

1H-Pyrrole, 1-(2-methylpropyl)-

XVII.A-4

61480-97-5

1

0

0

1H-Pyrrole, 1-(1-oxobutyl)-

XVII.A-4

699-22-9

1

0

0

1H-Pyrrole, 1-pentyl-

XVII.A-4

635-90-5

1

0

0

1H-Pyrrole, 1-phenyl-

XVII.A-4

50691-29-7

1

0

0

1H-Pyrrole, 1-(2-phenylethyl)-

XVII.A-4

5145-64-2

1

0

0

1H-Pyrrole, 1-propyl-

XVII.A-4

1551-08-2

0

1

0

1H-Pyrrole, 2-propyl-

XVII.A-4

71646-51-0

1

0

0

1H-Pyrrolecarbonitrile, methyl-

89145-04-0

0

1

0

1H-Pyrrolecarboxaldehyde

72692-79-6

1

0

0

1H-Pyrrolecarboxylic acid, ethyl ester

84499-92-3

0

1

0

1H-Pyrrole-1-acetic acid, 2-(ethoxymethyl)-5-formyl-

61837-43-2

0

1

0

1H-Pyrrole-1-acetic acid, 2-ethyl-5-formyl-D-(2methylpropyl)-

IV.A-3, XVII.A-4

60026-07-5

0

1

0

1H-Pyrrole-1-acetic acid, 2-formyl-D-(1methylethyl)-

IV.A-3, XVII.A-4

XI-2, XVII.A-4 III-12, XVII.A-4 V-3, XVII.A-4 IV.A-3, X-2, XVII.A-4

CHO

N CH

CH(CH3)2

HOOC

60026-08-6

0

1

0

IV.A-3, XVII.A-4

1H-Pyrrole-1-acetic acid, 2-formyl-D-(1methylpropyl)N

CHO

CH HOOC

60026-09-7

0

1

0

CH(CH3)-CH2-CH3

IV.A-3, XVII.A-4

1H-Pyrrole-1-acetic acid, 2-formyl-D-(2methylpropyl)N

CHO

CH HOOC

CH2-CH=(CH3)2

1

0

0

1H-Pyrrole-1-acetic acid, 2-formyl-5-hydroxymethylD-(2-methylpropyl)-

II.A-5, IV.A-3, XVII.A-4

61837-42-1

0

1

0

1H-Pyrrole-1-acetic acid, 2-formyl-D,5-dimethyl-

IV.A-3, XVII.A-4

61837-35-2

0

1

0

1H-Pyrrole-1-acetic acid, 2-formyl-D-hexyl-

IV.A-3, XVII.A-4

60026-30-4

0

1

0

1H-Pyrrole-1-acetic acid, 2-formyl-D-methyl-

61837-38-5

0

1

0

1H-Pyrrole-1-butanoic acid, 2-formyl-

61837-39-6

0

1

0

1H-Pyrrole-1-butanoic acid, 2-formyl-J-methyl-

IV.A-3, XVII.A-4

61837-44-3

0

1

0

1H-Pyrrole-1-butanoic acid, 2-formyl-5-methyl-

IV.A-3, XVII.A-4

61837-40-9

0

1

0

1H-Pyrrole-1-hexanoic acid, 2-formyl-

IV.A-3, XVII.A-4

61837-41-0

0

1

0

1H-Pyrrole-1-octanoic acid, 2-formyl-

IV.A-3, XVII.A-4

70898-32-7

0

1

0

1H-Pyrrole-1-octanoic acid, 2-formyl-5-methyl-

IV.A-3, XVII.A-4

61837-37-4

0

1

0

1H-Pyrrole-1-propanoic acid, E-ethyl-2-formyl-

IV.A-3, XVII.A-4

61837-36-3

0

1

0

1H-Pyrrole-1-propanoic acid, 2-formyl-E-methyl-

IV.A-3, XVII.A-4

IV.A-3, XVII.A-4 II.A-5, IV.A-3, XVII.A-4

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1753

11/24/08 1:57:38 PM

1754

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

72693-01-7 4513-94-4 26173-92-2

S

T

S T

1

0

0

1H-Pyrrole-2-acetaldehyde, D-hydroxy-

III-12, XVII.A-4

1

0

0

1H-Pyrrole-2-acetaldehyde, D-oxo-

III-13, XVII.A-4

Name (per CA Collective Index)

1

0

0

1H-Pyrrole-2-carbonitrile

1

0

0

1H-Pyrrole-2-carbonitrile, methyl-

1

0

0

1H-Pyrrole-2-carbonitrile, 5-methyl-

Selected structures

Chapter Table

XI-2, XVII.A-4 {2 isomers}

XI-2, XVII.A-4 XI-2, XVII.A-4

1003-29-8

1

1

1

1H-Pyrrole-2-carboxaldehyde

III-12, XVII.A-4

13788-32-4

0

1

0

1H-Pyrrole-2-carboxaldehyde, 1-(2-furanylmethyl)-

III-12, XVII.A-4

13678-79-0 2167-14-8

0

1

0

1H-Pyrrole-2-carboxaldehyde, 1-(3-methylbutyl)-

III-12, XVII.A-4

1

0

0

1H-Pyrrole-2-carboxaldehyde, ethyl-

III-12, XVII.A-4

1

0

0

1H-Pyrrole-2-carboxaldehyde, 1-ethyl-

III-12, XVII.A-4

1

0

0

1H-Pyrrole-2-carboxaldehyde, methyl-

III-12, XVII.A-4

1192-58-1

1

1

1

1H-Pyrrole-2-carboxaldehyde, 1-methyl-

29813-44-3

1

1

1

1H-Pyrrole-2-carboxaldehyde, 5-(hydroxymethyl)-1methyl-

III-12, XVII.A-4

52115-69-2

0

1

0

1H-Pyrrole-2-carboxaldehyde, 5[(acetyloxy)methyl]-

III-12, XVII.A-4

1192-79-6

1

1

1

1H-Pyrrole-2-carboxaldehyde, 5-methyl-

III-12, XVII.A-4

4551-72-8

1

0

0

1H-Pyrrole-2-carboxamide

XIII-1, XVII.A-4

634-97-9

1

0

0

1H-Pyrrole-2-carboxylic acid

IV.A-3, XVII.A-4

3220-74-4

0

1

0

1H-Pyrrole-2-carboxylic acid, 2,5-dihydro-

IV.A-3, XVII.A-4

3757-53-7

1

0

0

1H-Pyrrole-2-carboxylic acid, 5-methyl-

IV.A-3, XVII.A-4

3284-51-3

1

0

0

1H-Pyrrole-2-carboxylic acid, 5-methyl-, ethyl ester

V-3, XVII.A-4

1194-97-4

1

0

0

1H-Pyrrole-2-carboxylic acid, 5-methyl-, methyl ester

V-3, XVII.A-4

1193-62-0

1

0

0

1H-Pyrrole-2-carboxylic acid, methyl ester

XVII.A-4

1

0

0

1H-Pyrrole-3-acetonitrile

XVII.A-4

II.A-5, III-12, XVII.A-4

7126-38-7

1

0

0

1H-Pyrrole-3-carbonitrile

17619-39-5

1

1

1

1H-Pyrrole-3-carboxaldehyde, 2-methyl-

III-12, XVII.A-4

XVII.A-4

103002-58-0

0

1

0

1H-Pyrrole-3-carboxaldehyde, 4,5-dihydro-2-methyl-

III-12, XVII.A-4

78210-62-5

1

0

0

1H-Pyrrole-3-carboxaldehyde, 5-ethyl-

III-12, XVII.A-4

936-12-9

1

0

0

1H-Pyrrole-3-carboxylic acid, 2-methyl-, ethyl ester

487-90-1

0

1

0

1H-Pyrrole-3-propanoic acid, 5-(aminomethyl)-4(carboxymethyl)-

541-59-3

1

1

1

1H-Pyrrole-2,5-dione

29720-92-1

1

1

1

1H-Pyrrole-2,5-dione, ethylmethyl-

XIV-2, XVII.A-4

128-53-0

1

0

0

1H-Pyrrole-2,5-dione, 1-ethyl-

XIV-2, XVII.A-4

{maleimide}

V-3, XVII.A-4 IV.A-3, XII-2, XVII.A-4 XIV-2, XVII.A-4

5997-61-5

1

0

0

1H-Pyrrole-2,5-dione, 3-ethyl-

61892-73-7

1

0

0

1H-Pyrrole-2,5-dione, 3-(hydroxymethyl)-

II.A-5, XIV-2, XVII.A-4

XIV-2, XVII.A-4

61892-71-5

1

0

0

1H-Pyrrole-2,5-dione, 3,4-bis(hydroxymethyl)-1methyl-

II.A-5, XIV-2, XVII.A-4

17825-86-4

1

1

1

1H-Pyrrole-2,5-dione, 3,4-dimethyl-

61892-72-6

1

0

0

1H-Pyrrole-2,5-dione, 3-ethyl-4-(hydroxymethyl)-

20189-42-8

1

1

1

1H-Pyrrole-2,5-dione, 3-ethyl-4-methyl-

XIV-2, XVII.A-4 II.A-5, XIV-2, XVII.A-4 XIV-2, XVII.A-4

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1754

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1755

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1072-87-3

1

0

0

1H-Pyrrole-2,5-dione, 3-methyl-

XIV-2, XVII.A-4

60026-19-9

0

1

0

1H-Pyrrole-2,5-dione, 3-propyl-

XIV-2, XVII.A-4

3317-61-1

1

0

0

2H-Pyrrole, 3,4-dihydro-2,2-dimethyl-, 1-oxide

121197-26-0

1

0

0

2H-Pyrrole-2,4(3H)-dione, 3-butyl-5-(2methylpropyl)-

XVII.C-1, XVII.A-4

XVII.A-4

121197-16-8

1

0

0

2H-Pyrrole-2,4(3H)-dione, 3-butyl-5-propyl-

XVII.C-1, XVII.A-4

121197-27-1

1

0

0

2H-Pyrrole-2,4(3H)-dione, 3,5-bis(2-methylpropyl)-

XVII.C-1, XVII.A-4

121197-23-7

1

0

0

2H-Pyrrole-2,4(3H)-dione, 3,5-dibutyl-

XVII.C-1, XVII.A-4

121197-14-6

1

0

0

2H-Pyrrole-2,4(3H)-dione, 3,5-dipropyl-

XVII.C-1, XVII.A-4

121197-21-5

1

0

0

2H-Pyrrole-2,4(3H)-dione, 5-(2-methylpropyl)-3propyl-

XVII.C-1, XVII.A-4

121197-24-8

1

0

0

2H-Pyrrole-2,4(3H)-dione, 5-butyl-3-(2methylpropyl)-

XVII.C-1, XVII.A-4

121213-26-1

1

0

0

2H-Pyrrole-2,4(3H)-dione, 5-butyl-3-propyl-

XVII.C-1, XVII.A-4

72692-82-1

1

0

0

1H-Pyrrolemethanol

123-75-1

1

1

1

Pyrrolidine

II.A-5, XVII.A-4 4 5

71607-78-8 71607-79-9

1

0

0

Pyrrolidine, diethyl-

XVII.A-4

3 N H

2

XVII.A-4

1

0

0

Pyrrolidine, dimethyl-

1

0

0

Pyrrolidine, 2.5-dimethyl-, 1-nitroso-

71607-80-2

1

0

0

Pyrrolidine, ethyl-

XVII.A-4

4030-18-6

1

1

1

Pyrrolidine, 1-acetyl-

XVII.A-4

5979-94-2

1

1

1

Pyrrolidine, 1-acetyl-2-(3-pyridinyl)-, (S){N’-acetylnornicotine}

7335-06-0

XVII.A-4 XV-8, XVII.A-4

1

0

0

Pyrrolidine, 1-ethyl-

0

1

0

Pyrrolidine, 1-ethyl-2-(3-pyridinyl){N’-ethylnornicotine}

120-94-5

1

1

1

Pyrrolidine, 1-methyl-

930-55-2

1

1

1

Pyrrolidine, 1-nitroso-

XIII-1, XVII.B-4, XXI-3 XVII.A-4 XVII.B-4, XXI-3 XVII.A-4 XV-8, XVII.A-4

{NPYR} N NO

7335-07-1

1

0

0

Pyrrolidine, 1-propyl-

XVII.A-4

91907-45-8

0

1

0

Pyrrolidine, 1-propyl-2-(3-pyridinyl){N’-propylnornicotine}

XVII.B-4, XXI-3

117642-93-0

0

1

0

Pyrrolidine, 1-(10-methyl-1-oxododecyl)-2-(3pyridinyl)-

XIII-1, XVII.B-4

120376-92-3

0

1

0

Pyrrolidine, 1-(10-methyl-1-oxoundecyl)-2-(3pyridinyl)-

XIII-1, XVII.B-4

117642-94-1

0

1

0

Pyrrolidine, 1-(10-methyl-1-oxoundecyl)-2-(3pyridinyl)-, (S)-

XIII-1, XVII.B-4

120042-36-6

0

1

0

Pyrrolidine, 1-(11-methyl-1-oxododecyl)-2-(3pyridinyl)-, (S)-

XIII-1, XVII.B-4

120376-93-4

0

1

0

Pyrrolidine, 1-(12-methyl-1-oxotridecyl)-2-(3pyridinyl)-

XIII-1, XVII.B-4

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1755

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1756

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

69730-91-2

1

1

1

Pyrrolidine, 1-(1-oxobutyl)-2-(3-pyridinyl)-, (S)-

XIII-1, XVII.B-4

115849-75-7

0

1

0

Pyrrolidine, 1-(1-oxododecyl)-2-(3-pyridinyl)-, (S)-

XIII-1, XVII.B-4

74173-71-0

1

0

0

Pyrrolidine, 1-(1-oxoheptyl)-2-(3-pyridinyl)-, (S)-

XIII-1, XVII.B-4

38854-09-0

1

1

1

Pyrrolidine, 1-(1-oxohexyl)-2-(3-pyridinyl)-, (S)-

XIII-1, XVII.B-4

1

0

0

Pyrrolidine, 1-(1-oxo-?-octenyl)-2-(3-pyridinyl)-, (S)-

XIII-1, XVII.B-4

38854-10-3

1

1

1

Pyrrolidine, 1-(1-oxooctyl)-2-(3-pyridinyl)-, (S)-

XIII-1, XVII.B-4

120042-35-5

0

1

0

Pyrrolidine, 1-(1-oxotridecyl)-2-(3-pyridinyl)-, (S)-

XIII-1, XVII.B-4

61893-12-7

1

0

0

Pyrrolidine, 1-(2-furanylmethyl)-

115849-82-6

0

1

0

Pyrrolidine, 1-(3-hydroxy-10-methyl-1-oxododecyl)2-(3-pyridinyl)-

II.A-5, XIII-1, XVII.B-4

115849-79-1

0

1

0

Pyrrolidine, 1-(3-hydroxy-10-methyl-1-oxoundecyl)2-(3-pyridinyl)-

II.A-5, XIII-1, XVII.B-4

116353-95-8

0

1

0

Pyrrolidine, 1-(3-hydroxy-12-methyl-1oxotetradecyl)-2-(3-pyridinyl)-

II.A-5, XIII-1, XVII.B-4

115849-84-8

0

1

0

Pyrrolidine, 1-(3-hydroxy-12-methyl-1-oxotridecyl)2-(3-pyridinyl)-

II.A-5, XIII-1, XVII.B-4

120042-33-3

0

1

0

Pyrrolidine, 1-(3-hydroxy-14-methyl-1oxopentadecyl)-2-(3-pyridinyl)-

II.A-5, XIII-1, XVII.B-4

115849-80-4

0

1

0

Pyrrolidine, 1-(3-hydroxy-1-oxododecyl)-2-(3pyridinyl)-

II.A-5, XIII-1, XVII.B-4

120042-32-2

0

1

0

Pyrrolidine, 1-(3-hydroxy-1-oxohexadecyl)-2-(3pyridinyl)-

II.A-5, XIII-1, XVII.B-4

120042-34-4

0

1

0

Pyrrolidine, 1-(3-hydroxy-1-oxopentadecyl)-2-(3pyridinyl)-

II.A-5, XIII-1, XVII.B-4

115849-85-9

0

1

0

Pyrrolidine, 1-(3-hydroxy-1-oxotetradecyl)-2-(3pyridinyl)-

II.A-5, XIII-1, XVII.B-4

115849-83-7

0

1

0

Pyrrolidine, 1-(3-hydroxy-1-oxotridecyl)-2-(3pyridinyl)-

II.A-5, XIII-1, XVII.B-4

60026-17-7

0

1

0

Pyrrolidine, 1-(3-methyl-1-oxobutyl)-

1

0

0

Pyrrolidine, 1-(3-pyridinemethyl)-2-cyano-

96552-73-7

1

0

0

Pyrrolidine, 1-(4-methyl-1-oxohexyl)-2-(3-pyridinyl)-

XIII-1, XVII.B-4

77829-17-5

0

1

0

Pyrrolidine, 1-(6-hydroxy-1-oxooctyl)-2-(3-pyridinyl)-

XIII-1, XVII.B-4

96574-02-6

1

0

0

Pyrrolidine, 1-(6-methyl-1-oxoheptyl)-2-(3-pyridinyl), (S)-

XIII-1, XVII.B-4

77829-18-6

0

1

0

Pyrrolidine, 1-(7-hydroxy-1-oxooctyl)-2-(3-pyridinyl)-

XIII-1, XVII.B-4

61480-99-7

1

0

0

Pyrrolidine, 1-[(5-methyl-2-furanyl)methyl]-

69730-92-3

0

1

0

Pyrrolidine, 1-[4-(dimethylamino)-1-oxobutyl]-2-(3pyridinyl)-, (S)-

1

0

0

Pyrrolidine, 2-acetyloxy-methyl-

13603-04-8

1

0

0

Pyrrolidine, 2,4-dimethyl-

XVII.A-4

3378-71-0

1

0

0

Pyrrolidine, 2,5-dimethyl-

XVII.A-4

1003-28-7

1

0

0

Pyrrolidine, 2-ethyl-

XVII.A-4

X-2, XVII.A-4

XIII-1, XVII.A-4 XVII.A-4

XVII.A-4 XII-2, XIII-1, XVII.B-4 V-3, XVII.A-4

765-38-8

1

0

0

Pyrrolidine, 2-methyl-

XVII.A-4

34375-89-8

1

0

0

Pyrrolidine, 3-methyl-

XVII.A-4

28882-68-0

1

0

0

Pyrrolidinecarboxylic acid

32389-40-5

0

1

0

Pyrrolidinecarboxylic acid, oxo-, (S)-

IV.A-3, XVII.A-4 III-13, IV.A-3, XVII.A-4

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1756

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The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1757

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

29134-29-0

1

0

0

1-Pyrrolidineacetonitrile

3760-54-1

1

1

1

1-Pyrrolidinecarboxaldehyde

Name (per CA Collective Index)

Selected structures

Chapter Table XI-2, XVII.A-4 III-12, XVII.A-4

78914-62-2

1

0

0

1-Pyrrolidinecarboxaldehyde, 2-methyl-, (R)-

38840-03-8 3000-81-5

1

1

1

1-Pyrrolidinecarboxaldehyde, 2-(3-pyridinyl)-, (S){N’-formylnornicotine}

III-12, XVII.A-4

69730-90-1

0

1

0

1-Pyrrolidinecarboxylic acid, 2-(3-pyridinyl)-, ethyl ester, (S)-

V-3, XVII.B-4

56078-08-1

1

1

1

1-Pyrrolidinecarboxylic acid, 2-(3-pyridinyl)-, methyl ester, (S)-

V-3, XVII.B-4

56879-46-0

0

1

0

2-Pyrrolidineacetic acid

III-12, XVII.B-4, XXI-3

IV.A-3, XVII.A-4

0

1

0

2-Pyrrolidineacetic acid, 1-nitroso-

61480-98-6

0

1

0

2-Pyrrolidinecarboxaldehyde

IV.A-3, XV-8, XVII.A-4 III-12, XVII.A-4

28115-37-9

1

0

0

2-Pyrrolidinemethanol, 5-methyl-, cis-

II.A-5, XVII.A-4

14498-44-3

1

0

0

2-Pyrrolidinepropanol, 1-methyl-

II.A-5, XVII.A-4

60026-15-5

0

1

0

3-Pyrrolidinecarboxaldehyde, 2-methyl-

III-12, XVII.A-4

121197-25-9

1

0

0

2,4-Pyrrolidinedione, 3-butyl-5-propylidene-

III-13, XVII.A-4

121197-20-4

1

0

0

2,4-Pyrrolidinedione, 5-butyl-3-propylidene-

III-13, XVII.A-4

121197-28-2

1

0

0

2,4-Pyrrolidinedione, 3-butylidene-5-(2methylpropyl)-

III-13, XVII.A-4

121197-18-0

1

0

0

2,4-Pyrrolidinedione, 3-butylidene-5-propyl-

III-13, XVII.A-4

121197-17-9

1

0

0

2,4-Pyrrolidinedione, 5-(2-methylpropyl)-3-(2methylpropylidene)-

III-13, XVII.A-4

121197-22-6

1

0

0

2,4-Pyrrolidinedione, 5-(2-methylpropyl)-3propylidene-

III-13, XVII.A-4

121197-19-1

1

0

0

2,4-Pyrrolidinedione, 3-(2-methylpropylidene)-5propyl-

III-13, XVII.A-4

121197-15-7

1

0

0

2,4-Pyrrolidinedione, 5-propyl-3-propylidene-

123-56-8

1

1

1

2,5-Pyrrolidinedione

III-13, XVII.A-4

{succinimide} O

4

3

5

1 2

N H

XIV-1, XVII.A-4 O

15542-96-8

1

0

0

2,5-Pyrrolidinedione, 1,3-dimethyl-

XIV-1, XVII.A-4

33425-47-7

1

0

0

2,5-Pyrrolidinedione, 3,4-dimethyl-

XIV-1, XVII.A-4

5835-19-8 58467-27-9

1

0

0

2,5-Pyrrolidinedione, 3-ethyl-

XIV-1, XVII.A-4

1

0

0

2,5-Pyrrolidinedione, ethyl-methyl-

XIV-1, XVII.A-4

15542-97-9

1

1

1

2,5-Pyrrolidinedione, 3-ethyl-1-methyl-

XIV-1, XVII.A-4

77-67-8

1

1

1

2,5-Pyrrolidinedione, 3-ethyl-3-methyl-

XIV-1, XVII.A-4

1

1

1

2,5-Pyrrolidinedione, 3-ethyl-4-methyl-

XIV-1, XVII.A-4

16824-61-6

1

1

1

2,5-Pyrrolidinedione, 3-ethyl-4-methyl-, (Z)-

XIV-1, XVII.A-4

1

0

0

2,5-Pyrrolidinedione, 3-ethylene-4-methyl-

XIV-1, XVII.A-4

14156-12-8

1

0

0

2,5-Pyrrolidinedione, 3-ethylidene-

XIV-1, XVII.A-4

61892-74-8

1

0

0

2,5-Pyrrolidinedione, 3-ethylidene-1-methyl-

XIV-1, XVII.A-4

16395-79-2

1

1

1

2,5-Pyrrolidinedione, 3-ethylidene-4-methyl-

18366-19-3

1

0

0

2,5-Pyrrolidinedione, 3-hydroxy- (S)

XIV-1, XVII.A-4 II.A-5, XIV-1, XVII.A-4

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1757

11/24/08 1:57:40 PM

1758

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

1121-07-9

1

1

1

2,5-Pyrrolidinedione, 1-methyl-

XIV-1, XVII.A-4

5615-90-7

1

1

1

2,5-Pyrrolidinedione, 3-methyl-

XIV-1, XVII.A-4

72693-03-9

1

0

0

2,5-Pyrrolidinedione, 3-(1-methylethyl)-

XIV-1, XVII.A-4

15542-99-1

1

0

0

2,5-Pyrrolidinedione,1-methyl-3-(1-methylethyl)-

XIV-1, XVII.A-4

71099-03-1

1

1

1

2,5-Pyrrolidinedione, 1,3,4-trimethyl-

XIV-1, XVII.A-4

25110-79-6

1

0

0

2-Pyrrolidinol, 1-methyl-5-(3-pyridinyl)-

28261-54-3

1

0

0

Pyrrolidinone

616-45-5

1

1

1

2-Pyrrolidinone

Name (per CA Collective Index)

Selected structures

Chapter Table

XVII.B-4 XVII.A-4

{Ȗ-butyrolactam}

4 5

XVII.A-4, XVII.C-1

3 2

1

O

N H

1

0

0

2-Pyrrolidinone, 1,?-dimethyl-

XVII.A-4, XVII.C-1

872-50-4

1

1

1

2-Pyrrolidinone, 1-methyl-

XVII.A-4, XVII.C-1

2555-05-7

1

0

0

2-Pyrrolidinone, 3-methyl-

XVII.A-4, XVII.C-1

2996-58-9

1

1

1

2-Pyrrolidinone, 4-methyl-

XVII.A-4, XVII.C-1

108-27-0

1

0

0

2-Pyrrolidinone, 5-methyl-

XVII.A-4, XVII.C-1

75202-09-4

1

0

0

2-Pyrrolidinone, 1-methyl-5-(3-pyridinyl)-

XVII.B-4, XVII.C-1

486-56-6

1

1

1

2-Pyrrolidinone, 1-methyl-5-(3-pyridinyl)-, (S){cotinine}

XVII.B-4, XVII.C-1 N

O

CH3

N

1

0

0

2-Pyrrolidinone, 1-methyl-5-(3-pyridinyl)-, 1-oxide {cotinine 1-oxide}

XVII.B-4, XVII.C-1

61892-90-8

1

0

0

2-Pyrrolidinone, 1-(2-oxopropyl)-

XVII.A-4, XVII.C-1

5980-06-3

1

0

0

2-Pyrrolidinone, 5-(3-pyridinyl)-, (S)-

98-79-3

0

1

0

5-Pyrrolidinone-2-carboxylic acid

XVII.B-4, XVII.C-1

{norcotinine}

{5-oxoproline}

IV.A-3, XVII.A-4, XVII.C-1 O

61892-89-5

1

0

0

3-Pyrrolidinone, 1-methyl-5-(2-oxopropyl)-

18028-53-0

1

0

0

2H-Pyrrolium, 3,4-dihydro-1-methyl-, chloride

17266-64-7

1

0

0

1H-Pyrrolizin-1-one, 2,3-dihydro-

COOH

N H

XVII.A-4 XVII.A-4, XVIII.B-3 III-13

O

N

13939-91-8

1

0

0

1H-Pyrrolo[1,2-c]imidazole-1,3(2H)-dione

XIV-1

O

N

N-H

O

5768-79-6

1

0

0

1H-Pyrrolo[1,2-c]imidazole-1,3(2H)-dione, tetrahydro-

O

N

XIV-1

N-H

O

54036-77-0

1

0

0

2H-Pyrrol-2-one

XVII.A-4, XVII.C-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1758

11/24/08 1:57:41 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1759

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

62003-47-8

1

0

0

2H-Pyrrol-2-one, 1,3-dihydro-5-(3-pyridinyl)-

XVII.B-4, XVII.C-1

4031-15-6

1

0

0

2H-Pyrrol-2-one, 1,5-dihydro-

XVII.A-4, XVII.C-1

13950-21-5

0

1

0

2H-Pyrrol-2-one, 1,5-dihydro-1-methyl-

XVII.A-4, XVII.C-1

78210-72-7

1

0

0

2H-Pyrrol-2-one, 1,5-dihydro-1-methyl-5-(1methylethylidene)-

XVII.A-4, XVII.C-1

4030-23-3

1

0

0

2H-Pyrrol-2-one, 1,5-dihydro-3,4,5-trimethyl-

XVII.A-4, XVII.C-1

4030-22-2

Name (per CA Collective Index)

Selected structures

Chapter Table

1

0

0

2H-Pyrrol-2-one, 1,5-dihydro-3,4-dimethyl-

XVII.A-4, XVII.C-1

1

0

0

2H-Pyrrol-2-one, 1,5-dihydro-3,5-dimethyl-

XVII.A-4, XVII.C-1

1

0

0

2H-Pyrrol-2-one, 1,5-dihydro-3,5-dimethyl-4-ethyl-

XVII.A-4, XVII.C-1

1

0

0

2H-Pyrrol-2-one, 1,5-dihydro-4,5-dimethyl-3-ethyl-

XVII.A-4, XVII.C-1

27406-77-5

1

0

0

2H-Pyrrol-2-one, 1,5-dihydro-3-methyl-

XVII.A-4, XVII.C-1

61892-80-6

1

0

0

2H-Pyrrol-2-one, 1-acetyl-3-ethyl-1,5-dihydro-4methyl-

XVII.A-4, XVII.C-1

766-36-9

1

0

0

2H-Pyrrol-2-one, 3-ethyl-1,5-dihydro-4-methyl-

XVII.A-4, XVII.C-1

78210-71-6

1

0

0

2H-Pyrrol-2-one, 3-ethyl-1,5-dihydro-5-methylene-

XVII.A-4, XVII.C-1

115600-67-4

1

0

0

2H-Pyrrol-2-one, 4-ethyl-1,5-dihydro-

XVII.A-4, XVII.C-1

4030-24-4

1

0

0

2H-Pyrrol-2-one, 4-ethyl-1,5-dihydro-3,5-dimethyl-

XVII.A-4, XVII.C-1

766-45-0

1

0

0

2H-Pyrrol-2-one, 4-ethyl-1,5-dihydro-3-methyl-

XVII.A-4, XVII.C-1

60026-28-0

0

1

0

1H-Pyrrolo[2,1-c][1,4]oxazine-6-carboxaldehyde, 3,4-dihydro-3-oxo-4-(phenylmethyl)-

III-12, VI-3, XVII.D-2

CHO CH2 N O O

35674-33-0

0

1

0

1H-Pyrrolo[2,1-c][1,4]oxazine-6-carboxaldehyde, 3,4-dihydro-4-methyl-3-oxo-

III-12, VI-3, XVII.D-2

CHO CH3 N O O

274-45-3

1

0

0

Pyrrolo[1,2-a]pyrazine

XVII.E-6

N N

19179-12-5

1

0

0

Pyrrolo[1,2-a]pyrazine-1,4-dione, hexahydro-

XVII.C-1

19943-28-3

1

0

0

Pyrrolo[1,2-a]pyrazine-1,4-dione, hexahydro-3methyl-, (3R-trans)-

XVII.C-1

5654-86-4

1

0

0

Pyrrolo[1,2-a]pyrazine-1,4-dione, hexahydro-3-(2methylpropyl)-

XVII.C-1

26626-89-1

1

0

0

Pyrrolo[1,2-a]pyrazine-1,4-dione, hexahydro-3propyl-, (3S-trans)-

XVII.C-1

1

0

0

Pyrrolo[1,2-a]pyridine

1

0

0

1H-Pyrrolo[2,3-b]pyridine

271-63-6

XVII.E-6 {7-azaindole}

XVII.E-6 N

78249-85-1

N H

1

0

0

1H-Pyrrolo[2,3-b]pyridine, C3-alkyl-

XVII.E-6

1

0

0

1H-Pyrrolo[2,3-b]pyridine, diethyl-

XVII.E-6

1

0

0

1H-Pyrrolo[2,3-b]pyridine, ethyl-

XVII.E-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1759

11/24/08 1:57:41 PM

1760

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

72692-80-9

1

0

0

1H-Pyrrolo[2,3-b]pyridine, methyl{at least 4 methyl isomers other than the 1- and 2methyl- compounds}

XVII.E-6

27257-15-4

1

0

0

1H-Pyrrolo[2,3-b]pyridine, 1-methyl-

XVII.E-6

23612-48-8

268-91-7

Name (per CA Collective Index)

Selected structures

1

0

0

1H-Pyrrolo[2,3-b]pyridine, 2-methyl-

XVII.E-6

1

0

0

1H-Pyrrolo[2,3-g]pyridine, diethyl-

XVII.E-6

1

0

0

1H-Pyrrolo[2,3-g]pyridine, dimethyl-

XVII.E-6

1

0

0

1H-Pyrrolo[2,3-g]pyridine, ethyl-methyl-

XVII.E-6

1

0

0

1H-Pyrrolo[2,3-g]pyridine, (1-methylethyl)-

XVII.E-6

1

0

0

1H-Pyrrolo[2,3-g]pyridine, methyl-(1-methylethyl)-

XVII.E-6

1

0

0

1H-Pyrrolo[2,3-g]pyridine, pentamethyl-

XVII.E-6

1

0

0

1H-Pyrrolo[2,3-g]pyridine, trimethyl-

XVII.E-6

1

0

0

Pyrroloquinoline

XVII.E-6

1

0

0

Pyrroloquinoline, dimethyl-

XVII.E-6

1

0

0

Pyrroloquinoline, methyl-

XVII.E-6

1

0

0

Pyrroloquinoline, trimethyl-

1

0

0

1H-Pyrrolo[2,3-b]quinoline

XVII.E-6 XVII.E-6 N H

N

33-36-3

Chapter Table

1

0

0

XVII.E-6

1H-Pyrrolo[2,3-f]quinoline HN

N

XVII.E-6

232-85-9

1

0

0

3H-Pyrrolo[3,2-f]quinoline

29036-02-0

1

0

0

Quaterphenyl

253-82-7

1

0

0

Quinazoline

64811-59-2

1

0

0

Quinazoline, dihydro-

XVII.E-6

64828-47-3

1

0

0

Quinazoline, ethyl-

XVII.E-6

64828-48-4

1

0

0

Quinazoline, methyl-

XVII.E-6

700-46-9

1

0

0

Quinazoline, 4-methyl-

XVII.E-6

H N

N

I.D-1 {1,3-benzodiazine}

XVII.E-6

580-22-3

1

0

0

2-Quinolinamine

91-22-5

1

1

1

Quinoline

XII-2

1

0

0

Quinoline, C3-alkyl-

XVII.E-6

1

0

0

Quinoline, alkyl-2-methyl-

XVII.E-6

1

0

0

Quinoline, alkyl-3-methyl-

XVII.E-6

1

1

1

Quinoline, alkyl-4-methyl-

XVII.E-6

{1-azanaphthalene}

XVII.E-6

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1760

11/24/08 1:57:42 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1761

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 611-34-7

S

T

S T

Name (per CA Collective Index)

1

0

0

Quinoline, 5-amino-

0

1

0

Quinoline, 5-amino-6,8-dimethoxy-

Selected structures

Chapter Table XII-2 X-2, XII-2

0

1

0

Quinoline, 5-amino-2-hydroxymethyl-6-methoxy-

53452-65-6

1

0

0

Quinoline, butyl-

II.A-5, X-2, XII-2

29968-14-7

1

0

0

Quinoline, dihydro-

XVII.E-6

65312-76-7

1

0

0

Quinoline, dihydroethyl-

XVII.E-6

65312-78-9

1

0

0

Quinoline, dihydromethyl-

XVII.E-6

28351-04-4

1

0

0

Quinoline, dimethyl-

XVII.E-6

26190-82-9

1

0

0

Quinoline, 2,5-dimethyl-

XVII.E-6

877-43-0

1

0

0

Quinoline, 2,6-dimethyl-

XVII.E-6

1463-17-8

1

0

0

Quinoline, 2,8-dimethyl-

XVII.E-6

XVII.E-6

1

0

0

Quinoline, 3.6-dimethyl-

XVII.E-6

2623-50-9

1

0

0

Quinoline, 5,8-dimethyl-

XVII.E-6

53123-73-2

1

0

0

Quinoline, ethyl-

XVII.E-6

1613-34-9

1

0

0

Quinoline, 2-ethyl-

XVII.E-6

19020-26-9

1

0

0

Quinoline, 4-ethyl-

XVII.E-6

78249-84-0

1

0

0

Quinoline, ethyl-5,6,7,8-tetrahydro-

XVII.E-6

56717-33-0

1

0

0

Quinoline, 2-ethyl-5,6,7,8-tetrahydro-

XVII.E-6

27601-00-9

1

0

0

Quinoline, methyl-

XVII.E-6

65312-74-5

1

0

0

Quinoline, methyltetrahydro-

XVII.E-6

78249-82-8

1

0

0

Quinoline, methyl-1,2,3,4-tetrahydro{several isomers present in MSS}

XVII.E-6

78249-83-9

1

0

0

Quinoline, methyl-5,6,7,8-tetrahydro-

XVII.E-6

91-63-4

1

0

0

Quinoline, 2-methyl-

XVII.E-6

2617-98-3

1

0

0

Quinoline, 2-methyl-5,6,7,8-tetrahydro-

XVII.E-6

612-58-8

1

0

0

Quinoline, 3-methyl-

XVII.E-6

491-35-0

1

1

1

Quinoline, 4-methyl-

XVII.E-6

7661-55-4

1

0

0

Quinoline, 5-methyl-

XVII.E-6

91-62-3

1

0

0

Quinoline, 6-methyl-

XVII.E-6

612-60-2

1

0

0

Quinoline, 7-methyl-

XVII.E-6

611-32-5

1

0

0

Quinoline, 8-methyl-

XVII.E-6

1333-53-5

1

0

0

Quinoline, (1-methylethyl)-

XVII.E-6

64828-52-0

1

0

0

Quinoline, propyl-

XVII.E-6

29832-78-8

1

0

0

Quinoline, tetrahydro-

XVII.E-6

635-46-1

1

0

0

Quinoline, 1,2,3,4-tetrahydro-

XVII.E-6

10500-57-9

1

0

0

Quinoline, 5,6,7,8-tetrahydro-

XVII.E-6

76602-27-2

1

0

0

Quinoline, tetramethyl-

XVII.E-6

51366-52-0

1

0

0

Quinoline, trimethyl-

XVII.E-6

4945-28-2

1

0

0

Quinoline, 2,3,8-trimethyl-

XVII.E-6

2739-16-4

0

1

0

1(2H)-Quinolinecarboxaldehyde, 3,4-dihydro-

III-12 III-12

4363-93-3

0

1

0

4-Quinolinecarboxaldehyde

64850-00-6

1

0

0

Quinolinecarbonitrile

XI-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1761

11/24/08 1:57:42 PM

1762

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

59551-02-9

1

0

0

5-Quinolinecarbonitrile

XI-2

23395-72-4

1

0

0

6-Quinolinecarbonitrile

XI-2

67360-38-7

1

0

0

7-Quinolinecarbonitrile

3778-29-8

0

1

0

2-Quinolinecarboxylic acid, 4,6-dihydroxy{6-hydroxykynurenic acid}

0

1

0

2,3-Quinolinedicarboxylic acid

1

0

0

8-Quinolinol

148-24-3

Name (per CA Collective Index)

Selected structures

Chapter Table

XI-2 IV.A-3, IX.A-22 IV.A-3 IX.A-22 N OH

13207-66-4

0

1

0

8-Quinolinol, 5-amino-

IX.A-22, XII-2

5541-68-4

1

0

0

8-Quinolinol, 7-methyl-

IX.A-22

91-19-0

1

0

0

Quinoxaline

64811-58-1

1

0

0

Quinoxaline, dihydro-

XVII.E-6

72692-77-4

1

0

0

Quinoxaline, dimethyl-

XVII.E-6

64828-46-2

1

0

0

Quinoxaline, ethyl-

XVII.E-6

64828-56-4

1

0

0

Quinoxaline, methyl-

XVII.E-6

7251-61-8

1

0

0

Quinoxaline, 2-methyl-

XVII.E-6

38917-65-6

1

0

0

Quinoxaline, 2-methyl- 5,6,7,8-tetrahydro-

XVII.E-6

13708-12-8

0

1

0

Quinoxaline, 5-methyl-

XVII.E-6

{1,4-benzodiazine}

XVII.E-6

34413-35-9

1

1

1

Quinoxaline, 5,6,7,8-tetrahydro-

XVII.E-6

72692-78-5

1

0

0

Quinoxaline, trimethyl-

XVII.E-6

1

0

0

Radicals, free

{GENERAL DISCUSSION}

XXVII-1

13982-63-3

1

1

1

Radium, isotope of mass 226

226

10043-92-2

1

0

0

Radon

Rn 226

Ra Rn

XX-5 XX-5

14859-67-7

1

1

1

Radon, isotope of mass 222

9037-80-3

0

1

0

Reductase

XXII-2

XX-5

9028-31-3

0

1

0

Reductase, aldose

XXII-2

9023-03-4

0

1

0

Reductase, cytochrome c (reduced nicotinamide adenine dinucleotide phosphate)

XXII-2

37256-44-3

0

1

0

Reductase, ferredoxin-nitrite

XXII-2

9001-48-3

0

1

0

Reductase, glutathione

XXII-2

9028-32-4

0

1

0

Reductase, glyoxylate

XXII-2

9032-06-8

0

1

0

Reductase, hydroxylamine

XXII-2

9028-35-7

0

1

0

Reductase, hydroxymethylglutaryl coenzyme A (reduced nicotinamide adenine dinucleotide phosphate)

XXII-2

9013-03-0

0

1

0

Reductase, nitrate

XXII-2

9029-27-0

0

1

0

Reductase, nitrate (reduced nicotinamide adenine dinucleotide (phosphate))

XXII-2

9080-03-9

0

1

0

Reductase, nitrite

XXII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1762

11/24/08 1:57:43 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1763

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

9029-29-2

0

1

0

Reductase, nitrite (reduced nicotinamide adenine dinucleotide (phosphate))

XXII-2

9029-17-8

0

1

0

Reductase, pyrroline-5-carboxylate

XXII-2

51848-43-2

Name (per CA Collective Index)

Selected structures

Chapter Table

0

1

0

Retine

0

1

0

Rhamnitol

XXII-2

0

1

0

Rhamnitol, 2,4-di-O-methyl-

0

1

0

Rhamnitol, 3,4-di-O-methyl-

II.A-5, X-2

0

1

0

Rhamnitol, 3-O-methyl-

II.A-5, X-2

H3C-(CHOH)4-CH2OH

II.A-5 II.A-5, X-2

0

1

0

Rhamnitol, 2,3,4-tri-O-methyl-

7440-15-5

1

1

1

Rhenium

Re

II.A-5, X-2

7440-16-6

1

1

1

Rhodium

Rh

83-88-5

0

1

0

Riboflavin

XX-5 XX-5 II.A-5, XVII.C-1

HO OH

HO

OH H3C

N

N

H3C

O NH

N O

146-17-8

0

1

0

Riboflavin 5'-(dihydrogen phosphate)

106777-19-9

0

1

0

D-Ribonic acid, 2-C-[(phosphonooxy)methyl]-

II.A-5, XVII.C-1 II.A-5

27442-42-8

0

1

0

D-Ribonic acid, 2-C-[(phosphonooxy)methyl]-, 5(dihydrogen phosphate)

II.A-5

0

1

0

Ribonucleic acid

XXII-2

9067-16-7

0

1

0

Ribonucleic acid (Bombyx mori fibroin-specifying messenger)

XXII-2

139872-63-2

0

1

0

Ribonucleic acid (tobacco clone .lambda.5A gene RB7 protein-specifying 1524-nucleotide messenger)

XXII-2

139872-64-3

0

1

0

Ribonucleic acid (tobacco clone .lambda.5A gene RB7 protein-specifying 1549-nucleotide messenger)

XXII-2

128285-01-8

0

1

0

Ribonucleic acid (tobacco clone .lambda.CHN17 chitinase basic isoenzyme-specifying messenger)

XXII-2

9014-25-9

0

1

0

Ribonucleic acids, transfer

XXII-2

3615-55-2

0

1

0

Ribose, 5-(dihydrogen phosphate)

50-69-1

0

1

0

D-Ribose

II.A-5, III-12 II.A-5, III-12

OH O HO-H2C

HO

OH

533-67-5

0

1

0

D-Ribose, 2-deoxy-

II.A-5, III-12

24259-59-4

0

1

0

L-Ribose

II.A-5, III-12

197-61-5

1

0

0

Rubicene

I.E-6

7440-17-7

1

1

1

Rubidium

Rb

XX-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1763

11/24/08 1:57:43 PM

1764

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

22537-38-8

0

1

0

Rubidium, ion

Rb

7440-18-8

1

1

1

Ruthenium

Ru

XX-5

Sa

XX-5

Name (per CA Collective Index)

7440-19-9

1

1

1

Samarium

129990-04-1

0

1

0

Saponin B, from tobacco

Selected structures +1

Chapter Table XX-5

7440-20-2

1

1

1

Scandium

Sc

XX-5

13967-63-0

1

1

1

Scandium, isotope of mass 46

46

XX-5

14391-97-0

0

1

0

Scandium, isotope of mass 49

49

XX-5

7782-49-2

1

1

1

Selenium

Se

XX-5

14265-71-5

1

1

1

Selenium, isotope of mass 75

75

XX-5

6898-95-9

1

1

1

Serine

HO-CH2-CH(NH2)-COOH II.A-5, IV.A-3, IV.B-7, XII-2

35688-48-3

0

1

0

D-Serine, N-(carboxyacetyl)-

Sc Sc Se

II.A-5, IV.A-3, IV.B-7, XII-2

56-45-1

0

1

0

L-Serine

5147-00-2

0

1

0

L-Serine, acetate (ester)

II.A-5, IV.A-3, IV.B-7, XII-2

5692-15-9

0

1

0

L-Serine, labeled with C

IV.A-3, IV.B-7, XII-2

142785-07-7

0

1

0

L-Serine, L-alanyl-L-prolyl-L-isoleucyl-L-prolylglycylL-valyl-L-methionyl-L-prolyl-L-isoleucylglycyl-Lasparaginyl-L-tyrosyl-L-valyl-

IV.A-3, IV.B-7, XIII-1

146440-48-4

0

1

0

L-Serine, L-methionyl-L-alanyl-L-lysyl-L-alanyl-Lleucyl-L-valyl-L-leucyl-L-phenylalanyl-L-glutaminylL-leucyl-L-seryl-L-valyl-L-leucyl-L-leucyl-L-leucylL-seryl-L-seryl-L-phenylalanyl-L-threonyl-L-valyl-Lvalyl-L-leucyl-

IV.A-3, IV.B-7, XIII-1

7631-86-9

1

1

1

Silica

SiO2

XX-5

H3C-COO-CH2-CH(NH2)-COOH IV.A-3, IV.B-7, V-3, XII-2

14

19088-13-2

0

1

0

Silicic acid, aluminum salt

Al2(SiO3)3

XX-6

7440-21-3

1

1

1

Silicon

Si

XX-5

12141-45-6

1

0

0

Sillimanite

Al2O(SiO4)

XX-6

7440-22-4

1

1

1

Silver

Ag

XX-5

14391-76-5

1

1

1

Silver, isotope of mass 110

110

XX-5

7440-23-5

1

1

1

Sodium

Na

XX-5

7647-14-5

0

1

0

Sodium chloride

NaCl

XX-6

1310-73-2

0

1

0

Sodium hydroxide

NaOH

XX-6 XX-6

Ag

1313-59-3

0

1

0

Sodium oxide

Na2O

17341-25-2

0

1

0

Sodium, ion

Na 24

16759-28-7

0

1

0

Sodium, isotope mass 24

62574-27-0

0

1

0

Spiro[4.5]dec-6-en-8-one, 2-[1-[(E-Dglucopyranosyloxy)methyl]ethenyl]-6,10-dimethyl-

+1

XX-5

Na

XX-5 7

O

6

8 9

II.A-5, III-13

CH3 4

10

5 1

3 2

CH3 CH2 OGlu

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1764

11/24/08 1:57:44 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1765

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

62574-29-2

0

1

0

Name (per CA Collective Index) Spiro[4.5]dec-6-en-8-one, 2-[2-(E-Dglucopyranosyloxy)-1-hydroxy-1-methylethyl]-6,10dimethyl-

Selected structures 7

O

II.A-5, III-13

CH3

6

8

4

9

5

10

3 2

1

CH3

CH3 GluO

62623-87-4

0

1

0

Spiro[4.5]dec-6-en-8-one, 2-[2-(E-Dglucopyranosyloxy)-1-hydroxy-1-methylethyl]-6,10dimethyl-

54878-25-0

0

1

0

Spiro[4.5]dec-6-en-8-one, 6,10-dimethyl-2-(1methylethenyl)-, [2R-[2D,5D(R*)]]-

Chapter Table

OH

II.A-5, III-13

O

III-13

CH3

CH3

CH2 H3C

0

1

0

Spiro[4.5]dec-6-en-8-one, 6,10-dimethyl-3-hydroxy2-(1-methylethyl)-

18444-79-6

0

1

0

Spiro[4.5]dec-6-en-8-one, 6,10-dimethyl-2-(1methylethylidene)-, (5R-cis)-

62574-25-8

0

1

0

Spiro[4.5]dec-6-en-8-one, 9-(E-Dglucopyranosyloxy)-6,10-dimethyl-2-(1methylethenyl)-, [5S-[5D(S*),9D,10E]]-

II.A-5, III-13 III-13 7

O

II.A-5, III-13

CH3

6

8

4

9

5

10

GluO

3 2

1

CH3 CH2 H3C

62623-88-5

0

1

0

Spiro[4.5]dec-6-en-8-one, 9-hydroxy-6,10-dimethyl2-(1-methylethenyl)-, [5S-[5D(S*),9D,10E]]-

7

O

II.A-5, III-13

CH3

6

8

4

9

5

10

HO

3 2

1

CH3 CH2 H3C

55784-90-2

0

1

0

Spiro[4.5]decane-6-carboxaldehyde, 8,9-dihydroxy10-methyl-2-(1-methylethenyl)-, [5S[5D(S*),6E,8E,9D,10E]]-

7

HO

HO

II.A-5, III-12

CH=O

6

8 9

4 5

10

3 2

1

CH3 CH2 H3C

35951-50-9

0

1

0

Spiro[4.5]decane-6-carboxaldehyde, 8-hydroxy-10methyl-2-(1-methylethenyl)-, [5S[5D(S*),6E,8E,10E]]-

7

HO 9

II.A-5, III-12

CH=O

6

8

4 10

5

3 2

1

CH3 CH2 H3C

162188-94-5

0

1

0

Spiro[benzofuran-6(2H),2'-[1,3]dioxolan]-2-one, 4,5,7,7a-tetrahydro-4,4,7a-trimethyl-, (r)-

5989-24-2

0

1

0

Spiro[furan-2(3H),2'(1'H)-naphtho[2,1-b]furan]5(4H)-one, decahydro-3,3'a,6',6',9'a-pentamethyl{Į-levantenolide}

X-2 H3C

VI-3, X-2

CH3 CH3 CH3 H3C

O ....... O O

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1765

11/24/08 1:57:44 PM

1766

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

30987-48-5

0

1

0

Name (per CA Collective Index)

Chapter Table

Selected structures

Spiro[furan-2(5H),2'(1'H)-naphtho[2,1-b]furan]-5one, 3'a,4',5',5'a,6',7',8',9',9'a,9'b-decahydro3,3'a,6',6',9'a-pentamethyl-, [2'S(2'D,3'aD,5'aE,9'aD,9'bE)]{ȕ-levantenolide}

H3C

VI-3, X-2

CH3 CH3 O

CH3

.......

CH3

O

O

0

1

0

Spiro[furan-2(5H),2'(1'H)-naphtho[2,1-b]furan]-5one, dodecahydro-3,3'a,6',6',9'a-pentamethyl{Į2-levantanolide}

VI-3, X-2

O O CH3

O

CH3

CH3 H3C

9005-25-8

0

1

0

Starch

39341-47-4

0

1

0

Starch, labeled with C

70226-57-2

0

1

0

83-46-5

1

1

1

CH3

VIII-3 13

{starch- C}

13

VIII-3

Starch, labeled with C

14

{starch- C}

14

Stigmast-5-en-3-ol, (3E)-

{E-sitosterol}

XXV-29 II.B-2 CH3

H3C

CH2CH3

HC-CH2CH2-CHCH=(CH3)2

H3C

HO

83-47-6

1

1

1

Stigmast-5-en-3-ol, (3E, 24S))-

{J-sitosterol}

II.B-2

3177-92-2

1

1

1

Stigmast-5-en-3-ol, 9,12,15-octadecatrienoate, [3E(9Z,12Z,15Z)]{ȕ-sitosteryl linolenate}

V-3

3577-13-7

1

1

1

Stigmast-5-en-3-ol, 9,12-octadecadienoate, [3E(Z,Z)]{ȕ-sitosteryl linoleate}

V-3

3712-16-1

1

1

1

Stigmast-5-en-3-ol, 9-octadecenoate, [3E(Z)]{ȕ-sitosteryl oleate}

V-3

41005-65-6

1

1

1

Stigmast-5-en-3-ol, dodecanoate, (3E){ȕ-sitosteryl laurate}

V-3

2308-85-2

1

1

1

Stigmast-5-en-3-ol, hexadecanoate, (3E){ȕ-sitosteryl palmitate}

V-3

34137-25-2

1

1

1

Stigmast-5-en-3-ol, octadecanoate, (3E){ȕ-sitosteryl stearate}

V-3

10473-40-2

1

1

1

Stigmast-5-en-3-ol, tetradecanoate, (3E){ȕ-sitosteryl myristate}

V-3

6869-99-4

0

1

0

Stigmast-7-en-3-ol, (3E)-

II.B-2

521-03-9

0

1

0

Stigmast-7-en-3-ol, (3E,5D)-

II.B-2

102491-96-3

1

1

1

Stigmasta-3,5,22-triene, (22E)-

I.C-1

81531-12-6

1

1

1

Stigmasta-3,5,22-triene, (22E,24[)-

I.C-1

86709-50-4

1

1

1

Stigmasta-3,5,24(28)-triene

I.C-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1766

11/24/08 1:57:45 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1767

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

79897-80-6

1

1

1

Name (per CA Collective Index)

Chapter Table

Selected structures

I.C-1

Stigmasta-3,5-diene, (24[)R

R = -CH=CH-CH(C2H5)-CH(CH3)2 83-48-7

1

1

1

II.B-2

Stigmasta-5,22-dien-3-ol, (3E,22E)- {stigmasterol} CH3

CH3

CH3

CH3

CH3 H3C

HO

71607-87-9

1

1

1

Stigmasta-5,22-dien-3-ol, 9,12,15octadecatrienoate, [3E(Z,Z,Z),22E]{stigmasteryl linolenate}

II.B-2

71278-15-4

1

1

1

Stigmasta-5,22-dien-3-ol, 9,12-octadecadienoate, [3E(9Z,12Z),22E]{stigmasteryl linoleate}

V-3

31615-93-7

1

1

1

Stigmasta-5,22-dien-3-ol, 9-octadecenoate, [3E(Z),22E]{stigmasteryl oleate}

V-3

20242-97-1

1

1

1

Stigmasta-5,22-dien-3-ol, dodecanoate, (3E,22E){stigmasteryl laurate}

V-3

2308-84-1

1

1

1

Stigmasta-5,22-dien-3-ol, hexadecanoate, (3E,22E){stigmasteryl palmitate}

V-3

23838-16-6

1

1

1

Stigmasta-5,22-dien-3-ol, octadecanoate, (3E,22E){stigmasteryl stearate}

V-3

20242-98-2

1

1

1

Stigmasta-5,22-dien-3-ol, tetradecanoate, (3E,22E){stigmasteryl myristate}

V-3

18472-36-1

1

1

1

Stigmasta-5,24(28)-dien-3-ol, (3E)-

17605-67-3

1

0

0

Stigmasta-5,24(28)-dien-3-ol, (3E,24E)-

II.B-2

481-14-1

0

1

0

Stigmasta-5,24(28)-dien-3-ol, (3E,24Z)-

II.B-2

2364-23-0

0

1

0

Stigmasta-5,25-dien-3-ol, (3E,24S)-

II.B-2

II.B-2

7212-91-1

0

1

0

Stigmasta-7,24(28)-dien-3-ol, (3E,5D)-

II.B-2

23290-26-8

0

1

0

Stigmasta-7,24(28)-dien-3-ol, (3E,5D,24Z)-

II.B-2

474-40-8

1

1

1

Stigmasta-7,24(28)-dien-3-ol, 4-methyl-, (3E,4D,5D,24Z){D-sitosterol}

II.B-2 CH3

H3C

CH=(CH3)2

HC-CH2CH2-C=CH-CH3

H3C

HO CH3

120056-15-7

1

0

0

Stigmasta-7,24(28)-dien-3-ol, 4-methyl-, (3E,5D)-

II.B-2

11040-28-1

1

1

1

Stigmasta-7,24(28)-dien-3-ol, 4-methyl-, (3E,5D)-

II.B-2

34350-85-1

0

1

0

Stigmasta-8,14,24(28)-trien-3-ol, (3E,5D)-

II.B-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1767

11/24/08 1:57:46 PM

1768

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

159169-58-1

0

1

0

Stigmasta-8,14,24(28)-trien-3-ol, 4-methyl-, (3E,4D,5D)-

II.B-2

Name (per CA Collective Index)

Selected structures

Chapter Table

34347-65-4

0

1

0

Stigmasta-8,14-dien-3-ol, (3E,5D)-

II.B-2

159169-57-0

0

1

0

Stigmasta-8,24(28)-dien-3-ol, 4,14-dimethyl-, (3E,4D,5D)-

II.B-2

57-92-1

0

1

0

Streptomycin

XXI-3

7440-24-6

1

1

1

Strontium

Sr

XX-5

14158-27-1

0

1

0

Strontium, isotope of mass 89

89

XX-5

10098-97-2

0

1

0

Strontium, isotope of mass 90

90

14808-79-8

1

1

1

Sulfate

SO4

XVIII.A-1, XX-5

18496-25-8

1

1

1

Sulfide

S

-2

XVIII.A-1, XX-5

Sr Sr

XX-5 -2

14265-45-3

1

1

1

Sulfite

-2 SO3

7704-34-9

1

1

1

Sulfur

S

7446-09-5

1

0

0

Sulfur dioxide

SO2

XVIII.A-1

2551-62-4

0

1

0

Sulfur hexafluoride

SF6

XVIII.B-3

7446-11-9

1

0

0

Sulfur trioxide

S03

XVIII.A-1

7664-93-9

0

1

0

Sulfuric acid

H2SO

XVIII.A-1, XX-6, XXI-3

7778-80-5

0

1

0

Sulfuric acid, dipotassium salt

K2SO

XVIII.A-1, XX-6

7757-82-6

0

1

0

Sulfuric acid, disodium salt

Na2SO

XVIII.A-1, XX-6

7757-83-7

0

1

0

Sulfurous acid, disodium salt

Na2SO

XVIII.A-1, XX-6

7773-03-7

0

1

0

Sulfurous acid, monopotassium salt

KHSO

XVIII.A-1, XX-6

XVIII.A-1, XX-5 XVIII.A-1, XX-5, XXI-3

11062-77-4

1

0

0

Superoxide (anion radical)

72506-68-4

0

1

0

Synthase, 1-aminocyclopropanecarboxylate

XXVII-1 XXII-2

37211-77-1

0

1

0

Synthase, 5-dehydroquinate

XXII-2

9068-73-9

0

1

0

Synthase, 5-enolpyruvoylshikimate 3-phosphate

XXII-2

144324-42-5

0

1

0

Synthase, 5-enolpyruvoylshikimate 3-phosphate (petunia clone pMON9531/pMON9556 reduced) 101-L-alanine-

XXII-2

144324-43-6

0

1

0

Synthase, 5-enolpyruvoylshikimate 3-phosphate (petunia clone pMON9531/pMON9556 reduced) 101-L-alanine-192-L-threonine-

XXII-2

9027-45-6

0

1

0

Synthase, acetolactate

XXII-2

9037-14-3

0

1

0

Synthase, aminolevulinate

XXII-2

9031-59-8

0

1

0

Synthase, anthranilate

XXII-2

37290-89-4

0

1

0

Synthase, cysteine

XXII-2

9055-59-8

0

1

0

Synthase, dihydrodipicolinate

XXII-2

56803-04-4

0

1

0

Synthase, flavanone

XXII-2

9013-48-3

0

1

0

Synthase, malate

XXII-2

108281-08-9

0

1

0

Synthase, mannopine

XXII-2

131754-88-6

0

1

0

Synthase, nicotine

XXII-2

9036-37-7

0

1

0

Synthase, porphobilinogen

XXII-2

9023-35-2

0

1

0

Synthase, pseudouridylate

XXII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1768

11/24/08 1:57:46 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1769

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

9077-14-9

0

1

0

Synthase, squalene

XXII-2

9014-52-2

0

1

0

Synthase, tryptophan

XXII-2

Name (per CA Collective Index)

Selected structures

Chapter Table

9031-56-5

0

1

0

Synthetase

XXII-2

37205-63-3

0

1

0

Synthetase, adenosine triphosphate

XXII-2

9028-02-8

0

1

0

Synthetase, aminoacyl-transfer ribonucleate

XXII-2

0

1

0

Synthetase, aminolevulinate

XXII-2

37205-35-9

0

1

0

Synthetase, arginyl-transfer ribonucleate

XXII-2

37332-51-7

0

1

0

Synthetase, p-coumaroyl coenzyme A

XXII-2

0

1

0

Synthetase, dehydroquinate

XXII-2

9023-70-5

0

1

0

Synthetase, glutamine

XXII-2

147626-93-5

0

1

0

Synthetase, glutamine (tobacco clone pcGS2-17 isoenzyme 2 subunit precursor reduced)

XXII-2

9068-76-2

0

1

0

Synthetase, glutamyl-transfer ribonucleate

XXII-2

39341-90-7

0

1

0

Synthetase, indoleacetate

XXII-2

9031-15-6

0

1

0

Synthetase, leucyl-transfer ribonucleate

XXII-2

0

1

0

Synthetase, methenyl tetrahydrofolate

XXII-2

9014-36-2

0

1

0

Synthetase, succinyl coenzyme A (guanosine diphosphate-forming)

XXII-2

9023-47-6

0

1

0

Synthetase, valyl-transfer ribonucleate

XXII-2

71010-48-5

0

1

0

D-Tabacenic acid

IV.A-3

71010-46-3

0

1

0

E-Tabacenic acid

IV.A-3

71010-47-4

0

1

0

J-Tabacenic acid

IV.A-3

1401-55-4

0

1

0

Tannins

7440-25-7

1

1

1

Tantalum

Ta

XX-5

13494-80-9

1

1

1

Tellurium

Te

XX-5

7440-27-9

0

1

0

Terbium

Tb

{tannic acid}

IV.A-3

1

0

0

Tergitol ether I :

R = CH3, x=1

XX-5 X-2

1

0

0

Tergitol ether II :

d

R = CH3, x=2

X-2

0

d

Tergitol ether III : R = CH3, x=3

X-2

0

d

1 1

0 0

d

Tergitol ether IV : R = H, x=1 The Tergitol ethers possessed the structures indicated:

X-2

d

O(CH2CH2O)xCH2R CH3CHCH2CHCH2CHCH2CHCH3 CH3

CH3

92-06-8 26140-60-3

1

0

0

1,1’:3’,1”-Terphenyl

2432-11-3

1

0

0

1,1’,3’-Terphenyl-2’-ol

CH3

I.B-1

{m-terphenyl}

IX.A-22

OH

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1769

11/24/08 1:57:47 PM

1770

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

92-94-4

1

0

0

1,1’:4’,1”-Terphenyl

1148-79-4

1

1

1

2,2':6',2''-Terpyridine

Name (per CA Collective Index)

Selected structures

I.B-1

XVII.B-6 N

N

494-04-2

1

1

1

Chapter Table

3,2':4',3''-Terpyridine

N

XVII.B-6

{nicotelline} N

N N

3,7

100-97-0

1

0

0

1,3,5,7-Tetraazatricyclo[3.3.1.1 ]decane {hexamethylenetetramine}

4181-95-7

1

0

0

Tetracontane

1

0

0

1,6,10,14,18,23-Tetracosahexaene, 2,6,10,15,19,23-hexamethyl{isosqualene}

7683-64-9

1

1

1

2,6,10,14,18,22-Tetracosahexaene, 2,6,10,15,19,23-hexamethyl-

111-02-4

1

1

1

2,6,10,14,18,22-Tetracosahexaene, 2,6,10,15,19,23-hexamethyl-, (all-E)- {squalene}

0

1

0

2,6,14,18,22-Tetracosahexaene, 2,6,10,15,19,23pentamethyl-

646-31-1

1

1

1

Tetracosane

28503-88-0

1

1

1

Tetracosane, methyl-

1560-78-7

XII-2

H3C-(CH2)38-CH3

I.A-10 I.B-1 I.B-1 I.B-1

I.B-1 H3C-(CH2)22-CH3

I.A-10 I.A-10

1

0

0

Tetracosane, 2-methyl-

I.A-10

1

1

1

Tetracosane, 3-methyl-

I.A-10

557-59-5

1

1

1

Tetracosanoic acid

42233-59-0

1

1

1

Tetracosanoic acid, docosyl ester

H3C-(CH2)22-COO-(CH2)21-CH3

V-3

42233-49-8

1

1

1

Tetracosanoic acid, dodecyl ester

H3C-(CH2)22-COO-(CH2)11-CH3

V-3

H3C-(CH2)22-COO-(CH2)19-CH3

42233-57-8

42233-58-9

{lignoceric acid}

1

1

1

Tetracosanoic acid, eicosyl ester

1

1

1

Tetracosanoic acid, ester with olean-12-en-3-ol, (3E){ȕ-amyrenyl tetracosanoate)

1

1

1

Tetracosanoic acid, heneicosyl ester

H3C-(CH2)22-COOH

IV.A-3

V-3 V-3

H3C-(CH2)22-COO-(CH2)20-CH3

V-3

1

1

1

Tetracosanoic acid, heptacosyl ester

H3C-(CH2)22-COO-(CH2)26-CH3

V-3

42233-54-5

1

1

1

Tetracosanoic acid, heptadecyl ester

H3C-(CH2)22-COO-(CH2)16-CH3

V-3

121878-03-3

1

1

1

Tetracosanoic acid, hexacosyl ester

H3C-(CH2)22-COO-(CH2)25-CH3

V-3

42233-53-4

1

1

1

Tetracosanoic acid, hexadecyl ester

H3C-(CH2)22-COO-(CH2)15-CH3

V-3

42233-56-7

1

1

1

Tetracosanoic acid, nonadecyl ester

H3C-(CH2)22-COO-(CH2)18-CH3

V-3

24897-95-8

1

1

1

Tetracosanoic acid, octacosyl ester

H3C-(CH2)22-COO-(CH2)27-CH3

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1770

11/24/08 1:57:47 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1771

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 42233-55-6

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1

1

1

Tetracosanoic acid, octadecyl ester

H3C-(CH2)22-COO-(CH2)17-CH3

V-3

1

1

1

Tetracosanoic acid, pentacosyl ester

H3C-(CH2)22-COO-(CH2)24-CH3

V-3

42233-52-3

1

1

1

Tetracosanoic acid, pentadecyl ester

H3C-(CH2)22-COO-(CH2)14-CH3

V-3

1001-43-0

1

1

1

Tetracosanoic acid, tetracosyl ester

H3C-(CH2)22-COO-(CH2)23-CH3

V-3

42233-51-2

1

1

1

Tetracosanoic acid, tetradecyl ester

H3C-(CH2)22-COO-(CH2)13-CH3

V-3

42233-60-3

1

1

1

Tetracosanoic acid, tricosyl ester

H3C-(CH2)22-COO-(CH2)22-CH3

V-3

H3C-(CH2)22-COO-(CH2)12-CH3

42233-50-1

1

1

1

Tetracosanoic acid, tridecyl ester

36378-43-5

0

1

0

Tetracosanoic acid, 22-methyl-

121877-84-7

1

1

1

Tetracosanoic acid, 22-methyl-, docosyl ester

V-3

121877-77-8

1

1

1

Tetracosanoic acid, 22-methyl-, eicosyl ester

V-3

0

1

0

Tetracosanoic acid, 23-methyl-

71608-05-4

1

0

0

Tetracosanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester, [R-[R*,R*- (E)]]-

506-51-4

1

1

1

1-Tetracosanol

63785-29-5

0

1

0

1-Tetracosanol, 22-methyl-

0

1

0

1-Tetracosanol, 23-methyl-

1

0

0

1-Tetracosene

H2C=CH-(CH2)21-CH3

I.B-1

1

0

0

1-Tetracosene, 2-methyl-

H2C=C(CH3)-(CH2)21-CH3

I.B-1

1

0

0

2-Tetracosene, (Z)-

H3C-CH=CH-(CH2)20-CH3

I.B-1

1

0

0

2-Tetracosene, (E)-

1

0

0

2-Tetracosene, 2-methyl-

H3C-C(CH3)=CH-(CH2)20-CH3

1

0

0

2-Tetracosene, 22-methyl-, (Z)-

H3C-CH=CH-(CH2)18-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Tetracosene, 22-methyl-, (E)-

I.B-1

1

0

0

2-Tetracosene, 23-methyl-, (Z)-

1

0

0

2-Tetracosene, 23-methyl-, (E)-

14490-79-0

1

0

0

15-Tetracosenoic acid

506-37-6

1

0

0

15-Tetracosenoic acid, (Z)-

IV.A-3

69521-46-6

0

1

0

Tetracosen-1-ol

II.A-5

58879-40-6

0

1

0

1,13-Tetradecadien-3-one

124-25-4

1

1

1

Tetradecanal

10192-32-2

V-3 IV.A-3

IV.A-3 V-3 H3C-(CH2)22-CH2OH

II.A-5 II.A-5 II.A-5

I.B-1

H3C-CH=CH-(CH2)19-CH(CH3)2

I.B-1

I.B-1 I.B-1

{nervonic acid}

IV.A-3

III-13 {myristaldehyde}

H3C-(CH2)12-CH=O

III-12

629-59-4

1

1

1

Tetradecane

H3C-(CH2)12-CH3

I.A-10

1560-96-9

0

1

0

Tetradecane, 2-methyl-

H3C-(CH2)11-CH=(CH3)2

I.A-10

0

1

0

Tetradecane, 3-methyl-

H3C-(CH2)10-CH(CH3)-CH2-CH3

0

1

0

Tetradecane, 2,6,10-trimethyl-

14905-56-7

I.A-10 I.A-10

821-38-5

1

0

0

Tetradecanedioic acid

544-63-8

1

1

1

Tetradecanoic acid

42232-05-3

1

1

1

Tetradecanoic acid, docosyl ester

H3C-(CH2)12-COO(CH2)21-CH3

V-3

{myristic acid}

HOOC-(CH2)12-COOH

IV.A-3

H3C-(CH2)12-COOH

IV.A-3

2040-64-4

1

1

1

Tetradecanoic acid, dodecyl ester

H3C-(CH2)12-COO-(CH2)11-CH3

V-3

22413-00-9

1

1

1

Tetradecanoic acid, eicosyl ester

H3C-(CH2)12-COO-(CH2)19-CH3

V-3

124-06-1

0

1

0

Tetradecanoic acid, ethyl ester

H3C-(CH2)12-COO-C2H5

V-3

{ethyl myristate}

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1771

11/24/08 1:57:48 PM

1772

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No. 42218-21-3

S

T

S T

Name (per CA Collective Index)

Selected structures

Chapter Table

1

1

1

Tetradecanoic acid, heneicosyl ester

H3C-(CH2)12-COO-(CH2)20-CH3

V-3

1

1

1

Tetradecanoic acid, heptacosyl ester

H3C-(CH2)12-COO-(CH2)26-CH3

V-3

18299-78-0

1

1

1

Tetradecanoic acid, heptadecyl ester

H3C-(CH2)12-COO-(CH2)16-CH3

V-3

80252-34-2

1

1

1

Tetradecanoic acid, hexacosyl ester

H3C-(CH2)12-COO-(CH2)25-CH3

V-3

2599-01-1

1

1

1

Tetradecanoic acid, hexadecyl ester

H3C-(CH2)12-COO-(CH2)15-CH3

V-3

124-10-7

1

1

1

Tetradecanoic acid, methyl ester

H3C-(CH2)12-COO-CH3

V-3

110-27-0

0

1

0

Tetradecanoic acid, 1-methylethyl ester

H3C-(CH2)12-COO-CH=(CH3)2

V-3

36617-28-4

1

1

1

Tetradecanoic acid, nonadecyl ester

H3C-(CH2)12-COO-(CH2)18-CH3

V-3

3234-81-9

1

1

1

Tetradecanoic acid, octadecyl ester

H3C-(CH2)12-COO-(CH2)17-CH3

V-3

121877-45-0

1

1

1

Tetradecanoic acid, pentacosyl ester

H3C-(CH2)12-COO-(CH2)24-CH3

V-3

18299-74-6

1

1

1

Tetradecanoic acid, pentadecyl ester

H3C-(CH2)12-COO-(CH2)14-CH3

V-3

18653-39-9

1

1

1

Tetradecanoic acid, tetracosyl ester

H3C-(CH2)12-COO-(CH2)23-CH3

V-3

3234-85-3

1

1

1

Tetradecanoic acid, tetradecyl ester

H3C-(CH2)12-COO-(CH2)13-CH3

V-3

42232-06-4

1

1

1

Tetradecanoic acid, tricosyl ester

H3C-(CH2)12-COO-(CH2)22-CH3

V-3

36617-27-3

1

1

1

Tetradecanoic acid, tridecyl ester

H3C-(CH2)12-COO-(CH2)12-CH3

V-3

1961-72-4

1

1

1

Tetradecanoic acid, 3-hydroxy-

H3C-(CH2)10-CHOH-CH2-COOH

IV.A-3

5502-94-3 5746-58-7

1

1

1

Tetradecanoic acid, 12-methyl-

H3C-CH2-CH(CH3)-(CH2)10-COOH

IV.A-3

121877-30-3

1

1

1

Tetradecanoic acid, 12-methyl-, docosyl ester

H3C-CH2-CH(CH3)-(CH2)10-COO-(CH2)21-CH3 V-3

121877-23-4

1

1

1

Tetradecanoic acid, 12-methyl-, eicosyl ester

H3C-CH2-CH(CH3)-(CH2)10-COO-(CH2)19-CH3 V-3

121877-28-9

1

1

1

Tetradecanoic acid, 12-methyl-, heneicosyl ester

H3C-CH2-CH(CH3)-(CH2)10-COO-(CH2)20-CH3 V-3

121877-56-3

1

1

1

Tetradecanoic acid, 12-methyl-, hexacosyl ester

H3C-CH2-CH(CH3)-(CH2)10-COO-(CH2)25-CH3 V-3

121877-08-5

1

1

1

Tetradecanoic acid, 12-methyl-, hexadecyl ester

H3C-CH2-CH(CH3)-(CH2)10-COO-(CH2)15-CH3 V-3

121877-17-6

1

1

1

Tetradecanoic acid, 12-methyl-, octadecyl ester

H3C-CH2-CH(CH3)-(CH2)10-COO-(CH2)17-CH3 V-3

121877-48-3

1

1

1

Tetradecanoic acid, 12-methyl-, pentacosyl ester

H3C-CH2-CH(CH3)-(CH2)10-COO-(CH2)24-CH3 V-3

121877-40-5

1

1

1

Tetradecanoic acid, 12-methyl-, tetracosyl ester

H3C-CH2-CH(CH3)-(CH2)10-COO-(CH2)23-CH3 V-3

121877-34-7

1

1

1

Tetradecanoic acid, 12-methyl-, tricosyl ester

H3C-CH2-CH(CH3)-(CH2)10-COO-(CH2)22-CH3 V-3

2485-71-4

0

1

0

Tetradecanoic acid, 13-methyl-

(H3C)2=CH-(CH2)11-COOH

121877-29-0

1

1

1

Tetradecanoic acid, 13-methyl-, docosyl ester

(H3C)2=CH-(CH2)11-COO-(CH2)21-CH3

121877-21-2

1

1

1

Tetradecanoic acid, 13-methyl-, eicosyl ester

(H3C)2=CH-(CH2)11-COO-(CH2)19-CH3

IV.A-3 V-3 V-3

121877-26-7

1

1

1

Tetradecanoic acid, 13-methyl-, heneicosyl ester

(H3C)2=CH-(CH2)11-COO-(CH2)20-CH3 V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1772

11/24/08 1:57:49 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1773

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

121877-49-4

1

1

1

Name (per CA Collective Index) Tetradecanoic acid, 13-methyl-, hexacosyl ester

Selected structures

Chapter Table

(H3C)2=CH-(CH2)11-COO-(CH2)25-CH3 V-3

71801-84-8

1

1

1

Tetradecanoic acid, 13-methyl-, hexadecyl ester

(H3C)2=CH-(CH2)11-COO-(CH2)15-CH3

121877-12-1

1

1

1

Tetradecanoic acid, 13-methyl-, octadecyl ester

(H3C)2=CH-(CH2)11-COO-(CH2)17-CH3

V-3 V-3 121877-35-8

1

1

1

Tetradecanoic acid, 13-methyl-, tetracosyl ester

(H3C)2=CH-(CH2)11-COO-(CH2)23-CH3

121877-32-5

1

1

1

Tetradecanoic acid, 13-methyl-, tricosyl ester

(H 3C)2=CH-(CH2)11-COO-(CH2)22-CH3

V-3 V-3 71607-88-0

1

1

1

Tetradecanoic acid, 3,7,11,15,19,23,27,31,35nonamethyl-2,6,10,14,18,22,26,30,34hexatriacontanonaenyl ester

V-3

62172-52-5

1

0

0

Tetradecanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester, [R-[R*,R*- (E)]]-

V-3

112-72-1

1

1

1

1-Tetradecanol

50313-71-8

0

1

0

1-Tetradecanol, 12-methyl-

15371-32-1

0

1

0

2,6,11,13-Tetradecatetraenal, 3,7,13-trimethyl-10(1-methylethyl)-, [S- (E,E,E)]-

H3C-(CH2)12-CH2OH

II.A-5 II.A-5 III-12

H3C H3C

7

CH3

8

5

12

10 9

11

4

2

3

5

13

CH2

CH3 CH=O

CH3

125572-76-1

1

1

1

2,6,11,13-Tetradecatetraenal, 3,7,13-trimethyl-10(1-methylethyl)-

III-12

150405-77-9

0

1

0

2,6,11,13-Tetradecatetraen-1-ol, 3,7,13-trimethyl10-(1-methylethyl)-

II.A-5

30790-23-9

0

1

0

Tetradecatrienoic acid

1120-36-1

1

1

1

1-Tetradecene

H2C=CH-(CH2)11-CH3

I.B-1

1

0

0

1-Tetradecene, 2-methyl-

H2C=C(CH3)-(CH2)11-CH3

I.B-1

H3C-CH=CH-(CH2)10-CH3

1652-97-7

IV.A-3

1

0

0

2-Tetradecene, (Z)-

1

0

0

2-Tetradecene, (E)-

I.B-1

1

0

0

2-Tetradecene, 2-methyl-

H3C-C(CH3)=CH-(CH2)10-CH3

1

0

0

2-Tetradecene, 12-methyl-,(Z)-

H3C-CH=CH-(CH2)8-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Tetradecene, 12-methyl-, (E)-

1

0

0

2-Tetradecene, 13-methyl-, (Z)-

I.B-1 I.B-1

I.B-1 H3C-CH=CH-(CH2)9-CH(CH3)2

I.B-1

1

0

0

2-Tetradecene, 13-methyl-, (E)-

26444-03-1

1

1

1

Tetradecenoic acid

56219-06-8

0

1

0

9-Tetradecenoic acid, methyl ester, (Z)-

14167-59-0

1

1

1

Tetratriacontane

H3C-(CH2)32-CH3

I.A-10

14167-65-8

0

1

0

Tetratriacontane, 2-methyl-

H3C-CH(CH3)-(CH2)31-CH3

I.A-10

66309-88-4 7440-28-0

I.B-1 IV.A-3 V-3

1

1

1

Tetratriacontane, 3-methyl-

H3C-CH2-CH(CH3)-(CH2)30-CH3

I.A-10

1

0

0

Tetratriacontanoic acid

H3C-(CH2)32-COOH

IV.A-3

1

1

1

Thallium

Tl

XX-5

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1773

11/24/08 1:57:50 PM

1774

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

420-12-2

0

1

0

Thiacyclopropane

533-74-4

0

1

0

1,3,5-Thiadiazine, 2-thio-3,5-dimethyl-tetrahydro{Dazomet®; Mylone®}

Name (per CA Collective Index)

Selected structures

{ethylene sulfide}

XVIII.A-1

S

XVIII.A-1, XXI-3 S

N N

288-47-1

1

1

1

Chapter Table

Thiazole

S

3

XVIII.A-1

5

4

N

S1 2

1

0

0

Thiazole, methyl-5-propyl-

XVIII.A-1

37645-61-7

1

0

0

Thiazole, 2-butyl-

XVIII.A-1

15679-09-1

1

0

0

Thiazole, 2-ethyl-

XVIII.A-1

19961-53-6

1

0

0

Thiazole, 2-ethyl-5-methyl-

XVIII.A-1

3581-87-1

1

0

0

Thiazole, 2-methyl-

XVIII.A-1

1

0

0

Thiazole, 2-(3-methylbutyl)-

XVIII.A-1

1

0

0

Thiazole, 2-(1-methylethyl)-

XVIII.A-1

1

0

0

Thiazole, 2-(1-methylpropyl)-

XVIII.A-1

18640-74-9

1

0

0

Thiazole, 2-(2-methylpropyl)-

XVIII.A-1

32272-49-4

1

0

0

Thiazole, 2,4-diethyl-

XVIII.A-1

541-58-2

1

0

0

Thiazole, 2,4-dimethyl-

XVIII.A-1

13623-11-5

1

0

0

Thiazole, 2,4,5-trimethyl-

XVIII.A-1

1

0

0

Thiazole, 2,5-diethyl-4-methyl-

XVIII.A-1

4175-66-0

1

0

0

Thiazole, 2,5-dimethyl-

XVIII.A-1

32272-48-3

1

0

0

Thiazole, 4-ethyl-2-methyl-

XVIII.A-1

52414-91-2

1

0

0

Thiazole, 4-ethyl-5-methyl-

XVIII.A-1

693-95-8

1

0

0

Thiazole, 4-methyl-

137-00-8

0

1

0

Thiazole, 4-methyl-5-(2'-hydroxyethyl)-

XVIII.A-1 H3C

CH2-CH2-OH S

N

41981-60-6

XVIII.A-1

1

0

0

Thiazole, 4-(2-methylpropyl)-

XVIII.A-1

1

0

0

Thiazole, 4-propyl-

XVIII.A-1

3581-91-7

1

0

0

Thiazole, 4,5-dimethyl-

XVIII.A-1

17626-73-2

1

0

0

Thiazole, 5-ethyl-

XVIII.A-1

38205-61-7

1

0

0

Thiazole, 5-ethyl-2,4-dimethyl-

XVIII.A-1

19961-52-5

1

0

0

Thiazole, 5-ethyl-2-methyl-

XVIII.A-1

31883-01-9

1

0

0

Thiazole, 5-ethyl-4-methyl-

XVIII.A-1

3581-89-3

1

0

0

Thiazole, 5-methyl-

XVIII.A-1

88381-44-6

0

1

0

4-Thiazolidinecarboxylic acid, 3-nitroso{N-nitrosothioproline}

IV.A-3, XV-9, XVIII.A-1 NO HOOC

N S

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1774

11/24/08 1:57:50 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1775

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

154-87-0

0

1

0

Thiazolium, 3-[(4-amino-2-methyl-5pyrimidinyl)methyl]-4-methyl-5-(4,6,6-trihydroxy3,5-dioxa-4,6-diphosphahex-1-yl)-, chloride, P,P'dioxide

XII-2, XVII.B-2, XVIII.A-1, XVIII.B-3

59-43-8

0

1

0

Thiazolium, 3-[(4-amino-2-methyl-5pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylchloride {thiamine}

II.A-5, XII-2, XVII.B-2, XVIII.A-1, XVIII.B-3

Name (per CA Collective Index)

Chapter Table

Selected structures

H3C

NH2

N

+

N

OH

S

Cl

N

-

CH3

67-03-8

0

1

0

Thiazolium, 3-[(4-amino-2-methyl-5pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylchloride, monohydrochloride {thiamine hydrochloride}

II.A-5, XII-2, XVII.B-2, XVIII.A-1, XVIII.B-3 H3C

NH2

N

+

N

OH

S

Cl

N CH3

58-85-5

0

1

0

1H-Thieno[3,4-d]imidazole-4-pentanoic acid, hexahydro-2-oxo-, [3aS-(3aD,4E,6aD)]-

36267-71-7

0

1

0

Thieno(3,4-d)pyrimidine, 5,7-dihydro-2-methyl-

-

.HCl

IV.A-3, XVII.E-8, XVIII.A-1 XVIII.A-1

N

S

H3C

N

302-04-5

1

0

0

Thiocyanate

463-56-9

1

0

0

Thiocyanic acid

HSCN

XVIII.A-1

XVIII.A-1

556-64-9

1

0

0

Thiocyanic acid, methyl ester

H3C-SCN

XVIII.A-1

(SCN)2

505-14-6

1

0

0

Thiocyanogen

137-26-8

0

1

0

Thioformamide, 1,1'-dithiobis(N,N-dimethyl {Thiram®}

22223-61-6

1

0

0

Thionitrous acid (HNOS), S-methyl ester

110-02-1

1

1

1

Thiophene

XVIII.A-1 XVIII.A-1, XXI-3 XVIII.A-1 XVIII.A-1

3

4 5

2

S

638-00-6

1

0

0

Thiophene, 2,4-dimethyl-

XVIII.A-1

25154-40-9

1

1

1

Thiophene, methyl-

XVIII.A-1

554-14-3

1

0

0

Thiophene, 2-methyl-

126-33-0

1

0

0

Thiophene, tetrahydro-, 1,1-dioxide

XVIII.A-1 {Sulfolan®}

XVIII.A-1, XXI-3 S

O

98-03-3

1

1

1

2-Thiophenecarboxaldehyde

5834-16-2

1

1

1

2-Thiophenecarboxaldehyde, 3-methyl-

O

XVIII.A-1

CH=O

S

13679-70-4

1

1

1

XVIII.A-1

2-Thiophenecarboxaldehyde, 5-methylH3C

149956-84-3

0

1

0

XVIII.A-1

CH3

Thioredoxin h2 (tobacco)

S

CH=O

XXII-2

7440-29-1

1

1

1

Thorium

Th

XX-5

14274-82-9

1

1

1

Thorium, isotope of mass 228

228

XX-5

Th

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1775

11/24/08 1:57:51 PM

1776

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

72-19-5

1

1

1

L-Threonine

32190-57-1

0

1

0

L-Threonine, N-[2-amino-4-(3-hydroxy-2-oxo-3azetidinyl)-1-oxobutyl]-

Name (per CA Collective Index)

0

1

0

L-Threonine, N-(1-deoxy-D-fructos-1-yl)-

7440-30-4

1

1

1

Thulium

50-89-5

0

1

0

Thymidine

Selected structures

Chapter Table

H3C-CHOH-CH(NH2)-COOH II.A5, IV.A-3, IV.B-7, XII-2 II.A5, IV.A-3, IV.B-7, XVII.A-1 II.A5, IV.A-3, IV.B-7, X-2 Tm

XX-5 II.A-5, X-2 O CH3

HN O

N

O HOCH2

OH

7440-31-5

1

1

1

Tin

Sn

XX-5

7440-32-6

1

1

1

Titanium

Ti

XX-5

50812-37-8 9014-48-6

0

1

0

Transaminase

XXII-2

0

1

0

Transferase, glutathione S-

XXII-2

0

1

0

Transketolase

XXII-2

0

1

0

Transmethylase

XXII-2

97-20-7

0

1

0

Trehalose

101-05-3

0

1

0

1,3,5-Triazin-2-amine, 4,6-dichloro-N-(2chlorophenyl){Anilazine®; Dyrene®}

21087-64-9

0

1

0

1,2,4-Triazin-5(4H)-one, 4-amino-6-tert-butyl-3(methylthio){Metribuzin®}

II.A-5, VIII-3 XVII.B-2, XVIII.B-3, XXI-3

XVII.B-2, XII-2, XVIII.A-1, XXI-3 (CH3)3C

N

O

N

N

S

CH3

NH2

66246-88-6

0

1

0

1,2,4-Triazole, 1-(2-(2,4-dichlorophenyl)pentyl){Penconazole®}

XVII.A-4, XVIII.B-3, XXI-3 Cl

Cl

N (CH2)2-CH3

55219-65-3

0

1

0

1H-1,2,4-Triazol-1-ethanol, 8-(4-chlorophenoxy)-Į(1,1-dimethylethyl}{Triadimenol®}

N N

X-2, XVII.A-4, XVIII.B-3, XXI-3 Cl

CHOH-C(CH3)3 N

O

N N

122836-35-5

0

1

0

1H-1,2,4-Triazol-1-yl)phenyl)methane-sulfonamide, N-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro3-methyl-5-oxo{Sulfentrazone®}

XVII.A-4, XVIII.A-1, XVIII.B-3, XXI-3 Cl CH3

N Cl

H3C

N

SO2

N

CHF2

O

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1776

11/24/08 1:57:52 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1777

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

27096-03-3

1

0

0

Name (per CA Collective Index)

Selected structures

5H-Tribenzo[a,f,l]trindene, 10,15-dihydro{5H-diindeno[1,2-a:1’,2’-c]fluorine {truxene}

Chapter Table I.B-6

638-68-6

1

1

1

Triacontane

H3C-(CH2)28-CH3

I.A-10

1560-72-1

1

1

1

Triacontane, 2-methyl-

H3C-CH(CH3)-(CH2)27-CH3

I.A-10

1

1

1

Triacontane, 3-methyl-

H3C-CH2-CH(CH3)-(CH2)26-CH3

I.A-10

1

0

0

Triacontanoic acid

H3C-(CH2)28-COOH

IV.A-3

H3C-(CH2)28-COO-(CH2)21-CH3

506-50-3 121878-07-7

104932-26-5 18435-53-5

638-67-5

1

1

1

Triacontanoic acid, docosyl ester

1

1

1

Triacontanoic acid, ester with olean-12-en-3-ol, (3E){ȕ-amyrenyl triacontanoate}

V -3

1

1

1

Triacontanoic acid, eicosyl ester

H3C-(CH2)28-COO-(CH2)19-CH3

1

1

1

1-Triacontanol

H3C-(CH2)28-CH2OH

1

0

0

1-Triacontene

H2C=CH-(CH2)27-CH3

I.B-1

1

0

0

1-Triacontene, 2-methyl-

H2C=C(CH3)-(CH2)27-CH3

I.B-1

1

0

0

2-Triacontene, (Z)-

H3C-CH=CH-(CH2)26-CH3

I.B-1

1

0

0

2-Triacontene, (E)-

1

0

0

2-Triacontene, 2-methyl-

H3C-C(CH3)=CH-(CH2)26-CH3

1

0

0

2-Triacontene, 28-methyl-, (Z)-

H3C-CH=CH-(CH2)24-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Triacontene, 28-methyl-, (E)-

1

0

0

2-Triacontene, 29-methyl-, (Z)-

1

0

0

2-Triacontene, 29-methyl-, (E)-

1

1

1

Tricosane

V-3 V-3 II.A-5

I.B-1 I.B-1

I.B-1 H3C-CH=CH-(CH2)25-CH(CH3)2

I.B-1 I.B-1

H3C-(CH2)21-CH3

I.A-10

1928-30-9

1

1

1

Tricosane, 2-methyl-

H3C-CH(CH3)-(CH2)20-CH3

I.A-10

13410-45-2

0

1

0

Tricosane, 3-methyl-

H3C-CH2-CH(CH3)-(CH2)19-CH3

I.A-10 IV.A-3

2433-96-7

1

1

1

Tricosanoic acid

H3C-(CH2)21-COOH

42233-37-4

1

1

1

Tricosanoic acid, docosyl ester

H3C-(CH2)21-COO-(CH2)21-CH3

V-3

42233-27-2

1

1

1

Tricosanoic acid, dodecyl ester

H3C-(CH2)21-COO-(CH2)11-CH3

V-3

42233-35-2

1

1

1

Tricosanoic acid, eicosyl ester

H3C-(CH2)21-COO-(CH2)19-CH3

V-3

42233-36-3

1

1

1

Tricosanoic acid, heneicosyl ester

H3C-(CH2)21-COO-(CH2)20-CH3

V-3

1

1

1

Tricosanoic acid, heptacosyl ester

H3C-(CH2)21-COO-(CH2)26-CH3

V-3

42233-32-9

1

1

1

Tricosanoic acid, heptadecyl ester

H3C-(CH2)21-COO-(CH2)16-CH3

V-3

121877-98-3

1

1

1

Tricosanoic acid, hexacosyl ester

H3C-(CH2)21-COO-(CH2)25-CH3

V-3

42233-31-8

1

1

1

Tricosanoic acid, hexadecyl ester

H3C-(CH2)21-COO-(CH2)15-CH3

V-3

2433-97-8

0

1

0

Tricosanoic acid, methyl ester

H3C-(CH2)21-COO-CH3

V-3

42233-34-1

1

1

1

Tricosanoic acid, nonadecyl ester

H3C-(CH2)21-COO-(CH2)18-CH3

V-3

42233-33-0

1

1

1

Tricosanoic acid, octadecyl ester

H3C-(CH2)21-COO-(CH2)17-CH3

V-3

1

1

1

Tricosanoic acid, pentacosyl ester

H3C-(CH2)21-COO-(CH2)24-CH3

V-3

42233-30-7

1

1

1

Tricosanoic acid, pentadecyl ester

H3C-(CH2)21-COO-(CH2)14-CH3

V-3

42233-39-6

1

1

1

Tricosanoic acid, tetracosyl ester

H3C-(CH2)21-COO-(CH2)23-CH3

V-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1777

11/24/08 1:57:53 PM

1778

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

42233-29-4

1

1

1

42233-38-5

1

1

1

Selected structures

Chapter Table

Tricosanoic acid, tetradecyl ester

H3C-(CH2)21-COO-(CH2)13-CH3

V-3

Tricosanoic acid, tricosyl ester

H3C-(CH2)21-COO-(CH2)22-CH3

V-3 V-3

Name (per CA Collective Index)

42233-28-3

1

1

1

Tricosanoic acid, tridecyl ester

H3C-(CH2)21-COO-(CH2)12-CH3

36332-96-4

1

1

1

Tricosanoic acid, 21-methyl-

H3C-CH2-CH(CH3)-(CH2)19-COOH IV.A-3

121877-82-5

1

1

1

Tricosanoic acid, 21-methyl-, docosyl ester

H3C-CH2-CH(CH3)-(CH2)19-COO-(CH2)21-CH3 V-3

121877-72-3

1

1

1

Tricosanoic acid, 21-methyl-, eicosyl ester

H3C-CH2-CH(CH3)-(CH2)19-COO-(CH2)19-CH3 V-3

121877-73-4

1

1

1

Tricosanoic acid, 21-methyl-, heneicosyl ester

H3C-CH2-CH(CH3)-(CH2)19-COO-(CH2)20-CH3 V-3

121877-63-2

1

1

1

Tricosanoic acid, 21-methyl-, nonadecyl ester

H3C-CH2-CH(CH3)-(CH2)19-COO-(CH2)18-CH3 V-3 (H3C)2=CH-(CH2)20-COOH

4730-63-6

1

1

1

Tricosanoic acid, 22-methyl-

71608-06-5

1

0

0

Tricosanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester, [R-[R*,R*- (E)]]-

3133-01-5

1

1

1

1-Tricosanol

H3C-(CH2)21-CH2OH

II.A-5

63907-54-0

0

1

0

1-Tricosanol, 22-methyl-

(H3C)2=CH-(CH2)20-CH2OH

II.A-5

540-09-0

1

1

1

12-Tricosanone

[H3C-(CH2)10]2=C=O

III-13

66309-85-1

1

1

1

5,9,13,17,21-Tricosapentaen-2-one, 6,10,14,18,22pentamethyl-

18835-32-0

IV.A-3 V-3

III-13

1

1

1

1-Tricosene

H3C-(CH2)20-CH=CH2

I.B-1

1

0

0

1-Tricosene, 2-methyl-

H2C=C(CH3)-(CH2)20-CH3

I.B-1

1

0

0

2-Tricosene, (Z)-

H3C-CH=CH-(CH2)19-CH3

1

0

0

2-Tricosene, (E)-

1

0

0

2-Tricosene, 2-methyl-

H3C-C(CH3)=CH-(CH2)19-CH3

1

0

0

2-Tricosene, 21-methyl-, (Z)-

H3C-CH=CH-(CH2)17-CH(CH3)-CH2-CH3 I.B-1

1

0

0

2-Tricosene, 21-methyl-, (E)-

1

0

0

2-Tricosene, 22-methyl-, (Z)-

1

0

0

2-Tricosene, 22-methyl-, (E)-

27519-02-4

0

1

0

9-Tricosene

30326-99-9

1

0

0

Tricosenoic acid

279-19-6

1

0

0

Tricyclo[2.2.1.02,6]heptane

I.B-1

1

0

I.B-1 I.B-1 I.B-1 IV.A-3

CH2 CH

HC

0

I.B-1

H3C-CH=CH-(CH2)18-CH(CH3)2

H2C

707-35-7

I.B-1 I.B-1

CH

I.C-1 CH2 CH

1.C-1

Tricyclo[3.3.1.1]decane, 1,3,5-trimethyl(CH3)3

472-97-9

0

1

0

Tricyclo[6.3.1.02,5]dodecan-1-ol, 4,4,8-trimethyl-, [1R-(1D,2D,5E,8E)]-

II.A-5

195-84-6

1

0

0

Tricycloquinazoline

XVII.E-6

28522-57-8

1

0

0

Tricycloquinazoline, 3-methyl-

XVII.E-6

129777-24-8

0

1

0

3,7-Tridecadiene-2,12-dione, 6-hydroxy-6-methyl-9(1-methylethyl)-

II.A-5, III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1778

11/24/08 1:57:53 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1779

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

60593-18-2

0

1

0

3,8-Tridecadiene-2,12-dione, 8-methyl-5-(1methylethyl)-, [S-(E,E)]-

10486-19-8

0

1

0

Tridecanal

H3C-(CH2)11-CH=O

Name (per CA Collective Index)

Selected structures

Chapter Table III-13 III-12

629-50-5

1

1

1

Tridecane

H3C-(CH2)11-CH3

I.A-10

1590-96-9

0

1

0

Tridecane, 2-methyl-

H3C-(CH2)10-CH=(CH3)2

I.A-10

0

1

0

Tridecane, 3-methyl-

H3C-(CH2)9-CH(CH3)-CH2-CH3

I.A-10

19780-80-4

0

1

0

Tridecane, 7-methylene-

[H3C-(CH2)5]2=C=CH2

I.B-1

505-52-2

1

0

0

Tridecanedioic acid

HOOC-(CH2)11-COOH

IV.A-3 IV.A-3

638-53-9

1

1

1

Tridecanoic acid

H3C-(CH2)11-COOH

36617-26-2

1

1

1

Tridecanoic acid, eicosyl ester

H3C-(CH2)11-COO-(CH2)19-CH3

V-3 V-3

1731-88-0

0

1

0

Tridecanoic acid, methyl ester

H3C-(CH2)11-COO-CH3

121877-24-5

1

1

1

Tridecanoic acid, 11-methyl-, heneicosyl ester

H3C-CH2-CH(CH3)-(CH2)9-COO-(CH2)20-CH3 V-3

121877-57-4

1

1

1

Tridecanoic acid, 11-methyl-, heptacosyl ester

H3C-CH2-CH(CH3)-(CH2)9-COO-(CH2)26-CH3 V-3

121877-07-4

1

1

1

Tridecanoic acid, 11-methyl-, heptadecyl ester

H3C-CH2-CH(CH3)-(CH2)9-COO-(CH2)16-CH3 V-3

121877-16-5

1

1

1

Tridecanoic acid, 11-methyl-, nonadecyl ester

H3C-CH2-CH(CH3)-(CH2)9-COO-(CH2)18-CH3 V-3

2724-57-4

1

1

1

Tridecanoic acid, 12-methyl-

(H3C)2=CH-(CH2)10-COOH

121877-25-6

1

1

1

Tridecanoic acid, 12-methyl-, docosyl ester

(H3C)2=CH-(CH2)10-COO-(CH2)21-CH3 V-3

121877-19-8

1

1

1

Tridecanoic acid, 12-methyl-, eicosyl ester

(H3C)2=CH-(CH2)10-COO-(CH2)19-CH3 V-3

IV.A-3

121877-22-3

1

1

1

Tridecanoic acid, 12-methyl-, heneicosyl ester

(H3C)2=CH-(CH2)10-COO-(CH2)20-CH3 V-3

121877-14-3

1

1

1

Tridecanoic acid, 12-methyl-, heptadecyl ester

(H3C)2=CH-(CH2)10-COO-(CH2)16-CH3 V-3

5129-58-8

0

1

0

Tridecanoic acid, 12-methyl-, methyl ester

(H3C)2=CH-(CH2)10-COO-CH3

121877-11-0

1

1

1

Tridecanoic acid, 12-methyl-, nonadecyl ester

(H3C)2=CH-(CH2)10-COO-(CH2)18-CH3 V-3

121877-09-6

1

1

1

Tridecanoic acid, 12-methyl-, octadecyl ester

(H3C)2=CH-(CH2)10-COO-(CH2)17-CH3 V-3

71608-07-6

1

0

0

Tridecanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester, [R-[R*,R*- (E)]]-

112-70-9

1

1

1

1-Tridecanol

H3C-(CH2)11-CH2OH

0

1

0

1-Tridecanol, 12-methyl-

(H3C)2=CH-(CH2)10-CH2OH H3C-(CH2)10-CO-CH3

V-3

V-3 II.A-5 II.A-5

593-08-8

0

1

0

2-Tridecanone

117210-51-2

0

1

0

2-Tridecanone, 4,8,12-trimethyl-

41678-34-6

0

1

0

Tridecatrienoic acid

59573-83-0

0

1

0

5,10,12-Tridecatrien-2-one, 6,12-dimethyl-9-(1methylethyl)-, [S-(E,E)]-

7774-82-5

0

1

0

2-Tridecenal

25377-82-6

1

1

1

Tridecene

H-(CH2)n-CH=CH-(CH2)(11-n)-H

IB-1

2437-56-1

1

0

0

1-Tridecene

H3C-(CH2)10-CH=CH2

IB-1

1

0

0

1-Tridecene, 2-methyl-

H2C=C(CH3)-(CH2)10-CH3

IB-1

1

0

0

2-Tridecene, (Z)-

H3C-CH=CH-(CH2)9-CH3

IB-1

1

0

0

2-Tridecene, (E)-

1

0

0

2-Tridecene, 2-methyl-

19150-20-0

III-13 III-13 IV.A-3 III-13

H3C-(CH2)9-CH=CH-CH=O

III-12

IB-1 H3C-C(CH3)=CH-(CH2)9- CH3

IB-1

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1779

11/24/08 1:57:54 PM

1780

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

60026-14-4 123-63-7

S

T

S T

1

0

0

2-Tridecene, 11-methyl-, (Z)-

H3C-CH=CH-(CH2)7-CH(CH3)-CH2-CH3 IB-1

1

0

0

2-Tridecene, 11-methyl-, (E)-

IB-1

1

0

0

2-Tridecene, 12-methyl-, (Z)-

1

0

0

2-Tridecene, 12-methyl-, (E)-

Name (per CA Collective Index)

Chapter Table

Selected structures

H3C-CH=CH-(CH2)8-CH(CH3)2

IB-1 IB-1

0

1

0

3-Tridecene-2,8-diol, 4,8,12-trimethyl-

II.A-5

1

0

0

Tridecenoic acid

IV.A-3

1

0

0

1,3,5-Trioxane, 2,4,6-trimethyl{paraldehyde; acetaldehyde trimer}

H3C

O 6 5

O

4

X-2

CH3

1

2 3

O

CH3

81901-03-3

0

1

0

3,5,9-Trioxa-4-phosphaheptacosadien-1-aminium, 4-hydroxy-N,N,N-trimethyl-10-oxo-7-[(1oxooctadecadienyl)oxy]-, hydroxide, inner salt, 4oxide

XII-2

70106-56-8

0

1

0

3,5,9-Trioxa-4-phosphaheptacosan-1-aminium, 4hydroxy-N,N,N-trimethyl-10-oxo-7-[(1oxooctadecatrienyl)oxy]-, hydroxide, inner salt, 4oxide, hexadehydro derivative, (R)-

XII-2

217-59-4

1

0

0

Triphenylene

60826-76-8

1

0

0

Triphenylene, dimethyl-

I.E-6

41637-89-2

1

0

0

Triphenylene, methyl-

I.E-6

60826-79-1

1

0

0

Triphenylene, trimethyl-

I.E-6

{9,10-benzophenanthrene}

I.E-6

76-87-9

0

1

0

Triphenylstannium hydroxide {Fentin hydroxide®}

3658-80-8

1

0

0

Trisulfide, dimethyl-

(C6H5)3ŁSn-OH

XX-6, XXI-3

630-05-7

1

1

1

Tritriacontane

H3C-(CH2)31-CH3

66214-27-5

1

1

1

Tritriacontane, 2-methyl-

(H3C)2=CH-(CH2)30-CH3

I.A-10

14167-69-2

1

1

1

Tritriacontane, 3-methyl-

H3C-CH2-CH(CH3)-(CH2)29-CH3

I.A-10

H3C-(CH2)31-COOH

IV.A-3

XVIII.A-1

1

0

0

Tritriacontanoic acid

9035-81-8

0

1

0

Trypsin inhibitor

150498-11-6

0

1

0

Trypsin inhibitor, TTI (tobacco isoform 1 reduced)

6912-86-3

0

1

0

Tryptophan

73-22-3

0

1

0

L-Tryptophan

I.A-10

XXII-2 XXII-2 IV.A-3, IV.B-7 IV.A-3, IV.B-7 COOH

NH2 N H

14

60738-11-6

0

1

0

L-Tryptophan, labeled with C

7440-33-7

1

1

1

Tungsten

IV.A-3, IV.B-7 W

XX-5

0

1

0

Tyrase

55520-40-6

0

1

0

Tyrosine

IV.A-3, IV.B-7

XXII-2

587-45-1

0

1

0

Tyrosine, 3-hydroxy-

IV.A-3, IV.B-7

© 2009 by Taylor & Francis Group, LLC

78836_C030.indd 1780

11/24/08 1:57:55 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1781

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

60-18-4

0

1

0

Name (per CA Collective Index)

Chapter Table

Selected structures

IV.A-3, IV.B-7

L-Tyrosine CH 2-CH(NH 2)-COOH

HO

34393-22-1

0

1

0

L-Tyrosine, N-(1-deoxy-D-fructos-1-yl)-

120904-94-1

0

1

0

Ubiquitin, poly-

129970-88-3

0

1

0

5,9-Undecadienal, 6,10-dimethyl-2-methylene-

55976-13-1

0

1

0

1,4-Undecadiene, (E)-

53837-34-6

IV.A-3, IV.B-7 XXII-2 III-12 H3C-(CH2)5-CH=CH-CH2-CH=CH2

I.B-1

1

0

0

5,9-Undecadien-2-ol, 6,10-dimethyl-

II.A-5

0

1

0

5,8-Undecadien-2-one, 6,10-dimethyl-

III-13

65017-84-7

0

1

0

5,8-Undecadien-2-one, 6,10-dimethyl-10-hydroxy(E,E)-

II.A-5, III-13

689-67-8

0

1

0

5,9-Undecadien-2-one, 6,10-dimethyl-

3796-70-1

1

1

1

5,9-Undecadien-2-one, 6,10-dimethyl-, (E){geranylacetone}

3879-26-3

1

1

1

5,9-Undecadien-2-one, 6,10-dimethyl-, (Z){nerylacetone}

152209-56-8

0

1

0

6,10-Undecadien-2-one, 8-hydroxy-8-methyl-5-(1methylethyl)-11-(tetrahydro-2-methyl-2-furanyl)-

51297-36-0

0

1

0

8,10-Undecadien-4-one, 2,10-dimethyl-7-(1methylethyl)-, (E)-(±)-

112-44-7

0

1

0

Undecanal

H3C-(CH2)9-CH=O H3C-(CH2)9-CH3

1120-21-4

1

1

1

Undecane

1

0

0

Undecane, dimethyl-

17301-23-4

0

1

0

Undecane, 2,6-dimethyl-

7045-71-8

1

1

1

Undecane, 2-methyl-

1002-43-3

1

1

1

1852-04-6

1

1

1

112-37-8

1

1

1

Undecanoic acid H3C-(CH2)9-COOH

71608-08-7

1

0

0

Undecanoic acid, 3,7,11,15-tetramethyl-2hexadecenyl ester, [R-[R*,R*- (E)]]-

1731-86-8

0

1

0

Undecanoic acid, methyl ester

III-13 H(CH2-C(CH3)=CH-CH2)2-CH2-CO-CH3 III-13 III-13 II.A-5, III-13, X-2 III-13 III-12 I.A-10 I.A-10 I.A-10 (H3C)2=CH-(CH2)8-CH3

I.A-10

Undecane, 3-methyl-

H3C-CH2-CH(CH3)-(CH2)7-CH3

I.A-10

Undecanedioic acid

HOOC-(CH2)9-COOH

IV.A-3 IV.A-3 V-3

H3C-(CH2)9-COOCH3

V-3

112-42-5

1

1

1

1-Undecanol

H3C-(CH2)9-CH2OH

1731-81-3

0

1

0

1-Undecanol, acetate

H3C-(CH2)9-CH2-OOC-CH3

38713-13-2

0

1

0

2-Undecanol, 6,10-dimethyl-

H-[CH2-CH(CH3)-(CH2)2]2-CH2-CHOH-CH3 II.A-5

112-12-9

1

1

1

2-Undecanone

1604-34-8

1

1

1

2-Undecanone, 6,10-dimethyl{tetrahydrogeranylacetone}

0

1

0

6-Undecanone

141-10-6

1

1

1

3,5,9-Undecatrien-2-one, 6,10-dimethyl{pseudoionone}

III-13

3548-78-5

0

1

0

3,5,9-Undecatrien-2-one, 6,10-dimethyl-, (E,E){pseudoionone}

III-13

{methyl nonyl ketone}

H3C-(CH2)8-CO-CH3

II.A-5 V-3

III-13 III-13

H3C-(CH2)4-CO-(CH2)4-CH3

III-13

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1781

11/24/08 1:57:56 PM

1782

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

13927-47-4

0

1

0

3,5,9-Undecatrien-2-one, 6,10-dimethyl-, (E,Z){pseudoionone}

III-13

112-45-8

0

1

0

10-Undecenal

III-12

Name (per CA Collective Index)

Chapter Table

Selected structures

821-95-4

1

0

0

1-Undecene

H3C-(CH2)8-CH=CH2

31613-73-7

0

1

0

5-Undecene, 5-methyl-

H3C-(CH2)4-CH=C(CH3)-(CH2)3-CH3 1.B-1

1.B-1

129777-22-6

0

1

0

5-Undecene-2,10-dione, 4-hydroxy-4-methyl-7-(1methylethyl)-, (E)-

II.A-5, III-13

692-86-4

0

1

0

10-Undecenoic acid, ethyl ester

29093-90-1

0

1

0

5-Undecen-2-one, 10-hydroxy-6,10-dimethyl-

V-3

160115-56-0

0

1

0

6-Undecen-2-one, 10-(acetyloxy)-8,11-dihydroxy-8methyl-5-(1-methylethyl)-11-(tetrahydro-5-hydroxy2-methyl-2-furanyl)-

7440-61-1

1

1

1

Uranium

U

XX-5 XIII-1

II.A-5, III-13 II.A-5, III-13, V-3, X-2

XX-5

13966-29-5

0

1

0

Uranium, isotope of mass 234

234

57-13-6

1

1

1

Urea

H2N-CO-NH2

3060-89-7

1

1

1

Urea, N’-(4-bromophenyl)-N’-methoxy-N’-methyl{Metobromuron®; Patoran®}

U

XVIII.B-3, XXI-3 OCH3 Br

NH-CO-N CH3

XXI-3

19937-59-8

0

1

0

Urea, N'-(3-chloro-4-methoxyphenyl)-N,N-dimethyl{Metoxuron®}

1746-81-2

1

1

1

Urea, N’-(4-chlorophenyl)-N-methoxy-N-methyl{Linuron®, 30% of Molipan®}

35367-38-5

1

1

1

Urea, 1-(4-chlorophenyl)-3-(2,6-difluorobenzoyl){Diflubenzuron®}

XXI-3

330-55-2

1

1

1

Urea, N’-(3,4-dichlorophenyl)-N-methoxy-N-methyl{Monolinuron®, 20% of Molipan®}

XVIII.B-3, XXI-3

150-68-5

0

1

0

Urea, 1,1-dimethyl-3-(4-chlorophenyl)

XVIII.B-3, XXI-3

330-54-1

0

1

0

Urea, 1,1-dimethyl-3-(3,4-dichlorophenyl)

XVIII.B-3, XXI-3

{Monuron®}

XVIII.B-3, XXI-3

Cl

{Diuron®}

CH3 Cl

NH-CO-N CH3

97-59-6

0

1

0

Urea, (2,5-dioxo-4-imidazolidinyl)-

{allantoin}

XIII-1, XVII.A-4 H2N

H N

O

HN

NH

O

O

9002-13-5

0

1

0

Urease

XXII-2

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1782

11/24/08 1:57:57 PM

The Alphabetical Index to Chemical Components in Tabacco, Tobacco Smoke, and Tobacco Substitute Smoke

1783

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

58-96-8

0

1

0

Name (per CA Collective Index)

Chapter Table

Selected structures

Uridine

II.A-5, X-2

O HN O

N

O

HOCH2

OH OH

133-89-1

0

1

0

Uridine 5'-(trihydrogen diphosphate), P'-D-Dglucopyranosyl ester

V-3

3616-06-6

0

1

0

Uridine 5'-(trihydrogen diphosphate), P'-D-Dxylopyranosyl ester

V-3

19253-25-9

0

1

0

Uridine 5'-(trihydrogen pyrophosphate), mono(6deoxymannopyranosyl) ester

V-3

58-97-9

0

1

0

5'-Uridylic acid

O

H N

O HO

P

O

O

O

IV.A-3, V-3

N

OH HO

9026-22-6

0

1

0

Uridylyltransferase, glucose 1-phosphate

94414-19-4

0

1

0

Urs-12-en-28-oic acid, 3,23-dihydroxy-, (3E,4D)-

77-52-1

0

1

0

Urs-12-en-28-oic acid, 3-hydroxy-, (3E)-

638-95-9

1

1

1

Urs-12-en-3-ol, (3E)-

OH

XXII-2 II.A-5, IV.A-3 II.A-5, IV.A-3 {D-amyrin}

II.A-5

CH3 H3C

CH3

H3C

CH3 CH3

HO H3C

7004-03-7

1

1

1

Valine

72-18-4

0

1

0

L-Valine

0

1

0

L-Valine, N-(1-deoxy-D-fructos-1-yl)-

0

1

0

Valine, N-(2-chloro-4-(trifluoromethyl)phenyl)-, cyano(3-phenoxyphenyl)methyl ester {Fluvalinate®}

102851-06-9

CH3

(H3C)2=CH-CH(NH2)-COOH IV.A-3, IV.B-7 IV.A-3, IV.B-7 X-2 Cl

O H N

F3C

H3C

CN O

O

CH3

V-3, X-2, XI-2, XVIII.B-3, XXI-3 7440-62-2

1

1

1

Vanadium

V

XX-5

1314-62-1

0

1

0

Vanadium pentoxide

V2O5

XX-6

12001-76-2

0

1

0

Vitamin B

7732-18-5

1

1

1

Water

H2O

XIX-5

92-83-1

1

0

0

9H-Xanthene

II.A-5 {dibenzopyran}

9

X-2

O

6279-07-8

1

0

0

9H-Xanthene, 2-methyl-

90-47-1

0

1

0

9H-Xanthen-9-one

X-2 {xanthone}

O

III-13

O

9014-63-5

0

1

0

Xylan

II.A-5, VIII-3

0

1

0

Xylan, 4’-O-methylglucuronyloxy)-

II.A-5, VIII-3

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1783

11/24/08 1:57:58 PM

1784

The Chemical Components of Tobacco and Tobacco Smoke

Alphabetical Index to Chemical Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke CAS No.

S

T

S T

9025-57-4

0

1

0

Xylanase, endo-1,4-E-

87-99-0

0

1

0

Xylitol

Name (per CA Collective Index)

Selected structures

Chapter Table XXII-2

HO-H 2C

OH

OH

II.A-5

HO

82796-87-0

1

0

0

D-Xylonic acid, G-lactone

25990-60-7

1

1

1

Xylose

II.A-5, VI-3 I.A-5, X-2

O OH OH

HO

OH

31178-70-8

0

1

0

D-D-Xylose

II.A-5, X-2

31178-71-9

0

1

0

E-d-Xylose

II.A-5, X-2

0

1

0

E-Xylosidase

7440-64-4

1

1

1

Ytterbium

Yb

7440-65-5

1

1

1

Yttrium

Y

XXII-2 XX-5 XX-5

10098-91-6

0

1

0

Yttrium, isotope of mass 90

90

Y

XX-5

7440-66-6

1

1

1

Zinc

Zn

XX-5

12122-67-7

0

1

0

Zinc, [[1,2-ethanediylbis[carbamodithioato]](2-)]{Zineb®}

XVIII.A-1, XX-5, XXI-3 Zn2+ S-

S-

S

S HN

18920-65-5

0

1

0

Zinc, bis(thiocarbamato)-

23713-49-7

0

1

0

Zinc, ion

Zn

13982-39-3 7440-67-7 Totals

XVIII.A-1, XX-6

+2

XX-5

Zn

XX-5 XX-5

1

1

Zinc, isotope of mass 65

65

1

1

1

Zirconium

Zr

5 3 1 5

4 9 9 4

1 8 7 9

1

NH

There were 292 partially identified isomers listed in the preceding index. Thus, the number of identified/partially identified components in tobacco and tobacco smoke totals 8622 (8430 + 292 - 100).

© 2009 by Taylor & Francis Group, LLC 78836_C030.indd 1784

11/24/08 1:57:58 PM