Teratogens: Chemicals Which Cause Birth Defects (Studies in Environmental Science, 31)

TERATOGENS Chemicals Which Cause Birth Defects

Fifteenthcentury miniature showing the internal organs of the female sex (The Bettmann Archive).

To Cal, who chose this picture seven years ago as a cover for our booklet on teratogens.

Studies in Environmental Science 31

TERATOGENS Chemicals Which Cause Birth Defects

Edited by

Vera Kolb Meyers Department of Chemistry, University of Wisconsin-Parkside, Kenosha, WI 53 14 1, U.S.A.

ELSEVIER Amsterdam

- Oxford - New York -Tokyo

1988

ELSEVIER SCIENCE PUBLISHERS8.V. Sara Burgerhartstraat25 P.O. Box 2 1 1, lo00 AE Amsterdam, The Netherlands Disrriburors for the Unired Stet86 and Canad8:

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ISBN 0-444-42914-X (Val. 31 1 ISBN 0444-41696-X (Series)

0 Elsevier Science Publishers B.V., 1988

All rights reserved. No part of this publicationmay be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the publisher, Elsevier Science Publishers B.V./ Science &Technology Division, P.O. Box 330, lo00 AH Amsterdam, The Netherlands.

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Special regulationsfor readers in the USA This publicationhas been registeredwith the Copyright Clearance Center Inc. (CCC), Salem, Massachusetts. Information can be obtained from the CCC about conditions under which photocopiesof parts of this publiktion may be made in the USA. All other copyright questions, including photocopying outside of the USA, should be referred to the publisher.

No responsibilityis assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operationof any methods, products, instructionsor ideas contained in the material herein. Because of rapid advances in the medical sciences, the Publisher recommends that independent veriiication of diagnoses and drug dosages should be made.

Printed in The Netherlands

V Other volumes in this series

1 Atmospheric Pollution 1978 edited by M.M. Benarie

2 Air Pollution Reference Measurement Methods and Systems edited by T. Schneider, H.W. de Koning and L.J. Brasser

3 BiogeochemicalCycling of Mineral-Forming Elements edited by P.A. Trudinger and D.J. Swaine

4 Potential Industrial Carcinogens and Mutagens by L. Fishbein 5 Industrial Waste Water Management by S.E. Je~rgensen

6 Trade and Environment: A Theoretical Enquiry by H. Sieben, J. Eichberger, R. Gronych and R. Pethig

7 Field Worker Exposure during Pesticide Application edited by W.F. Tordoir and E.A.H. van Heemstra-Lequin

8 Atmospheric Pollution 1980 edited by M.M.Benarie 9 Energetics and Technology of Biological Elimination of Wastes edited by G.Milazzo 10 Bioengineering, Thermal Physiologyand Comfort edited by K. Cena and J.A. Clark

11 Atmospheric Chemistry. FundamentalAspects by E. MBszAros 12 Water Supply and Health edited by H. van Lelyveld and B.C.J. Zoeteman 13 Man under Vibration. Suffering and Protection edited by G. Bianchi, K.V. Frolov and A. Oledzki 14 Principlesof Environmental Science and Technology by S.E. Je~rgensen and 1. Johnsen

15 Disposalof RadioactiveWastes by Z. Dlouhy 16 Mankind and Energy edited by A. Blanc-Lapierre 17 Quality of Groundwater edited by W. van Duijvenbooden, P.Glasbergen and H. van Lelyveld 18 Educationand Safe Handling in Pesticide Application edited by E.A.H. van Heemstra-Lequinand W.F. Tordoir

19 PhysicochemicalMethods for Water and Wastewater Treatment edited by L. Pawlowski

20 Atmospheric Pollution 1982 edited by M.M. Benarie 21 Air Pollution by Nitrogen Oxides edited by T. Schneider and L. Grant 22 EnvironmentalRadioanalysis by H.A. Das, A. Faanhof and H.A. van der Sloot

23 Chemistry for Protection of the Environment edited by L. Pawlowski, A.J. Verdier and W.J. Lacy

24 Determinationand Assessment of Pesticide Exposure edited by M. Siewierski

VI 25 The Biosphere: Problems and Solutions edited by T.N. VeziroQiu 26 Chemical Events in the Atmosphere and their Impact on the Environment edited by G.B. Marini-Bettblo

27 Fluoride Research 1985 edited by H.Tsunoda and Ming-Ho Yu 28 Algal Biofoulingedited by L.V. Evans and K.D. Hoagland

29 Chemistry for Protectionof the Environment 1985 edited by L. Pawlowski, G. Alaerts and W.J. Lacy 30 Acidification and its Policy Implicationsedited by T. Schneider

VII CONTRIBUTORS

G.S. Danford

Environmental Teratology Information Center Environmental Mutagen, Carcinogen, and Teratogen Information Program Information Research and Analysis Section Biology Division O a k Ridge National Laboratory' P.O. Box Y, Building 9207 MS 003 Oak Ridge. Tennessee 37831 USA

S. De Boer

Netherlands Institute f o r Brain Research Meibergdreef 33 1105 AZ Amsterdam 20 The Netherlands

Kari Hemminki

Institute of Occupational Health Topeliuksenkatu 41 a A SF-00250 Helsinki Finland

F.M. Holland

Environmental Teratology Information Center: vide supra for complete address

Mathilde J. Kland

Lawrence Berkeley Laboratory University of California Berkeley, California 94720

USA Doris K. Kolb

Chemistry Department Bradley University Peoria, IL 61625

USA Vera Kolb Meyers

Department of Chemistry University of Wisconsin-Parkside Kenosha. WI 53141 USA

Marja-Liisa Lindbohm

Institute of Occupational Health: vide supra f o r complete address

Blaine C. McKusick

Haskell Laboratory for Toxicology and Industrial Medicine E . I . DuPont de Nemours & Co. Wilmington. Delaware 19898 USA

K.C. Miller

Environmental Teratology Information Center: vtde supra f o r complete address

M. Mirmican

Netherlands Institute for Brain Research; vide supra for complete address

qperated by Martin Marietta Energy Systems, Inc., under Contract No. DE-AC05-840R21400with the U.S. Department of Energy.

VIII H.B. Morgan

Environmental Teratology Information Center vfde supra for complete address

E.T. Owens

Environmental Teratology Information Center vide supra for complete address

B.E. Ricci

Environmental Teratology Information Center vide supra f o r complete address

S.Y. Uppuluri

Environmental Teratology Information Center; vide supra for complete address

J.S. Wassom

Environmental Teratology Information Center; vide supra for complete address

IX TABLE OF CONTENTS INTRODUCTION. Vera Kolb Meyers

1

CHAPTER 1. H.B. Morgan, G.S. Danford, F.M. Holland, K.C. Miller, E.T. Owens, B.E. Ricci. S.Y. Uppuluri. and J.S. Wassom: HOW TO OBTAIN INgORMATION ABOUT THE TERATOGENIC POTENTIAL OF CHEMICALS

6

1. 2.

3. 4. 5. 6.

Introduction Data Bases Specializing in Teratology Secondary Literature Sources Containing Toxicological Information Reference Books Teratology Information Services Conclusion

CHAPTER 2. Vera Kolb Meyers: REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES AS A SOURCE FOR COMPILING A LIST OF TERATOGENS Appendix I Appendix I1 (These Appendices contain a list of 4,974 chemicals from RTECs which cause reproductive effects.) CHAPTER 3. Kari Hemminki and Marja-Liisa Lindbohm: REPRODUCTIVE HAZARDS IN INDUSTRY: IDENTIFICATION AND PREVENTION 1. 2.

3. 4. 5.

Introduction Mechanisms of Reproductive Toxicity Evidence on Occupational Hazards Prevalent Exposures Clues from Experimental Data Conclusions

CHAPTER 4, Doris K. Kolb: TERATOGENIC CHEMICALS IN UNDERGRADUATE GENERAL CHEMISTRY LABORATORIES

1. 2.

3. 4.

Potential Teratogens in Laboratory Manuals Potentially Teratogenic Potentially Teratogenic Potentially Teratogenic Potentially Teratogenic Conclusions

6 7 21

33 34 36

42 48 223

239 239 239 240 241 243 245

247

General Chemistry Metals Inorganic Compounds Organic Compounds Gases

*By acceptance of this article, the publisher or recipient acknowledges the U.S. Government's right to retain a nonexclusive. royalty-free license in and to any copyright covering this article.

X CHAPTER 5. Blaine C. McKusick: SAFE HANDLING OF TERATOGENIC CHEMICALS 1. 2.

3.

Handling Teratogens in the Laboratory Handling Teratogens in Inqustrial Operations Handling Teratogens in the Community

CHAPTER 6. Marja-Liisa Lindbohm and Kari Hemminki: USE OF RWjISTEFtED DATA IN STUDIES OF OCCUPATIONAL EXPOSURE AND PREGNANCY OUTCOME 1. 2.

3. 4. 5. 6.

Introduction Study Strategy Registers on Pregnancy Outcome Registers on Occupational Groups Examples Conclusions

260 260 260

262 264 265 269

CHAPTER 7. M. Mirmiran and S. De Boer: LONG-TERM EFFECTS OF CHEMICALS ON DEVELOPING BRAIN AND BEHAVIOR 1. 2.

3.

4. 5. 6.

Chemical Hazards for Developing Brain and Behavior Passage of Potentially Noxious Substances into the Fetus and Infant Derangements of Brain Development Effects on Behavioral State Development Experimental Effects of Chemicals on Behavioral Development Methodological Aspects of Neurobehavioral Teratology

CHAPTER 8 . M.J. Kland: TERATOGENICITY OF PESTICIDES AND OTHER ENVIRONEMTAL POLLUTANTS 1. 2.

3.

4. 5. 6. 7.

a.

9.

Introduction The Organohalogen Aromatic and Cyclic Pesticides and Related Compounds The Haloalkanes and Related Pesticides Miscellaneous Halogenated and Other Alkanes and Alkenes of Industrial Importance Miscellaneous Insecticides: Fumigants Organophosphorous Pesticides and Related Compounds Carbamate Pesticides and Related Compounds Miscellaneous Pesticides Summary

SUBJECT INDEX

315 319 365 366 376 382 390 402

405

465

XI

PREFACE

-

T h i s monograph d e a l s w i t h t h e p r a c t i c a l aspect o f t e r a t o g e n s which

cause b i r t h d e f e c t s .

A special

chemicals

e f f o r t has been made t o cover such

p r a c t i c a l issues as how t o o b t a i n i n f o r m a t i o n about t h e t e r a t o g e n i c p o t e n t a1 o f chemicals ( C h a p t e r 1,by Morgan e t a l , ) . c l o s e t o 5,000 undergraduate Chapter 4, Chapter

5

chemicals i n Chapter 2. general

chemistry

I have p r o v i d e d a l i s t o f names o f

The i s s u e o f t e r a t o g e n i c chemicals i n

laboratories

is

addressed

by

D.

K.

KO b,

w h i l e t h e s a f e h a n d l i n g o f t e r a t o g e n i c chemicals i s discussed i n by

McKusick.

environmental p o l l u t a n t s , important subject

The

teratogenicity

of

pesticides

as d e a l t w i t h b y Kland i n Chapter 8,

up t o date.

The two chapters,

3 and 6,

and

other

brings t h i s

b y Hemminki and

Lindbohm deal w i t h new r e s e a r c h r e s u l t s on o c c u p a t i o n a l exposure and pregnancy outcome, industry.

and

identification

and

prevent ion

of

reproductive

hazards

in

Long-term e f f e c t s o f chemicals on t h e d e v e l o p i n g b r a i n a r e d e s c r i b e d

i n Chapter 7 b y M i r m i r a n and de Boer. We

hope

that

this

monograph

will

be

useful

to

chemists

and

other

professionals working w i t h teratogens.

Vera K o l b Meyers August 1987

This page intentionally left blank

1

VERA KOLB MEYERS The purpose of this monograph is to make chemists and those working with chemicals aware of the practical aspects--the existance and dangers--of chemical teratogenesis. Chemicals are unavoidable in the modern world. Chemical industry employs numerous women. Chemistry is taught at various levels at the universities. Nurses are exposed to various anesthetics. Hair dressers, dry cleaners, farmers are working with numerous chemicals. Housewives are using a wide range of chemicals for household cleaning, for painting the house, etc. It is difficult to think about a profession which does not require, at one time or another, at least some exposure to chemicals. Chemists are the most heavily exposed group in most cases. Often they work with new chemicals which have not been tested for any type of toxicity, including teratogenicity. Women chemists are likely to be exposed to chemicals during their reproductive years. Thus, a great concern is raised about the identification of teratogens in the working place. In 1982 we drew attention to this problem in the article “What every chemist should know about teratogens--chemicals that cause birth defects“ (ref. 1). One year later we addressed the teratogen problem from the point of view of research chemists (ref. 2). Earlier, we have accumulated a list of over 500 teratogenic chemicals, proven or suspected, from the Registry of Toxic Effects of Chemical Substances (ref. 3. 4). Various chapters in this monograph are aimed at helping chemists recognize and assess the danger of teratogens in the work place and the environment. Several new and useful references published since

1983 (ref. 2 ) are reviewed in this introduction. The new references together with this monograph should represent good, practical, up-todate sources of information on chemical teratogenesis and related issues. An excellent book by Zielhuis et al. appeared in lg84--”Health

Risks to Female Workers in Occupational Exposure to Chemical Agents“ (ref. 5). It devotes chapters covering the following topics: organic solvents, carbon disulfide, pesticides, polychlorobiphenyls and polybromobiphenyls, plastic monomers, carbon monoxide, metals in general, inorganic lead, cadmium, mercury. health risks of the operating mom personnel, of the health care personnel, in the pharmaceutical industry, in the chemical industry and laboratories, in the rubber industry, and of the beauticians-hairdressers.

2 A book of interest is "Chemically Induced Birth Defects," by Schardein (ref. 6). Th:ts reference book contains data on human and animal studies on birth defects and teratogens. Drugs are covered

extensively. Chemicals discussed are: pesticides, metals, industrial solvents, diagnostic agents, dyes, radioactive chemicals, plastics, toxins, food additives, air-water-soil pollutants, personal chemicals, etc. Fabro and Scialli's book, "Drug and Chemical Action in Pregnancy" (ref. 7) is a useful reference. Of special interest are three chapters on teratogenesis and a chapter on sources of information concerning the use of drugs in pregnancy. These chapters would be of interest also to medicinal chemists working on syntheses of such drugs. A more pharmacologically oriented monograph "Prenatal Drug Exposure: Kinetics and Dynamics.'' by Chiang and Lee (ref. 8) in the references 6 and 7. complements the coverage Mutagenicity, carcinogenicity, and teratogenicity of industrial pollutants are discussed in a book edited by Kirsh-Volders (ref. 9). The pollutants covered are metals, insecticides, various industrially important monomers and halogenated hydrocarbon solvents. A recent book edited by Dixon (ref. 10) addresses reproductive toxicology mostly from the physiological point of view. However, several chemically oriented chapters are of interest--such as those on reproductive effects of chemical agents, assessing risk of reproductive dysfunction associated with chemical exposure. and regulatory aspects of reproductive toxicity. "Prevention of Physical and Mental Congenital Effects; Epidemiology. Early Detection and Therapy, and Environmental Factors", edited by Marois (ref. 11). discusses epidemiological methods (including teratoepidemiology, birth defects and environmental pollution, detection and investigation of subtle epidemics), population screening. prenatal diagnosis (including early diagnosis of fetal structural abnormalities), prenatal thernpy, occupational hazards (including methodology for studying the effect of industrial exposure on adverse pregnancy outcome, design and execution of a very large birth defect case-control study. congenital defects and environmental factors during pregnancy in a nationwide surveillance, the possible contribution of industrial chemicals (organic solvents) to the incidence of congenital defects caused by teratogenic drugs and consumer goods, the relevance for man of animal data on reproductive toxicity of industrial chemicals, etc.

3

A very important article by Schardein et al. (ref. 12) concerns species sensitivities and prediction of teratogenic potential. A selective compilation of papers on safety evaluation and regulation of chemicals, including the impact of regulations and improvement of methods, has been published as a book, edited by Hornburger (ref. 13). Out of 34 papers, two are devoted directly to teratogens and address current in vfvo reproductive toxicity and teratology methods, and new perspectives in tests for teratogenicity. There are several excellent new books on safety in general (ref. 14-17). Although they usually do not single out teratogens from among other toxic chemicals, they are very worthwhile as the reference safety books. A much needed book on legal and ethical dilemmas in occupational health is now available (ref. 18). The chapter by Whorton, "Considerations About Reproductive Hazards", is of special interest. The book consists of 38 chapters grouped into five sections: occupational safety and health act issues, workers' rights and responsibilities, workers' compensation. job discrimination, and ethics. Hemminki et al. (ref. 19) have edited the book "Occupational Hazards and Reproduction", containing pertinent chapters on experimental teratogenicity and embryotoxicity of occupational chemicals, prediction and detection of teratogenicity, occupational exposure to chemicals among women--implications for reproduction, fertility outcome in some Swedish groups occupationally exposed to chemicals, congenital malformation surveillance system in Finland, etc. Since the concern of this monograph is teratogens, the effects of chemicals on sperm and male reproduction are not dealt with. However,

for readers interested in the latter a recent review article by Schrag and Dixon, "Occupational Exposures Associated with Male Reproductive Dysfhction" (ref. 20)is recommended. Chapters on various aspects of male reproductive toxicology and on sperm production of men working under heavy-metal or organic-solvent exposure are presented by Hemminki et al. (ref. 19). The Royal Society of Chemistry publishes "Laboratory Hazards Bulletin" (ref. 21) containing much useful information about safety which is abstracted from the literature. Sections on "Chemical Hazards," "Biological Hazards," "New Precautions and Legislations," "General." etc., are concise and easy to follow. This bulletin also

4

features "Laboratory Hazards Data Sheets," for various common chemicals, which include reproductive hazard data. This monograph complements and broadens the topics already dealt with in the literature. A special effort was made to cover practical. issues, such as how to obtain information about the teratogenic potential of chemicals (chapter by Morgan et al.). A list of names of over 4000 teratogenic chemicals is provided in the chapter by Kolb-Meyers. The issue of teratogenic chemicals in undergraduate general chemistry laboratories is addressed by D. K. Kolb, while the safe handling of teratogenic chemicals is discussed by McKusick. A chapter on teratogenicity of pesticides and other environmental pollutants by Kland brings this important subject up to date. The two chapters by Hemminki and Lindbohm deal with new research results on occupational exposure and pregnancy outcome, and identification and prevention of reproductive hazards in industry. Long-term effects of chemicals on the developing brain are described in chapter by Mirmiran and DeBoer. This monograph is made possible by all the authors who have contributed to it and who have patiently stuck with the project from the beginning. Editing this monograph was a very challenging and time consuming task. Thanks are expressed to Professor Cal Y. Meyers for editorial help in preparing this Introduction and Chapter 2.

REFERENCES

R.E. Beyler and V. Kolb Meyers, What every chemist should know about teratogens-chemicals that cause birth defects, J. Chem. Ed.. 3,1982. 759-763. V, Kolb Meyers, Chemicals which cause birth defects-teratogens: A special concern of research chemists, Sci. Total Env., 1983, 1-12. V. Kolb Meyers and C.Y. Meyers, Chemicals Which Cause Birth Defects-Teratogens. A Brief Guide, paperback printed at Southern Illinois University, Carbondale, IL 1980, 37 pp. V. Kolb Meyers and R.E. Beyler, How to make an "educated guess" about the teratogenicity of chemical compounds, in S.M. Somani and F.L. Cavender. (Eds.), Charles C. Thomas, Publ.. Springfield, IL, 1981. pp. 124-161. R.L. Zielhuis. A. Stijkel, M.M. Verberk. and M. van de Poel-Bot. Health Risks to Female Workers in Occupational Exposure to Chemical Agents, Springer-Verlag. New York. 1984, 120 pp. J.L. Schardein. Chemically Induced Birth Defects, Marcel Dekker, Publ., New York, 1985, 904 pp. S. Fabro and A.R. Scialli, (Eds.). Drugs and Chemical Action in Pregnancy, Marcel Dekker, Publ., New York, 1986, 544 pp.

z,

5

8

9 10 11

12 13 14

15 16 17 18 19 20 21

C.N. Chiang and C.C. Lee, (Eds.). Prenatal Drug Exposure: Kinetics and Dynamics, NIDA Research Monograph 60, National Institute on Drug Abuse, Rockville. Maryland, 1985. 153 pp. M . Kirsch-Volders. Mutagenicity, Carcinogenicity, and Teratogenicity of Industrial Pollutants, Plenum Press, New York, 1984, 331 PP. R.L. Dixon, (Ed.), Reproductive Toxicology, Raven Press, New York. 1985. 341 pp. M . Marois. (Ed.). Prevention of Physical and Mental Congenital Defects, Pt.B., Epidemiology, Early Detection and Therapy, and Environmental Factors, Progress in Clinical and Biological Research. Vol. 163. Pt.B., Alan R. Liss, Publ., New York. 1985. 492 PP. J.L. Schardein, B.A. Schwetz. and M.F. Kenel, Species sensitivities and prediction of teratogenic potential, Environmental Health Perspective, Vol. 61, pp. 55-67. 1985. F. Homburger. (Ed.). Safety Evaluation and Regulation of Chemicals 2. Impact of Regulations-Improvement of Methods, Karger Publ., New York, 1985. 318 pp. J.R. Ridley. Safety at Work, Butterworths Publ.. Stoneham, Massachusetts, 1983. 707 pp. A.S. Goldfarb, G.R. Goldgraben, E.C. Herrick, R.P. Ouyellette. and P.N. Cheremisinoff, Organic Chemicals Manufacturing Hazards, Butterworths Publ.. Stoneham. Massachusetts, 1981. 430 pp. S.P. Levine and W.F. Martin, (Eds.). Protecting Personnel at Hazardous Waste Sites, Butterworths Publ., Stoneham. Massachusetts, 1984, 384 pp. D.B. Walters and C.W. Jameson. (Eds.). Health and Safety for Toxicity Testing, Butterworths Publ.. Stoneham, Massachusetts, 1984, 360 PP. J.S. Lee and W.N. Rom, (Eds.), Legal and Ethnical Dilemmas in Occupational Health, Ann Arbor Science Publ., Ann Arbor, Michigan, 1982, 485 pp. K. Hemminki, M. Sorsa. and H. Vainio. (Eds.). Occupational Hazards and Reproduction, Hemisphere Publ. Corp., Washington, DC, 1985, 333 PP. S.D. Schrag and R.L. Dixon. Occupational exposures associated with male reproductive dysfunction, Ann. Rev. Pharmacol. Toxicol., E , 1985, 567-92. Laboratory Hazards Bulletin, Royal Society of Chemistry, The University Nottingham NG7 2RD, England.

6

HOW TO OBTAIN INFORMATION ABOUT ME TERATOGENIC POTENTIAL OF CHEMICALS H.B.

E.T.

MORGAN, G.S. OWENS, B.E.

DANFORO, F.M. HOLLAND, K.C. R I C C I , S.Y.

MILLER,

UPPULURI, and J.S. WASSOM

1 INTRODUCTION The thalidomide tragedy o f the e a r l y 1960s served as an impetus f o r expanded research i n the f i e l d o f teratology. T h i s and the increased p o p u l a r i t y o f environmental and h e a l t h issues caused a r a p i d

acceleration

in

the

rate

of

publications

i n t h i s research area (Fig. 1). P r o l i f e r a t i o n o f modern pharmaceuticals and i n d u s t r i a l chemicals has r e s u l t e d i n a mushrooming o f the l i t e r a t u r e on t h e i r prenatal toxicology, which i s an important element i n the t o t a l spectrum o f t o x i c i t y information. The task o f a c q u i r i n g and searching l i t e r a t u r e i n the f i e l d o f t e r a t o l o g y i s p r e s e n t l y beyond the c a p a b i l i t y o f most researchers o r i n s t i t u t i o n s . This information sometimes i s d i f f i c u l t t o l o c a t e because i t i s widely scattered throughout

the

biomedical

l i t e r a t u r e and o f t e n

is

found i n t o x i c o l o g i c a l

a r t i c l e s whose t i t l e s do n o t mention the t e r a t o l o g y information included. Faced w i t h t h i s s i t u a t i o n , where does one f i n d o u t about the prenatal toxicity

of

a

specific

chemfcal?

The

approach toward f i n d i n g t e r a t o l o g y

If a information should be determined by the k i n d o f answer one desires. concise answer i s needed, there are several e x c e l l e n t books t h a t contain reviews o f what i s known about common agents. I t i s a l s o possible t o c a l l a

teratology specialists. useful

information

service

to

obtain

an

assessment

To the layman o r busy physician, t h i s

type

of

as i n t e r p r e t e d by answer

i s more

than a

long bibliography o f references t h a t have t o be located, read, and i n t e r p r e t e d . However, a researcher i n the f i e l d o f t e r a t o l o g y w i l l want an information on every dose l e v e l , r o u t e o f administration, in-depth answer

-

-

dosing period, t e s t animal, technique, etc., i n the l i t e r a t u r e about the agent o f i n t e r e s t . Review w r i t e r s and those i n government r e g u l a t o r y agencies also want a complete bibliography o f every paper w r i t t e n on a p a r t i c u l a r chemical. Only after each source has been studied can an evaluation be determined. I n these s i t u a t i o n s o r when a chemical i s n o t discussed i n any o f the books, one needs the help o f computer-searchable data bases* on toxicology and, even more s p e c i f i c a l l y , on teratology. T h e use o f th‘e term “data base” i n t h i s chapter r e f e r s t o those computer information systems c o n s i s t i n g o f b i b l i o g r a p h i c l i s t i n g s and keywords as w e l l as t o those containing numerical data.

7

14000

12000

10000

8000

6000

4000

2000

Number Documents 19611965

19001960

Year

19761980

19711975

19661970

19811985

]I lg

Fig. 1.

2

Increases in volume of teratology literature.

DATA BASES SPECIALIZING

2.1

1983-1985 are not complete

IN TERATOLOGY

The Environmental T e r a t o l o g y I n f o r m a t i o n Center o f Oak Ridge

2.1.1

I n t r o d u c t i o n , h i s t o r y , and g e n e r a l i n f o r m a t i o n

I n 1975, t h e N a t i o n a l I n s t i t u t e o f recognized

the

teratology

information

researchers

and

need

of

a

available

physicians,

Environmental

computerized in

the

system world

Health

literature.

research. for

Toxic

and

to

prevent

(NIEHS)

Individual

government r e s e a r c h and r e g u l a t o r y agencies, and

o t h e r i n s t i t u t i o n s needed easy access t o t h e l i t e r a t u r e assessment

Sciences

f o r the organization o f the

duplication

to

facilitate

health

o f e f f o r t i n the f i e l d o f teratology

Through t h e guidance o f Dr. R o b e r t E.

Staples,

Haskell

Laboratory

and I n d u s t r i a l Medicine, Newark, Delaware ( f o r m e r l y a s s o c i a t e d w i t h

8 NIEHS) , t h e Environmental T e r a t o l o g y I n f o r m a t i o n Center (ETIC) was o r g a n i z e d a t the

Oak

purpose

Ridge of

National

evaluation

of

activity,

Laboratory

collecting, chemical,

During the

bibliographic

data

(ORWL)

organizing,

and

biological,

succeeding base

and

years,

containing

a t Oak Ridge, Tennessee, f o r t h e

dlsseminating physical ETIC

over

information

agents

has

for

created

42,000 e n t r i e s ,

a

on

teratogenic computerized,

On-line r e t r i e v a l

s e r v i c e s a r e p r o v i d e d t h r o u g h t h e N a t i o n a l L i b r a r y o f M e d i c i n e ' s (NLM) the E T I C f i l e d i r e c t l y o n - l i n e , to

approximately

physicians, poison c o n t r o l centers,

research

technical

queries

centers,

citizens.

ETIC

in

Oak

Ridge

These q u e s t i o n s come f r o m

clinical

genetic

counseling

Because

the

ETIC

file

provides

thorough

o f an agent, i t i s e x t r e m e l y u s e f u l i n p r o v i d i n g r e l e v a n t

coverage

of

at

year.

hospitals,

references t o i n d i v i d u a l s i n the w r i t i n g o f need

staff

per

i n s t i t u t i o n s , i n d u s t r i e s , academic i n s t i t u t i o n s , r e g u l a t o r y

agencies, and p r i v a t e literature

the

400

TOXLINE

I n a d d i t i o n t o t h o s e u s e r s who search

(TOXicology i n f o r m a t f o n on-LINE) system. respond

the

additional

testing

and

review

papers.

locating experts i n

Determining

particular

the

areas o f

t e r a t o l o g y a r e o t h e r s e r v i c e s t h a t t h e d a t a base p r o v i d e s . 2.1.2

Scope o f ETIC m a t e r i a l

Each ETIC e n t r y , r e f e r r e d t o a s a r e c o r d , r e p r e s e n t s a p u b l i c a t i o n f r o m open

literature.

discuss

For

the

a paper t o be accepted f o r t h e ETIC d a t a base, i t must

the

testing

and

reproductive

effects

o f an agent, whether t h e r e s u l t s a r e p o s i t i v e , n e g a t i v e ,

evaluation

of

the

developmental

toxicity

o r inconclusive.

Agents may be chemical, b i o l o g i c a l , o r p h y s i c a l and a l s o

include dietary

deficiencies

and

disease

conditions

in

t h e mother.

focuses m a i n l y on t h e a d m i n i s t r a t i o n o f an a g e n t t o a p r e g n a n t animal examination functional

of

the

offspring

anomalies.

Also

at

or

contained

near in

birth the

for

ETIC

or may ETIC

and

the

either structural or file

are

reports

of

e p i d e m i o l o g i c a l s t u d i e s and c l i n i c a l cases i n humans, t e s t i n g methods, i n v i t r o studies,

proposed

reproductive

and/or

reproductive e f f e c t includes

those

rapid

screening

fertility of

agents

methods,

studies,

placental

and

administered

those before

that

transfer

studies,

are studies o f the

pregnancy.

The

latter

s t u d i e s i n which males were t r e a t e d w i t h a g e n t s b e f o r e m a t i n g .

Research t h a t r e p o r t s on agents a d m i n i s t e r e d d i r e c t l y t o t h e a v i a n egg, t o embryo,

or

to

f i s h i s a l s o i n scope f o r t h e ETIC f i l e . acceptance

the

t h e aqueous environment o f e a r l y l i f e stages o f amphibians and

criteria

if t h e y

newborn, w i t h m a l f o r m a t i o n s o f p r o b a b l e environmental cause.

are

C u r r e n t l y , papers

concerned

genetic

origin,

do

not

meet

the

w i t h agents administered t o the or

with

defects

without

a

9

2.1.3

Locating a r t i c l e s The most

ETIC uses a v a r i e t y o f methods t o l o c a t e p u b l i c a t j o n s o f i n t e r e s t . productive

method

is

manual s e a r c h i n g o f 5 5 key j o u r n a l s t h a t r e g u l a r l y

the

the

p u b l i s h d a t a on t e r a t o l o g y s t u d i e s ( T a b l e 1) and o t h e r a r e a s w i t h i n

These j o u r n a l s a r e scanned

the center (discussed i n the previous section).

of

a s soon a s t h e y become a v a i l a b l e , and papers

selected

to

they

scope

yield

approximately

of

50%

the

be i n c l u d e d i n t h e ETIC d a t a base, i n c l u d i n g t h e 10% f r o m

the journal Teratology.

References from o t h e r

publications

are

obtained

by

searching

l a r g e computerized d a t a bases such as those produced by t h e Chemical

Abstracts

Service

Abstracts

and

(CAS),

Information (Automatic

of

Library

the

Biological

EioSciences

Subject

Citation

teratology

and

reproductive

lledica

publications. by

are

'

screened

the

secondary

sources from

acquired

by

is

freauent.ly

ETIC

and

Scientific

the

to

terms

National

relevant

sources

to

such a s

Lookout,

and

books, symposia, and o t h e r overlap gaps

obtain personal

the

of

Teratology

world

in

the

exist

literature

which

comprehensive collections assist

make i t coverage.

of

ETIC's

several

literature

sending r e p r i n t s o f t h e i r work and c o p i e s o f r e l a t e d m a t e r i a l

f r o m j o u r n a l s and hooks p u b l i s h e d i n t h e i r c o u n t r i e s . sources.

(Biological

for

secondary

are

as

the

t e r a t o l o g i s t s , and t e r a t o l o g i s t s around compilations

Other

sources,

necessary t o screen a l l o f these been

sets

considerable

Papers

have

Service),

I n d e x Eledicus,

information

Service

Institute

These f i l e s a r e searched b y u s i n g

specific

manually,

Ever1 though t h e r e i s

the

Alert

toxicology.

G e n e t i c s A b s t r a c t s , C u r r e n t Contents,

covered

,

M e d i c i n e (I-IEDLIFIE and TOXLINE).

c a r e f u l l y designed p r o f i l e s , w h i c h a r e

Exccrpta

Information

Abstracts/RRM)

the

only

means

of

obtaining

T h i s k i n d o f cooperation

infornat.ion

f r o m some f o r e i g n

R e l e v a n t a r t i c l e s o t h e r w i s e o v e r l o o k e d a r e sometimes l o c a t e d when t h e

staff

peruses

references

appearing

in

t.he b i b l i o g r a p h i e s o f a r t i c l e s

already i n the ETIC f i l e , 2.1.4

Indexing

I n an e f f o r t t o a v o i d r e p r o d u c i n g i n d e x i n g e r r o r s f r o m o t h e r copy

of all

articlps

selected

for inclusion i n t o

o b t a i n e d b e f o r e i n f o r m a t i o n i s e n t e r c d i n t o t h e ETIC copy

of

computer.

an

article

is

the

d a t a base i s

file.

hard

systens,

llhen

a

always complete

i n hand, t h e b i b l i o g r a p h i c d a t a a r e e n t e r e d i n t o t h e

The f i e l d s t h a t a r e e n t e r e d i n c l u d e

the

author,

title,

citation,

literature

type, language o r t r a n s l a t i o n notes, secondary source, and s e l e c t e d

abstracts.

The t e c h n i c a l

parameters

t h a t a l l o w s e a r c h i n g i n a v a r i e t y o f ways s p e c i f i c t o t h e i n t e r e s t s

o f the users.

staff

then

Only t h a t p o r t i o n o f t h e

indexes papcr

the

data

concerned

using with

experimental teratology

or

10 TABLE 1. Key p u b l i c a t i o n sources used by ETIC Teratology American J o u r n a l o f O b s t e t r i c s and Gynecology Lancet T o x i c o l o g y and A p p l i e d Pharmacology O b s t e t r i c s and Gynecology B r i t i s h Medical J o u r n a l Pedi a t r i c Research Oyo Yakuri ( P harmacometri c s ) Anatomical Record C o n g e n i t a l Anomalies (Senten I j o ) Comptes Rendus Hebdomadaires des Seances de L ' Academie des Sciences F e d e r a t i o n Proceedings, F e d e r a t i o n o f American S o c i e t i e s f o r Experimental B i o l . Journal o f P e d i a t r i c s J o u r n a l o f t h e American Medical A s s o c i a t i o n New England J o u r n a l o f M e d i c i n e Proceedings o f t h e S o c i e t y f o r Experimental B i o l o g y and M e d i c i n e Journal o f N u t r i t i o n Pediatrics B r i t i s h J o u r n a l o f O b s t e t r i c s and Gynecology Nature (London) Science U.S. N a t i o n a l T e c h n i c a l I n f o r m a t i o n S e r v i c e Government R e p o r t s D i s s e r t a t i o n A b s t r a c t s I n t e r n a t i o n a l ( S e c t i o n ) B: The Sciences and E n g i n e e r i n g Arzneimittel-Forschung Experie n t ia J o u r n a l o f Embryology and Experimental Florphology Progress i n C l i n i c a l and B i o l o g i c a l Research American J o u r n a l of Diseases of C h i l d r e n B i o l o g y o f t h e Neonate Journa 1 of Reproduction and F e r t i 1it y Neurobehavioral T o x i c o l o g y and T e r a t o l o g y Food and Chemical T o x i c o l o g y J o u r n a l o f Dental Research T a x i c o l ogy B u l l e t i n o f Environmental Contamination and T o x i c o l o g y Environmental H e a l t h P e r s p e c t i v e s Minerva G i necol o g i c a I y a k u h i n Kenkyu Toxicology L e t t e r s J o u r n a l o f T o x i c o l o g y (and Environmental H e a l t h Pledical J o u r n a l o f A u s t r a l i a J o u r n a l o f Experimental Zoology E n d o c r i no1ogy N u t a t i o n Research American J o u r n a l o f Epidemiology F e r t i l i t y and S t e r i l i t y Proceedings o f t h e C o n g e n i t a l Anomalies Research A s s o c i a t i o n of Japan.Abstracts Gigiena i S a n i t a r i y a B i r t h Defects, O r i g i n a l A r t i c l e S e r i e s I A R C Elonographs on t h e E v a l u a t i o n o f t h e C a r c i n o g e n i c Risk t o Humans (Geneva) B u l l e t i n of Experimental B i o l o g y and M e d i c i n e (USSR) Canadian Medical A s s o c i a t i o n J o u r n a l J o u r n a l o f Animal Science Environmental Research K i s o t o Rinsho ( C l i n i c a l R e p o r t )

11 r e p r o d u c t i o n i s indexed and i n c l u d e s : Taxonomic and common name(s) and s t r a i n ( s ) o f t e s t o b j e c t ( s ) C e l l t y p e ( s ) , t i s s u e ( s ) , o r g a n ( s ) , o r whole embryo(s1 c u l t u r e d ( i n v i t r o studies only) B i o l o g i c a l end p o i n t ( s ) examined i n o f f s p r i n g t o assay e f f e c t s (does n o t imply positive e f f e c t ) A g e n t ( s ) t e s t e d , most o f which a r e chemicals Chemical A b s t r a c t s S e r v i c e R e g i s t r y Number(s) [chemical a g e n t ( s ) o n l y ] Sex(es) o f t r e a t e d animal ( s ) E x p e r i m e n t a l c o n d i t i o n s ( o t h e r t h a n those i n s t a n d a r d i n v i v o s t u d i e s ) I n d u c e r ( s 1 ( a g e n t s employed t o a l t e r microsomal p r o d u c t i o n and/or enzyme a c t i v i t y ) Developmental s t a g e ( s ) o f t r e a t e d a n i m a l ( s ) ( c o l d - b l o o d e d o r invertebrate only) B i o l o g i c a l end p o i n t ( s ) examined i n t h e mother t o assay m a t e r n a l t o x i c i t y (does n o t i m p l y p o s i t i v e e f f e c t ) The i n d e x i n g scheme o f ETIC has e v o l v e d t h r o u g h t h e y e a r s t o meet t h e of

its

users

and

to

needs

r e f l e c t t h e changes t h a t occur i n t e r a t o l o g y r e s e a r c h .

Three d a t a elements ( i n d u c e r , e x p e r i m e n t a l c o n d i t i o n s , and stage t r e a t e d )

were

i n 1902 t o accommodate papers on m e t a b o l i c a c t i v a t i o n and t h o s e on c o l d -

added

blooded o r i n v e r t e b r a t e animals. prescreens

for

The proposed use o f

sex t r e a t e d , was added a t t h e same t i m e because papers

lower

dealing

of

w i t h t r e a t m e n t o f t h e male p a r e n t .

requests

these

additional

f o u r d a t a elements.

forms

as

Another f i e l d , from

users

for

Only papers a c q u i r e d s i n c e

19112 ( w i t h ETIC a c c e s s i o n numbers g r e a t e r t h a n 26,500)

include

animal

t e r a t o g e n i c i t y has made these a r e a s i m p o r t a n t .

have

been

indexed

to

I n 1986, t h e m a t e r n a l t o x i c i t y

f i e l d was added. An example o f an ETIC r e c o r d i s g i v e n i n T a b l e 2. each

biological

The assay f i e l d d e s c r i b e s

end p o i n t observed o r l o o k e d f o r i n t h e o f f s p r i n g .

p o i n t s may be h i g h l y s p e c i f i c

(e.g.,

Apgar

score)

or

very

These end

general

(e.g.,

m u s c u l o s k e l e t a l system) as seen i n t h e l i s t o f a c c e p t a b l e e n t r i e s ( T a b l e 3 ) . CAS R e g i s t r y Number i s a unique number assigned t o each chemical

the

computer-based

CAS

chemical

registry

system.

substance

A in

The CAS R e g i s t r y Number

i t s e l f has no chemical s i g n i f i c a n c e , b u t i t a s s o c i a t e s a l l synonyms o f a unique chemical

structure,

a l l o w i n g a more complete search o f t h e l i t e r a t u r e t h a n i s

p o s s i b l e by chemical name alone. tested

and

to

inducers.

ETIC a s s i g n s CAS R e g i s t r y Elumbers

to

agents

The m a t e r n a l e f f e c t s f i e l d d e s c r i b e s b i o l o g i c a l end

p o i n t s observed o r l o o k e d f o r i n t h e mother ( T a b l e 4 ) . 2.1.5

F i l e facts

E T I C ' s 42,000 r e c o r d s were s e l e c t e d from 3600 p r i m a r y l i t e r a t u r e sources of

late

1986.

Foreign

language

papers

A p p r o x i m a t e l y 31% o f t h e papers r e p o r t on human s t u d i e s , and w i t h o r i g i n a l d a t a on

as

r e p r e s e n t a b o u t 15.5% o f t h e f i l e . journal

animal s t u d i e s comprise 4 2 % o f t h e f i l e ,

articles

w h i l e 16% a r e

12

TABLE 2. E x a m p l e o f an E T I C r e c o r d ACCESSION NUMBER AUMOR TITLE '

C ITAT ION LITERATURE TYPE PRIVATE KEYWORDS SECONDARY SOURCE TRANSLATION NOTE COMMON NAME TAXONOMIC NAME TISSUE EXPER. CONDITIONS ASSAY AGENT CAS REGISTRY NO. AGENT CAS REGISTRY NO. AGENT CAS REGISTRY NO.

004841 SIMKHOVICK, B.Z.;LUKEYITS, E.YA.;ZELCHAN, G.I.; ZAMRAEVA, T. V. ;MZUROV , V. I. EFFECT OF SOWE ORGANOSILICON COI4POUNDS ON COLLAGEN SYNTHESIS I N CARTILAGENOUS TISSUE OF Q i I C K ENBRYOS BIOCH ENISTRY (USSR 1 42: 679-883.1977 JOURNAL ARTICLE

EYE,6-12-70 CA 87-79039 (TRANSLATED FROtl BIOKH I D I Y A 42:1120-1133,1977) AVES,Ui ICKEN ORGAN CULTURE GALLUS DOMESTICUS T I B I A L OSSICLES IN VITRO MUSCULOSKELETAL SYSTEM; B IOCH EM ISTRY AND METABOLISM M E M Y L S I LATRANE 2288-13-3 EMOXYSILATRANE 3463-21-6 CHLOROMEMYLSILATRANE 42003-39-4

TABLE 3. B i o l o g i c a l end p o i n t s e x a m i n e d i n o f f s p r i n g t o assay e f f e c t s C o n t r o l l e d v o c a b u l a r y t e r m o n TOXLINE ABNORMALITIES (NOT SPECIFIED) APGAR SCORE BEHAVIOR AND PSYCHOLOGIC PROCESSES BIOCHEMISTRY AND METABOLISM CARDIOVASCULAR SYSTEM CRANIUI.1 AND FACE CYTOLOGY D I GESTI VE SYSTEM DRUG DEPENDENCE DRUG DISTRIBUTION DRUG INTERACTIONS ENDOCRINE SYSTEM E XTRA-EMBRY ON I C STRUCTURES GENETICS GROWTH HEMIC AND LYMPHATIC SYSTEMS HOMEOSTASIS HOST-MEDIATED AGENT

1 Added

i n 1982.

IMllUNITY AND RETICULOENDOM E L I A L SYSTEM INFECTIOUS DISEASES MATERNAL-FETAL EXCHANgE MULTIGENERATION STUDYMULTIPLE ARNORMALITIES MULTIPLE BIRTHS MUSCULOSKELETAL SYSTEM NEOPLASMS NERVOUS SYSTEM NO ABNORMALITIES OISERVED REGENERATION STUDYREPRODUCTIVE TOXICOLOGY~ RESPIRATORY SYSTEM SENSE ORGANS SEX RATIO S K I N AND S K I N APPENDAGES UROGENITAL SYSTEM V I A B I L I T Y , F E R T I L I T Y , AND MORTALITY

13 TABLE 4. B i o l o g i c a l end p o i n t s exarnined i n the mother t o determine maternal t o x i c i t y C o n t r o l l e d vocabul8ry t e r m on TOXLINE ~~~

~

~~

~~

~~

~

IlATERNAL FETAL LOSS SYSTEM GESTATION DURATION NATERNAL MATERKAL B E H A V I O R MATERNAL RIOCH ENISTRY AND t~lETABOLISf1 MATERNAL MATERNAL MATERNAL CARDIOVASCULAR SYSTEM MATERNAL MATERNAL CYTOLOGY MATERNAL HATERNAL DEATH MATERNAL NATERNAL DIGESTIVE SYSTEM MATERNAL MATERNAL DRUG DEPENDENCE MATERNAL MATERNAL DRUG DISTRIBUTION MATERNAL MATERNAL ENDOCRINE SYSTEM MATERNAL IIATERNAL FERTILITY MATERNAL MATERNAL GENETICS MATERNAL H E M I C AND LYNPHATIC SYSTEMS MATERNAL HATERNAL MATERNAL HOMEOSTASIS

published a b s t r a c t s , chemicals

in

the

10% are

and ETIC

data

review

IEIHUNITY AND RETICULDENDOTHELIAL IHFECTIOUS D I S E A S E LIVER HUSCULOSKELETAL SYSTEV EIEOPLASMS NERVOUS SYSTEM NUTRITION RESPIRATORY SYSTEV SENSE ORGAMS S K I N All0 S K I M APPENDATES TOXICITY (NO SYMPTOMS SPECIFIED) UROGENITAL SYSTEH VAGINAL OR UTERINE BLEEDING WEIGHT CHANGES

articles.

total

approximately 4400.

Registry

Numbers

Examples o f these a r e

agents

such

as

the

physical

agents

such

agent

850.

is

used

to

generate

x-rays;

anticonvulsants.

of

Toxic

The ETIC

data

p u b l i c a t i o n s , s p e c i a l i z e d indexed b i b l i o g r a p h i e s ,

computer-readable tapes, and m i s r o f i c h e . Registry

as

f i e l d , ETIC a l s o indexes parameters o f e p i d e m i o l o g i c a l studies,

maternal d i e t a r y d e f i c i e n c i e s , and maternal disease c o n d i t i o n s .

the

total

viruses, p l a n t s , and p l a n t e x t r a c t s ; and chemical

group names such as f l u o r i d e s , p o l y c h l o r i n a t e d biphenyls, and

base

of

e n t r i e s i n t h e agent f i e l d w i l l never have CAS R e g i s t r y Numbers and t o t a l

biological In

number

base w i t h CAS R e g i s t r y Numbers i s approximately

7400, w h i l e t h e number o f chemicals w i t h o u t CAS Some

The

Effects

The i n f o r m a t i o n i n E T I C

is

used

by

o f Chemical Substances (RTECS) t o update i t s

r e p r o d u c t i v e t o x i c o l o g y f il e s . 2.1.6

To

Agent R e g i s t r y F i l e supplement

Environmental

its

search

Mutagen

methods,

Information

ETIC

and

its

sister

(EMIC) ,

Center

have

center, constructed

computerized Agent R e g i s t r y F i l e which c o n s i s t s o f a l l the chemical the

ETIC and

EMIC

data bases. to

each e n t r y

in

(Table

the

5).

addition

Registry

Numbers.

Terms may be

of

pertinent

T h i s Agent R e g i s t r y F i l e

enables t h e user t o l o c a t e and associate synonyms f o r chemical t h e i r CAS

a in

The Agent R e g i s t r y F i l e has been l i n k e d w i t h

r e l e v a n t supplementary i n f o r m a t i o n , r e s u l t i n g i n f o r m a t i o n parameters

agents

the

agents

through

searched s i n g l y o r i n combination

14

TABLE 5. Components o f the Agent Registry F i l z E M I C p r e f e r r e d name CAS Registry Number CAS p r e f e r r e d name CAS synonyms

Wolecular formula Molecular weight Wiswesser Line Formula Chemical Notation Number o f E M I C references Teratogenic data a v a i l a b i l i t y flutagenic data a v a i l a b i l i t y Carcinogenic data a v a i l a b i l i t y Environmental occurrence T o x i c i t y data a v a i l a b i l i t y Chemical information a v a i l a b i l i t y Chemical fragment names Animals used i n t e r a t o l o g y t e s t i n g o f the chemical Mutagenicity assays i n which the chemical was t e s t e d EPA Gene-Tox review information

5

EMIC, Environmental Mutagen Information Center; CAS, Chemical Abstracts Service; EPA, Environmental P r o t e c t i o n Agency; Gene-Tax, Genetic Toxicology

w i t h other terms using Boolean l o g i c . of

Also included i n t h i s f i l e i s a program substructural searching t h a t makes i t possible t o draw c o r r e l a t i o n s between

chemically a c t i v e groups and b i o l o g i c a l a c t i v i t y , a c a p a b i l i t y t h a t could value

in

p r e d i c t i n g the

teratogcnic p o t e n t i a l o f new chemicals.

have

A user can

i d e n t i f y and l i s t compounds w i t h s i m i l a r s t r u c t u r a l features. By searching the molecular formula f i e l d , i t i s possible t o compile l i s t s o f agents t h a t have For example, ETIC l i s t s 30 agents which

common elements. their

chemical

Registry

formulas.

File w i l l

P r o t e c t i o n Agency

If

contain (EPA)

the

compound

summary

Gene-Tax

has

information

contain mercury

in

been evaluated, the Agent from

Program (evaluation

the

Environmental

o f current status o f

bioassays i n genetic toxicology).

2.1.7 Computerized searching o f the E T I C data base Questions concerning the searching o f the ETIC data base may be d i r e c t e d to: Environmental Teratol ogy I n f o r m a t ion Center Oak Ridge National Laboratory P. 0. Box Y, B u i l d i n g 9207 MS3 Oak Ridge, Tennessee, USA 37831 Phone: (615) 574-7871 FTS: 624-7871 The primary funding source o f ETIC's a c t i v i t i e s since i t s beginning i n 1975 has been the NIEHS/National Toxicology Program. T h i s program i s i n v o l v e d i n

15

ascertaining the t o x i c i t y of chemicals a n d disseminating toxicological information r e l a t i v e t o public health and environment. Investigators a n d other i n t e r e s t e d individuals a r e encouraged to search thc f i l e s d i r e c t l y through the TOXLINE system. TOXLIHE i s the WLM's extensive collection of computerized toxicology information. TOXLINE a n d i t s BACK f i l e s contain more t h a n two million references to published human and animal t o x i c i t y s t u d i e s , e f f e c t s of environmental chemicals and p o l l u t a n t s , adverse d r u g r e a c t i o n s , and a n a l y t i c a l methodology a n d a r e p a r t of NLEI's computer system called MEDLARS (NEDical L i t e r a t u r e Analysis and Retrieval System). The ETIC data base i s one of f i f t e e n component s u b f i l e s t h a t provide material t o TOXLICIE and i t s BACK f i l e s . I n s t r u c t i o n s f o r searching the ETIC f i l e s on TOXLINE a r e in the addendum t o t h i s chapter. The ETIC f i l e a s a p a r t of TOXLINE i s a v a i l a b l e in Japan through the Japan Information Center o f Science and Technology's On-Line Information System (JOIS), and i t i s a v a i l a b l e t h r o u g h other on-line systems t h r o u g h o u t the world. Teratology Data Extraction F i l e I n order t o b e t t e r access, u t i l i z e , and i n t e r p r e t e x i s t i n g teratology and reproduction t o x i c i t y d a t a , a comprehensive data e x t r a c t i o n p r o j e c t funded by the EPA i s in progress a t ETIC. Specific experimental data a r e extracted from selected ETIC master f i l e documents. These data a r e entered in approximately 60 data f i e l d s , which comprise a data e x t r a c t i o n f i l e record. These data f i e l d s include information such a s the i d e n t i f i c a t i o n of the t e s t agent, t e s t animals, experimental protocol, and r e s u l t s . Data f i e l d i d e n t i f i e r s a r e l i s t e d i n Table 6 . The data e x t r a c t i o n f i l e i s networked with a l l other Environmental Mutagen, Carcinogen, and Teratogen Information Program f i l e s including the ETIC master f i l e , the Teratology Scanning Data Base (which contains the r e s u l t s o f a screening process by which documents a r e selected a s data e x t r a c t i o n f i l e 2.2

c a n d i d a t e s ) , the Environmental Mutagen Information Center master f i l e , and the Environmental Carcinogen Information Center master f i l e . Currently, t h e r e a r e approximately 5400 records in the combined data e x t r a c t i o n f i l e s with data on 95 chemical agents which a r e primarily drugs and environmental p o l l u t a n t s (Table 7 ) . The next s e t of documents t o be added t o the f i l e w i l l come from the U.S. Environmental Protection Agency Genetic Toxicology (Gene-Tox) Program c l a s s i f i c a t i o n scheme, Class 2. This Category 2 c o n s i s t s of acyl h a l i d e s , aryl h a l i d e s , halogenated e t h e r s and halohydrins, saturated alkyl h a l i d e s , and unsaturated alkyl halides. Information about this f i l e may be obtained by contacting the ETIC o f f i c e a t Oak Ridge, Tennessee.

TABLE 6. Teratology data extraction f i l e f i e l d i d e n t i f i e r & ~~

RECID ACCNO AGENT CASRN STUDYS IT SOURCE PURITY ANMLCMMN* ANMLTAXN* SUPPLIER AGE BODYWT VM ICLE* SEX DAYOO ROUTE@$ ANALTY PE STATt4ETH@# STATDESC EXTCOM AUTHCOM IRLGCOM EXPIDS EXPDESIG# DOSE DOSPERD NLRITRTD NUblIMPL NUFlLIT DAYEXAM NUMLIV NUllDEAD NUlLIMF

2 *,

Record identification number Accession number Agent CAS Registry Number of the agent Study site Source of agent Purity of agent Test animal s - c m o n name Test animals-taxonomic name Supplier of t e s t animals Age of test animals Body weight of t e s t animals Solvent, vehicle, or c a r r i e r Sex of test animals Day zero of gestation Route of administration of the agent Analysis type (by fetus or l i t t e r ) S t a t i s t i c a l methods used (coded) Other s t a t i s t i c a l methods used (uncoded) Extractor's comments Author's comments Peer review comments Experimental test identification Experimental d e s i g n Dose, concentration or level of agent tested Dosing period or treatment schedule Number of animals treated Number of implantation s i t e s Number of litters Day of examination Number of l i v e fetuses Number of dead fetuses Number of l i t t e r s malformed or affected

controlled vocabulary; @, coded f i e l d ;

NUMRESOR PCTLIV PCTDEAD PCTLIMF PCTRESOR NUNRD PCTRD NWlFET DATACOM EXAI-1TYPE@ EXAMDESC PlATEFFEC*# MATDESC FETEFFEC*# FETDESC NUMMALF# PCTFlALFB OUALTERA QUALLEM QUALGROW QUALNTOX QUALETOX IRLGTERA

IRLGLETH IRLGGROIl IRLGMTOX IRLGETOX

#, repeating f i e l d ;

~

Number of resorbed fetuses Percentage of live fetuses Percentage of dead fetuses Percentage of l i t t e r s malformed or affected Percentage of resorbed fetuses Number of fetuses resorbed and dead Percentage of fetuses resorbed and dead Total number of fetuses Cumnents on numeric data Examination type ( coded) Exam3 nati on description Maternal e f f e c t s Maternal toxicity e f f e c t s description Fetal e f f e c t : observed malformations and other e f f e c t s Fetal e f f e c t s description Number of malformed or affected fetuses Percentage malformed or affected fetuses Qualitative results - teratogenicity Q u a l i t a t i v e r e s u l t s - embryo-fetal l e t h a l i t y Oualitative r e s u l t s - growth retardation Q u a l i t a t i v e r e s u l t s - maternal toxicity Q u a l i t a t i v e r e s u l t s - embryo-fetal toxicity Peer review evaluation of r e s u l t s teratogeni ci ty Peer review evaluation of results embryo-fetal l e t h a l i t y Peer review evaluation of r e s u l t s growth retardation Peer review evaluation of r e s u l t s maternal toxicity Peer review evaluation of r e s u l t s embryo-fetal toxicity

$, authority l i s t .

17 TABLE 7. L i s t o f chemical agents (CAS R e g i s t r y Numbers) i n t h e Teratology Data E x t r a c t i o n F i l e A c e t y l s a l i c y l i c a c i d (00050-73-2) A 1 coho1 (00064-17-5) Amethopteri n (00059-05-2) Aminopteri n (00054-62-6 1 Azathioprine. (00446-86-6) Bendectin (08064-77-5 ) Bisphenol A (00080-05-7) Busulfan (00055-98-1 1 B u t y l a t e d hydroxytol uene (00128-37-0) C a f f e i n e (00058-08-2 1 Carbaryl (00063-25-2) Carbon t e t r a c h l o r i d e (00056-23-5 1 Chlorambuci 1 (00305-03-3) Chloramphenicol (00056-75-7 ) Chlorampheni c o l hemi succinate (03544-94-3 ) Chloroform (00067-66-3) Chl oroqui ne d i phospha t e (00050-63-5 Clomiphene (00911-45-5) C1omiphene c i t r a t e (00050-41-9) Col c h i c i n e (00064-86-8) C o r t i sone (00053-06-5 1 Cortisone acetate (00050-04-4) Cyclohexylamine (00108-91-8) Cyclohexylamine s u l f a t e (19834-02-7) Cyclophosphamide (00050-18-0 1 Cytosine arabinoside (00147-94-4) Daunomyci R (20830-81-3) Diazepam (00439-14-5 1 D i b r omoc h1or0 p r opa ne ( 00096 -12-81 Diethylene g l y c o l dimethyl e t h e r (00111-96-6) D i e t h y l s t i 1b e s t r o l (00056-53-1 1 D i e t h y l s t i l b e s t r o l , disodium s a l t (63528-82-5) Diphenhydramine hydrochloride (00147-24-0) D i uron (00330-54-1 1 E t hy 1ene c h 1or0 hydr in ( 00107 -07 -3 Ethylene g l y c o l (00107-21-1) gamma-LSndanc (00058-89-9) H a l o p e r i do1 (00052-86-8 1 Halothane (00151-67-7) H y d r o c h l o r o t h i a z i d e (00058-93-5) L i t h i um carbonate (10377-37-4) LSD (00050-37-3) LSD t a r t r a t e (17676-08-3) Mercuric acetate (01600-27-7 1 Methotrexate (00059-05-2 1 Methotrexate, sodium (15475-56-6 Methylmercuric c h l o r i d e (00115-09-3) Methylmercury c h l o r i d e (00115-09-3) Methylmercury dicyandiamide (00502-39-6) Methylmercury hydroxide (01104-57-2) N i r e x (02385-85-5) M i sul ban (00055-98-1 1 Myelosan (00055-96-1)

18 Table 7. (continued) ~-

~

~

Myleran (00055-98-1) N-Oesacetyl -methyl c o l c h i c i ne (00477-30-5) N-Desacetyl-thiocol c h i c i ne (02371-16-0 1 N i c o t i n e (00054-11-5) N i c o t i n e s u l f a t e (00065-30-5) N i t r o f e n (01836-75-5) N i trofurazone (00059-87-0) Nitrogen mustard (00055-86-7 N i t r o u s oxide (10024-97-2) Phenobarbital (00050-06-6) Phenobarbital, sodium (00057-30-7) Phenytoin (00057-41-0) Phenytoin, sodium (00630-93-3) Predni solone (00050-24-8) Progesterone (00057-83-0) Propyl t h i o u r a c i l (00051-52-5 1 Pyrimethami ne (00058-14-0) R e t i n o i c acid, sodium s a l t (13497-05-7) R e t i no1 (00068-26-8 Salicylamide (00065-45-2) S a l i c y l i c a c i d (00069-72-7) S a l i c y l i c acid, i s o b u t y l e s t e r (00087-19-4) S a l i c y l i c acid, methyl e s t e r (00119-36-8) S a l i c y l i c acid, phenyl (00118-55-8) S a l i c y l i c acid, sodium (00054-21-7) S a l i c y l i c acid, t h i o (00147-93-3) Serotonin (00050-67-9) Serotonin c r e a t i nine s u l f a t e monohydrate (00061-47-2) Sodium f l u o r i d e (07601-49-4) Styrene (00100-42-5) Sul f i s o x a z o l e (00127-69-5) Testosterone (00058-22-0) Thal idomide (00050-35-1 1 Theophyl l i n e (00058-55-9) To1butamide (00064-77-7 1 Tolbutamide, sodium s a l t (00473-41-6) T r i ethylene-me1 am1ne (00051-18-3 1 V i n y l idene c h l o r i d e (00075-35-4) Vitamin A (11103-57-4) Vitamin A acetate (00127-47-9) Vitamin A a c i d (00302-79-4) Vitamin A acid, sodium s a l t (13497-05-7) Vitamin A p a l m f t a t e (00079-81-2) Warfarin, sodium (00129-06-6 1 1-Methyl-1-nitrosourea (00684-93-5) 1,2,4,5-T (00093-76-51 2,4,5-T (58% as amyl e s t e r ) (00093-76-5) 2,4,5-T, butoxyethyl e s t e r (02545-59-7) 2,4,5-T, sodium s a l t (00136-32-3) 2,3,7,8-Tetrachl o r o d i benzo-P-dioxi n (01746-01-6 1 5-Fluorouraci 1 (00051-21-8) 6-Mercaptopuri ne (00050-44-2 ) 6-Methyl t h i o u r a c i 1 (00056-04-2)

19 Human Drug-Related T e r a t o g e n i c i t y R i s k s Data Base

2.3

D r . Tomas Pexieder, A s s o c i a t e P r o f e s s o r a t t h e

Universite

de

Lausanne

in

S w i t z e r l a n d , has c r e a t e d a d a t a base on human d r u g - r e l a t e d t e r a t o g e n i c i t y r i s k s The s t o r e d i n f o r m a t i o n was e x c e r p t e d from p u b l i s h e d monographs

( r e f . 1).

and

o r i g i n a l papers d e s c r i b i n g human e x p e r i e n c e s w i t h d r u g s d u r i n g pregnancy. d a t a elements are: drug

a c t i v e substance name and synonyms, commercial

name,

group, number o f drug-exposed pregnancies and number o f abnormal c h i l d r e n

r e s u l t i n g , t y p e o f m a l f o r m a t i o n s , and n a t u r a l and given

malformation.

drug-dependent

enhanced

by

assessment.

risk

for

a

The d a t a base i s c o n t i n u o u s l y updated and c o n t a i n s o v e r a

thousand a c t i v e substances o r combinations t h e r e o f . is

Some

drug

the

immediate

availability

of

S i n g l e case r e p o r t s can be g i v e n a

The v a l u e o f t h e d a t a base numbers

lesser

necessary f o r r i s k

weight

when

compared

w i t h e p i d e m i o l o g i c a l s t u d i e s c o v e r i n g hundreds o f thousands o f pregnancies, and t h e r e b y t h e degree decisions.

The

of

risk

main

is

put

purpose

of

into this

proper data

perspective

base

is

for

clinical

t o provide f a c t s f o r

c o u n s e l i n g p h y s i c i a n s when a d r u g has t o be p r e s c r i b e d f o r a p r e g n a n t woman in

the

case

of

inadvertent

drug

outcome f o r m t o be r e t u r n e d a f t e r

intake.

delivery

or

Requesters a r e s e n t a pregnancy or

pregnancy

termination.

When

case r e s u l t forms a r e r e t u r n e d , t h e d a t a a r e e n t e r e d i n t o a d a t a base a s

these

r e f e r e n c e f o r subsequent c o u n s e l i n g .

F o r i n q u i r i e s address:

Tomas Pexieder, M.D., Associate Professor I n s t i t u t d ' H i s t o l o g i e e t d'Embryologie U n i v e r s i t e de Lausanne Rue du Bugnon 9 CH-1011 Lausanne CHUV, S w i t z e r l a n d Phone: (021) 23 22 92, e x t e n s i o n 7 1 2.4

T e r a t o l o g y Lookout The

Toxicology

Stockholm.

Sweden,

Information publish

a

Services monthly

at

the

Karolinska

T h i s e x c e l l e n t source o f r e f e r e n c e s o f i n t e r e s t t o and

clinicians

is

compiled

by

an

Institutet

advisory

experimental

panel.

teratologists

The secondary sources

B i o l o g i c a l A b s t r a c t s , B i o l o g i c a l Abstracts/RRM, and Chemical A b s t r a c t s and MEDLARS

data

bases

are

scanned

by

p e r t i n e n t materia.1.

Keywords have been

references

author

include

addresses.

the

use

added The

of to

Embryology

and

Developmental

F u n c t i o n , Epidemiology, and Techniques.

the

computer p r o f i l e s t o s p o t each

contents

reference,

and

most

a r e d i v i d e d i n t o seven

s e c t i o n s e n t i t l e d C l i n i c a l Cases and Syndromes, G e n e t i c F a c t o r s , Agents,

in

b u l l e t i n e n t i t l e d T e r a t o l o g y Lookout.

Environmental

P h y s i o l o g y and Pharmacology, P l a c e n t a l

20 2.5

Teratogen I n f o r m a t i o n System The Teratogen I n f o r m a t i o n System o f The U n i v e r s i t y o f Texas H e a l t h

Center

at

Dallas

is

Science

b e i n g developed t o p r o v i d e c l i n i c i a n s w i t h a c c u r a t e and

c u r r e n t i n f o r m a t i o n on t h e e f f e c t s o f d r u g s and o t h e r agents t o w h i c h women may be exposed d u r i n g pregnancy ( r e f . 2 ) .

The system c o n s i s t s o f a s e r i e s o f a g e n t

summaries, each o f w h i c h i s based on a comprehensive summaries

are

reviewed

probable teratogens are nationally R.L.

recognized

B r e n t , M.D.,

M.D.;

and

T.H.

Ph.D.;

by

literature

All

search.

l o c a l s p e c i a l i s t s , and summaries on suspected and

also

reviewed

by

an

Advisory

Board

comprised

a u t h o r i t i e s i n t h e f i e l d o f human t e r a t o l o g y .

J.M. Friedman, Ph.D.;

Cordero, M.D.;

J.F.

Shepard, M.D.

of

They a r e

J.I.I. Hanson,

Each summary i s updated e v e r y 18 months.

Teratogen I n f o r m a t i o n System i s a c c e s s i b l e t h r o u g h an e x t e n s i v e i n d e x

of

This drug

and chemical names and CAS R e g i s t r y Numbers v i a a l o c a l t e r m i n a l w i t h modem. C a t a l o g o f T e r a t o g e n i c Agents, Update V e r s i o n

2.6

Dr. Thomas H . Shepard a t t h e U n i v e r s i t y o f Washington, S e a t t l e , i s dial-up

offering

access t o t h e d a t a i n h i s C a t a l o g o f T e r a t o g e n i c Agents: F i f t h E d i t i o n

(ref. 3).

T h i s o n - l i n e system i s updated on a r e g u l a r

state-of-the-art

teratology

information.

basis

to

include

the

Agents may be accessed v i a synonyms

o r CAS ' R e g i s t r y Numbers. 2.7

R e p r o d u c t i v e T o x i c o l o g y Center Another c e n t e r t h a t p r o v i d e s t e r a t o l o g y i n f o r m a t i o n

(ref. 4).

Membership

entitles

an by

an

birth

t h i s center.

obstetrician,

in

the

center

($100

annual

contribution

and

other

chemical

or

o n - l i n e i n t e r a c t i v e computer system c a l l e d REPROTOX.

up-to-date i n f o r m a t i o n induced

the

required)

i n d i v i d u a l t o an u n l i m i t e d number o f c l i n i c a l i n q u i r i e s r e g a r d i n g

t h e p o t e n t i a l r e p r o d u c t i v e hazards o f drugs agents

for

o r r e s e a r c h e r i n r e p r o d u c t i v e t o x i c o l o g y i s i n Washington, D.C.

neonatologist',

defects

on

the

etiology

and

prevention

of

physical Access t o

environmentally

and mental r e t a r d a t i o n i s a v a i l a b l e 24 hours a day a t

The address i s :

R e p r o d u c t i v e T o x i c o l o g y Center Columbia H o s p i t a l f o r Women Medical Center 2425 L S t r e e t , N.W. Washington, D.C. 20037 Phone: (202) 293-5137 2.8

Human Teratogen I n f o r m a t i o n System The Food and

teratogen

Drug A d m i n i s t r a t i o n

i n f o r m a t i o n system

(FDA)

as p a r t of i t s

mafntains

a

adverse d r u g

computerized

human

reaction reporting

21 program.

This

information

FDA

on

system

more

than

a b o r t i o n s , and 130,000 hundred

drugs

with

has

access

25,000

normal

to

birth

first-trimester defect

outcomes.

cases,

Possible

drug-exposure

4,500

spontaneous

associations

of

several

s e v e r a l hundred t y p e s o f s p e c i f i c d e f e c t outcomes i n many

d a t a sources on a w o r l d w i d e b a s i s a r e a c c e s s i b l e ( r e f . 5 ) .

Case

reports

are

s o l i c i t e d from h e a l t h p r o f e s s i o n a l s , and t h e FDA r e c e i v e s from t h e \!orld H e a l t h Organization a t a b u l a t i o n o f b i r t h varied

scope

defects

by

suspected

drug

exposure.

M i c h i g a n M e d i c a i d pregnancy d a t a ( r e f . 61, t h e C o l l a b o r a t i v e P e r i n a t a l (ref.

Project

7 ) . t h e Group H e a l t h C o o p e r a t i v e o f Puget Sound ( r e f . 81, t h e U n i v e r s i t y

o f C a l i f o r n i a C h i l d Development Study, and o t h e r s . data

A

o f i n f o r m a t i o n i s o b t a i n e d from pregnancy c o h o r t s t u d i e s such as

are

gathered

from

the

Boston

R e t r o s p e c t i v e case

control

U n i v e r s i t y Drug Epidemiology U n i t B i r t h

D e f e c t Study, Yale U n i v e r s i t y , t h e I n t e r n a t i o n a l Clearinghouse f o r B i r t h D e f e c t Surveillance,

and

other

sources.

The

S u r v e i l l a n c e handles about 500 pregnancy annually

and

welcomes

information

FDA

Division

drug-exposure

exchange.

of

Epidemiology

queries

and

and

reports

The t e l e p h o n e number i s (301)

443-6410. 2.9

N a t i o n a l Cancer I n s t i t u t e The C l i n i c a l Epidemiology Branch o f t h e N a t i o n a l Cancer I n s t i t u t e (NCI)

developed

a

computerized

agents ( r e f . 9 ) .

has

r e g i s t r y o f p r e g n a n c i e s exposed t o chemotherapeutic

I n f o r m a t i o n i s compiled on

medical

and

obstetric

history,

d r u g and r a d i a t i o n exposure, and b i r t h outcome, and t h e r e i s a weekly c h r o n i c l e o f t h e pregnancy. language

blost o f t h e case h i s t o r i e s were e x t r a c t e d f r o m

literature,

but

some

D o c t o r s a t t h e C l i n i c a l G e n e t i c s s e c t i o n welcome women

the

English

a r e f r o m women who have been p a t i e n t s a t N C I . the

opportunity

to

counsel

who have r e c e i v e d chemotherapy and who a r e c o n s i d e r i n g h a v i n g a c h i l d o r

women who a r e a l r e a d y pregnant. 3 3.1

SECONDARY LITERATURE SOURCES CONTAINING TOXICOLOGICAL INFORMATION Pub1ic a t i o n s Sometimes i t i s necessary t o use t h e r e s o u r c e s o f l a r g e a b s t r a c t i n g s e r v i c e s

to

scan t h e l i t e r a t u r e f o r t e r a t o l o g y i n f o r m a t i o n .

I n 1977 t h e r e were no l e s s

t h a n 3000 a b s t r a c t i n g and i n d e x i n g s e r v i c e s t h r o u g h o u t t h e w o r l d engaged i n t h e surveillance

of

published

literature

( r e f . 10).

Those o f most v a l u e i n t h e

area o f t o x i c o l o g y a r e l i s t e d i n Table 8, n o t i n any o r d e r o f precedence. 3.2

O n - l i n e computer systems Large a b s t r a c t i n g f a c i l i t i e s employ automated methods i n t h e

transfer

of

information.

A

list

of

on-line

computer

retrieval

and

systems c o n t a i n i n g

b i b l i o g r a p h i e s t h a t i n c l u d e toxicology i n f o r m a t i o n i s given ' i n Table 9 .

N

TABLE C. Secondary l i t e r a t u r e sources ( p u b l i c a t i o n s ) containing toxicological information

rG

Publication t i t l e

Pub1 i stier

Subject matter and numerical i n forma t i on

Biological Abstracts

BioSciences Information Service, Phi lade: phi;, Pennsyl vani a

Life sciences. 9,000 source publications f r o n 110 c o u n t r i e s

A subject-oriented, author-indexed coll e c t i o n of a b s t r a c t s published bimonthlv under the t i t l e Biological Abstracts. Computerized searches a v a i l a b l e from either the producer o r the i n s t i t u t i o n s t h a t have purchased these t a p e s f o r use i n t h e i r search s e r v i c e s (Table 9)

Ei ol ogi cal Abstracts/RRll

nioSciences Information Service, Philadelphia, Pennsylvania

L i f e sciences. Over 160.000 a r t i c l e s from

A monthly publication containing b i b l i o graphical information and some a b s t r a c t s . Computerized searches a v a i l a b l e from e i t h e r the producer or i n s t i t u t i o n s t h a t have purchased these tapes f o r use i n their search s e r v i c e s (Table 9 )

Chemical Abstracts

American Chemical Society, Columbus, Ohio

the following sources a r e reported annually: institutional reports, bib1 iographies, l e t t e r s , notes, preliminary rep o r t s , reviews, government reprints, semipopu l a r j o u r n a l s , symposia, t r a d e journals Iiorld chemical l i t e r a t u r e Approximately 12,000 journals p l u s 2,000 proceedings of synposi a ~

Description

A weekly c o l l e c t i o n of a b s t r a c t e d information t h a t has been indexed according t o s u b j e c t keyword, numerical p a t e n t , p a t e n t concordance, and author. Magnetic tapes a v a i l a b l e from producer f o r s a l e t o customers f o r searching; searches a l s o a v a i l a b l e from i n s t i t u t i o n s t h a t have purchased these tapes f o r use i n their search s e r v i c e s (Table 9 )

Table C.

(continued) Subject matter and n timer i ca 1 i n forms t i on

Dr s c r i p t i on

Publication t i t l e

Pub1 i sher

Current Contents

Institute for Scientific Information, P h i l a d e l p h i a , Pennsylvania

Life s r i e n r e s . Ppproximately G , P O @ ,ictirnals

weekly c c l l w t i o n of t h e t a b l e s of cont c p t s o f scrrcnec' jotirnal s. Conputcrizee scPrches of t a b l e s of contents of key ioiirnals by journal nme c.nd/or t i t l e I'cv\lords a v a i l a b l e ; s e r v i c e c a l l p d A K A (Putonated Science Center A l e r t )

Excrrpta fledica

Excerpta Kedi c s Foundation. Amsterdam, Tl?e Netherlsnds

llorld b i o m d i c a l l i t e r attire. Approximately 3,500 j o w n a l s

A monthly c o l l e c t i o n of siihject- and

Canbri dge S c i e n t i f i c A b s t r a c t s , Bethesda, flarylanc!

L i t e r a t u r e of g c n e t i c s and relat-ed d i s c i p l i n e s . 5,000 j o u r n a l s

A vonthly c o l l e c t i o n cf

l!ational Library of flcdici ne, Ila shi ngton,

Diomec!icAl l i t e r a t u r e . P,pproximatel y 2,600 sources of p e r i o d i c a l 1i t e r a t u r e

A monthly subject- a n d aut.hcr-

Giomedical and physical sciences a n d technology. Over 3,300 j o u r n a l s

P, himonthly i n t e g r a t e < ! 1iterat.ur-e ser:rcb

Geneti c s Abstracts

Index lledi cus --

D.C.

Science C i t a t i o n

InCex-

Institute fcr S c i e n t i f i c Infornation, Philadclphia, Pennsylvania

author-indexed a b s t r a c t s

subject-indexed a b s t r a c t s

indexed bibliography; informat i o n computerized and searchable v i a IIEPLIVE (Table 9 ) system c o n s i s t i n g of t h r e e s e p a r a t e b u t r e l a t e d indexes: t h r C i t a t i o n Index, t h e Source Index, a n d the P e r n u t e r m j e c t v m m u t c r i z e c ' searches a m r from t h e producer or i n s t i t u t i o n s t h a t have purchzsec! t h e s e tapes f o r use i n t h e i r search s e r v i c e s (Table 9 )

TABLE 9.

Secondary information sources (on-line computer systems) containing toxicological information

Name BRS Bibliographic Retrieval Ser v i ces , Latham, Mew York

F i l e , number of records, and period covered AGRICOLA Agriculture On-line Access 1,345,000

1970-present

File description WAT IOMAL AGRICULTURAL L I BRAkY Worldwide i n d e x t o the l i t e r a t u r e o f a g r i c u l t u r e and a l l i e d sciences. Cites journal a r t i c l e s , monographs, government documents, special r e p o r t s , and proceedings. Corresponds t o t h e Bibliography Agriculture and the National Agricultural Library Catalog

BIOSIS Previews 3,700,000 1969-present

BICSCIENCES INFORMATION SERVICE Worldwide coverage of research i n t h e l i f e sciences from more than 9,000 j o u r n a l s , a s well a s monographs, r e p o r t s , and symposia proceedings. Subj e c t s include microbiology, p l a n t and animal science, biochemistry, botany, environmental biology, experimental medicine, g e n e t i c s , public h e a l t h , toxicology, virology, and o t h e r i n t e r d i s c i p l i n a r y areas. C i t a t i o n s from both Biological Abstracts and Biological AbstracWRRM

CA SEARCH 2,500,000 1967-presen t

CHMICAL ABSTRACTS SERVICE (CAS) Bibliographic data, keyword phrases, i n d e x e n t r i e s , general s u b j e c t headings, and CAS Registry Number(s) f o r documents covered by Chemical Abstracts Service

DISSERTATION ABSTRACTS ON-LINE 845,000 1861-present

UNIVERSITY MICROFILMS INTERNATIONAL Subject, t i t l e , and author guide t o doctoral d i s s e r t a t i o n s from a c c r e d i t e d universities (predominantly U.S. 1. Based on D i s s e r t a t i o n Abstracts International, American Doctoral D i s s e r t a t i o n , and Comprehensive DissertaIndex -

H AZARDLINE 3,900 substances

-

OCCUPATIONAL HEALTH SERVICES, IEIC. Provides chemical names, formula, CAS Registry Number(s1, RTECS number, physi ca 1 d e s c r i p t i o n , chemical and physical p r o p e r t i e s , toxicology , permissible exposure l e v e l s , symptoms o f exposure, disposal methods, protective procedures, t e x t references, government r e g u l a t i o n s and many o t h e r a r e a s of information on s p e c i f i c chemical substances

N rp

Table 9. ( c o n t i n u e d )

Name

F i l e , number o f r e c o r d s , and p e r i o d covered

F i l e description -

CAS ONLINE American Chemical Soci e t y , Columbus, Ohio

f4E DL Iti E flEOLARS On-Line 4,450,000 1960-present

NATIONAL LIBRARY OF M E D I C I N E C o n t a i n s r e f e r e n c e s f r o m more t h a n 3,000 b i o m e d i c a l j o u r n a l s p u b l i s h e d t h r o u g h o u t t h e w o r l d . Monographs and conference p r o c e e d i n g s added i n 1976. Corresponds t o I n d e x Medicus. C o n t a i n s f u l l b i b l i o g r a p h i c c i t a t i o n s and i n d e x terms for-rSome a b s t r a c t s i n c l u d e d . SDILINE, t h e m o n t h l y update t o t h e main f i l e , used f o r c u r r e n t aware-rvice

NTIS 1,540,000 1964-present

NATIONAL TECHNICAL INFORT4ATION S E R V I C E A broad i n t e r d i s c i p l i n a r y f i l e c o n t a i n i n g c i t a t i o n s and a b s t r a c t s o f government-sponsored R&D r e p o r t s and o t h e r r e p o r t s p r e p a r e d by cont r a c t o r s and g r a n t e e s o f t h e f e d e r a l government. Some f o r e i g n language t r a n s l a t i o n s i n c l u d e d . Corresponds t o Weekly Government A b s t r a c t s and Government R e o o r t s Announcements

POLLUTION ABSTRACTS 102,000 1970-present

CAMBRIDGE SC IEHT I F I C ABSTRACTS Covers f o r e i g n and domestic r e p o r t s , j o u r n s l s , c o n t r a c t s , and symposia Includes a i r , i n t h e a r e a s o f p o l l u t i o n , i t s sources, and i t s c o n t r o l . water, and l a n d p o l l u t i o n , sewage and w a t e r t r e a t m e n t , and l e g a l developments

CAS ONLINE The Chemical Search System From Chemical Abstracts Service 1967-present

CHEMICAL ABSTRACTS SERVICE E q u i v a l e n t o f t h e p r i n t e d Chemical A b s t r a c t s ( C A ) . B i b l i o g r a p h i c data, keyword phrases, i n d e x ent-neral s u b j e c t headings, and CAS R e g i s t r y Number(s1 f o r c h e m i s t r y - r e l a t e d p u b l i c a t i o n s i n 50 languages from 150 c o u n t r i e s . I n c l u d e s w o r l d w i d e p a t e n t documents. Easy c r o s s over t o t h e CAS CHEMICAL REGISTRY

-

01 N

t5

Table 9. (continued)

Name

CIS Chemical Information Systems, Inc., Baltimore, Maryland

m

F i l e , number of r e c or ds , and period covered

File de sc ription

CAS CHEMICAL REGISTRY 8,000,000 compounds

CHEMICAL ABSTRACTS SERVICE The w orld' s l a r g e s t f i l e of substance inforwation, including coordination compounds, polymers, incompletely defined substances, a l l o y s , mixtures, and minerals. In eacb re co rd, t h e r e g i s t r y number i s linked t o molecular s t r u c t u r e diagram, molecular formula, Ch index name, synonyms, and the ten most re cen t re fe ren ces i n Chemica1 Abstracts. Easy crossover t o t he bi bl i ogra ph ic f i l e

CESARS Chemical Eva1 uation Search and Retrieval System 189 chemicals

OFFICE OF HATERIALS CONTROL OF THE STATE OF tIICHICAI~!'S CEPARTIIEIIT OF NATURAL RESOURCES Detailed information and e va lua tio n s on a group o f chemicals cf p a r t i c u l a r importance i n t h e Great Lakes Ecasin. Each record contains up t o 185 da ta f i e l d s with re fe re nc e s t o th e s t u d i e s used i n t h e i r documentation

CHRIS Chemicel Hazard Information System 1,016 substances

U.S. COAST GUARD

CTCP C linic a l Toxicology of Commercial Products 23,000 products

CLINICAL TOXICOLOGY OF COIIIIERCIAL PRODUCTS Rased on t h e F i f t h Edition of the book of the save t i t l e by Drs. Gosselin, S m i t h , and Hodge. Information on manufacturer, uses, composition, and toxicity

FRSS Federal Register Search System 150,000 r e f e r e nc e s 1977-present

ENVIRONNENTAL PROTECTION AGENCY A chemical index t o the d a i l y Federal R eg ist er

Information on l a b e l i n g , physical and chemical p r o p e r t i e s , hea lth hazards, f i r e hazards, chemical r e a c t i v i t y , water p o l l u t i o n , and h a z a r d classification

T a b l e 9. ( c o n t i n u e d )

Name

F i l e , Number o f r e c o r d s , and p e r i o d covered

F i l e description

OHMTADS O i l and Hazardous M a t e r i a l s Technical A s s i s t a n c e Data System 1,402 substances

ENVIRONMENTAL PROTECTIC" AGENCY The 126 d i f f e r e n t d a t a f i e l d s c o n t a i n p h y s i c a l , chemical, b i o l o g i c a l , t o x i c o l o g i c a l , and commercial d a t a w i t h emphasis on t h e h a r a f u l e f f e c t s t o water q u a l i t y

RTECS Registry o f Toxic E f f e c t s o f Chemical Substances 80,000 c h e m i c a l s

NATIONAL INSTITUTE OF OCCUPATIONAL SAFETY AND HEALM C o n t a i n s i n f o r m a t i o n a b o u t chemical substances, i n c l u d i n g t h r e s h o l d l i m i t v a l u e s , recommended s t a n d a r d s i n a i r , a q u a t i c t o x i c i t y d a t a , t o x i c e f f e c t s d a t a , r e g u l a t o r y i n f o r m a t i o n , r e v i e w i n f o r m a t i o n , and r e f e r e n c e s t o s p e c i f i c t o x i c i t y d a t a . The o n - l i n e v e r s i o n o f NIOSH's R e g i s t r y o f T o x i c E f f e c t s o f Chemical Substances, r e v i s e d q u a r t e r l y

--

DIALOG Dialog Information Services, Inc., Palo Alto, Cal if o r n i a

TSCATS T o x i c Substances C o n t r o l A c t T e s t Submissions 4,200 submissions on 2,228 substances

ENVIRONMENTAL PROTECTION AGEEICY Unpublished h e a l t h and s a f e t y s t u d i e s s u b m i t t e d t o t h e EPA. mechanism f o r o r d e r i n g m i c r o f i c h e c o p i e s of s t u d i e s

AGRICOLA

See e n t r y under BRS system

BIOSIS Previews

See e n t r y under BRS system

CA SEARCH

See e n t r y under BRS system

DISSERTATION ABSTRACTS

See e n t r y under BRS system

EMBASE 2,999,200 June 1974-present

EXCERPTA I l E D I C A A b s t r a c t s and c i t a t i o n s o f a r t i c l e s f r o m over 4,000 b i o m e d i c a l j o u r n a l s published throughout the world. Covers e n t i r e f i e l d o f human m e d i c i n e and r e l a t e d d i s c i p l i n e s

Provides a

t 4 .3

rn

Table 9. (continued)

Name

D?,

F i l e , number of r e c o r d s , and period covered

File description

ENERGYLINE approximately 68,000 1971-present

ENVIRONMENT INFORMATION CENTER Comprehensive coverage of 20 d i f f e r e n t energy-related a r e a s , i n c l u d i n g environmental impact

ENVIROLINE 81,000 1971-present

ENVIRONMENT INFORMATION CENTER Covers the w o r l d ' s environmental information by indexing and a b s t r a c t i n g more than 5,000 i n t e r n a t i o n a l primary and secondary soiirce p u b l i c a t i o n s r e p o r t i n g on a l l a s p e c t s of the environment. Also i n c l u d e s r u l i n g s from the Federal Register and p a t e n t s from the O f f i c i a l Gazette.

INTERNATIONAL PHARMACEUTICAL ABSTRACTS 90,000 1970-present

AMERICAN SOCIETY OF HOSPITAL PHARMACISTS More than 500 pharmaceutical, medical, and r e l a t e d j o u r n a l s a r e indexed and a b s t r a c t e d

LIFE SCIENCES COLLECTION 624,000 1978-present

CAM8RIDGE SCIENTiFfC ABSTRACTS A b s t r a c t s o f worldwide l i t e r a t u r e i n t h e f i e l d s of animal behavior, biochemistry, ecology, entomology, g e n e t i c s , immunology, microbiology, toxicology, and virology

MEDLINE

See e n t r y under DRS system

NTIS

See e n t r y under BRS system

OCCUPATIONAL SAFETY AND HEALTH (NIOSH) 106,000 1972-present

NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH TECHNICAL INFORMATION CENTER Includes c i t a t i o n s t o more than 400 journal t i t l e s a s well a s over 70,000 monographs and technical r e p o r t s

POLLUTION ABSTRACTS

See e n t r y under BRS system

U.S.

Table 9 . (continued)

Name

F i l e , number o f r e c o r d s , and p e r i o d covered SC ISEARCH 6,969,500 197 4- p r e s e n t

MEDLARS National Library o f Medi c i ne, Bethesda, Maryland

CANCERLIT Cancer L i t e r a t u r e 572,904 1963-present

F i l e description INSTITUTE FOR SCIENTIFIC INFORt1ATION M u l t i d i s c i p l i n a r y i n d e x t o t h e l i t e r a t u r e o f s c i e n c e and technology, i n c l u d i n g animal and p l a n t science, b i o c h e m i s t r y , d r u g r e s e a r c h , e x p e r i mental m e d i c i n e , and m i c r o b i o l o q y . Unique f e a t u r e i s i n d e x i n g c i t e d papers. Corresponds t o t h e p r i n t e d Science C i t a t i o n s Index NATIONAL CANCER INSTITUTE Cancer t h e r a p y and chemical, p h y s i c a l , and v i r a l c a r c i n o g e n e s i s f r o m C a r c i n o g e n e s i s A b s t r a c t s and Cancer Therapy A b s t r a c t s

CANCERPROJ Cancer P r o j e c t s 10,183 Current research ( 3 f i s c a l years)

NATIONAL CANCER INSTITUTE, CURRENT CANCER RESEARCH PROJECTS ANALYSIS CENTER C o n t a i n s summaries o f ongoing cancer r e s e a r c h p r o j e c t s t h a t have been p r o v i d e d by cancer s c i e n t i s t s i n many c o u n t r i e s

MEDLINE

See e n t r y under BRS system

RTECS

See e n t r y under C I S system

TOXNET T o x i c o l o g y Data Network 4,100 c h e m i c a l s

NATIONAL LIBRARY OF MEDICINE; OAK R I D G E NATIONAL LABORATORY An i n t e r a c t i v e f i l e o f b i o l o g i c a l , chemica.1, p h a r m a c o l o g i c a l , t o x i c o l o g i c a l , and e n v i r o n m e n t a l i n f o r m a t i o n on s e l e c t e d chemical substances Each t h a t a r e p o t e n t i a l l y hazardous t o man and t h e environment. r e c o r d c o n t a i n s a p p r o x i m a t e l y 140 d a t a elements

N Eo

w 0

Table 9. (continued)

Name

F i l e , .number of records, and period covered TOXLINE Toxicology Information On-Line Current f i l e 931,000 1981-present Backf i l e s (TOXEACK) 1,154.200 1480 and o l d e r m a t e r i a l

File d e s c r i p t i o n NATIONAL LIBRARY OF MEDICINE, TOXICOLOGY INFORMATION PROGRAM An e x t e n s i v e c o l l e c t i o n of toxicology information w i t h r e f e r e n c e s t o human and animal t o x i c i t y studies, e f f e c t s o f environmental chemicals, pestic i d e s , and p o l l u t a n t s , adverse drug r e a c t i o n s , and a n a l y t i c a l methodology. A b s t r a c t s and/or indexing terms included i n a d d i t i o n t o f u l l b i b l i o g r a p h i c c i t a t i o n s . Information d e r i v e d from f i v e major secondary sources and e i q h t s p e c i a l c o l l e c t i o n s of m a t e r i a l : 1. CBAC (Chemical-Biological A c t i v i t i e s ) from CAS; 1965-present 2. HEEP (Health E f f e c t s o f Environmental P o l l u t a n t s ) from BIOSIS; 1970present 3 . IPA ( I n t e r n a t i o n a l Pharmaceutical A b s t r a c t s ) from American Society of HOSDital Pharmacists: 1969- o r e s e n t 4. TOXBIB ( T o x i c i t y B i b i i o raphy) from NLM; 1965-present formerly H A P A B ) from EPA; 1966-1981 5. PESTAE (Pesticide& 6. Haves Fi'le on P e s t i c i d e s from EPA: 1940-1968 1 . EMIC (Environmental Mutagen Information Center) from ORNL; 1950present 8. TMIC (Toxic I t a t e r i a l s Information Center) from ORNL; 1940-1973 9. ETIC (Environmental Terato7ogy Information Center) from ORNL; 1950present 10. RPROJ (Current Government Supported Research P r o j e c t s 2 Toxicology) f r o v Smithsonian Science Information Exchange 11. TD3 (Database of government r e p o r t s and other s o u r c e s ) from NTIS; 12. HNTC (Hazardous M a t e r i a l s Technical Center) from Dynamac Corporation; 1981-present 13. ILO ( I n t e r n a t i o n a l Labor O f f i c e ) from United Nations' I n t e r n a t i o n a l Occupational S a f e t y x H e a ' T t I n f o r m a t i o n Center; 1981-present 14. ANEUPL (Aneuploidy F i l e ) from ORNL; 1970-present 15. EIS (Epidemiology Information System) from O R N L ; 1930-present

Table 9. ( co n tin u ed )

Name ORBIT System Development Corporation, Santa Monica, Calif o r n ia

F i l e , number of r e c or ds , and period covered

F i 1e de s c r i p t i on

CAS82, CAS77, CAS72, CAS67

See e n t r y e n t i t l e d CA SEARCH under BRS system

EN V I RO L IN E

See e n t r y under D I A L O G system

NTIS

See entry under BRS system

PESTDOC approx. 130,000 1968-present

DERWENT PUBLICATIONS LIllITED Covers worldwide journal l i t e r a t u r e on p e s t i c i d e s , he rbi cides , a n d pl ant prote c tion. Includes a n a l y s i s , biology, chemistry, and toxicology

RINGDOC Pharmaceutical Li t e r a t u r e Documentation approx. 450,000 1976-present

DERWEMT PUBLICATIONS LIMITED Covers s c i e n t i f i c journal 1i t e r a t u r e on pharmaceuticals. S p e c i f i c a l l y designed to meet the information requirements of manufacturers. Includes papers from over 750 worldwide j o u r n a l s

TSCA PLUS Toxic Substances Control Act 50,OCO chemicals

OFFICE OF TOXIC SUBSTANCES, ENVIRONMENTAL PROTECTION AGENCY Chemical substances, complex re ac t io n products, and b io lo gi cal m a t e r i a l s in TSCA public a tions. Includes information on manufacturers

VETDOC Veterinary L i te r a tr ir e Documontat i on approx. 70,000 1968-present

DERNENT PUBLICATIONS LIllITEO Covers journal l i t e r a t u r e concerning developments a n d usage of drugs, hormones, vaccines, growth promoters, e t c . , i n farm and domestic animals. Incl tides a n a l y s i s , chemistry , t h e r a p e u t i c s , pharmacology, toxicology, and management

32 3.3

Designing p r o f i l e s When s e a r c h i n g by computer those b i b l i o g r a p h i c d a t a bases as l i s t e d i n Table

9, one has t o d e v i s e a group o f words and/or word fragments t h a t w i l l r e s u l t i n the r e t r i e v a l o f a c i t a t i o n . along

with

their

This grouping

associated

p r o f i l e t h a t generates a

useful

bibliography

words

and/or

is

a

process

I n t h e area

of

fragments Designing a

requiring

teratology

use c e r t a i n terms t o f i n d r e l e v a n t c i t a t i o n s ( h i t s ) .

t r u n c a t i o n symbol, these terms a r e EMBRYOLEMAL:,

word

some

Several r e v i s i o n s may be necessary t o l i m i t r e t r i e v a l t o t h a t

trial-and-error.

which s a t i s f i e s p a r t i c u l a r i n t e r e s t s . must

of

Boolean l o g i c i s c a l l e d a p r o f i l e .

TRANSPLACENTAL:,

TERATOG:, and

s u f f i c i e n t l y d i s c r i m i n a t i n g , as i t s

TERATOL:,

EMBRYDTOX:. use

retrieves

a

FETOTOX:,

The

searcher

W i t h t h e c o l o n as a term

FOETOTOX:,

TERATO:

literature

on

i s not

teratomas.

Other suggested terms a r e : ABORT : EMBRYO: FETAL ORGANOGEN: FETUS:

GESTAT : :NATAL CLEFT L I P CLEFT PALATE PLACENT:

RESORP: PREGNANC : PREGNANT :

An example o f an e f f e c t i v e t e r a t o l o g y p r o f i l e i s BIRTH :,

CONGENITAL:,

DEVELOPMENT:,

LITTER:,

one

in

which

the

terms

OFFSPRING, o r PROGENY should n o t the

The l a t t e r terms

ANOMAL:,

DEFECT:,

DEFORW:,

MALFORM:, o r TOXIC:.

record

-

cause a h i t u n l e s s one o f t h e f o l l o w i n g terms a l s o appears i n ABNORMAL:,

should n o t cause a h i t u n l e s s one o f t h e former terms a l s o appears.

D r . Robert B r e n t ( r e f . 11) has helped c o n s t r u c t t h e that

is

in

use

at

the

c o n t a i n s over 50 terms.

if

citation;

the

hit

if

the

on

To reduce f a l s e h i t s ,

some

terms

teratology

This p r o f i l e

carry

a

negative

word and i t s n e g a t i v e c i t a t i o n occur i n t h e same t i t l e , t h e

a r t i c l e w i l l n o t be r e t r i e v e d . a

profile

I n s t i t u t e f o r S c i e n t i f i c Information.

F o r example, t h e stem word FETUS w i l l n o t cause

term CAMPYLOBACTER a l s o appears i n t h e C i t a t i o n .

Twenty-three

b o t a n i c a l j o u r n a l s have been g i v e n a n e g a t i v e c i t a t i o n t o e l i m i n a t e

references

i n which t h e term EMBRYO r e f e r s o n l y t o a p l a n t embryo. PIEOLIIIE (FlEDlars on-LINE), of

the

world,

indexes

its

NLII's o n - l i n e d a t a base on t h e m e d i c a l l i t e r a t u r e e n t r i e s by use o f MESH ( I I E d i c a l S u b j e c t Heading)

terms, which i s a c o n t r o l l e d vocabulary. default index i s

to

the

MESH

searched.

heading The

Nhen s e a r c h i n g o n - l i n e ,

terms e n t e r e d

index unless a m o d i f i e r s p e c i f i e s t h a t another

following

MESH

headings

are

useful

for

finding

t e r a t o l o g y i n f o r m a t i o n on MEDLINE: TERATOGENS PRENATAL EXPOSURE DELAYED EFFECTS AB N0 RMA L I T IE S , DRUG - IN DU C E D* MATERNAL-FETAL EXCHANGE FETAL ALCOHOL SYNDROME INt d e f i n e s t h e t e r n ABNORMALITIES as c o n g e n i t a l a b n o r m a l i t i e s .

33 T o p i c a l subheadings can m o d i f y t h e MESH h e a d i n g s These

subheadings

and

narrow

CLEFT PALATE/CHEMICALLY INDUCED i s u s e f u l t o t h e e x p e r i m e n t a l eliminating

their

a r e e n t e r e d w i t h a s l a s h a f t e r t h e MESH term.

scope.

F o r example,

teratologist

by

I t i s recommended

papers d e a l i n g w i t h c o r r e c t i o n o f c l e f t p a l a t e .

t h a t t h e f o l l o w i n g MESH headings be m o d i f i e d w i t h /CHEMICALLY INDUCED: CLEFT PALATE HEART DEFECTS, CONGENITAL NEURAL TUBE DEFECTS FETAL DEATH ABORTION

CLEFT SPINA FETAL FETAL

LIP BIFIDA DISEASES GROWTH RETARDATION

The subheading /DRUG EFFECTS can be used w i t h MESH t e r m s FETUS, EMBRYO, BIRTH

WEIGHT.

The

subheading /ETIOLOGY i s u s e f u l t o m o d i f y terms d e s c r i b i n g

a b n o r m a l i t i e s and FETAL GROWTH RETARDATION, FETAL subheading

can

/OCCURRENCE

DEATH,

and

4

ABORTION.

The

be used t o r e t r i e v e r e f e r e n c e s on e p i d e m i o l o g y o f

s p e c i f i c d e f e c t s t h a t a r e MESH terms o r can be used t o m o d i f y ADMORMALITIES.

and

the

broad

term

The subheading /CONGENITAL can be used w i t h d i s e a s e s t a t e s .

REFERENCE EOOKS There a r e s e v e r a l books t h a t

are

essential

reference

sources

for

those

s e e k i n g summarized i n f o r m a t i o n on t h e t e r a t o g e n i c i t y o f c h e m i c a l s . The a n n o t a t e d C a t a l o g o f T e r a t o g e n i c Agents: F i f t h E d i t i o n ( r e f . 3 ) i n c l u d e s discussions

of

1553

agents

that

have

been

tested

for

their teratogenic

p o t e n t i a l i n a n i m a l s and man and i s u s e f u l f o r a c q u i r i n g i n f o r m a t i o n specific

chemical compounds, v i r u s e s , and p h y s i c a l agents.

regarding

klhen p o s s i b l e , C A S

R e g i s t r y Numbers have been added t o each a g e n t e n t r y . C h e m i c a l l y Induced B i r t h D e f e c t s ( r e f . 1 2 ) i s a r e v i e w o f t h e t e r a t o g e n i c i t y of

drugs

and

other

t h e r a p e u t i c use. metals,

and

food

chemicals.

Drugs a r e grouped i n t o 18 c h a p t e r s by t h e i r

Chemicals a r e grouped i n t o 11 c h a p t e r s additives.

such

as

pesticides,

Each c h a p t e r has one o r two d e t a i l e d t a b l e s t o

i n d i c a t e i f an a g e n t was t e r a t o g e n i c i n t h e v a r i o u s a n i m a l s

used

in

testing,

and

Neonatal

and each c h a p t e r has an e x t e n s i v e b i b l i o g r a p h y . Drugs i n -Risk ( r e f .

Pregnancy 13)

g e n e r i c d r u g name. available

d"d L a c t a t i o n : A

contains

short

Each d r u g has been

information

on

Reference Guide t o

Fetal

monographs a r r a n g e d i n a l p h a b e t i c a l o r d e r by assigned

a

f e t a l r i s k i s summarized.

risk

classification,

and

T a b l e s a r e i n c l u d e d when

b i r t h d e f e c t s a r e suggested i n a s s o c i a t i o n w i t h use o f t h e d r u g . R e p r o d u c t i v e Hazards o f I n d u s t r i a l Chemicals ( r e f . 1 4 ) r e v i e w s i n d e t a i l industrial studies,

compounds and

subdivided

a

in

summary

48

a c o n s i s t e n t f o r m a t c o m p r i s i n g a n i m a l s t u d i e s , human with

evaluation.

Animal

and

human

studies

are

i n t o s e c t i o n s on pharmacology and t o x i c o l o g y , e n d o c r i n e and gonadal

34 e f f e c t s , f e r t i l i t y , pregnancy, fertility

and

pregnancy

where a v a i l a b l e .

mutagenicity,

include

and

carcinogenicity.

teratogenicity

Data

on

and m u l t i g e n e r a t i o n s t u d i e s

The 46 compcunds i n c l u d e many s u b s t a n c e s w i t h w i d e s p r e a d

use

as s o l v e n t s and c h e m i c a l r e a c t i o n i n t e r m e d i a t e s . I h t a g e n i c ity, C a r c i n o g e n i c i t y , (ref.

15)

contains

pollutants.

summaries

Teratogenici ty

Industrial

Pollutants

o f t e r a t o g e n i c i t y i n f o r m a t i o n about i n d u s t r i a l

Discussions o f these p o l l u t a n t s

are

divided

into

four

groups:

heavy m e t a l s , i n s e c t i c i d e s , monomers, and h a l o g e n a t e d h y d r o c a r b o n s o l v e n t s . I n B i r t h D e f e c t s and outcomes

of

Drugs

drug-exposed

Pregnancy

women

in

t a b l e s proposing the r i s k r a t e s i n pregnant Many

of

(ref.

the

71,

authors

report

more t h a n 50,000 p r e g n a n c i e s and i n c l u d e women

taking

various

medicines.

t h e n e w e s t d r u g s a r e n o t i n c l u d e d s i n c e t h e p r e g n a n c i e s r e v i e w e d were

between 1959 and 1965.

F o r t h o s e d r u g s l i s t e d , a n a n x i o u s woman who

has

been

exposed t o a d r u g c a n be r e a s s u r e d t h a t a c e r t a i n number o f p r e g n a n t women were exposed t o t h e d r u g w i t h o u t a d v e r s e e f f e c t s i n t h e i r b a b i e s . C l i n i c a l Aspects o f t h e T e r a t o g e n i c i t y o f Drugs ( r e f . 16) p r o v i d e s a t a b u l a r compilation o f data e x t r a c t e d from t e r a t o l o g y papers. i n t e r p r e t e d more t h a n 2000 r e f e r e n c e s ;

book

this

The a u t h o r s r e v i e w e d and

is

a

suhstantial

aid

to

individuals

or

p h y s i c i a n s and o t h e r s w o r k i n g i n h e a l t h s c i e n c e s .

5 5.1

TERATOLOGY INFORMATION SERVICES C a l i f o r n i a Teratogen R e g i s t r y Numerous c e n t e r s i n t h e U n i t e d S t a t e s can r e a d i l y s u p p l y t o

p h y s i c i a n s i n f o r m a t i o n a b o u t d r u g s , c h e m i c a l s , and p h y s i c a l a g e n t s w h i c h may be teratogenic. Registry,

One o f t h e f i r s t o f t h e s e c e n t e r s was

which

is

a

state-wide

the

program operated

California by

the

P e d i a t r i c s a t t h e U n i v e r s i t y o f C a l i f o r n i a , San D i e g o ( r e f s . 17,181. includes

two

volunteers. potential

The s t a f f c o l l e c t s , teratogens.

The

Information concerning

analyzes,

Registry

offers potential

a

and

disseminates

provides referral

teratogens

community system is

for

The s t a f f

a

information

education related

on

through services.

provided by t h e R e g i s t r y t o

p r e g n a n t women, d o c t o r s , and o t h e r h e a l t h p r o f e s s i o n a l s . area,

of

c o o r d i n a t o r s , a p e d i a t r i c d y s m o r p h o l o g i s t , a n d 30 h i g h l y t r a i n e d

l e c t u r e s and d i s p l a y s and

Diego

Teratogen

Department

F o r those i n t h e

San

f r e e p e d i a t r i c dysmorphologic examination i s o f f e r e d a f t e r t h e

b i r t h of the child.

Data from these examinations a r e

d a t a b a s e and used i n s u b s e q u e n t c o u n s e l i n g . o f California; out-of-state t h r o u g h F r i d a y f r o m 9 a.m.

c a l l s a r e n o t accepted. t o 5 p.m.

added

to

the

Registry

Services are l i m i t e d t o the s t a t e

The a d d r e s s i s :

The c e n t e r i s open

Monday

35

California Teratogen Registry Department of P e d i a t r i c s , H-814B University of California Medical Center, San Diego La J o l l a , California 92093 Phone: (610) 294-3504 Toll f r e e : ( C O O ) 532-3749 ( i n C a l i f o r n i a ) Genetic Amniocentesis Office of the University of Michigan Michigan's counseling c e n t e r , which i s located a t the University of Michigan, Ann Arbor ( r e f s . 1 9 , 2 0 ) , has provided a state-wide prenatal 5.2

counseling service f o r o b s t e t r i c i a n s and pregnant p a t i e n t s since 1974.

By

use

of a t o l l - f r e e telephone number, thousands of i n q u i r i e s have been made r e l a t e d t o genetic conditions, exposure t o potential teratogens, a n d o b s t e t r i c or medical complications during e a r l y pregnancy. Up-to-date and accurate information i s supplied by a team of nurses a n d physicians w i t h backgrounds i n genetics or maternal-fetal medicine. Calls a r e taken by perinatal nurse counselors and r e f e r r e d t o the appropriate medical s p e c i a l i s t . This center receives

inquiries

on weekdays between 8 a.m.

and 5 p.m. by telephone: (313)

763-4264 or Michigan WATS (800) 482-1545. 5.3

Other information services Many other medical centers

offer

counseling

concerning

teratogenicity.

Those which have been described in the l i t e r a t u r e a r e a t the University of Kansas Medical Center, Kansas City ( r e f . 2 1 ) ; National Birth Defects Center i n Boston

(refs.

22,231;

Pennsylvania Hospital

i n Philadelphia ( r e f s . 24,251;

University of Colorado Health Sciences Center, Denver ( r e f . 2 6 ) ; University Arkansas

Fledical

School,

Little

Rock

of

( r e f . 2 7 ) ; two locations in Wisconsin

( r e f . 2 8 ) ; University of Washington, S e a t t l e ( r e f . 2 9 ) ; University of Connecticut, Farmington ( r e f . 3 0 ) ; University of Utah, S a l t Lake City ( r e f . 31); University of Vermont College of Medicine, Burlington ( r e f . 32); University of Medicine and Dentistry of New Jersey, Camden ( r e f . 3 3 ) ; and Tufts New England Medical Center, Boston ( r e f . 3 4 ) . 5.4

European information services The Dutch Teratology Information Center of The Netherlands i s consulted by physicians, pharmacists, midwives, c l i n i c a l g e n e t i c i s t s , and v e t e r i n a r i a n s . Relevant p a t i e n t data a r e stored in a computer. Whether a pregnancy i s aborted or c a r r i e d t o term, information i s kept on the conception products involved i n each case ( r e f . 3 5 ) . I n P a r i s , the Centre de Renseignements sur l e s Agents Teratogenes supplies t o medical professionals information on teratogenic risk when conception i s

36 f o l l o w e d by exposure t o v a r i o u s agents.

The c l i n i c a l f i n d i n g s on

of

These

these

pregnancies

are

recorded.

case

histories

the are

outcome aides

in

subsequent c o u n s e l i n g as t h e y augment t h e d a t a p r o v i d e d by t h e l i t e r a t u r e ( r e f . 36). 6

CONCLUSION To a s o c i e t y concerned w i t h t h e h e a l t h and q u a l i t y o f l i f e o f

the

finding

of

specific

information

in

the

fields

its

progeny,

o f t e r a t o g e n i c i t y and

r e p r o d u c t i v e t o x i c o l o g y i s v i t a l as humans a r e exposed t o i n c r e a s i n g l y therapeutic today

to

agents and environmental p o l l u t a n t s . those

toxicology.

seeking

Sometimes

information teratology

computer

searching

of

Wany r e s o u r c e s a r e a v a i l a b l e

developmental

reference

e x p e r t i n t h e f i e l d may be c o n s u l t e d . on-line

on

complex

and

reproductive

books p r o v i d e t h e answer, o r an

Hhen t h e s e sources

prove

insufficient,

f i l e s concerned w i t h t o x i c o l o g y i s e s s e n t i a l .

The use o f these computerized i n f o r m a t i o n systems i s necessary t o keep

current

w i t h t h e enormous volume o f papers p u b l i s h e d a n n u a l l y i n t h e r e s e a r c h a r e a . ETIC i s t h e most comprehensive o f t h e o n - l i n e computer systems t h a t access

to

The ETIC f i l e i s c o n t i n u o u s l y updated and improved t o meet t h e of

those

provide

t h e worldwide l i t e r a t u r e o f t e r a t o l o g y and r e p r o d u c t i v e t o x i c o l o g y . responsible

for

testing,

changing

needs

e v a l u a t i n g , and r e g u l a t i n g substances t o

which humans a r e exposed. The focus o f t h i s primarily

in

the

chapter United

has

been

States,

on

There

c o u n t r i e s t h a t have n o t been covered.

information are,

resources

available

no doubt, r e s o u r c e s i n o t h e r

The a u t h o r s welcome i n q u i r i e s c o n c e r n i n g

t h e t o p i c s discussed i n t h i s paper. ADDENDUM

SEARCHING ETIC O N TOXLINE The ETIC f i l e has been d i v i d e d i n t o t h r e e d i f f e r e n t p o r t i o n s by t h e system.

References d a t e d 1976 t o 1980 appear i n a while

MEDLARS

The ETIC c i t a t i o n s f r o m 1981 t o t h e c u r r e n t d a t e a r e found on TOXLINE. those

separate

file

entitled

TOXBACK76,

c i t a t i o n s through 1975 and p r e v i o u s y e a r s a r e found i n TOXBACK65.

Search s t r a t e g y on t h e s e t h r e e f i l e s i s i d e n t i c a l .

Terms may be e n t e r e d s i n g l y

o r may be combined by means o f t h e Boolean o p e r a t o r s AND, OR, and AND NOT. The most i m p o r t a n t s t e p i n o b t a i n i n g t e r a t o l o g y i n f o r m a t i o n from

the

TOXLINE, TOXBACK76, and TOXBACK65 f i l e s i s t o separate t h e ETIC r e f e r e n c e s f r o m those o f t h e o t h e r s u b f i l e s . then,

by u s i n g t h e

Type i n t h e acronym ETIC as

o p e r a t o r AND,

j o i n the

subsequent

a

search

term

and

search terms w i t h t h e

37

subset number formed by the term E T I C . This procedure assures t h a t your search will be limited t o developmental toxicology without s e l e c t i n g terms t h a t w i l l c r e a t e a subset of t h i s information and avoids duplicate references ( t h e same c i t a t i o n often appears on several of the component f i l e s ) . Use of the term E T I C eliminates the need for thinking of a l l possible terms t o i n d i c a t e teratology. If s p e c i f i c terms such a s teratology or t e r a t o g e n i c i t y a r e used with the E T I C f i l e , references t h a t would be useful may be l o s t because those terms may not appear i n the t i t l e s or a b s t r a c t s of these records. On T O X L I N E , f i e l d names a r e i d e n t i f i e d by a two-letter mnemonic. A l i s t of E T I C f i e l d s and t h e i r f i e l d i d e n t i f i e r s on T O X L I N E appears in Table 10. I f the two-letter i d e n t i f i e r i s n o t used in searching, r e t r i e v a l d e f a u l t s t o f r e e - t e x t searching of an index created by s i n g l e words from a l l searchable f i e l d s . Thus, i f one does not use i d e n t i f i e r s , a search f o r a c e t y l s a l i c y l i c acid must be worded E T I C AND A C E T Y L S A L I C Y L I C AND A C I D . Individual words i n only the T I , KCI, and AB f i e l d s a r e searchable via t e x t words (TW). Indexing terms i n most of the technical f i e l d s have been p u t i n t o the keyword ( K t l ) f i e l d . T A B L E 10. E T I C f i e l d s on T O X L I N E

Field name

Prefix

ACCESSION NUMBER A U M OR TITLE C I T A T ION JOURNAL A B B R E V I A T I O N , VOLUME ( I S S U E NUMBER): PAGES, YEAR OR P U B L I S H E R , PLACE OF P U B L I C A T I O N , PAGES, YEAR PUBLICATION TYPE LANGUAGE CODEN SECONDARY SOURCE ABSTRACT AGENT T E S T E D CLASS OF T E S T OBJECT COMMON NAME OF T E S T OBJECT S C I E N T I F I C NAME OF T E S T OBJECT S T R A I N OF T E S T O B J E C T T I S S U E CULTURED SEX TREATED (F, M. or B ) EXPERIMENTAL CONDITIONS B I O L O G I C A L END P O I N T ASSAYED MATERNAL EFFECTS INDUCER STAGE TREATED CAS R E G I S T R Y NUMBER

SI AU TI

so

PT LA CD AB AB KV KW KW KW KW KW KW KH KW KW KW KW RN

38 S e a r c h i n g f o r i n f o r m a t i o n on t h e t e r a t o g e n i c i t y o f a s i n g l e c h e m i c a l i s most e f f i c i e n t l y a c h i e v e d b y e n t e r i n g t h e CAS R e g i s t r y Number o f t h e c h e m i c a l . example, o n TOXBACKG5, t h e e n t r y o f ETIC AND 50-78-2 for

acetylsalicylic

search

statement

references.

201

For

references

a L i d and i t s synonyms, a s p i r i n and a c e t y l s a l i c y l a t e .

hND

ETIC

The

retricves

keywords

c h a r a c t e r s , i n c l u d i n g spaces.

ACETYLSALICYLIC are

directly

(Ktf)

ACID

retrieves

up

searchable

the

to

only

41

first

39

a

F o r example, e a c h o f t h e f o l l o w i n g i s

The

valid,

l o g i c a l search statement: ETIC AND

17BETA-HYDROXY-4,4,17ALPHA-TRI:

(KII)

ETIC AND VITAtlIN A DEFICIEHCY (KCI) ETIC AND 64-17-5 AND SPRAGUE-DA\ILEY (KH) AND CARDIOVASCULAR SYSTEPI (KU) When s e a r c h i n g s p e c i f i c keywords, e n t r i r s m u s t b e made r x a c t l y a s t h e y been e n t e r e d i n t o t h e d a t a base. a l l p u b l i c a t i o n s w h i c h have smoke, searchable

fields.

smoking, smokes, smoked, e t c . i n any o f

commas

in

t h e t e r m u s u a l l y have no space a f t e r t h e comma.

OCCUPATIOtI,PATERt.IAL and PLAIIT,VERATRUfl CALIFORNICUFl. through

one

or

(PRT

DL).

By

scenning

the

keywords,

a

Agents

Examples a r e

The u s e r needs t o

n o r c r e c o r d s t o f i n d t h e c o r r e c t i n d c x i n g term.

one c a n e n t e r t h e t e r m s ETIC AND SllOKIrlG and t h e n format

the

To s e l e c t o n l y t h o s e t h a t d e a l w i t h smoking t o b a c c o r a t h e r

t h a n w i t h i n d u s t r i a l smoke, one m u s t u s e ETIC At10 CIGARETTE SMOKE (KH). with

have

F o r e x a n p l e , ETIC and ALL SFIOK: w i l l r e t r i e v e

browse

F o r example,

ask

for

the

t e r m CIGARETTE SllClKE i s

detailed

print

located. Searches may be l i m i t e d t o s p e c i f i c y e a r s o f p u b l i c a t i o n , secondary author,

language,

or

TOXLIEIE a l l o w s o n l y one acccptable

terms

publication

type

these (PT)

source,

are a l l searchable elements. per

record

and

linits

its

monograph,

patent,

technical

report,

thesis,

and

Languages a p p e a r i n t h e LA f i e l d a s t h r e e - l e t t e r a h b r e v i a t i o n s such a s

EHC, JPtl, CER, FRE, and SPA.

phrase

typc;

t o the f o l l o w i n g : j o u r n a l a r t i c l e , l e t t e r t o e d i t o r , m w t i n q

a b s t r a c t , meeting paprr, other.

publication

AND

NOT

FOR ( L A ) .

All

foreign

languages

are

eliminated

by

the

Examplrs o f search statements t h a t l i m i t r e t r i e v a l

a r e as f o l l o w s : ETIC AND 50-00-0 AHD FROll 8 1 TO C3 ETIC AND DRENT RL AIJD NOT IlEETING ABSTRACT (PT) ETIC AIID DOG AKD NOT FOR ( L A )

I f a keyword c o n s i s t s o f a p h r a s e w h i c h Rooleari AND). end

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39 C i t a t i o n s may be p r i n t e d o n - l i n e a t t h e mailed

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to

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t h e user from t h e National L i b r a r y o f Fledicine. a

complete

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identification of

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bibliographic

t e c h n i c a l i n d e x i n g and, i n some r e c o r d s , t h e a b s t r a c t . format

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s e a r c h i n g TOXLINE.

I n o u i r i e s s h o u l d be d i r e c t e d t o :

MEDLARS Management S e c t i o n National Library o f tledicine W O O Rockville Pike B e t h e s d a , N a r y l a n d 20294 Phone: ( 3 0 1 ) 496-6103 AC K I! C I:LE DGEl1EFITS

The a u t h o r s acknowledge t h e h e l p f u l s u p p o r t o f Carcinogen,

and

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Ridge National Laboratory Eiology D i v i s i o n L i b r a r y . funded

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National

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Program/National

E n v i r o n m e n t a l H e a l t h S c i e n c e s tinder c o n t r a c t number Y01-ES-40128; e x t r a c t i o n p r o j e c t was f u n d e d by t h e U.S. c o n t r a c t number 11C1-1181-A1. Department

of

Energy

number DE-AC05-840R21400. to

by

Kutagen,

I n f o r m a t i o n Program s t a f f and t h e s t a f f o f t h e Oak is

Institute of t h e ETIC d a t a

E n v i r o n m e n t a l P r o t e c t i o n Agency u n d e r

These c o n t r z c t s a r e a d m i n i s t e r e d f l a r t i n M a r i e t t a E n e r g y Systems,

for

the

U.S.

Inc. under c o n t r a c t

The a u t h o r s a l s o w i s h t o e x p r e s s t h e i r

appreciation

MS. F l o r e n c e J o r d a n , E T I C ' s tJTP/tIIEHS P r o j e c t O f f i c e r , f o r a l l h e r h e l p and

encouragement d u r i n g t h e p r e p a r a t i o n o f t h i s c h a p t e r . REFEREIICES T. P e x i e d e r , F i v e y e a r s e x p e r i e n c e w i t h t h e human d r u g - r e l a t e d teratog e n i c i t y r i s k s d a t a base o p e r a t i o n , T e r a t o l o g y , 3 ? ( 3 ) ( 1 9 2 6 ) 52C. R . L i t t l e , J . I I . F r i e d m a n , P. B o s t , L. G e r r i t y , S. R i z e and \ I . S i n g l e t o n , T e r a t o g e n I n f o r m a t i o n System: a u t h o r i t a t i v e i n f o r m a t i o n on p o t e n t i a l human t e r a t o g e n s f o r c l i n i c i a n s , J. Am. C o l l . T o x i c o l . , 4 ( 1 3 8 5 ) 367. T. H . Shepard, C a t a l o g o f T e r a t o g e n i c Agents, 5 t h edn., Johns H o p k i n s U n i v e r s i t y P r e s s , B a l t i m o r e , 1986. N . A . Brown and A . R . S c i a l l i , REPROTOX: a c o m p u t e r i z e d i n f o r m a t i o n s y s t e m i n r e p r o d u c t i v e t o x i c o l o g y , T e r a t o l ogy, 3 3 ( 3 ) ( 1 9 0 6 ) 50C-51C. F.U. Rosa, C. H e r n a n d e z and H . A . C a r l o , G r i s e o f u l v i n t e r a t o l o g y , i n c l u d i n g t w o t h o r a c o p a g u s con.joined t w i n s , L a n c e t , 1 ( 1 3 0 7 ) 171. F.II. Rosa, C o m p u t e r i z e d o n - l i n e M e d i c a i d p h a r m a c e u t i c a l s u r v e i l l a n c e s y s t e m (COMPASS) human t e r a t o l o g y , T e r a t o l o g y , 3 ? ( 3 ) ( 1 9 8 6 ) 54C. 0. P. H e i n o n e n , D. S l o n e a n d S. S h a p i r o , B i r t h D e f e c t s and Drugs i n Pregnancy, P u b l i s h i n g S c i e n c e s Group, I n c . , L i t t l e t o n , l l a s s a c h u s e t t s , 1077. H . J i c k , L. B. Holmes, J . R. H u n t e r , S. l l a d s e n and A. S t e r g a c h i s , F i r s t t r i m e s t e r d r u g use and c o n g e n i t a l d i s o r d e r s , J. Am. Med. A s s . , 246 ( 1 9 8 1 ) 343-346.

40

9 J . J . tlulvihill and K.R. Stewart, A r e g i s t r y of p.regnancies exposed t o chemotherapeutic agents, Teratology, 33(3) (1986) 8OC. 10 E . L. Hess. Secondary science information, Fed. Proc., 36 (1977) 1. 11 R . L. Brent, Computer program f o r searching the biomedical l i t e r a t u r e in teratology, developmental biology, and reproductive biology, Teratology, 25 (1982) 273-275. 12 J . L. Schardein, Chemically Induced Birth Defects, blarcel-Dekker, Inc., New York, 1985. 13 G . G . Brioas. T. If. Bodendorfer. R . K . Freeman and S. J. Yaffee. Druqs i n Pregnancy'"8nd Lactation: A Reference Guide t o Fetal and Neonatal kisk. ifilliams and tlilkins, Baltimore, 1W3. 14 S. El. Rarlow and F. 11. Sullivan, Reproductive Hazards of Industrial Chemic a l s . An Evaluation of Animal and Human Data, Academic Press, London, 1982. 15 11. Kirsch-Voldcrs, rlutagenicity, Carcinogenicity, and Teratogenicity of Industrial P o l l u t a n t s , Plenum Press, Hew York, 1981. 16 ti. Nishimura and T. Tanimura, Clinical Aspects of the Teratogenicity of Drugs, Exccrpta ENedica, Amsterdam, 1976. 1 7 K.L. Jones, K.A. Johnson, A.R. Aylor a n d L.M. Dick, The California Teratogen Registry, Teratology, 33(3) (198G) 54C. 18 J . Adams, K. L. Jones and E . Courchesne, A postnatal follow-up program established with the California Tcratogen Registry, Teratology, 33(31 (19C6) 54C-55C. 19 I1.F. Rayburn, J. Hanman, G.I. Louwsma and F1.Z. Johnson, Counseling by t c l e phone: a t o l l - f r e e service t o improve prenatal c a r e , J . Reprod. rled., 27 (19C2) 551-556. 20 GI. Rayburn, G. Ililson, J . Schreck, G . Lowsma and J . Hamman, Prenatal counseling: a state-wide telephone service, Obstet. Gynccol., 60 (1982) 243-246. 21 C. R. King, Genetic counseling for teratogen exposure, Obstct. Cynccol., 67 (1986) 843. 22 J . O'Brien, S . Rosenwasser a n d 1.1. Feingold, Teratogen Information Service preliminary a n a l y s i s of d a t a , Teratology, 33(3) (1986) 50C. 23 S. Rosenwasser, J . O'Drien and 11. Feingold, Teratogen Information Service, Teratology, 33(3) (1986) 94C. 24 B. 1. Vogt and R. J. L i b r i z z i , The Pregnancy Healthline: c h a r a c t e r i s t i c s o f c a l l e r s . exposures and u t i l i z a t i o n , Tcratology, 33(3) (1986) 51C. 2 5 E. L. Vogt, R . J . Librizzi and S. \leiner, Prenatal t e s t i n g r e f e r r a l s of p a t i e n t s c a l l i n g teratoqen information programs: impact and income, Teratology, 33(3) (1966) 9%. 2G D. Elanchestcr, U. Petersen, E. Sujansky, J . Capra, A. Davis, L . Colightly, K . llruk and 8. Rumach, Teratogcn information: use o f c x i s t i n g resources t o contain c o s t s , Teratology, 33(3) (1986) 51C. 27 J . G. Quirk, D. Hill, L. Keppen, F. Char, M. Prewster, B. Butler, F. Hawks, I t . Hale and D. b. Ilattison, Teratology information and counseling in a r u r a l s t a t e , Tcratology, 33(31 (19OC) 52C. 28 B. El. Giesecker, P. Feldman and L. Ileik, Clinical tcratology p r o j e c t s in llisconsin, Tcratology, 33(3) (19DG) 53C. 29 T. t l . Shepard, A . G. F a n t e l , E . Flirkes and D. Pelson, Teratogen Information Service: 25 years of experience by the Central Laboratory f o r Human Embryology, Teratology, 33(3) (1986) 53C. 30 S. A. Shulman, D. L. Quinn and S.D. Cassidy, Connecticut Pregnancy Exposure Information Service, Teratology, 3 3 ( 3 ) (1986) 53C. 31 L. P. flartinez, S. A . Gunderson, J . C. Carey, M. K . Kochenour, M. G . Emery, C. Stock, t l . FlcCormick, T. Hells and P. C . Van Dyck, Pregnancy P i s k Line: teratology information service f o r the s t a t e of U t a h , Teratology, 3 3 ( 3 ) (1986) 53C. 32 E. F. Allen and H . E . Hoyme, The Vermont Teratogen Information Hetworl', Tcratology, 33(3) (19CG) 55C. 33 M . K . rlcCormack, Clinical teratology, Am. Fam. Physician, 20(6) (1983) 153161,

41

34 35

36

J. Lockwood, S. Koch, 0. Dubner and f4. Feingold, A telephone s e r v i c e f o r questions r e l a t e d t o genetics and environmental exposures during pregnzncy, B i r t h Defects O r i g . A r t i c . S e r . , 19 (1983) 218-219. P.W.J. Peters and J.t.1. Garbis, The o p e r a t i o n o f the Dutch Teratology I n f o r mation Center, Teratology, 3 3 ( 3 ) (1986) 55C-5GC. E. E l e f a n t and C . Roux, Risk e v a l u a t i o n and i n f o r m a t i o n about drug-induced teratogenesis, Therapie, 40 (1985) 297-300.

42

RWISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES AS A SOURCE FOR COMPILINO A LIST OF TERATOOENS VERA KOLB MEYERS

For the past several years the number of publications i n the f i e l d of teratology has been about 2.500 per year ( r e f . 1). However, this explosion of information did not lead t o any s i g n i f i c a n t breakthroughs i n the understanding of the mechanism of teratogenesis or t h e structurea c t i v i t y relationship (SAR) of teratogenic chemicals. The o l d dream t h a t one can predict teratogenicity of a chemical j u s t by looking a t i t s s t r u c t u r e is still far from becoming true. However, steady progress i s being made i n t h i s complex f i e l d . Significant e f f o r t s have been made t o assemble teratogenic data bapes with peer-reviewed evaluations ( r e f . 1). New avenues f o r the SAR studies have been opened, such a s quantitative methods f o r s t r u c t u r a l superposition of molecules and f o r superposition of t h e i r r e a c t i v i t y c h a r a c t e r i s t i c s (ref. 2 ) . Emphasis has been placed on the e l e c t r o s t a t i c properties of the molecules, such as the molecular e l e c t r o s t a t i c potential. the electric f i e l d s , and the p o l a r i z a b i l i t y terms calculated from perturbation expansions (ref. 2 ) . Computer-assisted multivariate SAR which deals with m a n y variables simultaneously has been advanced (ref. 3). Predictive value of animal data f o r the human s i t u a t i o n has been thoroughly analyzed by Schardein e t al. ( r e f . 4 ) . These authors pointed out t h a t there are many chemicals which are teratogenic i n laboratory animals but whose teratogenicity i n humans is not yet certain. A table l i s t i n g 84 such chemicals was given. Possibly t h i s discrepancy could be associated with the low s e n s i t i v i t y of humans t o c e r t a i n teratogens or the lack of appropriate data i n humans. However, these authors also pointed out t h a t the animal data predict the e f f e c t s of most chemicals f o r which adequate human data are available (mostly drugs). They concluded that i t is prudent t o assume that animal data are also predictive of the human responses t o chemicals f o r which adequate human data (mostly environmental and occupational chemicals) are not available. They suggested that a l l reproductive and developmental data should be used to predict the safety of a chemical, not j u s t data on malformation. Their analysis of the successful use of various animal species i n modeling the human reaction gave t h e following r e s u l t s . The rat and mouse were t h e best, but the rabbit gave the fewest f a l s e positive findings. The greater the number of species with positive

43

r e s u l t s , t h e g r e a t e r the likelihood of teratogenic e f f e c t i n humans. Chemists and workers i n the chemical industry and various laboratories represent the population group most exposed t o various chemicals of unknown teratogenicity.

Often, t h i s exposure s t r e t c h e s

over a period of many years of reproductive p o t e n t i a l .

A question is

posed about the best way of deciding whether a p a r t i c u l a r chemical should or should not be considered teratogenic, and, thus, how i t should be handled. The Registry of Toxic Effects of Chemical Substances (RTECS)(ref.

5) represents a valuable basic guide i n making such decisions.

RTECS is

a compendium of toxicity/teratogenicity d a t a abstracted from the scientific l i t e r a t u r e . RTECS is available i n a printed e d i t i o n o r on computer tape, but updated annually, microfiche i s s u e s , updated quarterly, and v i a on-line computer d a t a bases. a l s o updated quarterly. The annual p r i n t i n g of the complete f i l e of t h e RTECS became impractical due t o the rapid growth of the d a t a base and the r e s u l t a n t bulk of t h e book edition.

For t h i s reason a 1983 Supplement t o the

1981-82 Printed Edition w a s published i n place of the complete Registry. This supplement contains 18,893 e n t r i e s (and 93.263 synonyms) and the complete Registry (as of January 1984) lists 66.957 substances and

180,638 synonyms. Since approximately 6.000 new substance e n t r i e s are made each year, t h e printed e d i t i o n of the Registry becomes rapidly outdated. Due t o a l a r g e number of e n t r i e s i n t h e RTECS. chemists need t o have a s u b f i l e on teratogens. so t h a t they can quickly check t o determine i f the compounds or types of compounds they are working with

are l i s t e d a s teratogens. I n 1979, t h e s u b f i l e of the RTECS "Tumorigenic. Teratogenic. and Mutagenic Citationsn w a s published i n microfiche form (ref. 6). I n 1980 a list of 527 teratogenic chemicals from t h e RTECS w a s published (ref.

7 ) . I n 1981 a new list with 86 additional substances became available (ref. 8). The computer search of the RTECS w a s reasonably straightforward a t t h a t time.

The key word "teratogen" was used and the

RTECS data base searched for t h e names of compounds under t h i s

classification. entries).

The s i z e of the printed f i l e w a s reasonable (500-600

A copy of t h e f i l e could be posted i n t h e laboratory, with a

short explanation t h a t the list of teratogens should be viewed with caution due t o the f a c t t h a t d a t a f r o m the RTECS are unevaluated and t h a t uncertainties e x i s t about animal-human extrapolations.

Any

l i b r a r i a n having access to NLM-MEDLARS (National Library of Medicine-

44

Medical L i t e r a t u r e Analysis and R e t r i e v a l System), f o r example, could do the search,

The l i s t could be q u i c k l y updated as needed.

However, with t h e r e c e n t r e o r g a n i z a t i o n of t h e RTECS, such a simple s e a r c h bedame impossible.

I n October 1985 when t h i s a u t h o r ordered a

computer s e a r c h o f t h e RTECS under t h e keyword " t e r a t o g e n s , " t h e l i b r a r i a n reported back t h a t t h i s key word does n o t e x i s t i n t h e RTECS. The l i b r a r i a n must have e r r e d , we thought.

However, i t w a s discovered

t h a t t h e c l a s s i f i c a t i o n of compounds as t e r a t o g e n s under t h e o l d RTECS code "TER" indeed had been abandoned.

I n s t e a d , i n t h e new RTECS

( p r i n t e d e d i t i o n o f 1981-1982) 91 d i f f e r e n t reproductive e f f e c t s were introduced and c l a s s i f i e d as t o x i c e f f e c t s coded T O l - n l :

Paternal

E f f e c t s , TOl-Mg, r e l a t i n g ,to e f f e c t s on spermatogenesis, testes, p r o s t a t e , impotence, b r e a s t enlargement, etc; Maternal E f f e c t s , T l l - T l g , r e l a t e d t o oogenesis. o v a r i e s , f a l l o p i a n tubes, u t e r u s , c e r v i x . vagina, menstrual c y c l e , b r e a s t s , l a c t a t i o n , p a r t u r i t i o n , postpartum, e t c . ; E f f e c t s of F e r t i l i t y . T21-T29, such as mating performance, female f e r t i l i t y , male f e r t i l i t y , pre- and post- implantation m o r t a l i t y , l i t t e r s i z e . a b o r t i o n , e t c . ; E f f e c t s on Embryo or F e t u s , T31-T39, r e l a t e d t o e x t r a embryonic s t r u c t u r e s , m a t e r n a l - f e t a l exchange, c y t o l o g i c a l changes, f e t o t o x i c i t y , f e t a l d e a t h , e t c ; S v e c i f i c Develovment Abnormalities, T41-T69. such as c e n t r a l nervous system, eye, e a r , c r a n i o f a c i a l , s k i n , body wall, musculoskeletal, c a r d i o v a s c u l a r , blood, r e s p i r a t o r y , g a s t r o i n t e s t i n a l , h e p a t o b i l i a r y , endocrine, u r o g e n i t a l , and immune systems, g e n i t a l tumors, t r a n s p l a c e n t a l tumorigenesis, e t c . ; E f f e c t s on Newborn, V l - T g l , such as s t i l l b i r t h s , l i v e - b i r t h index, s e x

ratio, apgar s c o r e , v i a b i l i t y index, weaning or l a c t a t i o n index, growth s t a t i s t i c s , germ-cell e f f e c t s i n o f f s p r i n g , drug dependence, behavioral, p h y s i c a l , and delayed e f f e c t s , e t c . These new c l a s s i f i c a t i o n s o f reproductive e f f e c t s appear to be s c i e n t i f i c a l l y q u i t e precise.

It r e q u i r e s a good d e a l of knowledge of anatomy. physiology, and g e n e r a l medical s c i e n c e t o understand, even vaguely, what t h e various c l a s s i f i c a t i o n s mean.

While t h i s new format

may be considered an improvement by t h e v a r i o u s s p e c i a l i s t s i n t h e f i e l d , such as t e r a t o l o g i s t s , embryologists, and medical d o c t o r s , i t is undoubtedly a step i n t h e wrong d i r e c t i o n f o r chemists, l e t alone t h e average worker i n t h e chemical i n d u s t r y . To a chemist or o t h e r non-medical s p e c i a l i s t , some u n c e r t a i n t y may

e x i s t about t h e meaning of t h e RTECS reproductive-effect codes.

For

example, i t may n o t be c l e a r how code T27, a b o r t i o n , compares with code T35, f e t a l d e a t h , and how t h e l a t t e r code compares with code T25,

the

45

post-implantation m o r t a l i t y .

Likewise, t h e significance o f

c l a s s i f i c a t i o n o f developmental a b n o r m a l i t i e s i n t o

28 c a t e g o r i e s is n o t

obvious, except when i t p e r t a i n s t o humans. s i n c e t h e organ systems or t i s s u e s a f f e c t e d i n l a b o r a t o r y animals are n o t n e c e s s a r i l y p r e d i c t i v e of

4). 91 d i f f e r e n t f i l e s for 91 r e p r o d u c t i v e e f f e c t s is

t h e type o f response i n humans (ref. Having t o create

i m p r a c t i c a l , time consuming, and expensive.

The o v e r l a p of e f f e c t s

l i s t e d i n files is. moreover, s u b s t a n t i a l .

For example, on October 8. 1985. we wanted t o o b t a i n t h e s u b f i l e o f chemicals a s s o c i a t e d with reproductive e f f e c t s and t h e corresponding T

To do t h i s w e obtained an o f f - l i n e c i t a t i o n list. generated by

codes.

MEDLAR 11. which contained 308 pages with 4.508 names i n a l p h a b e t i c a l However, no T codes were given with t h e chemical names, and thus

order.

t e r a t o g e n s could n o t be s i n g l e d o u t from o t h e r e n t r i e s .

Thus, although

t h e MEDLAR list is reasonably easy t o o b t a i n , it s u f f e r s a disadvantage i n t h a t i t is n o t s p e c i f i c for t e r a t o g e n s . The list o f

4.508 names o f chemicals a s s o c i a t e d with reproductive

e f f e c t s is given i n t h e Appendix I t o t h i s c h a p t e r .

T h i s l i s t could be

made more p r a c t i c a l i n a s h o r t e r v e r s i o n , t o p o s t i n t h e l a b o r a t o r y , f o r example.

The list o f

4,508 names c o n t a i n s many c l u s t e r s o f names o f For example, e n t r y #239

v a r i o u s d e r i v a t i v e s of a p a r t i c u l a r compound.

i n t h e list is androsta-l.4-diene-3.17-dione, t h e first o f 110 androstane d e r i v a t i v e s l i s t e d i n numerical o r d e r .

Thus, t h e list could

be shortened by c o n t a i n i n g only t h e f i r s t of t h e d e r i v a t i v e s under i t s

#239, followed by t h e next type o f compound under i t s e n t r y ( i n t h i s case. a n g i o t e n s i n 11. #349). The gap between t h e e n t r i e s original entry

would i n d i c a t e t h e number of t o x i c d e r i v a t i v e s o f t h e foregoing e n t r y type. A quick check o f t h e "androsta" e n t r y and t h e gap between t h e e n t r i e s provides a chemist with t h e valuable information t h a t a l a r g e number o f androstane d e r i v a t i v e s e x h i b i t reproductive e f f e c t s . S i m i l a r l y , a c l u s t e r o f 13 d e r i v a t i v e s of b a r b i t u r i c a c i d can be i d e n t i f i e d (compounds

.

#452-462)

Such s h o r t e n i n g of t h e l i s t must be done c a r e f u l l y . keeping i n mind t h a t c e r t a i n d e r i v a t i v e s bear l i t t l e resemblance t o t h e p a r e n t e n t r y o t h e r than prime name. entry

For example, a c e t i c a c i d is g i v e n i n t h e l i s t as

#52. Its d e r i v a t i v e s are t h e next 61 compounds.

Although acetic

a c i d i t s e l f is n o t a dangerous teratogen. c e r t a i n t y p e s o f its d e r i v a t i v e s can be h i g h l y t e r a t o g e n i c , e. g. , 2,bdichlorophenoxy- and

2.4.5-trichlorophenoxyacetic a c i d .

Such c l u s t e r s could be s i n g l e d o u t

under headings l i k e "acetic a c i d , chlorophenoxy c l u s t e r , compounds 67-

46

80,"for example, when the shorter list is prepared. The February 1987 update of the October 1985 RTECS list of chemicals which cause reproductive hazards, had 6,917 entries. We selected the following T codes: TO1-TO9 (paternal effects), T25 (postimplantation mortality), T31-T59 (effects on embryo or fetus, and specific developmental abnormalities), and T65 (transplacental tumorigenesis). All but the first ones (T01-Tog) would fit into a classical definition of teratogens. The paternal effects were included in line with the recommendation by Schardein ( v i d e supra), and also to incorporate the newest data on this long neglected subject. We were successful in obtaining the list with the above T codes from CIS (Chemical Information System) in February, 1987. The original list which we ordered through CIS contained the names of 1301 chemicals, their Chemical Abstract numbers (CAS), NIOSH numbers, and teratogenic data broken down by T codes. Type of animals tested and route of administration were also given. Surprisingly, there is a great overlap between the paternal effects (T01-Tog) and other T codes above. All of the chemicals listed under these codes were classified as "teratogens" in this CIS search. The original list was 325 pages long. It was arranged in order of increasing CAS numbers and not alphabetically. Out of 1301 chemicals, 841 were already contained in the above described list of 4,508 names (Appendix I). The names of 460 chemicals were separated. These chemicals, arranged in alphabetical order, appear as Appendix I1 to this chapter. In cases where there is a recognized possibility of birth defects, such as pregnant chemists working with chemicals which are known o r suspected teratogens or structurally related to them, more and better quality information is needed. These women may need to consult the Environmental Teratology Information Center (ETIC) (described in the chapter by Morgan et al. in this monograph) for peer-reviewed results of teratogenicity studies on the types of compounds they are working with. Thanks are expressed to Professor Cal Y. Meyers for editorial help and fruitful discussion. REFERENCES 1 2

3

J.S. Wasson. Use of Selected Toxicology Information Resources in Assessing Relationships between Chemical Structure and Biological Activity, Environmental Health Perspectives, 61, (1985) 287-294. H. Weinstein, J. Rabinowitz, M.N. Liebman, and R . Osman, Determinants of Molecular Reactivity as Criteria for Predicting Toxicity: Problems and Approaches, ibid., pp. 147-162. T.R. Stouch and P.C. Jurs, Computer-Assisted Studies of Molecular Structure and Genotoxic Activity by Pattern Recognition Techniques, ibid., pp. 329-343.

47

4

J.L. Schardein. B . A . Schwetz. and M.F. Kenel, Specits Sensitivities and Prediction of Teratogenic Potential, ibid., pp. 55-67.

5

Registry of Toxic Effects of Chemical Substances, National Institute for Occupational Safety and Health. Cincinnati, Ohio

6

NIOSH. Tumorigenic. Teratogenic. and Mutagenic Citations: Subfiles of the Registry of Toxic Effects of Chemical Substances, NIOSH, GPO Stock 017-033-00352-1. 1979 (microfiche). V. Kolb Meyers and C.Y. Meyers. Chemicals which Cause Birth Defects--Teratogens. A Brief Guide". paperback printed at Southern Illinois University, Carbondale. Illinois, 1980, 37 pp. V. Kolb Meyers and R.E. Beyler. How to make an "educated guess" about the teratogenicity of chemical compounds, in S.M. Somani and F.L. Cavender (Eds.). Charles 0. Thomas, Publ.. Springfield, Illinois, 1981. pp. 124-161.

45226.

7 8

Appendix I CHEMICALS IN RTECS AS OF 10/8/85CAUSING REPRODUCTIVE EFFECTS

1 N1

- ABROMA ALEUSTA L i n n . ,

2 NJ

- AERUS

r o o t extrcct

PRECATORIUS L i n n . ,

root extract

RN

-- ACENAPHTHENE, 5-NITRO602-87-9 -- ACETALDEHYDE 75-07-0 ACETAtlIDE -- 60-35-5 -- ACETAflIDE. N-(~-EENZIHIDAZOLYLI21202-05-1

7

Nl RN

- ACETAMIDE - 40068-20-0

8

N1

3

Nl

RN 4

Nl RN

5

N1

RN 6

Nl

RN 9

N1 RN

10

Nl RN

11 N1

t

2 - l p - ( B I S ( 2-CHLOROETHYL ) M I N O IPHENYL )-N-ETHYL-

ACETIHIDEB N ~ l 2 ~ l 6 ~ C H L O R O ~ 5 ~ f l E ~ H O X r - I H ~ I M ) O L ~ 3 ~ Y L l E T H Y L J ~ -- 63762-74-3 - ACETAMIDE, N ~ l 2 ~ l 6 ~ C H L O R O ~ 5 ~ f l E M O X Y ~ 3 ~ I ~ O L Y L I ~ 1 ~ ~ E T H Y L E T H Y L l - 68935-46-6 - wACETAflIOE, Z-(p-CHLOROPHENOXY I-N-(Z-(DIETHYLAMINOIETHYL)compd. i th 4-6UTYL-1~2-DIPHENYL- 3.5-PYRAZOLIDINEDIMJE (1:lI - 17449-96-6

- ACETAflIDC. ~r2-OICHLORO-N-Ibetc-HYDROXY-alpha-lH~ROX~ETHYLl-p-~~ETHYL5ULFO0-threo-It I

12

RN

- NYLIPHENETHYLI-9 15318-45-3

N1

-

ACETAMIDEt

2~2-DICHLORO-N-Ibeta-HYDROXY-alphe-~HYOROxY~EMYLl-p-NIfROPHLNEMRN 13 N1 RN 14

N1

15 N1

-

YLI-, D4-I-threo56-75-7

- ACETA~~IDEI 2,2-DICHLORO-N-~betcr-HYDROXY-alpha-(HYDROXYflETHYLl-p-NITRO~ENETHalpha ESTER w i t h SODIUn SUCCINATE - YL-. 982-57-0 - ACETAflIDE. N,N-DIEMYL-N'-(1~2r3r4-TETRAHYDRD-l-NIPHTHrL)- ACETAHIDE, 2-l~1~2-DIH~RO-5~6~17~I9~2l-PE~~YDROXY~23~~ETHOXY-2~4~12~~6~1~,20,22-

HEPTAMETHYL-J~l1-DIDXO-2~7~fEPOXYPENTADECA~l~11~13lTRIENIflIM)lNAPHMO( 2.1-b IFURAN-9-YLlOXY 1- NpH-OXETHYL-. 21-ACETATE

RN 16

N1

RN 17 N1

- 2750-76-7 -- ACETA~~IDEI NvN-DIflETHYL127-19-5 - ACETAHIDEI

N-15-flIlrl-DI~ETHYLETnYL~A~M)lSULFONTL~-l~S~4~~IMI*LOL-Z-YL~-9 flONOSODIUn SALT

18 N1

RN 19

NL RN

20

N1 RN

21 N 1 RN

-- ACETAMIDE, 28314-03-6 -- ACETAWIDEr 53-96-3 -- ACETAHIDE. 28322-02-3 - ACETAMDEI

- 640-19-7

N-FLUOREN-1-YLN-tLUOREN-2-YLN-FWMIEN-4-YL2-FLUORO-

49 22

N1 RN

23

N1 RN

24

N1 RN

25

N1

RN 26

N1 RN

27

N1 RN

28

N1 RN

29

N1 RN

30

N1 RN

31

N1 RN

32

N1 RN

33 N 1 RN 34

N1 RN

35

N1 RN

36

N1 RN

37

N1 RN

38

-- ACETAMIOE. 62106-00-7

--

---

N1

41

N1 RN

42

N1 RN

RN

43 N 1 44

N1 RN

45

N1 RN

46

Nl RN

47

N1 RN

48

N1

ACETAtlIDE. 3424-27-7

N-l5-SULF~YL-l~3~4-THIADIUOL-~-YLI-r )IONOSOOIU( SALT

ACETAMIDEI N-SULFANILY L144-80-9

-- ACETIMIDEB N-( 2-14-THIAZOLYL1-5-BENZIMIDAZOLYL 27192-25-2 ACETAHIDE, THIO-- 62-55-5 -

40

1-NAPHTHYLI-

v

N1

N1

ACETAHIOEI 2-FLUORO-N-METHYL-N-I 5903-13-9

NIN'-HEXAHETHYLENEBISI~,~-DIC~LORO-N-ETHYL-- ACETAMIDE, 3613-89-6 -- ACETAMID€+ 2 ~ ~ p - ~ 2 - H ~ O R O X Y - 3 ~ l I S O P R O P Y L A r ( I N O l P R O PIPHENYLIOXY 29122-68-7 -- ACETAHIDE, N-~2-~5-METHOXYIM)OL-3-YLlETHYLl73-31-4 N-~2-15-METHOXY-2-METHYL-3-IMOLrL~€THYLl~ -- ACETAHIDE, 68935-42-2 -- ACETAHIDEn N-METHYL79-16-3 N-l4-15-NITRO-2-FURYL)-2-THIUOLYL)-2r2r2-TRlFLUORO-- ACETIMIOE. 42011-48-3 -- ACETAMIDEv N,N1-OCTAHETHYLENEBIS(2~2-D1CHLORO1477-57-2 -- ACETAMIDEI NIN'-I p-PHENYLENEDIHETHYLENE )BISI 2 ~2-DICHLORO-N-€THY L1477-20-9 -- ACETAHIDE, N - I 2 - W I N O L Y L l T H I O - ~ HYDROCHLORIDE 69365-68-0 -- ACETAMIDEI N - I 5-SULFAMOYL-1 3~4-THIADIAZOL-2-YL)59-66-5

RN 39

N~~2-16~FLUORO~5~ME~~Y-lN-I~OL~3~YLIE~YLl-

1-

ACETAHIDINEI 2-ANILINO-N-~2-Im-CHLOROPHENOXYlPROPYLI-, HONONYORMHLORIOEI NONOHYDRATE 30123-b6-5

- IUYNO-p-TOLUENESULF ACETAMIDINE, N-(2-In-HETHOXYPHENOXY IPROPYL)-2-(m-TOLYL)-, ONATE - 6443-40-9 - ACETANILIDE 3'-( 2-( B I S I 2-BROWETHYL IAMINO IETHYL )-4-M€THOXT3'-~IBIS(2-BRO~ETHYL)AHINOlMETHYLl-4'-EMOXT-- ACETANILIDE, 56266-58-1 -- ACETANILIDE 4 ' -I B I S I 2-CHLOR0ETHYL)AHINO)1215-16-3 - ACETANILID€ 3 '-t 2- B I S I 2-CH LOROETHYL ) M I N O )ETHYL 1-4 '-ETHOXY 4 ' - I E I S f 2-CHLOROETHYL IAHINO l-2-FLWRO-- ACETANILIDEI 1492-93-9 3'-I ( B I S I 2-CHLOROETHYL IAHINO IHETHYL )-4'+lETHOXY-- ACETANILIDE 56288-29-0 -- 56266-61-6 ACETANILIOEI 3 ' - f I 2-BRWOElHYUnINO)METHYLI-4'-EMOXY-- ACETANILIDE, 4'-HYOROXT103-90-2 I

v

9

(

1

-

ACETANILIDEr 4'-HYDROXY-, CAFFEINE

Conpd. w i t h 0 - E T H O X Y B E W I D E .nd

50 49

N1 RN

50

N1 RN

51 N1 RN 52

N1 RN

53 N l RN 54

Nl RN

55

N1 RN

56

N1 RN

57

N1

RN 58

N1

RN 59

N1 RN

60

N1

AN 61 N1 RN 62

MI RN

63 N1 RN

64 N1 RN 65

N1 RN

66

MI RN

67

N1

RN 68

N1 RN

69

N1 RN

70

N1

RN 71 N1 RN

72

N1

RN 73

MI

-------

ACETANILIDE. 4 ' - l 2 - H Y D R ~ Y - 3 - t I ~ P R D P Y L l l l I N O J P R O P O X Y b667)-35-4 ACETANILIDE, 2113-47-5

ACETANILIDE, m-TOLYLAZO64046-59-9 ACETIC ACID 64-19-7 ACETIC ACID, 4-ALLYLOXY-3-CHLOROPHENYL22131-79-9 ACETIC ACIDS (2-BENZOYL-4-nETHYLPHENOXY 72942-62-2

-- ACETIC ACID, 10477-72-2

--

)-,

ETHYL ESTER

2-~p-~BIS~P-CHLOROETHYLlAHINO~PHEHYL~-

ACETIC ACID, Ip-lBISlL-CHLOROETHYLl~INOlPHENYLl~~ 2-HYOROXV-1,s-PROPANEOIYL ESTER 38358-06-4 ACETIC ACID, BIS($-CHLOROPHENYL)83-05-6

- ACETIC ACID, ESTER

.-

2'-PHENYL-

BIS(4-HYDROXY-2-OXO-2H-l-BENZOPYRAN-3-YL)-~ ETHYL

548-00-5

-- ACETIC ACID, 123-86-4 - ACETIC ACID, - 3544-35-2 -- ACETIC ACID, 94-74-6

BUTYL ESTER (~-CHLOROPHENOXY)*P 2-ISOPROPYLHYORAZIOE lI4-CHLORO-~-TOLYLlOXY l-

- ACETIC ACID, ((4-CHLORO-o-TOLYL)OXY)-. - 2698-36-6 - ACETIC ACIDS ((4-CHLORO-o-TOLYLlOXY I-. - 3653-48-3

ETHYL ESTER W O I W SALT

-- ACETIC ACID, 142-71-2

C O P P E R f t + I SALT

-

~lDIBENLYLSTIER(YLENEI D I T H I O I D I ~DIISOOCTYL ~ ESTER

ACID, - ACETIC 28675-83-4

- ACETIC ACIOt - 15307-79-6 - ACETIC ACID, - 94-15-7 - ACETIC ACIOI - 588-22-7 - ACETIC ACID,

o ~ ~ ~ ~ ~ - O I C H L O R O A N I L I "~D S ~ O~OEI uN) 1Y LSALT ~ ~

(214-OICHLOROPHENOXY I l3r4-DICHLOROPHENOXY I-

- 2307-55-3 1214-D1CHLOROPHENOXYI-r AMMONIUM SALT -- ACETIC ACIDS (2r4-DICHLOROPHENOXY 1-n BUTOXYETHYL ESTER 1929-73-3 -- ACETIC ACID, ~,~-DICHLOROPHENOXY-I BUTOXYPROPYL ESTER 1928-45-6 -- ACETIC ACIOI (2~4-DICHLOROPnENOXYI-. BUTYL ESTER 94-80-4 - ACETIC ACID, 2,4-DICHLOROPHENOXY-, BUTYL ESTER and ACID (45 .SL% 48.2% - 2,4r5-fRICHCOROPHENOXrACETIC 39277-47-9 - ACETIC ACID. 12r4-DICHLOROPHENOXY I - , compd. w l t h DIMETHYLAMINE 11:11 - 2008-39-1 )

RN

74

N1

RN

51 75 N 1 RN 76

N1 RN

77

Nl RN

78 N 1 RN 79

N1 RN

-- ACETIC ACID, 533-23-3 - ACETIC ACID, - 25168-26-7 - ACETIC ACID, - 94-11-1 - ACETIC A C I D t

- 1928-38-7 -- ACETIC ACID, 2702-72-9

(2,4-DICHLOROPHENOXY)-,

ETHYL ESTER

I~D~-DICHLMIOPHENOXY)-. ISOOCTYL ESTER 12.4-DICHLWOPHENOXYI-,

ISOPROPYL ESTER

12,4-DICHLOAOPHENOXY)-r

METHYL ESTER

12,4-OICHLOROPHENOXY)-I

SODIUM SALT

- ACETIC A C I D S (2.4-DICHLOROPNENOXYI- mixed with (2~4,5-TRICHLOROPHENOXY I A C E T I C ACID 1 2 : l I RN - 8 0 1 5 - 3 5 - 8 ~1 - ACETIC ACID, OICNLORO-. SODIUM SALT RN - 2 1 5 6 - 5 6 - 1 N 1 - ACETIC ACID, (4-llDIETHYLCARBAHOYLlHETHOXYl-3-HElHDXYPHENYLI-~

ao NI

a1 82

83

RN

ESTER - PROPIL 1421-14-3

N1

-

RN

84

N1 RN

85 N1 RN 86

N1 RN

87

Nl

ACETIC ACID, I I 2 s 3-OIHYORO-6 OXYI-. I-I56049-89-9

7-DICHLORO-2-METHYL-l-OXO-2-PHENY

L-1H-INDEN-5-YL

J-

- ACETIC ACID, 1~2~3-DINYORO-6~7-DICHLWO-2-METHYL~l-OXO-2~PHENYL~lH~I~EN~5-YL~-

0x11-, I+)57297-16-2 ACETIC ACID, l~2~3-DIHYORO-6~7-DICHL~O-Z-HETHYL-l-OXO-2-~ENYL-lH-I~EN-5-YLIOXYI-, ( + - I 5?296-63-6

- ACETIC ACID, - 627-03-2 - ACETIC A C I D )

ETHOXY-

2-12-~l5-ETHOXY-1-HETHYL-6-OXO-1~6-DIHYDROPYRIOAZIN-4-YL~AHINOIET-

HOXY 188

N1 RN

89

N1 RN

90

N1 RN

91

N1

92

N1 RN

93

N1

-

ACETIC ACID, 60-00-4

ACETIC ACID, (ETHYLENEOINITRILOITETRA-B O I S W I U n SALT 139-33-3 ACETIC ACID, 62-74-8

-

94

N1 RN

-- ACETIC ACID, 1600-27-7

95

N1 RN

-

96

N1

- ACETIC ACID,

97

N1

-

RN N1 RN

FLUORO-r

SODIUM SALT

- DIETHANOLAHINE ACETIC ACID, (4-(4-HYOROXY-3-IOOOPHENOXY SALT -- ACETIC ACID, IODO64-69-7

RN

98

(ETHYLENEDINITRIL0)TETRA-

ACETIC ACIO, 301-04-2

I-3~5-OIIOOOPHENYL~-~

L E A 0 ( 2 + I SALT MERCURYl2+) SALT

ACETIC ACID, METHOXY625-45-6

2-(p-l4-HElHOXYSALICYLOYL)PHENOXY~-~

ACETIC ACID, ( 5 1 13-tlETHYL-2-BUTENYLIOXY 1-2-13-(4-1 YL)-l-OX0-2PROPENYLIPHENOXYI64506-49-6

ACID, -- ACETIC 56856-83-8

ETHYL ESTER

13-METHYL-2-BUTENYLIOXY

HETHYLNITROSAHINOHETHYL ESTER

IPHEN-

52 99

N1 RN

100

N1 RN

101 N l 102

103 104

105

107

N1 Nl RN Nl

108 N 1 RN 109 N 1 RN 110 N1 RN

111 N1 RW

112 N1 RN 113 N1 RN

114 N 1 RN

115 N 1 RN

116 N 1 RN

117 N l RN 118 N l RN

119 N 1 RN N1 RN

121 N1 RN 122

N1 RN

123 N 1 RN 124

N1 RN

125

N1 RN

----

1~ - H E T H Y L - 4 - O X O - 5 - P I P E R l D I N O - L - M I M L T O I N Y U

1-8

73-09-6 ACETIC ACID, NITRILOTRI-, 18662-53-8

T R I S W I U I I SALT, MONOHYDRATE

ACETIC ACID, 2-l2-OXEPINYLAHINOlOXY-,

-- ACETIC ACID, 103-82-2 ~i - ACETIC ACID. N l - ACETIC ACID, RN - 302-33-0

RN

120

--

N1 RN

Rt4 106

- ACETIC ACID, ETHYL ESTER

ETHYL ESTER

PHENYL-

~-P~OWXYETHYL ESTER PROPYLDIPHENYL-,

2-IDIElHYLAMINO)ETHYL ESTER

ACETIC ACID, S W I W SALT, HWOHYORATE 31304-44-6 ACETIC ACID, THALLIUHCII SALT 563-68-8 ACETIC ACID, 93-76-5

f 2,4,5-TRICHLOROPHENY

B-

-- ACETIC ACIDS 2rQr5-TRICHLOROPHENOXY-* 2-BUTOXYPROPYL ESTER 3084-62-6 -- ACETIC ACIOI I ~ I ~ , ~ - T R I C H L O R O P H E F Y ) - .BUTYL ESTER 93-79-8 -- ACETIC ACIDI 2,4,5-TRICHLMIOPNENY-, ISOOCTYL ESTER 25168-15-4 - ACETIC

ACID. (2,4~5-TRICHLOROPHENY)-s - 13560-99-1 -- ACETIC ACID, VINYL ESTER 108-05-4 -- ACETIC ACID, ZINC( I11 SALT 557-34-6 -- ACETOHYOROXAHIC ACID 546-88-3

-------

ACETOHYDROXAHIC ACID. 2438-72-4

2-lp-WTOXVPNENYLI-

ACETOHYOROXAHIC ACID, 53-95-2

N-FLUWIEN-2-YL-

S W I U n SALT

ACETOHYOROXAMIC ACID, N-HETHYL13115-24-7 ACETONE 67-64-1 ACETOMITRILE 75-05-8 ACETONITRILEI 151-63-3

AHIN0-s BISULFATE

-- ACETONITRILE, 2~2'-lN-HITROSOIHINO)DI16339-18-7 -- p-ACETOPHENETIOIOE 62-44-2 -- ACETOPHENONE, 2-AMINO613-89-8 -- ACETOPHENONE t-ANILINO-4'-IBENLYLOXY )-E-PHENYC14293-15-3 - HVDROCHLORIDE ACETOPIIENONE. 2 ~ A N I L I N O ~ 4 ' ~ C 2 ~ I D I E T H Y L A M I ~ ~ E ~ O X Y ~ - t - P H E N Y L ~ r - 14406-57-6

53 126

N1

- 4ACETOPHENONE* '~~LORO-2-ll3-llO~ll-DIHYDRO-~~DI~E~lb~f~~EPIN~~~YLl~OPYLl~

RN

-

127 N1 128

N1 RN

129 N 1 130

N1 RN

131 N1

ETHYLAMINOI-. 26786-32 -3

- ACETOPHENWE. 2-CHLORa)IHYDROXY- ACETOPHENONES 3'-1l8-CINNA~YL-5~7-OIHYOROXY~2~2-OIMETHYL-2N~l~8ENZOPYRAN~6~YLl~ HETHYLI- 2'r4'.6'-~IHYOROXY-5'-HETHYL- 82-08-6 - 4ACETOPHEHONEr ' 4 2-1 OIETHYLAMINO IETHOXY ) - ~ - I ~ - ~ E T H ~ ~ Y N I L I N bO2 - R I E N Y L -

2'~4'-OIHYOROXY89-84-9 - ACETOPHEMNE, - ACETOPHENONE 3'-ll2~2-OIHETHYL~5-HYO~OXY~6~PHENYL-6~7-DIHYDRO-2H~8H-BENZOll,2-B

b:514-b'1 132

Nl

133 N1 134 N 1 135

Nl

136 N l RN

137 N l 138 N1

RN 139

N1 RN

140

N1 RN

141 N 1 RN

142 N1 RN 143 N1 RN 144

N1 RN

145 N l

146 N l RN 147 148

N1 RN Nl

RN 149

Nl

RN 150

N1

RN

HYDROCHLORIDE

-

OIPYR~N-~~~YL~~ETHYL~~~'~HETHYL~~'~~'~~'-TRIHYOROXY-

ACETOPHENONE, 2-lm-HEYHOXYPHENYL~-2-PHENYL-4'-l2-l1-PYRROLIOINYLIETn~Y~ACHYRANTHES ASPERA Lim.8

stem bark extract

- ACHYRANTHES ASPERA IAttARANTHRACEAEl STEM, BENZENE EXTRACT - ACHYRANTHES ASPERA IAMARANTHRACEAEI~ BENZENE EXTRACT -- 4757-55-5 ACRIOAN. 9~9-OIHETHYL-10~l3-lOIHETHYUnINOlPROPYL~-

-

9-ACRIOANONE,

6-~ETHOXY~10-lp-TOLYLSULFONYL)-

ACRIDINE. 6-CHLORO-9-134 N-I 2-CHLOROETHYL )-N-ETHY LAHINO )PROPYLAHINO )-2-METHOXY- 9 DIHYDROCHLORIOE 146-59-8

- 6-CHLORO-9-( ACRIOINE, - 83-89-6 14- IOIETHY LAMINO I-1-HETHY LBUTY L IAHINO I -2-HETHOXY- ACRIOINE, 6-CHLORO-9-114-1 OIETHY LAHINO )-l-HETHY LBUTYL )AMINO )-Z-HETHOXY- OIHYDROCHLORIOE 69-05-6

s

- 6-CHLORO-9-~l4-lDIETHYLAMINOl-l~METHYLBUTYL~AHINO~-2-METHOXY-~ ---ACRIOINE~

DIHYOROCHLORIOE B OIHYDRATE 6151-30-0

ACRIDINE. 9~9-DIMETHYL-10-13-IN~N-OIHETHYUnINO~PROPYL~-~ TARTRATE 3759-07-7 ACRIDINE.

l r 2 ~ 3 r 4 - T E T R U ( Y D R O - 4 - l N - B U T Y l A M I ~ ) - r HYOROCHLORIDE

82636-28-0 ACROLEIN 107-02-8

- ACROSTICHUM ALIREVII L t n n . , extract -- ACRYLAMIOE 79-06-1 -- ACRYLAHIDEI 2-1 2-FURYLl-3-15-NITRO-2-FURYLl3680-53-7 -- ACRYLAMIOEI 924-42-5 -- ACRYLAMIOEI 2210-25-5 -- ACRYLAMIDE, 1167-59-3

N-lHYDR0XYMETHYL)N-ISOPROPYLN-METHYL-

54 151 N1 RN 152

N1 AN

153 N1 RN 154

N1 RN

155

N1 RN

156

N1

----

ACRYLAMIOEr NIN'-IIETHYLENEBIS110-26-9 ACRYLIC ACID 79-10-7 ACRYLIC ACID, 3-p-ANISOYL-3-BRMIO-, 21739-91-3

ACID, 2-CIANO-, -- ACRYLIC 137-05-3 -- ACRYLONITRILE 107-13-1

SODIUM SALT, ( € 1 -

METHYL ESTER

- ~-(III-~LOROPHENYL)-~-PHENYL-~'-( 2-f -, -ACRYLOPHENONE~

I-PYRROLIDINYLIETHOXY1-

157

N1 RN

158 N1 159

N1

160

N1 RN

ACRYLOPHENONE, 4'-(2-(DIETHYLMINOJETHOXY 17575-62-1

ACRYLOPHENONEi 3-fp-f2-(DTETHYLAM1NO)ETHOXY )PHENYLI-L-PHENYL-

ACRY LOPHENONE 3-~3r4-DIIIETHOXYPNENYL)-2-PHENYL-4'.(2-(1-PYRROLIDINYL~E~OXY~-

ACRYLOPHENONEI 2 ~ 3 - D I P H E N Y L - 4 ' ~ 1 2 ~ I 1 ~ P ~ R O L I O I N Y L I E T N O X Y ~ 17575-63-2

161 N l

-

162

Nl

-

ACRYLOPHENONE,

163 N1 RN

--

ACTIHAEMYL 37239-28-4

164

N1 RN

165

N1 RN

166

N1 RN

167 N1 RN 168 N1 RN 169 N1 RN 170

N1 RN

171 N1 RN

172

N1 RN

173 N1 RN

174 N1

RN 175 N1 RN 176

N1 RN

177 N1

RN

1-2,I-DIPHENYL-

ACRYLOPHENONEv 3-f p- FLUDROPHENYL )-2-FiiENY L-4 ' -( 2-( 1-PY RROLIOINYL 1ETHOXY I

-

3-lp-METHOXYPHENYL~-2-PHENYL-Q'-l2-f1-PYRROLIDINYLlETHOXYl-

-- ACTIWMYCIN 1402-38-6 -- 8052-16-2 ACTINOIIYCIN C -- 50-76-0 ACTINOMYCIN D

------ 3414-62-8 -- 3'-lalph~-AMINO-p-METHOXYNYDR~I~A~~IDOI-S'-OEOXY-N,N-DInETHYL 1-ADAMANTANAMTNE, HYOROCNLORIDE 665-66-7 ADENINE 73-21-5

ADENINE. 9 - b e t ~ - D - A R A B I N O F U ~ S Y L 5536-17-4 ADENINE, N-HYDROXY5667-20-9

ADENINE, N-H~ROXT-9-RIBOF~ANOSYL-

ADENOSINE. 3'-AMINO-3'-DEOXY -NsN-DIHETHY L58-60-6 ADENOSTNE I 55-79-2

-- ADENOSINE, 146-77-0

--

L-CHLORO-

bDENOSINEB N-I 1-METNYL-Z-PHENYLETHYL I38594-96-6

, I R I-

-- ADENOSINE 5'-(PENTAHYDROGEN TETRAPHOSPHATE) 1062-98-2 -- 61-19-6 5'-ADENYLIC ACID

55 178

N1 RN

179

N1 RN

180

N1 RN

1 8 1 N1 RN 192

NI

RN

183 N1 RN 184

N1 RN

185

N1 RN

186

N1 RN

167 N1

la8

NI RN

189

N1 RN

190

N1 RN

191 N l

RN 192

N1

193

N1 RN

194

N1 RN

-- AOIPIC ACID, 103-23-1 -- AOIPIC ACID, 105-99-7 ACID, -- AOIPIC 849-99-0

BISI2-ETHYLHEXYLI ESTER OIBUTYL ESTER OICYCLOHEXYL ESTER

-

A C I O i DIETHYL ESTER - AOIPIC 141-28-6 -- AOIPIC A t 1 0 1 DIISOBUTYL ESTER 141-04-8 -- ADIPIC ACIO, DIMETHYL ESTER 627-93-0 -- ADIPIC ACID, DIPROPYL ESTER 106-19-4 -- AORIAHYCIN 23214-92-8 -- AFLATOXIN 1402-68-2

-

AFLATOXIN G 1 nixed w i t h AFLATOXIN B l

-

ALANINE, N-CU)BOXY-N-(C~LOROACETYLI-r

17R,21-alphn-DIHYDROXY-4-PROPYL-~ HYDROGEN TARTRATE -- AJMALANIM, 2589-47-1 N-BENLYLOXYCARBONYL-~-PHENYL-B l,L-D18ROtlOETHYL ESTER, L-- ALANINE, 64187-43-5 3-lp-B1S~2-CHLOROETHYL)AMINOlPHENYLl-~OL-- ALANINE, 531-76-0 -- ALANINE, 3-lp-~BIS~2-tHLOROETnYLlAHINOIPHENYLl-~ L148-82-3

-

ALANINE.

N-BENZYL ESTER

3-~lCAR8OXYHETHYLlTHIOl-~L-

638-23-3 ALANINE, N-CARBOXY-3-PHENYL-r 1161-13-3

N-BENZIL ESTER. L-

195

N1

- ALANINE,

196

N1

-

ALANINE, N-~CHLOROACETYLl-3-PENYL~N~~p-TOLYLSULFONYLl-

1 97

N1

-

RN

-

ALANINE, N-ll5-tHLORO-8-HYDROXY~3~~ETHYL-1-OXO-7~TSOCHROMANYL~CAR8ONYL~-3-PHENYL-, ( - 1 303-47-9

198

N1 RN

199

N1 RN

200 N 1 RN 201

N1

202

N1

203 N 1

RH 204

N1 RN

205 N 1

IN

-

N-CARBOXY-3-PHENYL-n

N-BENZYL 1-VINYL ESTER, L-

ALANINE, N-l~5-CHLORO-8-HYDROXY-3-METHYL-1-OXO-7-ISOCHROn*NYLlCARBONYL~-3-PHENYL-r SOOIUn SALT, ( - 1 -

89930-55-2

-- ALANINE. 3-(p-CHLW)OPHENYLl1991-78-2 -- ALANINE, 3-(p-CHLOROPHENYLl-~ DL7424-00-2 - ALANINE, 3-(p-CHLDROPHENYLI-r METHYL ESTER, HYDROCHLORIDE - ALANINE, ~-(~-CHLOROPHENYLI-I METHYL ESTER, HYDROCHLORIDE, -- ALANINE. 3-(3.4-DIHYDROXYPHEMYL)-~ L59-92-7 -- ALANINE. 3-I3.4-DIHYOROXYPHENYLl-Z-HE~YL-, L-(-1555-30-6 ALANINE. N-L-garnme-CiLUTMYL-3-~METHYLENECYCLOPROPYLl-- 502-37-4

DL-

56 206

N1 RN

207

N1 RN

208

Nl

209

Nl

210

N1 RN

213

RN

*

N1 RN N1

214

N1

215

N1

216

N1 RN

217

N1 RN

218

N1 RN

219 N 1 220

N1 RN

221 N1 RN 222

N1 RN

223

Nl RN 224 N1

ALANINEs 3-~4-~4-NYOROXI-3-IWOPXENOXIl-3~5-OIIM)OPHENYLl-r L6893-02-3 ALLNINE) PNENYL-, 63-91-2

L-

ALANINEt 3-PHENYL-r

- ALANINE,

-----

211 N1 RN 212

---

DL-P and L-~-(P-HYOROXYPHENYL)ALANINE (1:ll

3-PHENYL-N-TRYPTOPNYL-r

L-

ALANINE, 3 ~ ( 2 ~ 4 ~ 5 - T R I H Y D R O X Y P E N Y L Ll~, 27244-64-0 ALAZOPEPTIN 1397-84-8 ALEITOCIN 39301-00-3 ALCOHOL SULPHATE 61711-25-9 ALFALFA

--- 23564-05-8 --

A L L I W SATIMM Linn., ALLOPHANIC ACID. 23564-06-9 ALLOPHANIC ACID

powder

~I~'-~-PHENYLENEBIS(~-THIO-, DLETHYL ESTER

,

DIMETHYL ESTER

ALLOXAN 50-71-5

ALOSENN

-- ALVnINUM CHLORIOE 7446-70-0 -- ALUMINUM CHLORIDE, HEXAHYORITE 7784-13-6 -- ALUHINUI SULFATE 13:2) 10043-01-3 -- AHBISTRIN 8017-59-2 - AHHONIUHD t EIS(p- (DIMETHYLAHINOIPHENYL )METHYLENE )-2 rS-CICLOHEXMIEN-l-7L4-(

RN 225

Nl RN

226

Nl RN

227

N1

228

N1 RN

229

N1

RN

RN 230

N1 RN

231 N l RN 232

Nl

233

Nl RN

---- 55-97-0

IDENE I DIMETHYL-, CHLORIDE 548-62-9 AHHONIUH DIHEXADECYLOItlETHYL-r CHLORIDE 1812-53-9 AtWONIW, HEXMECYLTRIMETHYL-I EROHIOE 57-09-0 AMHONIW, HEXAMETHYLEWBIS~(CARBOXY~ETNYl~DItlETHYL-~ DICHLMIIDE, OIOOOECYL ESTER 3818-69-7 AHHONIUflr HEXAMETHYLENEBIS(TRIMETHYL-, DIERRMIIDE

- AHIIONIlNr ~2-HYDROXYETWYL~DIMETNYL~l-HE~YL~2~~E~THIAZIN~lO~YLE~YLl~~

---

CHLMIIOL 2090-54-2 AMPHOTERICIN 6 1397-89-3 AMPHOTERICIN 61 5 ~ 8 ~ 9 ~ T R I D E O X Y ~ 7 ~ l O ~ D I H Y D R O X Y ~ 5 ~ O X O ~ 12609-89-1

- AHSINCKIA INTERHEOIA -- ANABASAHINE, 20410-87-1 ( + )-

57 2 34

N1 RN 235 N1 RN 236 N1 237 N1

238 N1 239 N1 RN 240

Nl

241 N1 242

Nl RN

243

Nl

244 Nl 245 N1 246 N1 RN 247 N1 RN 248 N1 RN

249 N1 RN 250

Nl RN

251 N1 252 N1 253 N1 254 N1 RN 255 Nl RN 256 N1 RN 257 N1

RN 2 58

Nl

259 N1

-- ANABASINE 494-52-0 -- ANAGYRINE 486-89-5 - AIIANAS CMlOHlS L.. unripe fruit e x t r a c t - ANATOXIN. STAPHYLOCOCCAL - ANOROGRAPHIS WALL -- ANDROSTA-1~4-DIENE-3,L7-DIONE 897-06-3 - AWROSTA-1~4-OIENE-3~17-OIONE~19-HYDROXY-1 ACETATE

- ANORWTA-1.4-01ENEDIOE~ HETHYLHYOROXY-

-- ANDRMTA-2,5-DIENO~2r3-dlISOXAZOL-17-beta-OL~ 13074-00-5

- ANDROSTA-lr4-DIEN-3-ONErl7-beta119-DIHYOROXY-, 19-ACETATE - ANDROSTA-1,4-OIEN-3-ONE, - ANDROSTA-1,4-DIEN-3-DNE,

260 N1 RN

261 N1 RN

2,17-beta-OIHYDROXY-l7-HETHYL17-beta-HYOROXY-

- O-~2~4-OINITROPHENYLlOXIME ANDROSTA-1,4-DIEN-3-ONE, 17-beta-HYOROXY-,

- 33514-82-8 -- ANDROSTA-1.4-OIEN-3-ONE. 17-beta-NYDROXT-17-alpha-HETHYL72-63-9 -- ANDROSTA-1,4-OIEN-3-ONE, 17-beta-HYDROXY-. 10-WOECENOATE 13103-34-9 - ANOROSTANE-2-alpha-CARBONITRILE, - 4-alpha,5-olpha-EPOXY-l7-beta-HYDROXY-4~17-DIHETHYL-3-OXD71507-79-4 - 4-alpharS-EPOXY-17-beta-HYDROXY-3-OXO5-alpha-ANlJROSTANE-2-alpha-CARBONITRILE~ - 13647-35-3

-

WDROSTANE-3-alpha.17-be1a-DIOL

- 5-alpha-ANDRWTANE-S-olpha~17-beta-DIOL - 5-alpha-A~ROSTANE-3-beta,l7-beta-OIOL - ~3-(O-(p-NITROPHENYL)OXIHE - ~ ~ ~ ~ ~ - A N D R O S T A N E - ~ , ~2-alpha-BROHO-t ~-OIONEI I - 51354-35-9 - 5-alpha-ANDROSTANE-3,17-OIONEr 2-alpha-CHLORO-r 3-(O-(p-NITROPHENYL)OXIHE)

- 51354-33-7

-- 5-alpha-ANOROST*NE-3.i7-DIMEr S-(O-(p-NITROPHENYL)DXInE) 33510-45-1 - 5-alpha-ANDROSTANEl - 2-alpha~3-elpha-EPITHIO-17-beta-~1-METHOXYCYCLOPENTYLOXY121362-69-6 - ANDROSTANE-3,7,17-TRIONE

- ANDROSTAN-3-ONE, 4-NITROPHENYLIOXIHE 34 - 51354-31-5 - O-(p-NITROPHENYL)OXIME ~-~IP~~-AMROSTAN-~-MI - 51354-34-8 - 0-fp-NITROPHENYLIOXIHE~ ACETATE 04

RN

4~4.17-TRIHETHYL-

17-(ACETYLOXY)-2-U1LORO-. 1, (2-alpha ,S-olpha. 17-beta)-

2-alpha-BR~-17-beta-HYDR~Y-,

5-alpha-ANDROSTAN-3-ONE,

- 33510-44-0

2-BROr10-17-bcta-HYDROXY-, (ester1

58 262 N1 RN

263 N1

-

5-a~pha-ANDROSTAN-3-ONE. 2-alpha-CHLORO-17-beta-HYOROXY-~ 0-(p-NITR0PHENYL)OXIME 64584-59-4

-

- ANDROSTAN-17-ONE,

16-((OIIIETHYLAMINOl~ETHYLENE~-3-bata-HTDROXY-

264

N1

- 2-alpha,17-alpha-OIMETHYL-17-bete-HYOROXY-

265

N1 RN

-- ANDROSTAN-17-ONE, 53-41-8

266

N1

-

RN 267

N1

268

N1 RN

269

N1

270

N1 RN

271

N1 RN

272

N1

273 N 1

5-alphe-ANOROSTAN-3-ONE,

3-HYOROXY-.

5-alpha-AM)ROSTAN-3-ONE, 521-18-6

(3-alpha,B-alphaI-

17-bata-HYOROXY-

- 5-alpha-ANOROSTAN-l7-ONE, 3-alpha-HYOROXY- 5-beta-ANDROSTAN-3-ONE, 17-beta-HYOROXY- 571-22-2 - ANOROSTAN-~~-ONEI 3-(HYDROXYACETYL)-3-HYOROXY-~ OIACETATE l a s t e r ) -- 5-alpha-ANDROSTAN-3-ONE, 17-beta-HYOROXY-, BENZOATE 1057-07-4 - 5-alpha-ANOROSTAN-3-ONE, 17-beto-HYDROXY-, 0-BENZYLOXIME - 64584-65-2 - ANDROSTAN-3-ONEI 17-beta-HYDROXY-2-~1pha-lHYOROXYMETHYLl- ANOROSTAN-3-ONE,

~~-~~~P-HYOROXY-~-(HYOROXYMETHYLENE)-~~-~~~~~-METHYL-

274

275

N1

- 5-alpha,l7-bets-ANDROSTAN-3-MIE, 17-HYOROXY-2-1 HYOROXYIIETHYLENE)-17-METHYL-

RN

-

N1

- ANOROSTAN-3-ONE, 17-beta-HYOROXY-2-~HYDROXYMETHYLl-l7-nlpha-METHYL-

276 N1

-

277

N1 RN

-

278

N1

RN

5-alpha-ANORDSTAN-3-ONE, 17-bet~-HYDROXY-2-alpha-lHYOROXY~ETHYLl-l7-METHYL-

17-beta-HYOROXY-2-alphn-nETHrL- 5-alpha-ANOROSTAN-3-ONEI 58-19-5

-

5-alpha-ANDROSTAN-3-ONE, 521-11-9

17-beta-HYDROXY-17-METHYL-

RN

- 5-alpha-ANDROSTAN-3-ONE, 2-alpha-IHYDROXYIIETHYLl-17-beta-MYDROXY- 0-lp-NITR0PHENYL)OXIIIE 5-alpha-ANDROSTAN-3-ONEt 17-beta-HYOROXY-17-IIETHYL-, - 64584-51-6 - 5-alpha-ANOROSTAN-3-ONEl 17-beta-HYOROXY-, 0-METHYLOXIHE - 64625-46-3 - 5-alpha-ANDROSTAN-3-ONE, 17-beta-HYOROXY-, O-(p-NITROPHENYL)OXIME 17-beta-HYDROXY-, 0-lp-NITROPHENYLIOXIME -- ~-~PT~-ANOROSTAN-~-ONE, 64584-72-1 17-beta-HYORDXY-, - 5-alpha-ANOROSTAN-3-ONEl O - ( p - N I T R O P H E N Y L l O X I I I E ~ ACETATE ( e s t e r - 33510-68-8

N1

-

279

N1

280

N1

RN 281

434-07-1

N1

RN 282 N1 283

N1 RN

284

N1

1

285

RN 286

287

N1

- 0-(p-NITROPHENY 5-alpha-AN0ROSTAN-3-ONEI L IOXItlE,

HEPTANOATE ( e s t e r I 17-beta-HYOROXY-, NITRATE l e i t e r I

RN

-

N1

5-alpha-ANOROSTAN-3-ONE, 17-beta-HYOROXY-, - O-I4-NITRO-e-TOLYL IOXIIIE

RN 288

5-alpha-ANDROSTAN-3-ONEr 17-beta-HYOROXY-, 0-(p-NITROPHENYL)OXIME, 64584-47-0

N1

RN

-

64584-48-1

64584-61-8 5-beta-ANOROSTAN-3-ONEI 64584-74-3

17-beta-HYOROXY-,

0-PHENYLOXIME

59 289

N1 RN

290

N1 RN

-

5-alpha-ANDROSTAN-3-ONE~ 855-22-1

17-beta-HYDROXY-.

PROPIONATE

291

N1

292

N1 RN

) I1~ 2~ 510XADIUOL- 17- be t a- OL , 17-METHYL- 5-alpha-AM)ROSTAN0(2,3-c 1239-29-8 - ANOROSTAN0116.17)PYRAZDL-3-beta-OL -- 1'H-ANDROSTANOI 3,Z-c lPYRAZOL-17-OL, 17-METHYL-, ( 5 - a l p h a . 1 7 - b e t a ) 302-96-5

293

N1

-

294

N1 RN

295

N1

296

N1 RN

297

N1

RN

298

N1 RN

299

N1

300

N1 RN

301

N1 RN

302

N1

303

N1

304

N1 RN

305

N1 RN

306

N1

RN 307

N1

308

N1

RN 309

N1

310

N1 RN

311

N1

312

N1 RN

313

Nl

3-beta,l7-beta-DIHYDROXY-,

ANOROST-5-ENE-17-alpha-CARBONITRILE. OIACETATE

- 5-slpha-ANOROST-2-ENE-2-CARBONITRILE, 17-beta-HYDROXY- 1093-60-3 - ANDROST-4-ENE-17-alpha-CARBONITRILE, 17-HYDROXY-S-OXO-, ACETATE - ANOROST-5-ENE-2-alpha-CARBONITRILEt 17-beta-HYDROXY-4,4,17-TRIMETHYL-3-OXO- 4248-66-2 - 5-elpha-AN0ROST-2-ENE-Z-CARBOXALDEHYDE, 17-beta-HYDROXY-

- 601-16-1 -- ANOROST-5-ENE-3-beta~l7-beta-DIOL 521-17-5 - ANOROST-S-ENE-3-bet a, 17-bet a-OIOL, -

ANOROST-S-ENE-3-beta.17-beta-DIOL. 2297-30-5

17-alpha-EUTADIYNY LOIPROPIONATE

ANDROST-5-ENE-3t17-0IOL. 17-METHYL-,

(3-beta.17-betal

521-10-8

- ANDROST-4-ENE-3-beta~l7-beta-DIOL~17-11-METHYLALLYLl-r -

ANOROST-5-ENE-3-betav17-beta-DIOLs

3-ACETATE

17-PROPIONATE ( e s t e r )

ANOROST-4-ENE-3~17-DIONE - 63-05-8

-

ANOROST-~-ENE-~B~~-DION 9-FLUORO-11-beta-HYOROXYE~ 357-09-5

ANDROST-4-ENE-3,ll-DIONE, 9-FLWRO-17-beta-HYDROXY-17-METHYL- 465-69-0 - A N D R O S T - ~ - E N E - ~ , ~ ~ - D I O N E9-FLUORO-11-beta-HYDROXYV and PROLACTIN

-

314

Nl

315

N1

316

N1

-

317

N1

-

318

N1

-

319

N1 RN

-

ANDROST-4-ENE-3~17-DIONE~ 4-HYDROXY566-48-3 ANOROST-4-ENE-3,17-DIONE,

6-HYDROXY-,

ACETATE ( e s t e r )

ANOROST-4-ENE-3,11-DIONE, 5419-48-7

17-bets-HYDROXY-17-METHYL-

5-alpha-ANDROST-4-ENE-3,17-DIONE, 16-(METHYLENEPIPERIDINOI5-alpha-ANDROST-2-ENE-2-METHANOL, 566-53-0

17-beta-HYDROXY-

16-a1pha-ANDROST-5-ENOll6~17-c IFURAN-L'-ONE, 3-beta-HYDROXY-5' -METHYLENE-, ACETATE (er t e r 1

ANOROST-5-ENO~2.3-dlISOXAZOL-l7-beta-OL,

4,4,17-TRIMETHYL-

5-alpha-ANDROST-2-EN-17-beta-OL. 2,17-alpha-DIMETHYLANDROST-~-EN-~-OLP17-1(2-HYOROXYETHYL)IMINO)-~ 3-ACETATE

5-alpha-ANOROST-2-EN-l7-beta-OL, ANDROST-5-EN-3-OL, 3-ACETATE ANDROST-Q-EN-3-ONE, 855-19-6

17-METHYL-

17-l13-(1-PYRROLIDINYL)PROPYLlI~INOI-, 4-CHLORO-17-beta-HYDROXY-,

ACETATE

60 320

N1

-

ANDROST-4-EN-3-ONE,

9-beta,lO-alpha-ANDROST-4-EN-3-ONE~ 17-beta-HYOROXY-

17-b.ta-CINNAHOYL-

RN

- ANDROST-4-EN-3-ONE~ 1117-beta-OIHYDROXY-. 17-ACETATE - UJOROST-4-EN-3-ONEr 1 7 - b ~ t ~ ~ 1 9 - 0 I H Y O R O 19-ACETATE XY~~ - ANDROST-4-EN-3-ONED ll-bcta~l7-beta-OIHYDROXY-17-MElHYL- 1043-10-3 -- ANOROST-~-EN-~-ONEI 9-FLWRO-ll-bet~~17-b~ta-DIHYOROXY-17-METHYL76-43-7 -- 481-30-1 ANLlROST-4-EN-3-ONE$ 17-alpha-HYDROXY-- ANOROST-5-EN-17-ONEr 3-b.ta-HYOROXY53-43-0

327

N1 RN

-

328

N1

329

Nl RN

330

N1

321

N1

322

N1

323 N 1 RN 324

N1 RN

325 N1 RN

326 N 1

331

N1

332

N1 RN

333 N1 334

N1 RN

335

N1 RN

336

N1 RN

337

Nl

338

N1 RN

339

N1 RN

340

N1

341

N1 RN

342

N1

RN

RN 343

Nl RN

344

N1

345

N1 RN

346

N1

347

Nl

-

571-41-5 ANOROSTEN-17-ONE, S-~R~M-HYOROXY-,ACETATE

-

17-bet a-HYDROXY - 0-1 2 ,4-DINITROPHENY LIOXIME - ANDROST-4-EN-3-OH€ 33514-83-9 - ANDROST-5-EN-lT-ONE, 3-beta-HYDROXY-. ESTER with SWIUn SULFATE - ANOROST-~-EN-~~-ONEI3-HYOROXY-16-1000-- ANOROST-~-EN-~-ONEB 17-beto-HYOROXY-17-tlElHYL58-18-4 - ANDROST-~-EN-~~-ONEI3-beta-HYOROXY-METHYL-

-

t

1

ANDROST-~-EN-~-ONEV17-HYOROXY-7-HETHYL-~ (7-alpha,l7-betaI50880-57-4

-- 434-05-9 5-alpha-ANOROST-l-EN-3-ONEI 17-beta-HYOROXY-l-HElHYL-, ACETATE - 9-befa~lO-alph~-ANOROST-4-EN-3-ONE, a-HYOROXY-17-l2-METHYLALLYL l- 17-bet 2824-50-2 - ANDROST-4-EN-3-ONE, 17-beta-HYDROXY-17-IiETHYL-, and 19-NOR-17-alpha-PREGNA-l~3~5(lOl-TRIEN-20-YNE-3,17-010L 1300:11 -

ANOROST-4-EN-3-ONE9 17-bet a-HYOROXY -6-alpha-HETHY L - 1 7 4 1-PROPYWYL I 79-64-1

-

- ANOROST-4-EN-3-ONE, 17-beta-HYOROXY-6-alpha-METHYL-l7-(l-PROPYNYL)-~ and -

19-NOR-17-alpha8015-19-8

PREGNA-1~3~5~101-TRIEN-20-YNE-3r17-010L

ANOROST-4-EN-3-ONE, PROPIONATE 72030-21-8

17-beta-HYOROXY-17-HETNYL- w i t h TESTOSTERONE,

-- ANOROST-4-EN-3-ONE, 17-beta-HYOROXY-, 0-(p-NITROPHENYLIOXIHE 33514-91-9 - ANOROST-4-EN-3-ONE~ 17-~4-~~~3-beta,l7-alphal-17-HYOROXY-l9-NORPREGN-4-EN-2O-YN-3-YL~-

O X Y I - 1,4-OIOXOBUTOXYI-~ (17-bet al 61083-04-3

-- ANOROST-4-EN-3-ONE, 17-beta-HYOROXY-, O-l2-PYRIOYLIOXIME 53224-68-3 - ANOROST-~-EN-~~-ONEI3-beta-HYOROXY-, SULFONATE ( e s t e r ) - ANOROST-4-EN-3-ONE. 17-bet~-HY0i?OXY-, ,alpha,alpha-TRIFLUORO-p-TOLYLlOXIIiE - O-talpha 64584-80-1 - ANOROST-4-EN-3-ONEn 17-(2-IHIOAZOLIN-4-YL1- ANDROST-4-EN-3-ONE, 17-bata-(p-METHOXYCINNAMOYLI-

61

348

N1

- ~ ' H - A W R O S T - ~ - E E I O ( ~ ~ ~ ~ ~ - ~ I P Y R A Z O L 5'-HETHYL-~-~~~~-OLI

349

N1 RN

-

350

N1 RN

351

N1 RN

352

N1 RN

-- ANGIOTONIN 1407-47-2 -- ANILINE, NsN-DIHETHYL-p-( (p-CHLOROPHENYLIAZOI2491-76-1 - ANILINE, N,N-DIHETHYL-p-((p-FLUOROPHENYL)AZO)- 150-74-3

353

N1 RN

-

354

N1

355

N1 RN

356

N1 RN

357

N1 RN

358

N1 RN

359

N1

360

N1 RN

ANGIOTENSIN 11 11128-99-7

ANILINE, N~N-DIHETHYL-p-(3-FLUOROPHENYLAZO)332-54-7

- N,N-DIHETHYL-p-l6-HETHOXY-2-PHENYL-3~4-DIHYDRO-l-NAPHTHYL~ANILINE, -- 63019-14-7 ANILINE, N~N-OIHETHYL-p-l2-(1-NAPHTHYLlVINYL)- ANILINE, - 60-11-7 - ANILINE,

N,N-DIHETHYL-p-PHENYLAZO-

- 55-80-1 N,N-OIHETHYL-p-(ni-TOLYLAZO)N.N-OIHETHYL-4-(p-TOLYLAZO)-- ANILINE, 3010-57-9 - ANILINE, N~N-DIHETHYL-p-l~nlpha~nlphn~nlpha-TRIFLUORO-m-TOLYL~AZO~-

361

N1

362

N1 RN

363

N1 RN

364

N1 RN

2s4-DINITRO- ANILINE, 97-02-9 - ANILINE, N-ETHYL-p-I(p-NITROPHENYL)THIO)-- 612-64-6 ANILINE, N-ETHYL-N-NITROSO-- ANILINE, N-ETHYL-p-(PHENYLAZOI2058-67-5 -- ANILINE, N-HETHYL-N-NITROSO614-00-6

365

N1 RN

- ANILINE. - 621-90-9

N-METHYL-p-I PHENYLAZOI-

366

N1 RN

-- ANILINE, 101-80-4

4~4'-0XYD1-

367

N1 RN

368 N 1 RN

-

ANILINE, 60-09-3

- ANILINE. 119-59-5 -

p-IPHENYLAZ0)4,4'-SULFINYLDI-

ANILINE, 414'-THIODI139-65-1

369

N1 RN

370

N1 RN

371

Nl

372

N1 RN

373

N1

374

N1

-- o-ANISAHIDEB N-((l-ETHYL-2-PYRROLIDINYL)HETHYL)-I-SULFA11OYL15676-16-1 - ANNONA SQUAHOSA L i n n . , seed ertrnct - ANTERIOR PITUITARY EXTRACT ( 0 x 1

375

N1 RN

-

n- ANISAHIDE, 364-62-5

4-AMINO-5-CHLORO-tl-I

2-( DIETHY LAHINO IETHYL ) -

o-ANISAHIDEI 4-AHINO-5-CHLORO-N-(2-(OIETHYLAHINOIETHYL)-~ DIHYOROCHLORIOE, MONOHYDRATE

2-ANTHRACENAHINE 613-13-8

62 376

N1

- 2-ANTHRACENECAR8OXYLIC ACID, 9,10-DIHYORO-9,10-OIOX~-7-~alpha-D-GLUCOPYRAWSYL~-l-~E~YL-3~

377

Nl

- ~-~~~~~-D-GLUCOPYRANOSYL-~,IO-DIHYDRO-~~~I~~~-TETRAHYDROXY-~-

5~6~8-TLTRAHYDROXY-rSODIUH SALT

RN 378

N1 RN

379

N1 RN

380 N1 RN 381 N l RN

382 N1 RN

383 NI RN 384

NI RN

385 N1 RN

386 N1 RN 387

Nl

388

N1

389

N1

RN

RN

390 N1 391 N1 392

N1 RN

393

N1 RN

394

N1 RN

395

N1

396

N1

397

N1

398

MI.

399

N1 RN

400

NI RN

401 N l RN 402

Nl

2-ANTHRACENECARBOXYLIC ACID,

-

--

METHYL-9~10-010x0-e MONOLITHIWI SALT 12772-56-4 ANTHRANILIC ACID 118-92-3

-- ANTHRbNILIC ACID, 54-31-9 -- ANTHRANILIC ACID, 13710-19-5 -- ANTHRANILIC ACID, 644-62-2

4-CHLORO-N-FUAFVRYL-5-SULFA~YLN-( 3-CHLORO-0-TOLYL 1-

N-I2,6-OICHLORO-m-TOLYL)-

-- ANTHRANILIC ACID, 6385-02-0

N-l2~6-DICHLDRO-m-TOLYL)-r

-

nenw

ANTHRANILIC 134-20-3

ACID,

~ S D D I L M SALT

ESTER

-- ANTHRANILIC ACID, N-Ialpha.alpha,alpha-TRIFLVMlOm-TOLIL)530-78-9 - ANTHRANILXC ACID, N-talpha,alpha,alpha-TRIFLVORO-a-TOLYL)-r 2-( 2-HYDROXYETHOXY )ETHYL ESTER - 30544-47-9 -- ANTHRANILIC ACID, N-Itr3-XYLYLI61-68-7 - OIACETATE ANTHRAPUINONEB l r 4 ~ B I S ~ I 2 - l I 2 ~ H Y D R O X Y E T H Y L ~ A ~ I H O l E T H Y L ~ A ~ I ~ l - ~

---

70711-40-9 ANTHRAWINONEe 1~8-DIHYDROXY-, mixed uith BISl2-ETHYLHEXYLI 2-SULFOSWCINATE SOOIUn SALT 75418-11-0 ANTIBIOTIC 6 0 5 9 4 ANTIBUSTOKININ ANTI-alpha-FETDPROIEIN

ANTIPYRINE, 4-(DItlETHYLAMINO)58-15-1 ANTIPYRINE, 4-(DIMETHYLAMINO)- m o l e c u l a r complex wlth 5,5-DIETHYLBARBITURIC ACID I 2 : l ) 69401-33-8 ANTISERWIi t o CYCLMIXYGENASE

- ANTISERWr

---. -

IMWNOGLDBULIN 6

ANTIMONY OXIDE 1309-64-4

MONKEYI t o LUTEINIZING HORllONEi W I N E

ANTISERLMi t o PROLACTIN ANTISERUII, against PROSTA6LANOIN FZ-alpha, APOPLECTAL 8053-47-2 ARACHIDDNIC ACID 506-32-1 AR~ININEI MONOHVOROCHLORIDE~L1119-34-2 ARISTOLOCHIA I M I C A L.,

b i t t e r root e x t r a c t

lyophilized

63 403

Nl

404

N1 RN

405

N1 RN

406

N1 RN

407

N1 RN

408

N1 RN

409

N1 RN

410

N1 RN

411

Nl

412

N1 RN

413

N1 RN

414

N1 RN

415

N1

416

N1

417

N1 RN

418

N1 RN

419

N1

420

N1 RN

421

Nl RN

422

N1

RN 423

N1 RN

424

N1

425

N1 RN

426

N1 RN

427

Nl RN

428

Nl

RN

- ARISTOLOCHIA INDICA Linn., e x t r a c t -- ARSENIC 7440-38-2 -- ARSENIC ACID 7778-39-4 -- ARSENIC ACID. O I S O D I W SALT, HEPTAHYDRATE 10048-95-0 -- ARSENIC ACID. WDIW SALT 7631-89-2 -- 61136-62-7 ARSENIC ACID. T R I C E S I W SALT -- ARSENIC PENTOXIDE 1303-28-2 -- ARSENIC TRIOXIDE 1327-53-3 - ARSENIOUS ACID, oIswIun SALT -- ARSENIOUS ACID, HONOSODIM SALT 7784-46-5 -- ARSINE OXIDE, DIHETHYLHYDROXY75-60-5 -

DIHETnYLHYDROXY-r

-

ARSINE OXIDE, HYDROXYDI~ETHYL-,

--

ASPARTIC ACIDt SOOIUI SALT, 17090-93-6

OXIDE, - ARSINE 124-65-2

(

-

N1 N l

- AVROOHAK

431 N1

AYUSH-47

RN

1.-

- ASPARTIHIOE~ N-PHTHALYL-r (d.1)-- ATROPINE 51-55-8 -- ATROPINE. SULFATE 2:1 I 55-48-1 -- ATROPINIW. 8-NETHYL-s NITRATE 52-88-0 -- ATROPINIM. 8-(p-PHENYLBENZYLJ-r 511-55-7

430

N1

SODIUM SALT. TRIHYDRATE

- ARTOBOYRYS O D O R A T I S S I W Linn.. leaf e x t r a c t L-ASCORBIC ACID -- 50-81-7 L-ASPARAGINASE -- 9015-68-3 - L-ASPARAGINASE, from ERWINIA CAROTOVORA -- ASPARTIC ACID, D I S W I U I I SALT. 15598-53-0 -- 51321-79-0 L-ASPARTIC ACID, N-fPHOSWOE(OACETYL1-- ASPARTIC ACID, N-WTHALOYL-L66968-12-5

429

432

SODIUM SALT

-

BROnIDE

AVIDIN

5-alpho-4-AZAANOROSTANE-17-bct.-CARBOXAHIOEr

- N,N-OIETHYL-4-METnYL-3-OXa73671-86-0

64 433

N1

- 3-AZABICYCLO( 3.3.1 )NDNANE, 1:1 1 s teraol router

~ - M E T H O X Y - ~ - M E ~ Y L - ~ - P H E N Y L -CITRATE I

- ~~-AZA-D-HO~OPREGN-~-EN-~~~O-DIONEI (

RN 434 435

N1 Nl

RN

436 N 1 RN

437 N 1 AN 438

N1 RN

439 N 1 RN 440

N1 AN

441

N1 RN

442

N1

443

N1

444 N1 RN

445

N1 RN

446

N1 RN

447

N1 RN

448

N1 RN

449

N1

450

N1

RN 4 5 1 N1 RN

452 N1 RN

453 N l

454 N1

RW 455 N1 RN

456 N 1 RN 457

N1 RN

458

N1 RN

459 N 1 RN

460

Nl RN

21650-02-2

21-CHLORO-

- 83-(- ACYCLOPENTY ZA-l9-NOR~17~~l~h~~PREt"~l~3~5~lO~~TRIEN-2O-YN-l7-OL~ - 29199-51-7 LOXY 1-- 2212-67-1 1H-AZEPINE-1-ClBOTHIOIC ACID, HEXAHYDRO-p S-ETHYL ESTER -- 932-83-2 1H-AZEPINE. HEXAHYORO-1-NITROSO- 1H-AZEPINIMi IODIDE - HEXAHYDRO-1-~3-CARBAMOYL-3~3-DIPHENYLPROPYL~-l-~ETHYL-~ 15351-05-0 -- ZH-AZEPIN-L4NE, HEXIHYDRO105-60-2 -- AZETIDINE-2-CARBOXYLIC ACID, L2133-34-8 NvN'-( 1p4-CYCLOHEXYLENED1HETHYLENE)BIS-- 1-AZIRIOINEACETAHIDEi 10328-51-5

-

1-AZIRIOINEACETAHIDEi NrN'-IHEPTAMETHYLENE)BIS-

- 1-AZIRIDINEACETAWIDE, NIN'-(OCTAHETHYLENE)BIS-- 1-AZIRIDINEACETAHIDE~ NsN'-(p-PHENYLENEOIHETHYLENEIBIS10328-31-1 -- l3715-67-1 - A Z I R I D I N E C A R R B O X l ~ I D € N*N-OIHETHYL~ N-METHYL-- 1-AZIRIDINECARBOXAMIDE~ 13279-24-8 -- AZOXYBENZENEs ~~~'I~~~'-TE'IRACHLORO21232-47-3

--

BALAGRIN 71330-43-3 BALANITES ROXBURGHIII FRUIT PULP, ETHANOL EXTRACT

-- BARBITURIC ACID, 337-47-3 -- BARBITURIC ACID, 841-73-6

--

SODIUM SALT

5-ALLYL-5-(1-HEYHYLBUTYLl-2-THIO-,

5-BUTYL-1-CYCLOHEXYL-

BARBITURIC ACID, 5-BUTYL-5-ETHYL77-28-1

- BARBITURIC ACID, -- BARBITURIC ACID. 52-43-7 - BARBITURIC ACID. - 144-02-5 - BARBITURIC ACID, - 76-74-4 - BARBITURIC ACID, - 57-33-0 - BARBITURIC ACID, - 76-75-5

-- BARBITURIC ACID, 71-73-8 -- BARBITURIC ACID, 115-38-8

5-CYCLOHEXENYLMETHYL-5-METHYL-.

SODILAI SALT

SP~-OIALLYL5,s-DIETHVL-r

SODIUn SALT

5-ETHYL-5-( 1-HETHYLBUTYL)5-ETHYL-5-(1-HETHYLBUTYLl-~

SODIUM SALT

5-ETHYL-5-(l-HETHYLBUTYL)-2-THIO5-ETHYL-5-(1-METHYLBUTYL)-2-THIO-, 5-ETHYL-l-METHYL-5-PHENYL-

S O D I M SALT

65 461

N1 RN

462

N1 RN

463 N1 RN

-- BARBITVRIC ACID, 50-06-6

5-ETHYL-5-PHENYL-

- BARBITURIC ACID, 5-ETHYL-5-PHENYL-, - 57-30-7 - BARIUM CARBONATE 11: l ) - 513-77-9 - BARIUM CHLORIDE

464

N1 RN

465

N1 RN

466

N1 RN

- BARIUM FLUORIDE - 7787-32-6 - BARIUM IRON OXIDE - 12047-11-9

467

N1 RN

-- BENLALDEHYDE, 76217-33-9

468

N1 RN

469

N1 RH

470

N1

SOOIUn SALT

- 10361-37-2

O-I~-I~-~THOXYPHENYL~-~-TRI~OL-~-YL~-

- BENZAMIDE. ~ - * ~ I N O - ~ - C H L O R O - ~ - H E T H O ~ ~ N - ~ ~ - B E ~ Y ~ - ~ - P I P E R I O Y ~ ~ - B MALATE - 57645-91-7 - BENLAHIDE. 4-AMINO-5-CHLORO-2-MLTHOXY-N-14-PIPERIDYL~- 57645-49-5 - BENZAMIDEm 4-CHLORO-N-lHEXAHrDRO-4~7-~ETHWOISOLM)OL-2-YL~~3-SULF~YLv

cndo471

N1

472

N1 RN

473

Nl

-

BENZMIOE. N-13-CHLORO-2-H~ROXYPROPYLI-p-NJ~O~

-- BENZAHIOEr 4-CHLORO-N-I 2-HETHYL-l-JNDOLINYL)-3-SULF~YL26807-65-8 - BENZAMIDE. N-ll1-ETHYL-2-PYRROLIDINYLlMETHYL~-5-IETHYLSULF~L~-2-ME~HOXT-r HYDROCHLORIDE

475

Nl RN

- BENZAMIDEI ~-HYDROXY-~-~~-HYOROXY-~-~~~-HETHYL-~-PHENTLPROPYL~~INO~ET~YL~~B - MONMIYOROCHLORIDE 32780-64-6 -- BENZAHIDINE. p-MINO3858-83-1

476

N1 RN

- BENZANILIDE v - 5014-35-7

5-BROM-2-I 2-1 DIETHYLAMINO IETHOXY1-

477

N1 RN

-- BENZANILIDE, 17822-72-9

2'-CHLMIO-~-l2-lDIETHYlAMINO~EHOXY )-

478

N1 RN

- BENZANILIDEr - 7432-27-1

3-CHLORO-2-12~IDIETHYLAMINO~ETHOXY 1-

479

N1 RN

-- BENZANILIDEI 17822-73-0

3'~CHLORO~2~12~l~IETHYLA~IHO~ETHOXY 1-

N1

-

474

N1 RN

480

RN 4 81

N1 RN

482

N1 RN

483

N1 RN

484

N1 RH

485

Nl RN

486

N1 RN

4'~CHLORO-Z-l2-~DIETHYLAMINOIETHOXY I - BENZANILIOEs 17822-71-8 -- BENZANILIDE, 2-12-(DIETHYLAMINO)ETHOXY I 6376-26-7 - BENZANILIOE~2-1 2-l~IETHYLAMINO~ETHOXY)-3-METHYL- 17822-74-1 -- BENZ(o)ANTHRACENE-3,9-OIOL 56614-97-2 -- BENZIO)ANTHRACENE-~,~-OIDL, 7a12-DI?lETHYL67448-92-4 - BENZ(~)ANTHRACENE-3,9-DIOL, 7~12-0IMETHYL-, DIACETATE I8rt.r) - 80150-01-2 7-HETHYL-- BENZla)ANTHRACENE-3,9-DIOL, 80150-03-4

66 487 N1 RN

-- BENZ(&)*NTHRACENE-3,9-DIOL, 80150-02-3

489

N1 RN

---

490

N1 RN

BENZENAMINE, - 40226-25-3

4138 N 1 RN

491 N1 RN 492

N1 RN

493

N1 RN

494

N1

--

12-METHYL-

BENZt m)ANTHRACENE-7-ll€THANOLv 12-MTHYL568-75-2 BENZIa)[email protected]

BENZENAMINEi 40226-23-1

N-ll2-CHLORO-l-NIPHTHALENYL)ME~HrLENE)-2-METHOXT-

N-l~2~CHLORO~l-NAPHTHALENYL)~ETHYLENE)-2-~ETnYL-

BENZENAMINIlU9~3-1 Il O I M E T H Y L * n I ~ ~ C A R B O H I L)-NIN,N-TRINETHYL~O~ METHYL SULFATE 51-60-5

-- BENZENE 71-43-2

-

BENZENEACETAllIOEB N-( ANINOIMIHOnETHVL)-2 s6-DICNLORO-r HONOHYDROCHLORlDE 29110-48-3

495

N1 RN

496

N1 RN

497

N1

498

N1 RN

499

N1 RN

- BENZENEACETIC ACIOI alpha-llAMIHOtARBWYL)AMINo)-alpha-RIENYL- 6802-95-5 -- BENZENEACETIC ACIDS ~ - B E N Z O Y L - ~ ~ P ~ ~ - N E T HSOOIU31 Y L - I SALT 57495-14-4 - BENZEWELCETIC ACID, alpha-METHYL-4-1 Z-WTHYLPROPVL)-, 2-PYRIOINYLBETHYL ESTER - 64622-45-3 -- BENZENE. 4-ALLYL-1,2-lMETHYLENEOIOXY I 94-59-7 -- BENZENE, CHLORO108-90-7

500

N1

-

RN

RN

RN 5 0 1 N1 RN

502 N1

1,3-BENZENEOIMETHANOL~ a l p h a ( r u p 1)-( I l ~ l - O I M E T H Y L E T H Y L t A M I N O ) M E ~ Y L ~ ~ 4 - H Y DSULFATE R ~ Y ~ ~ (2:l) I SALT 3 51022-70-9

P-OINITRO-- BENZENE, 99-65-0 - 4-( l,Z-BENZENEOIOL, 2-( 3-(4-HYDROXYPHENY L I-1-METHY LPROPYL)*nINO IETHYL I - , HYOROCHLORIDEi ( + - I - 52663-61-7 -- m-BENZENEaISULFMABIOEi 4.5-DICHLMIO120-97-8 -- BENZENE, 1EPOXYETHYL)96-09-3 (

RN

503 N1 RN 504

N1 RN

505

N1 RN

506 N1

RN 507

N1

RN 508

N1 RN

509

N1 RN

510

N1

RH 511 N1 RN

--

BENZENEI ETHVL100-41-4

-- BENLENEv HEXACHLMIO118-74-1 -- BENZENE, l,P-(METHYLENEOIOXY t 4 - t 2-COCTYLSULF1NYL)PROPYL)120-62-7

---

BENLENEI NITRO98-95-3 BENZENE, PENTACHLORO608-93-5

-- BENZENE, 82-68-8

PENTACHLMIDNITRO-

4-AMINO-N-~4i6-OI~ETHO)CI~2-PVRIMIOI~L~~ -- EENZENESULFONAMIDE~ 155-91-9

67 512

N1

-

RN

-

BENZENESULFONAHIOE. 4-AHINO-N-~4,5-OIMETHYL-2-OXAZOLYLl-, lnixt, with 5 - ( ( 3 ~ 4 9 5 - TRIMETHOXYPHENYLlMETHlLl-2~4~PYRIMIDINEDIAMINE 57197-43-0

--

BENZENESULFONAMIDE, N-15-tert-BUTYL-l,3.4-THIAOIAZOL-2-YLl1492-02-0

N1 RN

--

BENZENESULFONAMIDEv N.N-DIETHYL1709-50-8

517

N1 RN

-- BENZENESULFONIC ACID, 42615-29-2

518

N1 RN

519

N1

513

Nl RN

514

N1 RN

515

N1 RN

516

520

N l

-- BENZENESULFONAMIOE * 4-CHLORO-N-I ICYCLOHEXYLCARBONYL )AMINO 1W3-03-1 2-CHLORD-5~~1-HYDRDXY~3-OXO~1-I51~OLlMLl-- BENZENESULFONAMIDE. 77-36-1 ALKYL deriu.

ACID, -- BENZENESULFONIC 68411-30-3 - BENZENESULFONIC ACID, SULFATE

-

linear ALKYL-I ALKYL deriv.

and TALLOW ALKYL ETHOXYLATE

~13-AMINO-2,4~6-TRICHLORDPHENYLIMETHYLENEl

BENZENESULFONXC ACID,

- HYDRAZIDE 53516-81-7 N 1 - BENZENESULFONIC ACID DISODIUM SALT RN - 27344-41-8 N 1 - BENZENESULFONIC ACID. RN - 70244-08-5

SODIUM SALT

RN 521

522 523

N1 RN

524

N1 RN

525

N1 RN

526

N1 RN

527

Nl RN

528

N1 RN

529

N1 RN

530

N1

RN

!is1

N1

532

N1 RN

533

N1 RN

534

N l RN

RN

535

N1 RN

536 N1 RN

-

9

BENZENESULFWIC ACID, MOMOSODIUM SALT 633-96-5

2.2'-(4.4'-BIPHENYLYLENEDIVIMLENE

2.5-DIHYDROXY-.

101-

*

POLYMER w i t h FORNALOEHYOC

4-~I2-HYOROXY-l-NAPHTHALENYLlALO)-~

- SALT BENZENESULFONIC ACID. 3 - ~ ~ 4 - ~ P H E N Y L A M I N D l P E N Y L ~ A ZMON0SM)IUM D)-~ - 587-98-4 -- BENZENESULFONIC ACID. p-VINYL-, SODIUM SALT, POLYMERS 25704-18-1 - BENZENE, 1,2.3,4-TETRACHLORO- 634-66-2 -- BENZENEI 1~2~3,5-TETIACHLORO634-90-2 -- BENZENE, I~LI~-TRICHLORO120-82-1 - BENZENEv ~3~5-TRIMETHYL~2~4~6-TRIS~3~5-DI-t-BUTYL-4-HYDROXYBENLIL)- 11709-70-2 - 1,2~4-BENZENETRIOLs 5-(2-AMINOETHYLl- 1199-18-4 - HYDRDtHLORIDE BENLHYOROL, 2-CHLORO-slpha-~2-IDIMETHYLAMINO~ETtiYLl-~

--

511-13-7 BENZIDINEt 313'-DICHLmO91-94-1

-- BENZIDINEI ~ ~ ~ ' - D I H E T H O X Y -DIHYDROCHLORIDE P 20325-40-0 -- BENZILIC ACID, 2-(DIETHYLAMINOlETHYL ESTER HYDROCHLORIDE 57-37-4 - BENZILIC

- 4 5 4 4 - 1 5 - 4 ACID, -- BENZIMIDAZOLEi 934-32-7

2-PIPERIDINDETHYL Z-AMINO-

ESTER. HYDROCHLORIOE

537

N1

538

N1 RN

539

N1 RN

540

N1

541 N1 RN 542

N1 RN

543

N1

544

N1

545 N 1

-----

BENZIMIDUOLEr 2~MINO-5-BUTYLBENZIMIDAZDLE~ 2-BENZYL621-72-7 2-BENZIHIDA~OLECARBAMICACID 18538-45-9

~ ~ M I N O - ~ - I ~ ~ T ~ I A ~ISDPROPYL OLYL~-I

5-BENZIMIDUOLECARBMIC ACID, ESTER

2-BENZIMIDUOLECARBAHIC ACIDS l-(BUTYLCARBAMOYLl-~ METHYL ESTER 17804-35-2 2-BENZIVIOAMLECAREAMIC ACID, 5-EUTYL-I 14255-87-9

2-BENZIHIDAZOLECARBAHIC ACID, 5-(CYCLOPROPYLCARBONLl-~ METHYL ESTER

5-(alpha-HYDROXYBENZYLI-, METHYL

2-BENZIMIDAZOLECARBMIC ACID, ESTER

- BENZENESULFONATE 2~BENZJ~IDAZOLECIRBA~IC ACID, (ester I

5-HYOROXY-r

546

N1 RN

--

547

N1

- 2-BENZIMIOAZOLECAR8AMIC ACID) (5:ll

548 N 1 549

Nl RN

550 551

N1 RN Nl

552

N1

553 N1 RN

554 N1 RN

555 N l RN 556

N1 RN

557 N l RN

558 N1

--

N1 RN

N1 RN

2-(4-THIAZOLYLI-r

METHYL ESTER

-- BENLIMIDAZOLE~ 2-METHYL615-15-6 -- BENZIMIDAZOLEs 2-(4-THIAZOLYLI148-79-8

- 2-BENZIMIDALOLINEBUTRYRIC

ACIOI

HYDROCHLORIDE - l~~ETHYL~5-BIS(2-CHLOROETHYLlAMINO-, 3543-75-7

-

2-BENZIMIDUOLINONEi 1-1 1-(4 +BIS( p-FLUOROPHENYL IBUTYL I-4-PIPERIDY 2062-78-4

L 1-

2-BENZIMIDUOLINWE~

1-1 l-( 4 r4-BIS(P-FLUOROPHENYL IBUTYL 1-4-PIPERTDY L l - 2062-78-4 - 2H-BENZIHIDALOL-2-ONE. 1~3~DIHYDRO-5~CHLORO~l~(l~~3~~2~3~DIH~RO~2~OXO~lH~BENZIMIDAZOL

-

560

~ - I ~ - T H I A Z O L Y L I - I ISOPROPYL ESTER

BENZIMIDAZOLE* l - ~ 2 ~ D I E T H Y L M I N O E T H Y L ~ ~ 2 - l ~ ~ E T H O X Y B E N I Y L l - 5 ~ NHYORMHLORIOE ITRO-~

562

RN

METHYL ESTER

2-BENZIMIDAZOLECARBAMIC ACID, 5-(PROPYLSULFONYLl-s METHYL ESTER 76167-28-7

561 N 1 RN

559 N1

METHYL ESTER and SODIUM NITRITE

2-BENZIMIDAZOLECARBMIC ACID, N-NITROSO-r

- 1-YLlPROPYLl-4-PIPERIDINLl3-14-1 -- lr2-BENZISOTHIAZOLIN-3-ONE, --

RN

METHYL ESTER,

2-BENZIMIDA~OLECARBAMICACID, METHYL ESTER 10605-el-7

-- 5-BENZIMIOAZOLECARBAMIC ACID, 26097-80-3 - 5-BENZIMIOAZOLECARBAMIC ACIOI

-

METHYL ESTER

57808-66-9

2H-BENZIMIDAZOL-2-ONE~ 1v3-OIHYORO-l-( DIWENYLMETHVLl-l-PIPERUI~L)WOPYL)~ 60607-34-3 l>l-OIOXIOE

81-07-2

1~2-BENZISOTHIAZOLIN~3~OME. 181-DIOXIDEi @ iLW I .S 128-44-9

-

SALT

lOH-BENZ0(4.5lCYCLMIEPTA( 1.2-b ITHIOPHEN-IO-ONE~

4~9-OINYORO-4-~l-METHYL-4~ PIPERIDINYLIOENEI~~(€1-2-BUTENEDIOATE (1:lI 34580-14-8

69 563

N1 RN

564

N1 RN

565 N1 RN

-- BENZWIAZEPINE 12794-10-4 - 1H-1~4-BENZOOIAZEPINE-3-CARBOXYLIC ACID, 7-CHLORO-2,3-OIHYORO-2-OXO-5-PHENYL-, HMJOWTASSIUH SALT, with POTASSIWl HYDROXIDE - 57109-90-7 -

N1

567

N1 RN

568

N1

-

RN

-

569 N 1 RN

lH-1~4-BENZM)IAZEPINE. 7-CHLMI0-2~3-DIHYDRO-l-RETHYL-5-PHENYL2898-12-6

- tlONOHYOROCHLORIOE ~H-~IQ-BENZWIAZEPINE~ 7-CHLMI0-2~3-DIHYORO-l-HETHYL-5-PHENYL-~

566

RN

compd.

-

2898-11-5

3H-1,4-BENZOOIAZEPINE~ 7-CHLORO-2-(HETHYLUII~)-S-PHENTL-, - 58-25-3 ~ H - ~ I ~ - B E N Z W I A Z E P I N7-CHLORO-2-HETHYLAHINO-5-PHENYL-, E~ MONOHYOROCHLORI 0E 438-41-5

4-OXIDE

4-0X10E~

- 5H-2,3-BENZWIAZEPINE, - 1-~3~4-DIHETHOXYPHENYL)-5-ETHYL-7~8-DIHETHOXY-4-HElHYL22345-47-7

RN

-

572

N1 RN

-- 1812-30-2 2H-1,4-BENZOOIAZEPIN-2-ONE,

573

N1

574

N1

-

RN

- 7-CHLORO-1-lCYCLOPROPYLtlETHYL)-5~~~~FLUOROPHENYLl-l~3-DIHYDRO25967-29-7

570

N1 RN

571

N1

RN

575

N1 RN

576

N1

-

1H-1~5-BENZOOIAZEPINE-2,Q(3H~5H~-OIONE~ 7-CHLORO-l-HETHYL-5-PHENYL22316-47-8

2H-lr4-BENZOOIAZEPIN-2-ONE. 7-BROM0-5-(2-CHLOROPHENYL 51753-57-2

)-1,3-DIHYDRO-

7-BRO~-1~3-DIHYORD-5-(2-PYRIDYLl-

2H~1,4-BENZWIAZEPIN-2-ONEt 7-CHLORO-5-~~-CHLOROPHENYL~-l~3-OIHYDRO-3-HYOROXY846-49-1

2H-1,4-BENZODIAZEPIN-2-ONE.

2H-1~4-BENZM)IAZEPIN-2-ONE, 7-CHLORO-1~3-DIHYDRO-3-HYDROXY-5-PHENYL604-75-1

- 2H-1~4-BENZOOIAZEPIN-2-ONE~ 7-CHLORO-1 3-OIHYORO-1-HETHY L-5-PHENY Ls

RN 577

N1 RN

578

N1 RN

579

N1 RN

580

N1

- 439-14-5 - 2H-1~4-BENZODIAZEPIN-2-ONE~7-CHLORO-1~3-OIHYORO-5-PHENYL- 1088-11-5 - 2-H-1~4-BENZODIAZEPIN-24NE~ 5-lo-CHLOROPHENYLI-1,5-DIHYORO-7-NITRO- 1622-61-3 - 2H-1,4-BENZODIAZEPIN-Z-ON€e 1~3-OIHYORO-7-CHLORO-l-lCYCLOPROPYL~ETHYL~-5-PHENYL- 2955-38-6 - 2H-lr4-BENZOOIAZEPIN-2-ONE, 1~3-0IHYORO-7-CHLORO-l-( 2-1 DIETHYLAHINO)ETHYL ) - 5 - ( o FLUOROPHENYLl 17617-23-1

581

N1

-

RN

-

2H-1~4-BENZOOIAZEPIN-Z-ONE~ 1,3-OIHYORO-5-1 2-FLUOROPHE"lL)-l-METHYL-7-NITRO1622-62-4

582

N1 RN

-

2H-1~4-BENZOOIAZEPIN-2-ONE, 146-22-5

583

N1

RN

RN

1~3-OIHYORO-7-NITRO-5-PHENYL-

- BENZOI6 7 1-1 4-DIAZEPINO-( 5n4-b )-OXAZOL-6-ONE lO-CHLORO-2~3,5.6~7,11b-HEXIHYDRO-2-METHYL-llb-PHENYL- 24143-17-7 p

I

D

70 584

N1

-

I~3-BENZOOIOXOLE-5-ACETALOEHYOE~

2,4-BISIPHENILttETHOXI IBENZOYLI- 40321-72-0 - 1~3-BENZOOIOXOLE, 5-(3,7-DIUETHYL-6~7-EWXT-e-OCTfNILOXI)- ~I~-BENZOOIOXOLE, 5-(16,7-EWXY-3-ETHYL-7-METnlL.e-OCTENYL)OXY)-- 2-BENZOFIRAWARBOXAUIOE~ N-lp-METHOXYPHENYL)-3-nETHYL34319-22-7 bats-(

RN

585

Nl

586

N1

587

N1 RN

588

N1

-

589

N1

-

590

N1 RN

591 N 1 RN 592

N1 RN

593

N1 RN

594

N1 RN

595

N1 RN

596

N1 RN

597

N1 RN

598

N1 RN

599

N1 RN

600 N1 601

N1 RN

602

Nl RN

603 N1 RN

604 N 1 RN

605 N 1 RN 606

N1 RN

607 N1 RN 608

N1

RN 609

N1 RN

------

BENZOFURAN. 3-1p-12-1 DIETHY LAPIXNO IETHOXY IPHENYL 1-6-IIETHOXY-2-PHENYL- t HYOROCHLOR I O E BENZOFURANn 3-~2-1OIET~YLPYRROLIOINOIETHOXYI-6-UETHOX~-2-WENTL-~ HIDROCHLMIIDE 2-BENZOFURANPROPANOIC ACID, alphatalpha-DIMETHYL-beta-ETHYL72236-76-1 6H-BENZOFUROI 3.2-c 11 1)BENZOPVRAN-6-ONE. 479-13-0

3.9-DIHOYROXY-

BENZOl~)HEPTALEN-9(5Hl-MIE, 6 ~ 7 - D I H Y D R O - l r 2 ~ 3 r l O - T E ~ A M E T H ~ Y 1420-08-2 BENZOIC ACIOi 4-l4~ACETYL-3-IM)OPHENOXrl-3~5-DIIODO1160-36-7 BENZOIC ACIOI P-AMINO150-13-0

-- BENZOIC ACIO, 2-AMINO-3-HVOROXY548-93-6 - BENZOIC ACID. 4 - ~ ~ 6 - 1 1 A U I N O I M I ~ E T H Y L l ~ I N O I ~ 1 - O X O H E X Y L l O X Y l ~ r ETHYL ESTER, MONOIIETHANEWLFONATE

----

56974-61-9 BENZOIC ACID, 3-(AUINOSULFONYLl-4-PHENOXY-5-(PYRROLLDIWLl~ 55837-27-9 BENZOIC ACIO, p-twt-BUTYL 98-73-7 BENZOIC ACIO, 2 - ~ ~ 3 - l 3 ~ 4 - O I M E T H O X Y P H E N Y L l - l - O X O - 2 - P a O P E N Y L l ~ I ~ l 53902-12-8

- BENZOIC At101 p-GUANIDINO-r 4-UETHYL-2-0XO-2H-l-BENZOPYRIN-7-YL ESTER -- BENZOIC ACID, p-WANIDINO-. p-NXTROPHENYL ESTER 21658-26-4 -- BENZOIC ACID, n-HYOROXY99-06-9 ACIO, 2-HYOROXY-v 2-CARBOXYRIENVL ESTER -- BENZOIC 552-94-3 -- BENZOIC ACID, ~-HYOROXY-I ETHYL ESTER 120-47-8 - BENZOIC ACID, 2-HYMIOXI-, UONOSODIW SALT mixed with 3~7-OIHYDRO-3~7-01~ElHYL-lH-PURINE~2~ 6-DIONE S W I W SALT - 8048-31-5 -- BENZOIC ACIOI 2-HYDROXI-, 3-PYRIDINYMETHYL ESTER, HYOROCHLORIDE 53690-73-6 -- BENZOIC ACIO, SODIUM SALT 532-32-1 - BENZOIC ACID, SODIW SALT, mlxt. with 3~7-DIHYORO-lr3r7~TRIHETHYL~lH~~INE~2~6-OI~~ 5~5-DIPHENYL-2r4-IMIOA~LIDINEDIONE?4DNDSoOIOn SALT .nd 5-ETHYL-5-PHENYL-2,416PYRIMIOINETRIONE 72981-66-3

-- BENZOIC ACID, 67330-25-0

2-1~3~~TRIFLvoRotlE~YLl~E~LlAHINOl-, BIJTYL ESTER

71 610 N1 RN

611 N1

- BENZOIC ACID 2-1 8'-TRIFLUOROMETHY L-4'-QLlINOLYLAHfNO IESTER - 2,3-DIHYOROXYPROPYL 23779-99-9 v

v

- 2-l4-l3-l2-CHLOROPHENOTHIAZIN-lO~YL~PROPYL~-l~PIPERAZINYL~ BEIlZOIC ACID, ~.~,~-TRIMETHOXY-I

ETHYL

RN 612 N1

-

ESTER 388-51-2

- 2-~4-l3-~2-CHLOROPHENOlHIAZIN-lO-YL~PROPYL~BENZOIC ACID, 3*4,5-TRIMETHOXY-,

1-PIPERA2INYL)ETHYL

RN 613 N1 RN

614 N1 RN

615 N1

RN 616 N1 RN 617 Nl RN 618 N1 RN 619 N1 620 N1

RN 621 N1 RN

622 N1 RN 623 N1 RN 624 N1 RN 625 N1 RN 626 N1 627 N1 628 N1

RN 629 N1 RN

630 N1 RN

ESTER, DIFUURATE 522-23-6

- BENZOIC ACSIDv 3.4~5-TRIMETHOXY-r DIESTER wlth TETRAHYORO-lH-1~4-DIAZEPINE-l~4l5HlOIPROPANOL~ DINYDR~LORIDE - 20153-98-4 - BENZOIC ACID, 3.4.5-TRIHETHOXY-. beta-lOIMETNYLAMINO~-betir-ETNYLPHENETNYL ESTER. HALEATE (1:l) - 34140-59-5 - BENZOIC K I D * 3*4.5-TRIHETHOXY-. ESTER, HYOROCHLORIDE - 3-lt3~3-DIPHENYLPROPYL)AMINO~PROPYL 24050-58-6 - BENZOIC ACID, 3,4.5-TRIMETHOXY-. 1~2-ETMANEOIYLBIStMETMYLI~INO~l2~ETHYL~2~l-ETHANEOIYL~ ESTER, lS-lR*,R*ll- OIHYOROCHLORIOE. 55769-64-7 - BENZONITRIL E V I 3-I t c r t -8UTY LAMINO 1-2-MYDROXY PROPOXY 1- , MONOH Y OROCHLOR IOE 0-

-

23093-74-5

-

64584-57-2

-

13004-40-5

- pBENZONITRILE, - I I 117-beta-HYDROXY-5-alpha-ANDROSTAN-3-YLIDENE

~AMINO~OXY j-

- BENZONITRILE~ p-lIHIDAZOl2~l-~lISOQUINOLIN-2-YL)-- BENZO(c1PNENANTHRENEr 2-HETHYL2606-85-1 -- BENZOIC~PHENANTHRJDIN-~I~~~I-MIE~ 9.lO-OIHYDRO2827-28-3 Z-HYDRaYY-+HETHOXY-- BENZOPHENONEI 131-57-7 - 4H-l-BENZOPYRAN-2-C4RBOXYLIC ACID, 3-lp-CHLOROPHENYL)-5.7-DIHYDROXY-4-OXO-I ETHYL ESTER - 43H-2-BENZOPYRAN-7-C4RBOXYLIC ACID, .6-DIHYDRO-8-HIDROXY-3~4~5-~IME~YL-6-0~-

- 4N-l-BENZOPYRAN-8-C4RBOXYLIC 518-75-2

ACID, 3-HETHYL-4-OXD-2-PHENYL-, 2-PIPERIDINOETHYL ESTER. HYDROCHLORIDE 3717-88-2

- l1-1-H - 2 - B E N L O P ~ A N - J - ~ T H ~7-FLOORO-3r4-OIHYDAO-l-PHENYL~I~ - lH-2-BENLOPYRAN-3-HETHANANINEr 7-FLUORO-3~4-DIHYDRO-l-PHENYL-~ I + 1- lH-2-BENZOPYRAN-3-M€THANAHINE, 7-FLWRO-3,4-DIHYDRO-l-PHENYL-, L

-

CIS-

van-52-0

- I2.3.718-TETRAHYDROXI1lBENZOPYRAN0~5.4r~-cde~ll lBEN.?OPYRAN-5,10-DIONE~ - 476-66-4

-

11~BENMPYRANO~3~4-bJFUR0f2.3-h~~l~8EN~OPYRAN-616aNl-ONE~ 1.2.12.12a83-79-4

TETRAHYDRO-2-~lpha-ISOPROPENYL-B~9-DIMETHOXr-

72 631 Nl RN 632 Nl

-

ZH-l-BENZOPYRAN-7-OL,

- PHENYLI-r IEl- 84394-36-5 - 2H-1-BENZOPYRAN-6-OLe

3~4-OIHYORO~2r2~DI~ETHYL~3~PHENYL~4-l4~~2~ll~PYRROLIOIHYL~E~OXY~-

3~4~OIHYOR0~2~5~7~8~TETRAHElHYL~2~l4~I~12~TRI~ETHYL~IOECYL~-r

RN 633 Nl

12R-l2R*l4R*,BR*)l).. 59-02-9

- 4H-l-BENZOPYRAN-4-ONE~

7-ll6-D-l6-OEOXY-elpha-L-~A~PYRA~~L~-b.t.-DYL~

RN 634

N1 RN

635 N1

-

OXYl-2~3-DIHYORO-5-HYOROXY~2~13-HYOROXY~4~HETHDXYPHEHYL~-~ RONOHETHYL ETHER 11013-97-1

-- 552549-17-4 H 4 1 lBENZOPYRANOl2e3r~blPYRIDINE-7-ACETIC ACIOI mlphm-METHYL-

- IH-l-BENZOPYRAN0(2,3-b)PYRIDIN-5-ONE, SALTS PENTAHYORATE 9-CHLORO-7-l1H-TETRAZDL-5-Y

636 H1

RN 637 N1 RN 6 38 N1

RN 6 39

H1 RN

640 N1

RH 641 Nl RN 642 N1 RN 643 N1 644 N1 RN 645 N1 RN 646 Nl RN

647 N1 PN

L 1-0 SOOIUn

- 2H-l-BENZOPYRAN-3,5,7-TAIOLI 2-(314-OIHYDROXYPHENYL)-3,4-OIHYDRO-, 1ZR-tranr)- 154-23-4 -- BENZOI BPYRENE 192-97-2 - 2H-BENZOlr)WINOLILIN-L-ONE~ 1~3~4~6~7~llb~HEXlHYORO~3~IMBUTIL~9~10~OI~ETHM(- 58-46-8 - ~-BENZOPUINONEI 2r5~BISl1~ALIRIOINTL~~3~l2~HYORM(Y~L~~ETHO~ETYL~~6~~TYL-~ CAREAHATE la1t e r 1 - 24279-91-2 - P-BENZWUINONE, 2~13~7~11~15~19~23~27~31~35~3V~0ECAHETHYL~2~6~10~14~18~~2 TETRACMMECAENYL1-5r6-0IIlETHOXY-’I-~ETHYL- 4.38303-98-0 -- P-BENZOQUINDNE~ 2~5-OIHYOROXY-3-IMDECYL550-24-3 - P-BENZWUINONE, ~13~HYOROXY~3r7r11~15~TETR~ETHY~EXAOECYL~~3~5~6-TRINETHYL- 27559-04-8 - ~-BENZMXIINONEI - RI~LTHYL-~ 2~13~HYOROXY~3~7~11~l5~TETR~ETHYLHEXIDECYL~~3~5~d 6 -l T -- P-BENZOQUINONE~ PHENYL 363-03-1 -- P-EENZOWIM)NE, 2~3~5~TRISll-AZIRIOINYL)~ 68-76-8 - 2H-lr2~4-BEHLO~IMIAZINE~3-CIRBOXrLle ACID, 7-1 AHINDSULFONYL)~6-CHLORO~3~4-0IHYORO2-NETHYL-t METHYL ESTERS - 1.1-OIOXIOL 42583-55-1 -- 2H-l,2,4-EENZOTHIAOIAZINE, 7-CHLORO-3-METHYL-v 1 ~ 1 ~ O I O X I O E 364-98-7

640 Nl RN

649 N1 RN

650 N1

-- 58-94-6

2 H - l r 2 ~ 4 ~ B L N Z O T I A D I U ~ E ~ 7 ~~-CHLORO-D ~ L F ~ I O 1s1-OIOXIO~ ~ ~

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RN 651 Nl RN

73 652

N1

RN 653

Nl RN

654

Nl RN

655

N1

RN 656

Nl RN

657

Nl

658

N1 RN

659

N1

660 N l RN 661 N1 RN 662

N1 RN

663

N1

664 N 1 RN 665

N1 RN

666 N1 RN

667

N1

668 N1 RN 669

N1 RN

670

N1 RN

671 N l RN 672

N1 RN

673

N1 RN

674

N1 RN

675

NL RN

676 N l RN

--

5-BENZOTHIAZOLEACETIC ACID. 2-PHENYL36774-74-0

-- BLNZOTHIUOLEe 2-Ip-lDI~ETHYWINO)STYRYL)1628-58-6 -- BENZOTHIUOLEe 2-lHORPHOLINOTHIOI102-77-2 - 2-BENZOTNIAZOLESULFMJIHIOE~ - 452-35-7

--

6-ETHOXY-

2-BENZOTHIAZOLETHIOL 149-30-4

- BENZOlblTHIOPHENE~ Z.S-DTPHENYL-6-METHOXY-- BENZOlblTHIOPHENE. 3-lp-METHOXYPHENYLt-5-NI~O-2-PHE~L36266-70-3 - BENZOlblTHIOPHEN-6-OL, Zs3-DIPHENYL-

-

IH-2-BEHZOmIOPYRAN-Q-OL, 3r4-DIHYORO-7~MFTHOXY~3-PHENYL-4~(4-(2-(Yl PHENY L 3 t HY OROCHLOR IDE 34289-02-6

-

1H-2-BENZOXACYCLOTETRMECIN-l-DNE~

-

56776-01-3

-

- 2H-l-BENZOTHIOPYR*H-4-OL, 1 3~4-DIHYDRO-7~~ETHOXY-3-PHEHIL-4~l4~12~l1~PYRROLIDINYL)ETHOXY PHENYLI-. HYDROCHLORIDE - 16879-01-9 - 0-BENZOTOLUIDIOE~ 3~-CHLORO-elpho-l~ETHYLl l~PHOLINOCARBMIYLlr(ETHYLlAMINOI-~ - HYDROCHLORIDE 24600-36-0 - 3H-1,2,3-BENZOTRIAZIN-4-ONE - lH-2-BLNZOXACYCLOTETRADECIN-l-ONE~ 3 r 4 r 5 ~ 6 ~ 7 ~ 8 ~ 9 ~ 1 0 ~ 1 1 ~ l ~ - D E C A H Y D R O ~ 7 ~ 1 METHYL-r 4~16~~IH~R~-313Sv7XI- 26538-44-3

3 ~ 4 ~ 5 ~ 6 ~ 7 ~ 8 ~ 9 ~ 1 0 - O C T ~ Y D R O - 1 4 ~ 1 6 - D I H Y D R O X Y - 3 - M E7-0x0-. THYL- 17924-92-4 LH-3~1-BEMXALINE-2~4(1HI-DIONE -- 118-48-9 - 2 H - ~ ~ 1 - B E N Z O X A Z I ~ E - 2 ~ 4 l l H l6-CHLORO-l-METHYL~DI~E~ -- 2H-3~l-BENZOXALIN~-2~4llH)-DIONE~ 1-METHYL10328-92-4 -- ~4693-02-1 H - ~ ~ ~ - B E N Z O X M I N E ~ ~ S ~ I6-NITRO~H~~OLONE~ -- 5-BENZOXAZOLEACETIC ACID. 2-14-CHLOROPHENYL I-dph.-METHYL51234-28-7 - BENLYL ALCIYIOLI 4-AMINO-alphr-~ltert-BUTYLAMINOl~ETHYLl-3.5-DI~LQRO-~ MONOHYDROCHLORIDE - 21898-19-1 -- BENZYL ALCOHOLS 61-16-5 -- BENZYL ALCWOLS 154-41-6 -- BENZYL AL(XIIOLS 51-41-2 -- BENZYL ALWIOLS 583-03-9 - HYDROCHLORIDE BENZYL AUOHOLI

IEI-

74 677 N l RN

678 N l RN

679

Nl

680

N1 RN

RN

681 N1 RN 682

N1 RN

683 N1 RN 684

N1

---

-

BENZYL ALCDHOLs ~ l p h . - l B U T Y ' U M I N O l ~ E ~ Y L l - 3 ~ 5 - D I ~ SULFATE ~R~-~ t2:11 23031-32-5 BENZYL ALCOHOL, ~ , ~ - D I H Y D R O X Y - ~ ~ I~Ip-HYDROXY-alpha-METHY ~P-I YL)13392-18-2

BENZYL ALCOHOLS 3.5-DIHYDROXY-alpha-l~lp-HYDROXY-~lpha-METHYL~ENE~YL~MINO~~(ETnYL)-i HYDROBROMIDE 1944-12-3 BENLYL ALCOHOLv 7683-59-2

~~~-OIHYOROXY~~~P~~~~~ISOPROPYLAMINO~HETHYL~-

BENLYL ALCOHOL, 586-06-1

~ , ~ - D I H Y D R O X Y - ~ P ~ MI -I SI O P R O P Y L A H I N O ~ H E T H Y L I ~

BENZYL ALCOHOLr 3,4-DIHYDROXY-.lphr-l HYDROCHLORIDE 51-30-9

I ISOPROPYl.AMINOlMETHYL)-r

BENZYL ALCOHOLS 314-DINYDROXY-alpha-I

( ISOPROPYLAMINO)HETHYLl~~

HYDROCHLORIDE^ - 5984-95-2

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LPHENETHYL )AMINOlMETH-

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BENLYL ALCOHOL, J , ~ - D I H Y D R O X Y - M ~ ~ ~I ISOPROPYLAMINOIMETHYLI~, ~-(

685

N l RN

(+I- HYDROCHLORIDEm 949-36-0 -- BENZYL ALCOHOL, 3,4-DIHYOROXY-~lphe-((METHYLAnTNO)nETHYL-~ 51-43-4

686

N1

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RN

RN 687

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BENZYL ALCOHOL, 3~4-DIHYOROXY-clph~~((METHYLAMIND~METHYLl-~

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RN 689

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690

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RN RN 691 N l

693

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- BENZYL ALCOHOL, ~-HYOROXY~~lph~~~l~lI~~HYDROXYPHENETHYLlAMINOlETHYL~-~

RN

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HYDROCHLORIDE. 23239-51-2

N1

N1 RN

695

N1 RN

696

- BENZYL ALCOHOLI 4-NYOROXY-3~5-DIMETHOXr-.lph~~llMETHYLMI~)~ETHYL)-~ HYDROCHLORIDE 22775-12-8

RN 694

0-HYOROXY-

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RN 692

- BENLYL ALCOHOLo - 90-01-7

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BENLYL ALCOHOL, -- 59-42-7

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(2:ll (salt) - 67-04-9 - BENZYL ALCoHOLv - p-HYOROXY-~lph~-~l-l~l-METHYL-2-PHENOXYETHYLlAHINO~ETHYLl395-28-8

75 697

Nl RN

698

N1 RN

699

N1 RN

700

N1 RN

701

N1 RN

702

N1 RN

703

N1 RN

704

Nl RN

705

N1 RN

706

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707

N1 RN

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N1 RN

709

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N1 RN

7 1 1 N1 RN 712

N1 RI1

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N1 RN

714

N1 RN

715

N1 RN

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RN 719

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BENZYL ALCOHOL, p-( ISOPROPYLTHIO)-~lpha-~ 1-( MTYLAMINO )ETHYL)-,

--

BENZYLAMINE. N-I 2-CHLOROETHYLI-N-I l-METHYL-2-PHENOXYETYL)59-96-1

erythro- 54767-75-8 -- SENZYL ALCOHOL. o-l5-~m-METHDXYPHENYLl-~-TRIAZDL-3-YL~75318-77-3 -- BENZYLAMINE. N~N-BIS~2~BROMOETHYL~-2-METHOXY-5-NITRO56537-95-2 -- BENZYLAHINE. N-~2-SROm)ETHYLl-2-IIETHOXY-5-NITRO61361-58-8 -- BENZYLAMINE, N-(2-CHLOROETHYL)-Z-ETHOXY-5-NITRO56538-02-4 N-12-CHLOROETHYLI-L~~ETHDXY-5-NITRD-- SENZYLAMINEB 56538-01-3

- BENZYLAIIINEP N-(2-CHLOROETHYLI-N-(l-IIETHYL-P-PHENOXYETYL)-r - HYDROCHLORIDE 63-92-3 -- BENZYLAHINE, N-METHYL-N-2-PROPYNYL555-57-7 N-HETHYL-N-2-PROPYNYL-, HYDROCHLORIDE -- BENLYLAIIINE, 306-07-0 -- 13a-ulph.-SERBINEi 2r3r9~10-TETRAIIETHOXY-~HYDROCHLORIDE 4880-82-4 NITRATE -- BERYLLIUM 13597-99-4 - BETEL NUT - BIBENLYL-4r4'-OISULFONIC ACIO, ~lpha,alpha'-DIETHYL-, DIPOTASSIUM SALT. meso- 13517-49-2 - SICYCLO~2.2.1lHEPTANE~ 2.2,5r6-TETRACHLMIO-lr7r7-TRIS(CHLOROnETHYL)-~ (5-mdOs6-eXO1- 51775-36-1 BIGUANIOE, -- 500-92-5 1-~p-CHLOROPHENYLl-5-ISOPROPYLl-(p-CHLOROPHENYL1-5-ISOPRDPYLHONOHYDRMHLORIDE -- SIGUANIDEI 637-32-1 v

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BIGUANIOEB 1,l-OIMETHYL-

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RN

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RN 722 N1 723 Nl 7Z4

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RN 728 N1 RN

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RN 739 N1 RN 740 Nl RN 741 Nl

RN 742 Nl RN 743 N1 RN 749 N1

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2~~'~3~3'i4~4'-HCXACHlORO-

-- 90-43-7 2-BIPHENYLOL

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- BRADYKININ 58-82-2 - 14-bete-BUFA-4,20,22-TRIENOLIDE, 3-beta-ll6-DEOXY-4-O-METHYL-alpha-L-MA~PYRANDSYLlOXYl14-HYDROXY-

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-- 87-68-3 ~.~-BUTADIENEB HEXACHLORO- N-I BUTANAHIDE, 3-ACETY L-4-l2-HYDAOXY-3-I~l-METHYLETHYL -

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1-BUTANAMINE, N-BUTYL-N-NITROSO- 924-16-3 - 1,4-BUTANEDIAHINE - 110-60-1

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BUTANE, 1,Z-EPOXY106-88-7

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- l-BUTANOL, 4-lp-CHLOROPHENYL)THIO- 2-BUTML9 4-~OIMETHYLAMINOl-3-METHYL-l~Z-OIPHENYL-~PROPIONATE ester I - (77-50-9 - ~-BUTANOLI 4-lDI~ETHYLAMINOl-3-nETHYL-l~2-OIPHENYL-~ PROPIONATE ( c s t e r l , HYOROCHLORIOE~ t t l -

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BUTYROPHENONE, 3-1p-CHLORCPHENYL I-2-PHENY L - 4 ' -1 2-1 1-PYRROLIDINY L IETHOXY I erythro31301-20-9

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CANNABIS 8063-14-7

- C A W I B I S SATIVAI exlract - CAPSELLA BURSAPASTORIS ( L . I Madlc. -- CARBAMIC ACID, N-l5-BENZOYLBENZIHIDAIOL-~-YL)-, HETHYL ESTER 31431-39-7 -- CARBAMIC ACID, B W Y L ESTER 592-35-8 -- CARBAHIC ACID, BWYL-, ETHYL ESTER 591-62-8 ETHYL ESTER -- CARBAIlIC ACID, N-BUTYL-N-NITROSO-. 6558-76-7 -- CARBAMIC ACIDS 3-1 p-CHLOROPHENOXY )-e-HYDROXYPROPY L ESTER 886-74-8 -- CARBAMIC ACID, DIETHYLDITHIO-P SWIW SALT 148-18-5 -- CARBAHIC ACID, DIMETHYLOITHIO79-45-8 -- CARBAMIC ACID, DIHETHYL-B ETHYL ESTER 687-48-9 -- CARBAMIC ACID, ETHYLENEBISIDITHIO-. D I S W I W SALT 142-59-6 ACID, ETHYL ESTER -- CARBAMIC 51-79-6 -- CARBAHIC ACID* ETHYLNITROSO-, ETHYL ESTER 614-95-9 -- CARBAMIC ACID, HYDROXI-. ETHYL ESTER 589-41-3 -- CARBAMIC ACID, 2-HYDROXYETHYL ESTER 5395-01-7 - CARBAMIC ACIDI HETHYL-. 2.3-DZHYDRO-B,~-DIMETHYL-7-BE~F~ANYL ESTER - 1563-66-2 - CARBAtlIC ACID, METHYL-. 4-DIMETHYUnINO-3.5-XYLYL ESTER - 315-18-4 ACID, HETHYL-r ETHYL ESTER -- CARBAMIC 105-40-8 -- CARBAHIC ACID, METHYL-, 0-ISOPROWXYPHENYL ESTER 114-26-1 -- CARBIHIC ACID. HETHYL-r 1-NAPHTHYL ESTER 63-25-2 ACID, N-METHYL-N-NITROSO-* ETHYL ESTER -- CARBAHIC 615-53-2 - CARBAMIC ACIDS ~5-~PHENYLSULFINYL~-lH-BENZI~IDALDL-~-YL~-~ METHYL ESTER - 53716-50-0 -- CARBAMIC ACIDS 67049-95-0

81 849 N1 RN

850 Nl RN 851 N1 RN

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857 N1 RN 858 N1 RN 859 N1 RN 860 N1 RN

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- CARBAMIC ACID, 15-lPROPYLTHIO)-1H-BENZIMIDAZOL-2-YL~-~METHYL ESTER - 54965-21-8 - CARBAMIC ACID, THIO-, S~S'-l2-IDIMETHYLAMINO)TRIflETHYLENE) ESTER, HYORMHLDRIOE -

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864 N1

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RN 865 N1 866

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CARBANILIC At101 mrN-DIMETHYLTHIO-. 0-2-NAPHTHYL ESTER 2398-96-1 CARBANILIC ACID, ISOPROPYL ESTER 122-42-9

9H-CARBAZOLE-2-ACETICACID, 6-CHLORD-olpha-METHYL-, I t - ) 53716-49-7 CARBON 7440-44-0

-- CARBON DIOXIDE 124-38-9 -- CARBON DISULFIDE 75-15-0

863 N1

862 N1

15263-52-2 CARBANILIC ACID. m-CHLORO-, ISOPRDPYL ESTER 101-21-3

- CARBANILIDE, 3,4,4'-TRICHLORO- mixed with 4~4'-DICHLORO-3-TRIFLUOROMETHYLCARBANILIDE I2:l) - CARBAZIC ACID, 3-11-PHTHALAZINYLI-r ETHYL ESTER, HYDROCHLORIDE, HYDRATE

-

861 N1

CARBAMIC ACID, PROPYL ESTER 627-12-3

CARBON DISULFIDE and HYDROGEN SULFIDE CARBONIC ACID, CYCLIC 3-CHLOROPRDPYLENE ESTER CARBONIC ACID. CYCLIC llp-~6-METHOXY-2-PHENYL-3r4-DIHYDRO-1-NAPHTHYL~PHENDXl~~ETHYL~ETHYLENE ESTER CARBONIC ACID, DIETHYL ESTER

- 105-58-8

-

CARBONIC ACID, DILITHIUH SALT and 2-CHlORO-10-13-lDIMETHYLAMINO)PROPYL)PHENOTHIAZINE

19:21

CARBONIC ACID, ZINC SALT 11:l) 3486-35-9 CARBON MONOXIDE 630-08-0

-- CARBON TETRACHLORIDE 56-23-5 - CARD-201 22 I-EWLIDE, ~-~I~-~,~-DIDEOXY-~-O-METHYL-~R~~-D-~~~~-HEXOPYRANOSYL-I~-~~-D-~,6-

RN 870 N1 871 N1 872 N1 RN 873 N1 RH

874 N1 RN

DIDEOXY-beta-D-rlbo-HEXOPYRAWSYL-~1-4~-2r6-DIOEOXY-beta-D-ribo-HEXDPYRAN0SYL)OXY)- 12,14-DIHYDROXY-, (5-beta,5-beta,lZ-b.t.)30685-43-9

- CARD-~O(~~I-ENOLIDEI 1,3,5,14,19-PENTAHYDROXY-, - CARICA PAPAYA Llnn., unripe fruit pulp extract - CARRAGEENAN, CALCIUnl I1 1 SALI

HYDRATE

- 9049-05-2 -

CARVACROLI 5-12-1N~N-01MElHYUnINO)ElHOXY1 - p

- HYDROCHLORIDE 964-52-3 -

CARZINOPHILIN 1403-28-7

ACETATEr

82 875

N1

876

N1

877

~1

878

N1

RN

- CASSAVA, - CELLRYL

MANIHDT U T I L I S S I M A

- CELLULOSE ACETATE PHTHALATE - CELLULOSE, CARBOXYHETHYL ETHER, - 9004-32-4

RN

- CELLULOSE, - 9004-62-0

880

N1 RN

-- CERIUM CITRATE 512-24-3

881

N1 RN

882

N1 RN

X I 1 1 NITRATE - CERIUM1 10108-73-3 -- alpha-CHACONINE 20562-03-2

883

N1 RN

-

884

N1

885

N1

886

N1

879

N1

RN 887

N1 RN

888

N1

RN 889 890

N1 RN

N1

RN 891

N1

RN 892 893

N1 N1 RN

894

N1 RN

895

Nl RN

896

Nl

RN 897

N1 RN

898

N1 RN

899

N1 RN

900

Ell RN

901

N1 RN

902

N1 RN

2-HYDRDXYETHYL

S O D I M SALT

ETHER

-

CHALCONE, 4-CHLORO-4'-1 15272-68-1

- CHALCDNEs - CHALCONE, -

2-(DIETHYLAMIND)ETHDXY I - a l p h a - P H E N Y L -

2'-CHLORD-Q,4'-DIFLUORD2'-CHLORO-4'-FLUORO-3,4-METHYLENEDIDXY-

CHALCONE. 2-CHLORO-alpha-PHENYL-4'-(2-(l-PYRRDLIDINYL~ETHDXY~24845-21-4

3'~CHLORD-~lph~~PHENYL-4'-12-Il-PYRRDLIDINYL)ETHOXY 1- CHALCONEi 24845-22-5

- CHALCONE, 4-CHLORO-a~pho-PHENYL-4'-~2-ll-P~RRDLXOINYL~ETHOXY~- 15272-64-7 - CHALCONEt 4-CHLORO-olpho-lp-~2-ll-PYRROLIDINYL~ETHOXYIPHENYLt-

17599-75-6

-- CHALCONE. 3,4-DICHLORD-alpha-PHENYL-4'-(2-(1-PYRRDLIDINYL~ETHOXY~15272-67-0 - CHALCOEIE, 2-1 1-PYRROLID1NYL)ETHOXY I - 3,4-DIVETHOXY-alpha-PHENYL-4'-I 15272-66-9 - CHALCONE, 4'-FLUORO-2'-HYDROXY-3~4-METHYLENEOIOXY- CHALCONE, 3-1 p-FLUOROPHENY L 1-alpha-PHENY 1-4' - 1 2-1 1-PYRROLIDINY L )ETHOXY 1-

24045-27-0

-- CHALCONE, 2-FLUORO-alpho-PHEElYL-4'-12-l1-PYRRDLIDINYL~ETH~XY I24845-25-8 -- CHALCONE 3-METHOXY-~lpha-PHENYL~4'-12-11-PYRROLIDINYL)ETHOXY 115288-31-0 - CHALCONE, 3 ~ 4 - HETHYLENEDIOXY I ) - a l p h a - P H E N Y L - 4 ' - 1 2-1 1-PYRROLID1NYL)ETHOXY B

-

)-

15272-65-8

- CHALCONE, 2',3,4'-lRIHYDROXY-4,6'-DIMETHOXY-, 4'-16-0-16-DEOXY-alpha-L-MANNOPYRANOSYL)- beta-D-GLUCDPYRANOSIDE) - 24292-52-2 -- CHLORIC ACID, MAGNESIUM SALT 10326-21-3 OXIDE -- CHLORINE 10049-04-4 - CHLOROFORH

- 67-66-3 -- 5-beta-CHOLAN-24-OIC 474-25-9 -- 5-bets-CHOLAN-24-DIC 128-13-2

ACID,

3-alpha,7-alpha-DIHYDROXY-

A C I O t 3-alpha,7-bata-DIHYDROXY-

83 903

N1 RN

-

904

N1 RN

-- CHOLANTHRENE. 56-49-5

905

N l RN

-

906

N1 RN

907

N1 RN

908

N1

909

N1

910

N1

911

N1 RN

912

N1 RN

913

N1 RN

914

N1 RN

915

N1 RN

916

N1

917

N1 RN

921

N1 RN N1

RN 923

N1 RN

924

Nl N1

RH 926

N l RN

927

Nl RN

928

N1 RN

929

N1

930

N1

mlphm-HYDROXY-

CHOLESTEROL

57-88-5 CHOLESTYRAHINE 11041-12-6

- CHOLINE. HYDROXIDE, S'-ESTER PYROPHOSPHATE , nncr sal t -

J

w i t h C Y T I D I N E 5'-lTRIHYOROGEN

1

987-78-0

-- CHONDROITIN. HYDROGEN SULFATE, SODIUM SALT 9082-07-9 - CHROHAN. 3,4-trans-2,~-DIHETHYL-3-PHENYL-4-p-~beta-PYRROLIDINOETHOXYlPHENYb-CHROHANOL, ACETATE

920

925

-

-

N1 RN

la.25-DIHYDROXY-

- 19477-24-8

Nl

919

SODIUH

- CHOLESTAN-3-alpha-OL - 3-alpha-CHOLESTANOLn HYDROGEN PHOSPHATEI MDNOSOOIUM S A L T - CHOLEST-5-EN-3-beta-OL. 2 4 - b e t a - E T H Y L - , SULFATE SALT 1 1 : l l - CHOLEST-5-EN-3-beta-DL, 14-HETHYLHEXAOECANOATE

L-7-HETHOXY-, 51023-56-4

H1 RN

3-alpha.l2-alpha-DIHYOROXY-,

3-HETHYL-

-- CHOLECALCIFEROL. 32222-06-3 -- CHOLECALCIFEROL, 57651-82-8

-

918

ACID,

3-METHYL-

1-CHOLANTHRENOL, 3342-98-1

RN

AN

922

5-beta-CHOLAN-24-OIC SALT 302-95-4

HYDROCHLORIDE

Z~5~7~B-TETRAHETHYL-2-l4~8~l2-TRIHETHYLlRIOECYLl-~

- 7695-91-2 - CHROMIC ACID, C A L C I M SALT 1 1 : l I - 13765-19-0 - CHROMIC ACID. DIPOTASSIUM SALT - 7789-00-6 - C H R O H I U H l I I I ) CHLORIDE 1 1 : 3 J - 10025-73-7 - C H R O H I U H I I I I I CHLORIDE, HEXAHYDRATE - 10060-12-5 - C H R O H I U H I V I ) OXIDE ( 1 : 3 ) - 1333-82-0 - CHROHOHYCIN A 3 - 7059-24-7 - CICHORIUM INTYBUS, ETHANOL EXTRACT - CINNAHALDEHYDE, 3,4,5-TRIHETHOXY- 34346-90-2 -

CINNAHIC ACID,

11:3:6)

3n4-DIHYDROXY-

- 331-39-5 - C I N N A H I C ACID, p-HYDROXY- 7400-08-0 - CINNAHIC ACID. 4-HYDROXY-3-HETHOXY-, - 537-98-4 - CISTANCHE TUBULOSA U l g h t . e x t r a c t - C I T R I C ACID, TRISOOIUM SALT. c o r p l e x

(€1-

w l t h CERIUM CHLORIDE

84 931 Nl RN

932 Nl RN

933 N1 RN

934 N1 RN

935 N1 936 Nl

RN 937 N1 RN

938 Nl RN

939 N1 RN

940 N1 RN

941 MI RN 942

N1

943 N1 944 N1 945 Nl RN 946 Nl

RN 947 Nl RN

948 N 1 RN

949 N1 950 N1 RN

951 N1 952 N1 RN

953 N1 RN 954 N1 RN

955 Nl RN

956 N1 RN

957 N1 RN 958 N1 RN

959 N1 RN

-- 546-46-3 -- 1332-58-7 -- 56939-74-3 -50

CITRIC ACIDS ZINC SALT IL:31

CLAY (KAOLIN) CLD

-

CLOPHEN A 8068-44-8

CNICUS SPICATUSD crud.

-- 8001-58-9 -- 13600-98-1 -- 7646-79-9 -- 7791-13-1 -- 10141-05-6

extract

COAL TAR CREOSOTE COBALTATE~~-)IHEXANITRO-8 TRISODIW

COBALT(2t) CHLORIDE COBALT(2*)

CHLMIIDE HEXAHYDRATE

COBALT(I1) NITRATE (1:P)

- CWINAMIDEr CYANIDE PHOSPHATE 3'-ESTER wlth 5,6-DInETHYL-l-alpha-DR I 9 O F V R A N O S Y L B ~ N Z I ~ I D A ~ L Einner r SALT - 68-19-9 - COCOA FATTY ACIDSI POTASSIW SALTS - COFFEE - COLA NITIDA. nut extract

--- 477-30-5 -- 2731-16-0

COLCMICINE 64-86-8 COLCHICINE, N-DEACETYL-N-METNYLCOLCHICINE, N-DEACETYL-10-THIO-

-- COLISTIWETHANESULFONIC ACID, TETRASODIW SALT 8068-28-8 - COHBRETODENDRON A F R I C M I Welwl, e x t r a c t

-- 11028-71-0 -- 7440-50-8 --- 1317-39-1 -- 7758-98-7 (III -- 8001-30-7

CWCANAVALIN A CONJUGATED ESTWSENIC HORMONES COPPER

COPPERtIJ CITRATE B66-82-0 COPPER( I) OXIDE COPPER

SULFATE (1:l)

CORN O I L

-- 50-22-6 -- 1173-26-8

CORTICDSTERONE

CaRTICOSTERONEr 21-ACETATE

-- CDRTICOTROPIN POOP-60-2

RN

-- alphalrup 1-24)-CORTICOTROPIN 55468-06-7 - CORTISOL - 50-23-7 -- CORTISOL, 21-ACETATE 50-03-3 -- CORTISOL, 17-BUTYRATE 13609-67-1

964

N1 RN

-

965

N1 RN

-- CORTISOLI 3863-59-0

966

N1

960

N1

RN 961 N l RN 362

N1 RN

963

N1

RN 967

N1

m l w t . uith Z I N C PHOSPHATE 13:Z)

CORTISOL, ~ ~ - B U T Y R A T E 21-PROPIONATE P 7Z590-77-5

- CORTISOL. - 125-04-2 - CORTISONE

21-IOIHYDROGEN PHOSPHATE) W C C I N A T E s -1UI

SALT

RN

- 53-06-5 -- CORTISONE 21-ACETATE 50-04-4 - CORYDALOID O I L IDeodorlred winterized) -- COTTONSEED 8001-29-4

971

N1 RN

-

972

N1

-- CWIIARIN, 81-81-2

RN 968

N1 RN

W9

Nl

970

N1

RN 973

N1 RN

974

N1 RN

975

N1 RN

976

N1

977

N1 RN

978

N1

979

N1

980

N1

981

N1

982

N1 RN

983

N1

COUHARIN 91-64-5

- COLMARINI - 129-06-6 - COUHARIN,

- 129-06-6 -- COVnARIN, 152-72-7

- COUURINI - COWARINI - 120-08-1 - COWARINi

- COUnARINi - COUHARINI - COWRIN, - COVnARINi - 90-33-5 - CWIIARINI

3-1alpha-ACETONYLBEWZYL)-4-HYDROXY3-l.lphr-ACETMiYLBENZYL)-4-HYDROXY-r

SODIUn SALT

S-Ialpha-ACETONYLBEWYL)-4-HYOROXY-,

S O D I W SALT

3-lalpha-AC€TONYL-p-NITR~€NZYL1-4-HYDROXY7 - l 2 - 1 0 I E T H Y W I 1 N O ~ E M O X Y )-3*4-DIPHENYL6,7-DIMETHOXY-

3,4-OIPHENYL-7-HYOROXY-,

ACETATE

(ester)

4-ETHY L-7-HYDROXY -5-lp-METH0XYPHENYL)-

~-HYOROXY-~-~~-METN~XYPN€NYL)-~C-PHENYL-

7-HYOROXY-3-Ip-HETHOXYPHENYL)-U-PHENYL-r ACETATE 1mstet-b 7-HYDROXY-4-METHYL-

4-1p-NYDROXY PHENYL 1 - 3 4 p-HETHOXYPHENYL 1-

v

ACETATE

( es t e r 1

984

Nl

RN 985

N1 RN

986

N1 RN

987

N1 RN

988

N1

RN

- COWARINI - 66-76-2 - CRESOATE, - 8021-39-4 - ni-CRESOL

- 108-39-4 -- m-CRESOL, 555-65-7

- p-CRESOL, - 5189-40-2

3,3'-1IETHYLENEBISI4-HYDROXY-

WOOD

alpha-IMINOOXT 8-6-BROm)-

alpha-CYCLOHEXYLIOENE-alpha-lp-HYOROXYPHENYLb

989

N1

990

N1 RN

991

N1

992

N1 RN

993

N1 RN

994

N1 RN

995

Nl

RN

RN

RN 996

N1

997

N1

998

N1

999

N1

1000

N1

1001 N1 RN

1002 N1 1003 N1 RN 1004

N1 RN

1005

N1

- p-CRESOL, alpha-CYCLDHEXYLIDENE-alpha-lp-HYDROXYPHENYLl-l DIACETATE

-

2624-43-3

-

p-CRESDL, a l p h a - I p-NYDRDXYPHENYL )-alpha-l 2-NETHYLCYCLOHEXYLIDENE8-1 DIACETATE 21327-74-2

-- p-CRESOL, 2,6-DI-tert-BUTYL128-37-0 - m-CRESOL, 4.4'-llr2-DIETHYLETHYLENE)DI- 85720-57-6 - 0-CRESOL, ~ I ~ ' - ( ~ ~ ~ - D I E T H Y L E T H Y L E N E ) D I - 10465-10-8 -- p-CRESOL, alpha-(2,2-DIHETHYLVINYL)-alpha-ETHYNYL63141-79-7 -- 0-CRESOLs 4r6-DINITRO-r AMMONIUM SALT 2980-64-5 - CRDTALARIA J W E A Linn..

-

seed e x t r a c t

COnINVn CYNINUN, seed e x t r a c t CURCUHA LONGA Linn.,

rhizoine e x t r a c t

CVRCWA ZEDOARIA Roscoe. r o o t e x t r a c t

- CUSCUTA REFLEXA Roxb.,

e x t r a c t e x c l u d i n g root.

-

CYCLIClL-ALANYL-L-alpha-GLUTAHYL-L-ALANYL-L-LYSYL)~

-

CYCLOGUANIDE

- HONOHVDRDCHLORIDE 53665-78-4 - 31e4-CYCLOHEXADIENE-1-CARBOXYLIC ACID, 4 B I S I 3-CARBDXY-4-HYDROXYPHENYL)HETHYLENE )-6-OXD-, TRIAMlONIUn - SALT 569-58-4 -- 2.5-CYCLOHEXADIEN-l-ONE, 4-IMINO3009-34-5 - DIHYDRDCHLORJDE 1,4-ClCLOHEXANEBISINETHYLANINE)~ NIN'-BISO-CHLOROBENLYL)-, IE 1- 366-93-8 P

RN 1006 N1 RN

- CYCLOHEXANECARBOXYLIC ACID, - 1197-18-8

1007 N1

- CYCLDHEXANECARBOXYLIC ACID. 3-1~3~f3r4-DIHYDROXYPHENYL)-l~OXO-2-PROPENYL)OXY)-

RN 1008 N1 RN 1009 N1 RN 1010

N1 RN

1011 N1

RN 1012 N1 RN

1013 N l RN 1014 N1

-

~-IAMINOHLTHYLI-I t r a n t -

1,4~5-TRIHYDRM(Y-~ IlS-~l-alpha~3-beta~4-alpha~5-alpha))327-97-9 CYCLDHEXANLGLYCOLIC ACID, alpha-PHENYL-e HYDROCHLORIDE

DIETHYLAWINO )-l-BUTYNY L ESTER, .. 4-( 1508-65-2

CYCLOHEXANE, 1,2,3,4,5,6~HEXACHLDRD-- 608-73-1 -- CYCLOHEXANEt I ~ O ~ ~ ~ Q I ~ , ~ - H E X A C H Lgnmlu-Isomer MO-~ 58-89-9 -- CYCLDHEXANESULFAHIC ACIDI CALCIlM SALT (2:1) 139-06-0 -- CYCLDHEXANESULFAHIC ACIDI ~ M D I l M SALT 139-05-9

--

CYCLDHEXANOL 108-93-0

- CYCLOHEXANDLr ~-(N-~~-AHIND-~~S-DIBRO~)BENZYL)*~INOJ-I HYDROCHLORIDE IE )-

87 1015

N1

- CYCLOHEXANOLr 2-I(DIMETHYUnINO~~ETHYL)-1-Im-METHOXYPHENYLl-r EI- HYDROCHLORIDE, 73806-49-2 -- CYCLOHEXANOL, 4-lDIPHENYLVETHYLENE)-2-ETHYL-3-VETHYL-r ACETATE 52236-34-7 -- CYCLOHEXANONE 108-94-1 2-Io-CHLOROPHENYL)-Z-IMETHYUnIWO)-, (+-I-- CYCLOHEXANDNE, 6740-88-1 -- CYCLOHEXANONE 2-( o-CHLOROPHENY L )-2-( HETHYLAHINO HYDROCHLORIDE 1867-66-9 - ETHYL 3-CYCLOHEXENE-1-CARBOXYLIC ACID, 2 - l D I M E T H Y L A V I N O I - l - P H E N Y L - ~ ESTER, HYDROCHLORIOE, trans-( + - I - 27107-79-5 (

RN 1016

N1 RN

1017

N1 RN

1018

N1 RN

1019

N1 RN

1020

N1 RN

1021

1022

N1

-

RN

- 5-ETHYL-4-lp-HYDROXYPHENYLl-6-HETnrL-, 21161-63-7

Nl

-

RN 1023

N1

1024

H1 RN

RN

1025

N1

RN 1026

N1

1027

N1 RN

1028

N1 RN

RN

1029

)-

I

N1 RN

1030

Nl

1031

N1

1032

N1

RN 1033 N1 1034 N l RN 1035

N1 RN

1036

N1

RN 1037 N1 RN 1038

N1 RN

1039

N1 RN

9

3-CYCLOHEXENE-1-CARBOXYLIC ACID, ACETATE (ester)

3-CYCLOHEXENE-1-CARBOXYLIC ACID,

SOOIVn SALT - 5-ETHYL-4-lp-HYDROXYPHENYLl-6-VETHYL-, 22921-18-2 - 3-CYCLOHEXENE-1-CARBOXYLIC ACID, 3-ETHYL-4-lp-nETHOXYPHENYL)-2-nETHYL- 1755-52-8 -- 3-CYCLOHEXENE-1-CARBOXYLIC ACID, S-ETHYL-6-METHYL-4-PHENYL7698-97-7

-

3-CYCLOHEXENE-1-CARBOXYLIC

ACID, 5-ETHYL-6-HETHYL-4-PHENYL-e

SALT - SOOIUM 16550-39-3 -- CYCLOHEXENE-1~2-DICARBOXIMIDE 27813-21-4 -- 4720-86-9 l-CYCLDHEXENE-1~2-DICARBOXI~IDE -- 4-CYCLOHEXENE-1~2-DICARBOXIVIDE 85-40-5 -- 469352-90-5 - C Y C L O H E X E N E - 1 ~ 2 - D I C A R B O X I M I D E ~ N-l2~6-OIOXO-3-PIPERIDYLl- l-CYCLOHEXENE-1~2-DICARBOXIMIDE~N-MEMYL- 4-CYCLDHEXENE-1~2-DICARBOXIMIDEt N-METHYL- N-Il1~1~2~2-TETRACHLOROETHYL)THIO)4-CYCLOHEXENE-1~2-DJCARBOXIVIDE~ - 2425-06-1 - CYCLOHEXENE-1,2-DICARBOXIMIDE, N-lITRICHLDRDnETHYL)THIO)-

-

N-lTRICHLOROnEMYL)THIO- 6-CYtLOHEXENE-lr2-DIClRBOXIMIDEt 133-06-2 -- CYCLWEXENE, l-tlETHYL-4-ll-~ETHYLElHENYL)-~ 1R)5989-27-5 -- CYCLOHEXYLAMINE 108-91-8 -- CYCLOHEXYLAMINE, 4.6-DIPHENYL-N-ISOPROPYL-s HYDROCHLDRIDE 14334-41-9 -- CYCLDHEXYLAMINEt HYDRMHLDRIDE 4998-76-9 SULFATE -- CYCLOHEXYLAHINE, 19834-02-7

88 1040

N1 RN

1041 N1 RN 1042

N1 RN

1043 N1

RN 1044 N1

- ~10-l~3~6-DJHYDRO-6-OXO-2H-PYRAH-2-YL~ H-CYCL~A~~~~-C~~~~-C'JOIFURAN-~~S~~~~~~H~~TETRON - HYDROXYMETHYL~-5r9~lO~ll-TElRAHYORO-4-HYDROXY-S-ll-HYOROXYHEP~~~~~ 21794-01-4 -- CYCLOPAMINE 4449-51-8 -- 77-97-4 ~~~-CYCLOPENTAOIENEI 1,2r3,4.5i5-HEXACHLDRO- CYCLOPENTAlcJFURO( 3' s2' $ 9 ~)FUR01 5 2 1 3 - h ) l l JBENZOPYRAN-11llHJ-ONE~ 1-HYDROXY-4-HETHOXY- 2,3r6a.9a-TETRAHYORO29611-03-8 - CYCLOPENTAISn6 )NAPHTHf ~ , ~ - ~ ) A L E P I N - ~ I ~ H ) - O N E I 4,5,6,7,7a,8,9~10110a1lOb,ll,l2-OOOECAH~RO-

~ - ~ ~ ~ ~ ~ - E T H Y N Y L - ~ - ~ ~ ~ ~ - H Y O R O X Y - ~ ACETATE ~ - N E T HlYe Ls t- eI r ) 1045 N1 RN 1046

N1 RN

1047

N1 RN

1048 N1 RN 1049

N1

RN

1050 N1

RN 1051 N1

-- CYCLOPENTANEHEPTANOIC ACIO, 745-62-0

-

3~5-DIHYDROXY~2~13~HYDROXY~l~OCTENYLJ~

CYCLOPENTANEHEPTANOIC ACID. IE)-tr.n.-l,Z,cia-Irf-

- 3-HYDROXY-2-~S-HYDROXY-l-NONENYLJ-5-0)(0-. 17711-13-6

-

CYCLOPENTANEHEPTANOIC A C I O n 3-HYOROXY-2-~3-HYOROXY-l-OCTENYLJ-5-OXO-~ 745-65-3

1-

CYCLOPENTANEHEPTANOIC ACID, 5~HYOROXY~2~IS~HYOROXY-1-OCTENTLJ-3-OXO17968-82-0

- CYCLOPENTAlC)PYRAN-9-CARBOXYLIC ACID, 1,Qa-alpha,5$7a-alpha-TETRAHYORO-1-NYOROXY-7- lHYOROXYHEWYL)-. METHYL ESTER - 6902-77-8

-- ~H-CYCLOPENTI~)OXACYCLOTRIDECIN-~-ONE, 3-CYCLOPENTENE-I-HEPTAMtIC 14152-28-4

ACID, 2-13-HYDROXY-l-DtlENYL)-5-~0-

S.617.8.11,11ar12,13r14~14a-OECAHYDRO-

12~14-DIHYDROXY-3-(PHENOXYHETHYLJ-~ I3R-(1E~3R*~9~1llaR*rl2S*~l4R*~l4~R*))

RN 1052

N1

- 62411-17-0 - 5H-CYcLOPENT~e)OXACYCLOTRIOECIN-5-oNE, 3~6~7~8~1l1lla112~13~14~14a-OECAHYDRO12 114-DIHYDROXY-S-I 2-PHENYLETHYL )-

RN 1053 N1 RN 1054 N1 RN 1055 N1

RN 1056 N1

- 13S-~1E~SR*r9Z~ll~S*~12R*~14S*~19aS*~~62411-15-8

- 6.7.8.11rlla~13~14~19n-~TAHYDRO-19-HYDROXYSH-CYCLOPENT~e)OXACYCLOTRIDECIN-5rle-DIOE~ 3-IL-PHENYLETHYL)-,

- 4,5,8,6ir,9,10,11,11a-OCTAHYORO-lO-HYOROXY-9-~3-NYOROXY- 3-METHYL-4-PHENYL-l-BUTENYLl- l,la-b~ta,lb-alpha,4,4.,7o-betJ,m,8r919rI 3s-I 1E 0 U1*,82111aS+,14Sril4dS* 62411-16-9

1 )-

UI-CYCLOPENT(b)OXECIN-2-ONEo

85761-26-8

5H-CYCLOPROPA(S~4)BENZll,2-e~A~LEN-S-~~

DECAHYORO-9a-alphat'lb-~lph~,9-brta~9.-~lphm-TETRAH~OROX~-3-~HYOROXYMEWYL)-1.1.6,8-alphaTETRAMETHYL17673-25-5

- 5N-CYCLOPROPAI 3AJBENL( 1,Z-• lAZULEN-5-ONEl l.la-bata.lb-alpha,414p17e-beta.7b18,9~9a-

O E C A H Y O R O - ~ ~ - ~ ~ ~ ~ ~ I ~ ~ - ~ ~ ? ~ ~ ~ - ~ ~ ~ ~ ~ ~ ~ ~ - ~ ~ ~ ~ - ~ E T R A H Y

RN 1057

N1

TETRMETHYL-. 9a-ACETATE 9-HYRISTATE - YMETHYL)-1,116r8-beta16561-29-8 - CYCLOPROPANECARBOXYLIC ACID, 3 ~ 1 ~ ~ 2 - D I B R D H O V J N Y L ) - ~ ~ 2 - 0 I M E ~ Y L - ~ METHYL ESTER, - CYAN013-PHENOXYPHENYL) 52820-00-5 C$S-I+)-

RN

89 1058 N 1

- CYCLOPROPANECARBOXYLIC ACID, 3-12~2-DICHLOROVINYLI-2~~-DIRETHYL-~ 3-PHENOXYBENZYL ESTER. I+- )-, ( c i s ,trans - 52645-53-1 - CYCLOPROPANECARBOXYLIC ACID, ~~~-OIMETHYL-~-I~-METHYLPROPENYL)-B )-

RN 1059

N l

RH

ESTER - 5-12-PROPYNYLIFURFURYL 23031-38-1 -- CYCLOPROPANEPROPIONIC ACIDS rlph.-AnIElO-2-HETHYLENE-, 156-56-9

Nl

-

RN 1060

1061

N1

3'H-CYCLOPROPA~lr2~PREG~-4~6-DIENE-3~2O-DI~E~ 6-CHLORO-17-HYORDXY-,

N1

-

1063

N1

-

1064

N1

1062

L-(*)-

ACETATE ( e s t e r 1

3'H-CYCLOPROPA~1~2lPREGNA-4~6-DIENE-3~2O-DIONE~ 17-HYDROXY-, ACETATE

RN

RN 1065

N1

1666 N l RN

3'H-CYCLOPROPAl1~2lPREGNA-l~4~6-TRIENE-3~2O-DIONE~ 6-CHLORO-l-beta,2-beta-DIHYDRO- 17-HYOROXY-

- 2098-66-0 - 3'H-CYCLOPROPAI1~~~PRE6t~-lr4~6-TRIENE-3r20-DIONE~ 6-CHLORO-l-beta,2-belo-DIHYDRO17-HYOROXY-.ACETATE

- 427-51-0 - CYCLOPROPA116rl7)PRE6N-5-EN-2O-Ci4E~ 1'.3'-DIH'IORO-3-bcIr-HYDROXY- 31H-CYCLOPROPI14,l5~ESTRA-lr3.5l10~-TRIEN-17-beta-OL~ 3-RETHM(Y-, 1 1 4 - b e t a .15-beta 1- 68247-73-4

1068

N1

-- CYCLOPROPYLAMINEi 2-PHENYL-, 3721-28-6 - CYCLOSILOXANE, PHENYLRETHYL-,

1069

N1

-

1070

N1

- CYCLOTETRASILOXANE,

~ , ~ - D I P H E N Y L - ~ ~ ~ ~ ~ ~ ~ , ~ ~ ~ - H( €E1 -X * ~ E T H ~ L - I

N1

- CYCLOTETRASILOXANEr

2~4-DIPHENYL-2.4.6.6.8.8-HEX*nE7nYL-,

raccmtc

2r4-DIPHENYL-2.4,6.6I618-HEX*nETHYL-~

12)-

1067

N1

RN

1071

TrMS-

mixed copolyiier

CYCLOSILOXANE, PHENYLRETNYL-, mixed copolyiiier end 1.1,1~5.5~5,5-HEPTARETHYL-3-13,33TRIFLUOROPR0PYL)TRISILOXANE

mixture 1072 N1 1073

N1

1074

N1

1075

Nl RN

1076

N1

1077

N1

1078

N1

1079

Nl

1080

ti1

- CYCLOTETRASILOXANEt - CYCLOTETRASILOXANEs - CYCLOTETRASILOXANEr - CYCLOTETRASILOXANEI

- 33204-76-1

2.6-DIPHENYL-2.4.4.6r8.8-HEXMETH*L-

2,6-DIPHENYL-2.4.4,6rl),B-HEXAnETHYL-,

I€)-

~ ~ ~ - D I P H E N Y L H E X * ~ E T H YZL-I

- CYCLOTETRASILDXANE~ HEPTAMETHYLPHENYL- CYCLOTETRASILDXANE, 2,2r4,4r6,6-HEXARETHYL-8-PHENYL- CYCLOTETRASILOXANE, PENTARETHYLTRIPHENYL- CYCLOTRISILOXANEI 2 , 4 - D I P H E N Y L - 2 ~ 4 ~ 6 r 6 - T E ~ A R E T H Y L - r I E ) - CYCLOTRISILOXANE~2,4-DIPHENYL-Zr4,6r6-TETRII(ETHrL-. ( 8 3 % t r M 1 r 17% c i s ) -

1081 N 1 1082

N1

1083

N1

RN 1084

N1

RN 1085

N1

RN

- CYCLOTRISILOXANEr

2,4,4.6r6-PENT*nETHYL-Z-~ENYL-

- CYCLOTRISILOXANEs 2 ~ 4 ~ 6 - T R I M E T H Y L - 2 . 4 , 6 - T R I ~ E N * L - . - lH-CYCL~ECldlfSOIMOLE-1~1112H~-DIM~ -

12)-

3-BENZYL-3~3-~l~h~~4~S~6~6-~1~h~~9~10~12~15DECAHYDRO-4rl2rlS~TRIHYDR~Y-4~10~12-TRIMETHYL-5-METHYLENE-~ 15-ACETATE 22144-77-0

-- 5CYSTEINE, L2-90-4 -- CYSTEINE, HYDROCHLORIDE, 10318-18-0

DL-

90 1086

N1 RN

1087

N1 RN

1088 N1 RN 1089

N1 RN

1090 N l RN

1091 N1 RN 1092

N1 RN

1093 N l RN

1094 N1 1095

N1

1096

N1

1097

N1

n E T n r L ESTER, HYDROCHLORIDE, -- CYSTLINE. 18598-63-5 -- CYSTINE. L56-89-3 -- CYTIDINEi 2'-DEOXY951-77-9 - CYTIDME, 2'-DEOXY-S-FLOORO- 10356-76-0 -- CYTOCHALASIN E 36011-19-5

--

CYTCCHRDME C 9007-43-6

-- CYTOSINE, 147-94-4 -- CYTOSINE, 69-74-9

-

1-beta-D-ARABIHOFW)INOSYL-

1-beta-0-ARABINOFURANOSYL-, mMOHYDROCHLORIDE

DAPHNE IENUUA Sieb et 2ucc.s crude extract DATURALACTONE 04

r o o t extract

DAUCUS CAROTA Linn.,

1099 N1

- DAUCUS CAROTA Linn.. -- OAUNOHYCIN 20830-81-3 - DEBENDOX

1100

-

1098 N1 RN

N1

1101 N l

RN 1102

N1 RN

1103

N1

1104 Nl

RN 1105

N1 RN

1106

N1 RN

1107

N1 RN

1108

N1

1109

N1

1110

N1 RN

1111 N 1 RN

1112

N1 RN

2,4-DECADIENAliIOE,

seed extract

N-ISOBUTYL-,

IE,E)-

-- l~lO-OECANEOIAlIIDE, N~N'-BISll-~ETHYL-4-PHENYL-~-PIPERIDY~E~YL~13018-50-3 -- DECANOIC ACID, NONADECAFLUORO335-76-2 - DECANDPHENONEi 2,3,4-TRIHYDROXY- ~2.4~6~8-DECATETRAENEDIDIC ACID, -~~I~-EPOXY-~~~-DI~ETHYL-~-HEXENYL)-~-~ETI(OXI-IDXASPIROI 2*5IOCT-6-YL ESTER - 23110-15-8 -- DENON 331P 56996-48-6 11-DEOXYCORTICOSTERONE -- 64-85-7 -- 86-47-3 11-DEOXYCORTICOSJERONE~ ACETATE - DETERGENTS, LIQUID CONTAINING AES

---

DETERGENTS, LIQUID CONTAINING LAS DEXTRAN 1 9004-54-0 DEXTRAN 2 9004-54-0

70 -- OEXTRAN 9004-54-0

1113 N 1

-

1114

-- DIALENE, DIETHYL-, 16301-26-1

N1 RN

L-

DIANTHUS SUPERBUS 1..

extract

1-OXIDE

91 1115 N1 RN

1116

N1

RN 1117 N1 RN

- HEXAHYORO-1~l4-*nINO-6~7~DIflETHOXI-2-W)INAZOLINYL~-4-l1-OXOBUIYL~IH-IPEI-DIAZEPINE.

-9 J’lONOHYDROCHLORIOE 52712-76-8

IACRIDINE -- D1BENZIa.j 224-42-0 -- 5H-OIBENZlb~f~AZEPINE-5-CARBOXAMIDE 298-46-4

1118 N 1

-

RN

-

1119

N1

5H-OIBENLlb,f )AZEPlNEe 3-CHLORO-5-l3-l4~CARBAm)YL~Q~PIPERIDINOPIPERIDI~~PRDPYL~-l0~11DIHYORO-, DIHYDRDCHLORIDEI MONOHYDRATE 28058-62-0

- 5 H -ll-DIHYDR0-3-CHLORD-5-l3-~ OIBENZlb~f)AZEPINE~ 0IMETHYLAflINO)PROPYL - 10303-49-1 I

RN 1120

N1

1121

N1

RN

RN 1122

N1

RN 1123

N1

RN 1124

N1

-

)-

5 H - D I B E N Z l b i f )AZEPINEe 1 0 9 11-OIHYDRO-3-CHLORO-5-l3-OIMETHYLAMINOIPROPYL IMONOHYDROCHLORIDE 17321-77-6

- 5H-OIBENZI b f IAZEPINE HALEATE 1 1 2 1 ) 21-78-8 - 510~11-OIHYORO-S-l3-lDI~ETHYLAMINO~-2-METHYLPROPYL~-~ H - O I B E N Z l b i f ) A Z E P I N E ~ 10~11-OIHYDRD-5-I3-lMETHYLAMINO)PROPYLJ-~ - 5MONOHYDROCHLWIOE - 58-28-6 5 H - 0 I B E N Z l b r f ) A Z E P I N E ~ 5-l3-lDIMETHYLAtlINO)PROPYLl-l0~ll-OIHYDRO-- 50-49-7 5H-DIBENZlbsf)AZEPINEs - 5-13-lDI~ETHYLAHINO)PROPYL~-lO~ll-DIHYDRO-, and 9

I

2-1 lp-CHLOROBENZY L ) 12-l DIliETHYLAMINOJETHYL~AMINOlPYRIOINE I1:l) 1125

N1

RN 1126

Nl RN

1127

N1

1128

N1 RN

MONOHYDROCHLORIDE 5-l3-DIJ’lETHYLAMINO~PROPYL~-lO~ll-DIHYDRO-~ - ~5H-DIBENZlb,f)AZEPINE, - O X I D E I MONOHYOROCHLORIOE - 19864-71-2 5H-DIBENZ(b,f)AZEPINE, 5-1 3-1OIMETHY LAMINO IPROPY L 1-10 11-DIHYORO113-52-D

~,~)BIPHENYLENE-~,~-DIOLI - lO-11-OIHYDRO-N.N.bcta-TRIMETHYL-,

DIBENZOI ~,6,6a-alp h~ l 6b- bct ar 11112112P- be~ ~ ~ l 2b- al ~ ha - O C T A H Y D R O -

-

5H-OIBENZOla~dlCYCLOHEPTENE-5-PROPANAflINE~ I*-)35941-65-2

1129

N1

RN

- SH-DIBENZOla,d)CYCLOHEPTENE-deltdsup 0-48-6 - 510.11-DIHYDRD-N.N-OIME1HYL-

1130

N1

-

RN 1131

Nl

RN 1132

N1

1133

N1

1134

N1

RN

1135

t

S).gamina-PROPYLAflINE.

SH-OIBENZOI o ,d )CYCLOHEPTENE-del t a l sup 5 1 .qamnina-PROPYLAMINE,

lO~11-DIHYDRO-N~N-OIMETHYL-~ NYOROCHLWIDE - 549-18-8 )CYCLOHEPTENE-deltalsup 5).galllma-PROPYLAHINE, - 5H-DIBENZOla,d OXIDE 317-14-0 - 410.11-DIHYDRO-N,N-DInETHYL-N- 5H-DIBENZOI~~d)CYCLOHEPTEN-S-DLr10~11-DIHYORO-5-CYCLOHEXIL- 5H-OIBENZOl~~d)CYCLOHEPTEN-5-ONE~ 10~11-0IHYORO-~ - I 2 - I D I M E T H Y L A M I N O ) E T H Y L ) O X I H E ~ HYDROCHLORIDE - O4985-15-3 - DIBENZOI )CYCLOOCTENE. 5~6-OIHYORO-3-lALLYLOXY )-1l-ETHYL-12-PHENYL4,.

RN

-

N1

- DIBENZOlare)CYCLOOCTENE, 5~6-DIHYDRO-8-lZ-IOIMElHYLAMINO~ETHOXY~~l2~ElHYL~ll-PHENYL-~

RN

-

85850-83-5

HYDRATE 1 1 : 4 1

92 1136

N1 RN

1137 N1

RN 1138 N1

RN 1139 N l

RN 1140

N1 RN

1141 N1 RN

1142

N1

RN 1143 N1 1144 N1 RN 1145

N1 RN

1146

N1

RN 1147 N1

RN 1148

N1

- DH-OIBENZOI br. If 1,~)DIAZEPINEI 8-CHLORO-ll-I4-METHYL~l~PIPERAZINYL~~

-- 3646-61-5 -----5786-21-0

OIBENZOIb,f ll1,5)DIUOCINE~ 2r8~OICHLORO~6~12~0IPHENYL~ OIBLNZO-p-DIOXIN, 2s7-DICHLORO33857-26-0 OIBENZO-p-DIOXIN, 34465-46-8

NEXACHLORO-

OIBENZO-P-OIOXIN, 1,2~3r4~6r7r8,9-OCTACUL~O3268-87-9 OIBEWO-P-OIOXINI lr3~6~8-~ETRACHLDRO33423-92-6 DIBENZO-P-DIOXINI 1746-01-6

2~3r7,8-TETRACHLORO-

- 312,6-DIACETYL-lr7~9-TRIHYOROXY-8,9b~DIMETHYL-~ ~~H)~OIBENZOFURANONEI 0-

--

OIBENTOFURWI 2,3r7,8-TETRACHLORO51207-31-9 6H-OIBENZOlbrd)P~AN-l~OL, ~~~~~~~~OP-TETRWYORO-~~~~P-TRIMETHYL-~-PENTY~1972-08-3

- 6H-Dl8ENZOlbrdlPYRAN~l~OL~ 6.6r9-TRInETNYL-3-PENTrL-

- 521-35-7 -- 6H-OIBENZOfb.dlPYRAN-6-ONE~ 3,7-DIHYDROXY-9-HETHOXY-l-HETHYL23452-05-3 - 9H-DIBENZOlbrd)PYRAN-9-WJL. 3-~l~l-OIMETHYLHEPTYL~-6~6a~7~8~lO~lOa-HEXAHYORO-l-HYORO~6.6-DlMETHYL-. - 51022-71-0 trans-I +)-

RN 1149 N l

RN 1150 N l 1151 N l

RN 1152 N1

RN 1153 N1

RN 1154 N l RN 1155 N1 RN 1156

N1

1157 N1

RN 1158 N1 RN

llSV

Nl RN

--

6N-DfBENZOlbrdlPYRAN-6-~~l-METHYL-3.7,9-TRIHYOROXY641-58-3 6H-OIBENZOlb,dlPYRAN-6-W~~ l-METHYL-3~7~9~TRIHYDROXYmd 3e9-OIHYDROXY-7-PIETHOXY-1METHYL-OIBENZOfbrd)PYRAN-6-ONE I1:l)

- OIBENZOfcrf)PYRUINOllr2-a)A2EPINE~ 1~2r3r4~1O~14b-HEX*HYORO-2-~ElH~L~r ~YORDCnlORlOE

- 1~3r4~14b-TETRAHYDRO-2~7~01METHYl~~ brf 121-2-2-CHLORO-ll-~4-~ETHYL-l-PIPERAZINYLl-b -21535-47-7

LH-OIBENZOI

)PYRAZINOl1.2-d I 1 I ~ ~ ) O W E P I N E I BUTENEDIOATE l1:ll

40132-36-3

OTBENZOIb,f l f l ~ 4 l l H I A Z E P I N E ~ 205B-52-8

OIBENZOI s f 11 184 IMIAZEPINE, 2-PIETHY L-11-1 4-METHY L-1-PIPERALINYL 5800-19-1 DIBENZO(b~f1THIEPIN~ 3~IALLYLOXY)~lO~ETHYL-ll~PHENYL~

85850-82-4

- OIBENZOlb,f ITHIEPINI 2 ~ C H L M I O - l l ~ I 2 ~ f O I M E T H Y L M I M l E T H O X1-Y - DIBENZOlb,f)THIEPINt 7-~2-~DIMETHYLAPIINO~ETNOXY~-ll-ETNYL~lO-PHENYL~

--

05850-77-7 OI8ENZOlbrflTHIEPIN~3-~ElHOXT-lO-~ETHYL-Il-PHENTL83807-06-1

- DIBENZO~b~~)THIEPIN-ll-OL~ 6 ,11-OIHYDRO-8-METHOXY-11-1 p-I 2-1 1-PYRROLIDINY L )ETHOXY IPHENYL HYDROCHLORIDE - 36541-32-7

J-8

)-

93 1160 N1 IN 1161 N1 RN

-

OJBENZOtbre )THIEPIN-deltml sup l l I 6 H ),gamma)-PROPYLAHINEs

NsN-OIHETHYL-e HYOROCHLORIOE - 897-15-4 -- 6H-DIBENZOI b.f )THIOCINs 3-1ALLYLOXY )-1l-ETHYL-12-PHENYL05850-84-6

1163 N1 RN

- 3-1 --

1164

N1 RN

- DIBENZ1b.f

1165

N1 RN

EI - 1977-10-2 ) ~ ~ ~ Q ) O X I L E P I N2-CHlORO-ll-I4-~ETHYL-I-PIPERUINIL)-- OIBENZlb,c)DXEPIN-3-ACETIC ACID. 6.11-DIHYORO-11-0x055689-65-1

1166

N1 RN

- OIBENZlbvf )OXEPINE, - 83807-07-2

1167

N1

1162

N1 RN

RN 1168

N1 RN

1169

N1 RN

1170

N1 RN

1171 N1 RN 1172

H1

1173 N1

6H-DIBENZO1 b * f JTHIOCINs 2-lO1liETHYUWINO)ETHOXY )-ll-ETHYL-l2-RIENYL85850-79-9 DIBEWI b .f )1 1.Q)OXUEPINE 257-07-8

3-IALLVLOXY )-lO-ETHYL-ll-PHENYL-

- DIBENZI b IOXEPINE 7-1Z-lOItiE~YLAliINO~ETHDXI~-1l-ETHYL-10-PHENYL- 85850-76-6 - DIBENZlb,eJOXEPIN-dcl~al~~ ll16H)rgaana)-PROPY~INE~ HYOROCHLWIDE - N,N-OItlETHYL-~ 1229-29-4 -- OIBENZYLAtiINE, N-12-CHLOl)OtTttYL)51-50-3 -- OICARBAOWECABORANEfl2)~ HEXYL20740-05-0 -- OICHROWIC ACID. OIPOTASSIU1I SALT 7778-50-9 - OICYCLOPENTAla.f)NAPHTHALENE-t-bate,7-betu-DIOL~ HEWDECAH~ORO-2-alpha~7-alpha-OIETHYNYL- 8a,lOa-OItlETHYL- OIETHYLAHINE. 2-1 2-1 p-CHLOROPHENYL )-In2 3,4-TETRAHYORO-l-NAPTHYL ) P H E W 1- s I

f

r

p-I

1174 N1 RN 1175

N1 RN

1176

N1

RN 1177

Nl RN

1178

N1 RN

1179

N1

1180

N1 RN

RN

1181 N1 RN

1182

1183

N1

--

p

HYOROCHLORIOE DIETHYLAHIIWE, 2,2'-DICHLORO-, 821-48-7

HYDROCHLWJDE

-- OIETHYLWINEe 2~2'-OICHLORO-N-PlETHYL51-75-2 -- OIETHYLWINE~ ~.~'-OICHLORO-N-VETHYLI HYOROCHLORIOE 55-86-7 2~2'-OICHLM1O-N-PlETHYL-~ N-OXIDE -- DIETHYLA~~JNEI 126-85-2 -- OIETHYLWINE, N-NITROSO55-18-5 -- OIETHYLENE BLYCOL 111-46-6 -- DIGITOXIN 71-63-6 -- OIOOXIN 20830-75-5 - 11,4:5~8-OIPlETHANONAPHTHAlENEr ~ 2 ~ 3 ~ 4 r 1 0 ~ 1 0 - H E X A C H L O R O ~ 6 ~ 7 ~ E P O X Y ~ 1 ~ 4 ~ 4OCTAHYORO-B 0r5~6r7~8~8~endo,endo-

RN

-

N1

- ~1 ~~ ~2:~S3I~~4-~O1I0~~E 1T H0 A- HH OENXAAP CH THHLAOL ERNOE~~6 r 7 - f W X Y - l ~ Q ~ 4 OCTAHYOROn d~5~6~7~8~8~-

RN

-

72-20-8

endo,cxo60-57-1

94 1184

Nl RN

1185

Nl RN

1186

N1

1187 N1 RN 1188 N1

- lr4:5r8-DI~ETHAHOII*PHTHALENE, ~ 2 r 3 ~ 4 ~ l O ~ l O - H E X A C H L O R O - l ~ 4 ~ 4 a ~ 5 ~ 8 ~ ~ - HcndoDexoEXAHYDRO-~ - l309-00-2 - 19,24-DINOR-l7-alph~-CHOLA-l~3~5llO~~7,2O,Z2-HEXAENE-3,l7-DIoL,

-

21.23-EPOXY-r 10322-73-3

3-ACETATE

- 1 8 ~ 1 9 - D I N O R P R E G N I ~ 1 ~ 3 ~ 5 l l O ) ~ T R X E N ~16-HYDROXY-3-HETHOXYZO~ONE~

- 18,19-DINOR-17-alpha-PREGNA-4~9~ll-TRIEN-2O-YN-3-fflE, -

18~19-DINORPREGNA-1~3~5110~-1R1ENE-20-YNE-3~17-D10L~ 13-ETHYL-, 3-IDI~ETHYLSULFAMATEI, (17-alpha)-

65323-80-0

13-ETHYL-17-HYDROXY-

RN 1189 N1 1190

N1 RN

1191 N1 RN 1192

N1 RN

1193 N1 RN 1194

N1

N1 RN

1196

18~19-DINORPREGN~4-ENE-3120-DIONE -- 2299-98-1 -- 18,19-DIHOR-l7-alpho-PREGN-4-EN-3-ONE, 13-ETHYL-17-HYDROXY797-58-0 -- 1235-15-0 18,19-DINOR-17-alpha-PREGN-4-EN-3-0NE~ 13-ETHYL-17-HYOROXY-, - 18rl9-DINORPREW~4-EN-20-YN~l7~01~ 13-ETHYL-ll-nETHYLENE-, 1l ? - a l p h a ) -

N1

I+)-

- ~~~~~-DINORPREGN-~-EN-~O-YN-~-ONEI - 18~l9-DINDR-17-rlpha-PRE6N-4-EN-20-YN-3-ONE~ 54024-22-5

17-lACETYLOXY)-13-ETHYL-,

3-OXItIE. 117-alpha 35189-28-7

NI+ 1195

16320-04-0

- 13-ETHYL-17-HYOROXY-, 18,19-OINOR-17-alpha-PREGNA-4~9~ll-TRIEN-ZO-YN-3-ONE, ond TESTOSTERONE

)-

~ ~ - C H L O R O - ~ ~ - E T H Y L - ~ ~ - H Y D R O XI+)Y-D 2415-28-3

- 18,19-DINOR-17-alph~-PREGN-4-EN-20-YN-3-OHE~ 13-ETHYL-17-HYDRDXY-. I+ )-

1197 N1

RN 1198

N1 RN

1199 N1 RN 1200

N1 RN

1201 N1

- 18,19-DINDR-17-alpha-PREGN-4-EN-20-YN-3-ONE~ 13-ETHYL-17-HYDROXY-r - 6533-00-2

I t-1-

- 18~19-DINDRPREGN-4-EN-20-YN-3-ONE, - 18-alpha.9-bota~10-alphar13-alpha~ - 18r19-DINORPREW3-4-EN-ZO-YN-3~~E, - mixed 18,19-DINOR-17-alpha-PREGN-4-EN-2O-YN-3-DNE~ - 16r19-OINOR-17-alphm-PREGN-4-EN-20-YN-3-OM, and

13-ETHYL-17-HYOROXY-, 14-beta)-

797-64-8

lS-ETHYL-17-HYOROXY-ll+lETHYLENE-, 54048-10-1

117-alpha)-

13-ETHYL-17-HYDROXYw l th 19-Noa- l7-alpha-PREGNI-1~3r5o-TRIEN-2-YNE-3~l7-DIOL 8056-51-7 13-ETHYL-17-HYDROXY-, I + - ) - ,

19-NOR-17-alpha-PREGNA-l,3~5llO~-TRIEN-2O-YNE-3~l7-DIOL

1202

HI RN

1203 N1

-- 18,19-DINOR-17-alpha-PREGN-4-EN-2O-YN-3-CNE, - A~19-DINORPRE6N-20-YNE-2~17~DIOl~ I2-alpha,5-alpha~ll-alpha - A~19-DINORPREGN-2O-YNE-2~17-DIOL, l2-beta~5-alpha,l7-alpha)-

17-HYDROXY-13-PROPYL-

1044-%-8

2-ETNYNYL-s

1-

1204

N1

120s N1

2-ETHYNYL-,

- A2-alpha r19-DI~PREGN-ZO-YNE-2~l7-DIOLt ,5-dphav 17-alph. 1-

- l2-betar5-alphr,l7-alpha~-

DIACETATE,

2-ETHYNYL-r DIPROPAWOATEI

(

RN 1206

Nl RN

64675-10-1

A~19-DI~RPREGH-2O-YNE-2~17~DIO 2-ETHYNYL-, l~

64675-08-7

DIPROPANOATEi

95 1207 Nl

-

3,8-DIOXABICYCLO(3.2.1lMTANE-l-beta-ACE~IC ACID. 7-NONENYL)-, 5-alphe-

4-beta-14.8-OIMETHYL-5-HYDROXY-

1208 N1 RN 1209 N1 RN

- p-OIOXANE, DIMETHYL- 25136-55-4 - III-OIOXANEP4,4-DIMETHYL

- 766-15-4

1213 N1

-

1214 N1

- I~~-DIOXOLANEI4-CHLMIM1ETHYL-2-MENYL-

1210 N1 RN 1211 N1 RN 1212 N1 RN

1215 Nl RN 1216 N1 RN

1218 N1 RN 1219 N1 RN

1220 N1 RN 1221 N1 RN 12t2 N1 RN 1223 Nl RN

1224 N1 1225 Nl RN 1226 Nl

RN 1227 N1

1228 NI RN

1,3-OIOXOLANE~4-CHLMlOnETHYL-2,2-OfMETNYL4362-40-7 l13-O1OXALANE~4-CHLOROnEnlYL-Z-METHYL-2-PEMYL36236-73-4 1,3-DIOXOLANE, 4-(CHLOROnETHYL)-2-(o-NLTROWENYL)-

- lr3-OIOXOLANE-4-HETHANOL - 5464-28-8 - (lr3lOIOXOL0(4~5-g)CINNOLINE-3-CARBOXYLIC ACID, 1,4-DIHYDRO-l-ETHYL-4-0XO- 28657-80-9

1217 N1 RN

~~~-OIDXA-~-SILACYCLOPENTANEI 4-(CHLOROnETHYL)-2.2-OIMETHYL75659-62-0

-

lr3~DIOXOLOI4~5~~~WINOLINE~7~CARBOXYLIC ACIDS 5~8-OIHYORO-5-METHOXY-8-OXO37065-29-5 DIPHENYLAMINE 122-39-4 OIPHOSPHONIC At101 (l-HYOROXYETHYIIOENE~-~DISWILM SALT 7414-83-7

2~2'-OIHYDROXY-N-NITROSO- DIPROPYLAMINE, 53609-64-6

- OIPROPYLAMINE, 2~2'-OIOXO-N-NITROSO- 60599-38-4 - OIPROPYLAMINE, N-NITROSO- 621-64-7 - DIPYRIDO(lrZ-ai2' ~1l-C)PYRAZINEOIILM, 6~7-OIHYORO-~ DIBROMIDE - 85-00-7

-

DISILOXANEI 1~3-OIPHENYL-l~lr3~3-TETR~ETHYL-

BISlDIE~YLTHIOCAR8AMOYLl - OISULFIOE~ 97-77-8 - OISULFIOE, BIS(DINETHYLTHIOCARBAMOYL1 - 137-26-6

-

1 ~ 3 ~ 2 - D I n l I A R S O L A N E ~ 4 1 5 - D I C A R 8 O X Y LACID. IC

-

~.~-BIS(DI~EMY~MINO)-. CHLORIDE - ~,~.~-DITHIUOL-L-IU(~ 3007-22-3

1230 N1

- ~-DITHIIN-2r3-DICARBOXI~IDEr5.6-DIHYDRO- 24519-85-5 - ~-0ITHIIN-2r3-DICIRBOXI~IDEr

1231 N1

-

1229 N1 RN

5 I6-OINYORO-N-~ 2 ,b-OIOXO-3-PIPERIOYL)-

~H-~-DI~IINO~~~~-~IPIRROLE-~I~-DIONEI 2,3~5,7-TETRANYORO-6-METHYL-

1232 N1 RN

1233 N1

-- 532-11-6 31-1.2-DITHIOLE-3-TnI~E. I-fp-~ETHOXYPHENYL)- 2t4-DODEUDIEM)IC ACID, ll-~EETHOXI-3~7~1l-TRI~ETHYL-~ ISOPROPYL ESTER

96 1234

N1 RN

1235

N1 RN

1236 N 1 1237 N1 RN 1238 N l 1239 N 1 RN 1240

N1

----- ~~,~~-DIHYORO-~~-BRO~~O-~~-HYDROXY-I DOOECA-2i4-DIENOIC 41096-46-2

ACIDB ~ ~ ~ P ~ ~ - T R I M E T H Y ETHYL L - I ESTER, (ZEIQEI-

DOW CORNING 360 FLU10 63148-62-9

ORYOPTERIS FILIX-MAS.

extract

DUALOnYCIN 1403-47-0 DYE C

EBIM 9013-42-7

EBVRNWENINE-14-CARBOXYLIC 1 4 - b e t a ,16-alpha 84964-12-5

ACID,

RN 1243

Nl

-

1244

N1

1142 N 1

1245 N1

METHYL ESTER, IS-alpha, (SALT)

I E )-2-BVTENEOIOATE I 1 :I

EBURNAMENINE-14-CARBOXYLIC ACID, -- 42971-09-5 -- E50814-62-5 USIMIYCIN

RN 1241 N 1 RN

1-9

ETHYL ESTER, 1 3 - m b h a 1 1 6 - a l p h ~ ) -

EHBELIA RIBES

- EHBELIA R I B E t i BENZENE EXTRACT - EHBELIA RIBES, drlcd b e r r y e x t r a c t

N1

-

EMBELIA RIBESr METHANOL EXTRACT

1247 N1

-

EHBELIA RIBES, PETROLELM ETHER EXTRACT

1246

1250 N 1 RN

- EIIBELIA RIBES b..root e x t r a c t - EHBELIA RIBES B u r s . f . , reed e x t r a c t -- EMETINE, OIHVDROCHLORIDE. HVDRATE 7083-71-8

1 2 5 1 N1

- EMETINE DIHER

1248 N 1 1249 N 1

1252

N1

1253 N1 1254 N 1 1255 N1 1256

N1

1257 N1 1258 N1 1259 N1 RN 1260

Nl RN

1 2 6 1 N1 RN 1262 N1

RN 1263 N 1 RN 1264 N1 AN

- ENOOTOXINI E. COLI - ENDOTOXIN, S A W E L L A ENTERITIOIS - ENDDTOXINe SERRATIA NARCESCENS - ENDOTOXINI VIBRIO CHOLERAE

-

ENTERO-EXOTOXINi CHOLERA EPHEDRINE COnPwND ELIXIR

- ~I~-EPIDITHIOPR€GNANE-~~ZO-DIONE

--- H2

CPIPODOPHYLLOTM(1N~ 4' -0EMETHY L- B 9-14,6-0-~-THENYLIDENE-beta-D-GL~O~RANOSIO€) 29767-20-2

EPIPMOPHYLLOTOXIN-beta-D-ETHYLIDEN-GLUCOSIDE, 33419-42-0

4'-DEHElHYL-

2-alpha13-~lpha-EPITMI0-5-elp~-~R~TAN-l7-b8t~-OL 2363-51-8

-

~ 7 - EPOXYPLMMECA~ ( 1~ 11~ 13~ TRIE NfH IN O~N A R2rl-b llt ( O~)FURAN-1 I 11(LI-OIONEI ~ ~ ~ I ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ H E X Y O R O X T - P ~ - N E ~ O X Y ~ ~ I ~ I ~ HYL-r PI-ACETATE 6996-60-3

-- 604-58-0 --

E W I L E N I N i BENZOATE

T W I L I N s BENZOATE '6030-60-4

97 1265

N1 RN

1266

N1 RN

1267

N1 RN

1268

N1 RN

1269

N1 RN

1270

N1

-

ERGOCALCIFEROL - 50-14-6 - ERGDCORNINE. 9.10-DIHYDRO- 25447-65-8 ERGOCRYPTINE -- 511-09-1 2-BR01)0-. METNANESULFCINATE -- aIpha-ER60CRYPTINEl 22260-51-1 - ERGOCRYPTINE, NONOnETHANESULFONATE fraltl - 2706-66-3 - ERGOLINE-8-ACETAMIDE. 6-METHYL-. IO-betab. IR-~R*~R*ll-2~3-OIHYOROXYBUTANEDIOAlE Il:21

RN

-

1274

N1 RN

-- E50-37-3 R G O L I N E - ~ - ~ ~ ~ ~ - C A R B O X A M ~I ~D~E~I- D I D E H Y D R O - N I N - D I E T H Y L - ~ - ~ T H ~ L -

1275

N1

-

ERGOLINE-8-beta-CARE30XAMIDEr

1276

N1

-

ERGOLINE-8-bata-CARBOXAMIOE~

RN 1271 N l 1272

N1

1273

Nl

RN 1277

N1

41562-69-0

E R W L I N E - ~ - ~ ~ ~ ~ - A C E T O N I T R I6-HETHYLLED ERGOLINE-8-ACETONITRILE,

RN 1279

N1 RN

1280 N1 RN 1281 N 1

~I~O-DIDEHYDRO-NIN-DIETHYL-~-METHYL-D TARTRATE

l l : l l e

9~10-OIDEHYDRO-N~N-DIElHYL-6-tlElHYL-~ TARTRATE ( 2 : l I

(

1:2 I

-

ERGOLIHE-8-CARBOXAnIDE~ 9~10-OIDEHYORO-N-f l-HYOROXYETHYLl-6-METHYL-~ 3343-15-5

-

ERGOLINE-~-~~~~-CARBOXI~~DES

-

DIMALEATE 29605-96-7

f 8-bat.)-

- ERGOLINE-8-betm-CARBOXA~IOE~ 9~10-DIDEHYORO-N-~fSl-2-HYDROXY-1-METHYLETHYLl-6-METHYL-~ MALEATE (1:lI (salt) - 129-51-1 ~~IO-DIDEHIDRO-N~~~-~HYDROXY~ETHYLIPROPYLI-~~~-DIMETHYL-I

- E9,IO-DIOEHYDRO-N-( RGOLINE-8-bcta-CARBIDEr S 1-I-f HYDROXTMETHYL)PROPYL b6-HETHYL-

RN

-

N1 RN

-- ERGOLINE. 548-42-5

1283

N1

-

113-42-8

8~9-OIDEHYDRO-6r8-DI~ETHYL-

ERGOLINE-8-METHANOL~ 8~9-DIDEHYDRO-6-METHYL- 546-43-6

-

1284

N1

1285

N1

1286

N1

1267

N1

- N-BENLYL-6-METHYL-rrIpha-IMETHYLSULFONYLIERGOLINE-8-beta-PROPIONAMIDE, - E R G O L I N E - ~ - P R O P I ~ I D Et-CHLORO-alpha-CY*NO-6-nE~YLD

1288

N1

-

1289

Nl

1290

N1

1 2 9 1 N1

d-

- 17676-08-3 - ERGOLINE-8-bcta-CARBOXWIDE, 9~10-DIOEHYORO-NIN-DIETHYL-~-METNYL-~ 0-• TARTRATE w i t h HETnYL

1282

RN

D-

~-BROHO-~I~O-OIOEHYDRO-N~N-OIETHYL-~-METHYL478-84-2

ALCOHOL 1 2 7 8 N1

6-METHYL-r

ERGOLINE-8-bcta-CARBOXAMIDE~

E R 6 0 L I N E - 8 - b e t a - P R D P I ~ D E . aIpho-ACEML-6-HETHYLE R G O L I N E - 8 - P R O P I O I D E ~ 6-ALLYL-alpha-CYANO-

ERGOLINE-8-PROPICWWIDE~ alpha-CYANO-6-ftYCLOPROPYLnETHYL1-

- ERGOLINE-~-PROPIONAMIDEDoI~a-CY*NO-2r6-DIWETHYL- ERWLINE-8-beta-PROPION*nlDE~ .Ipha-CY*M-N-ETHYL-6-nETnrL- ERGOLINE-8-PROPIONAMIDE, alpha-CYANO-6-ISDBUTYL-

1292

N1

- ERGOLINE-8-alpha-PROPIONAVIDEI

1293

N1

ERGOLINE-8-beta-PROPIONAt4IOE,

12%

N1

1295

N1

-

- ER60LINE-8-PROPIONAt4IDE.

alpha-CYANO-6-HETnYLalpha-CYANO-(-METHYL-

9~lO-DIDEHYDRO-alpha-CY~-6-HE~YL-

- ERGOLINE-8-beta-PROPIONAMIDE, - ERGOLINE-8-beta-PROPIONITRILE,

N-ETHYL-6-?lETHYL-a1pha-~METHYLWLF~YLl-

1296 N1 1297

N1

ER60LINE-8-b~tc-PROPI~HIDE~ 6-HETHYL6-HETHYL-alpha-t4-METHYL-l-PIPERA21NYLCAREONYLl-

1298 N l

- ERGOLINE-8-beta-PROPIONITRILE.

6-HETHY L-alpha- t HORPHOLINOCARBONTLI-

1299 N1

- ERGOLINE-8-betm-PROPIONITRILE, - ERGOLINE-8-beta-PROPIONIlRILE, - ERGOSTA-2,24-DIEN-26-OIC

6-METHY L-alpha-( PIPERIDINPKAREDNYLI-

1300 N1

6-HETHY L-alpha-( 1-PYRROLIDINYLCAREONYL t

1301 N l

1302 N1 RN 1303

N1

-

ACID, 6~7-EWXY-lrl2-DIOXO-5,11122-TRIHYDROXY-t alphar4-alphar7-olphar12-olpha,22St-

dclTa-LACTONE, 15-

- 6~7-EPOXI-5~l2~17-22-TETRAHYDROXY-l-OXO-~ ERGOSTA-2r24-DIEN-26-OIC ACIDS delta-LACTWE,

- ERGOSTA-t~24-DIEN-26-OICACID,

~5-alpha~6-alpha~7-alpha,12-alpha,22Sl41093-93-0 6~7-EWXY-5~12~17~22-TETRAHYDROXY-l-OXO-~delta-LACTONE mixed with BORON FLUORIDE

1304

N1 RN

1305

N1

1304

Nl

-- 5-alpha,8-alpha-ERGOSTI-6~22-DIEN-3-beta-DL.

5,8-EPIDIOXY-

2061-64-5

- ERGOST-24-EN-26-0IC ACID, 6~7-EPOXY-l-OX0-5,l2~17~22-TETRAHYOROXY-~ delta-LACTONE, f5-alpha, 6-alpha~7-alphe~12-alpha,Z2SI-

RN 1307 N1 RN 1308 N1 RN 1309 N1

- Ef 5R'G- aOlTp Ah Ma tA-N - ~ ' ~ ~ ' ~ ~ ~ - T R I12'-HYDROXY-~'~5'-BISIl-METHYLETHYL ONEI - 564-36-3

12'~HYOROXY-2',5'~BIStl-HEMYLETHYl (2)-2- ERGOTAIIAN-~'~~'I~~-TRIONEI ERM~AIIAN-~',~'~~(~-TRTMIEI (5'-alpha)-* BUTENEOIOATP t 1 : l ) 57432-60-7

(5'-alphal-, 2207-69-4

(SALT)

12'~H~DROXY~~'~5'~BISIl-HE~YLETHYLl-~ HETHANESULFONATE ( s a l t 1

- ERGOTAMAN-3',6',18-TRIONE, 12'-HYDROXY-2'-METHYL-51-(2-nETHYLPROPYLI-~

f5'-alphal-

nixt.

with ERGDSININE (3:ZI

1310 N1 RN 1311 N1

- ERGOTAMAN-~'~~'~~~-TRIONEI -

12'-HYDROXY-2 '-HETHYL-I'-l 2-HETHYLPROPYL J-, MONOMETHANESULFONATE I salt I 2624-03-5

- ERGOTAIIAN-~',~'~~~-TRIONEI

12 '-HYOROXY-2'-HETHY L-5I-t PHENYUIETHYLJ-B

RN 1312 N1 RN 1313 N1 RN 1314

N1 RN

1315

N1

t SALT) - IIONOM€THANESULFONATE 6045-59-6 -- ERMTAIIINE TARTRATE 379-79-3

- ERGOTIPIIN-~'~~'~~~-TRIONEI

15'-olpha)-r

( 5'-alph.

t-

,

t-BROIIO-I2'-HYDROXY-2'-l1-~ETHYLE~YLl-5'-alpha-l2-HETHYLPROPYL~- 25614-03-3 -- ERGOTOXZNE 8006-25-5 - ERGOTOXINE, HETHANESULFONATE

99 1316 N1 RN 1317 N1 1318 Nl 1319 Nl RN 1320 N1 1321 N1 1322 N1 1323 N1 1324 Nl 1325 Nl 1326 N1 1327 N1 RN 1328 N1 RN 1329 N1 RN 1330 N1 RN 1331 N1 1332 Nl RN 1333 N1 RN

1334 N1 RN 1335 Nl 13%

N1 RN

1337 Nl RN 1338 Nl RN 1339 N1 1340

N1 RN

1341

N1 RN 1342 N1 RN 1343 N1

RN 1344

N1

1345 N1 1346 Nl 1347 N1

HONOETHANESULFDNATE f SALT -- ERGOTOXINEI 8047-28-7 - ERBOT SCLEROTIA - ERGOVALINE. METHANESULFMUTE -- ERYTHROMYCIN 114-07-8 - ESCIN. SODIUN SALT - ESSENTIAL PHOSPnDLIPIDS - ESTRA-I.~-DIENE-~~~~-DIDNEI IO-HYDROXY- ESTRA-l,4-DIENE-3~17-OIONE, 10-HYDROXY-, ACETATE - ESTRA-1,4-DIEN-3-ONE. 10-beta-CHLORO-17-beta-HYDROXY)

--

ESTRA-1.4-DIEN-3-ONEn

10,17-b~ta-DIHYDROXY-~10-ACETATE

ESTRA-lr4-DIEN-3-ONEv 10.19-DIHYDROXY-r 10-ACETATE ESTRADIOL 50-28-2

-- 57-91-0 17-alpha-ESTRADIOL -- ESTRADIDL. 3-BENZOATE 50-50-0

ESTRAOIOL, 17-BENZOATE-3-n-WTYRATE -- 63042-19-3 - ESTRAOIOL, 3-BENZOATE mixed with PROGESTERONE f1:14

---

nioler)

ESTRADIOL, 17-CAPRYLATE 63042-22-8 ESTRADIOLp 17-CYCLOPENTANEPROPIONATE 313-06-4

-- ESTRAOIOL, DIPROPIONATE 113-38-2

-

ESTRADIOL. 17-HEMlSUCCINATE. conjugated to BOVINE SERUN A L W I N

-

ESTRAN-3-ONE. 17-beta-HYDROXY-17-alpha-HEltlYL-

--

bcta-ESTRA-1~3~5~7,9-PENTAEN-3.n-DrOL

-- 28014-46-2 ESTRADIOL, POLYESTER with PHOSPHORIC ACID -- ESTRAOIOL, 17-VALERATE 979-32-8 5-slpha-ESTRAN-3-ONE. 17-beta-HYDROXY-, O-i2~4-DINITROPHENYL~OXIHE -- 64584-77-6 -- 5-alpha-ES1RAN-3-ONEI 17-beta-HYDROXY-17-HETHYl6424-04-0 -- 6639-99-2 ~lpha-ESTRA-1,3t5,7,9-PENTAEN-3,17-OIOL 1423-97-8

ESTRA-l.3r5.7,9-PENTAEN-l7-ONE, 3-HYDROXY-- 517-09-9 - ESTRA-l,3,5ilO ~ ~ - T E T R A E N - ~ - O17-1 L I METHYLTHIO1- 8-alph~-ESTRA-l~3,5llO)-TRIENE-3~l7-beta-OIOL - ESTRA-lr 3 - 9 lO)-TRIENE-3.17-DIOL~ f6.7-(sup 3 )H,17-bcta)- ESTRA-l.3r5f10~-TRIENE-3117-DIOL 117-beta)-, 3-161% 2-CHLOROETMYL KARBAHATE 1 17-IDIHYDROGEN PHOSPHATE) DISOOIUH SALT - 52205-73-9 )I

9

RN

1348 N1 1349 N1 RN 1350 N1 1351 N1 1352 N1 1353 N I RN 1354

NI

- ESTRA-1~3,5llOl-TRIENE-3~17-beta-DIOL, -- ESTRA-l~3r5~101-TRIENE-16-alpha~17-betr-OIOL,

17-alpha-WTADIWL3-(CYCLDPLNrYLOXIl-

1169-79-5

- S-(CYCLOPENTYLOXY)-r ESTRA-lr3.5l1O l-TRIENE-16-alphm,I7-alpha-DIOL~ OIACETATE - ESTRA-1~3~5l101-~RIENE-l6-alphm~l7-alp~-DIDL~ 3-(CYCLOPENTYLOXYl-t OIPROPIONATE

- ESTRA~1~3~5~IOl-TRIENE-3~17-DIOL~ 1~3~5IlOI-TRIENE-3~17-DIOL~ DIBENLOITE

17-OIHYDROBEN

17-bmta-ESTRA HOMOPOLYHER

- PHOSPHATE, 34628-67-6

-

t 17-beta I - , ESTRA-1,3,51 lO)-TRIENE-3,17-DIOL 17-~2~2-OIMETHYLHYORAZINECAR~O~LATE~ 55081-70-4

- 6-alpha-ESTRA-1,3~5~10~-TRIENE-3r17-beta-DIOL~ 2-ETHYLN1 - 6-olpha-ESTRA-1,3~5110l-TRIENE-3.17-beta-DIOL, 16-beta-ETHYLN1 - ESTRA-l~3~5~10l-TRIENE-16-alph.,17-betm-DIOL~ 3-HETHOXYR N - 1474-53-9 N1 - ESTRA-1 .St.5( 10 l-TRIENE-16-betrr17-beta-DIOL. 3-HETHOXY-16-HETHYLRN - 5108-94-1 N1 - ESTRA-1,3,5~10I-TR1ENE-16-betr~l7-betr-OIOL, 3-HETHOXY-16-alphr-HETHYL-

RN

1355 N1 1356 1357 1356 1359 1360

N1

1361 N1 136t

N1

1363 N1 RN 1364 N1 1365 N1 1366 N1 1367 N1 RN 1366 N1 1369 N1 1370

N1 RN

1371 N l 1372 N1 1373 N1 1374 N1

1375 N1 1376

N1 RN

1377 N1 1378

N1

1379 N l RN

-

-

B-alpha-ES~RA-1,3,5~lOl-TRIENE-S~X7-beta-OIOL~ 2-METHYL-

6-rlpho-ESTRA-l~3~5(10~-TRIENE-3~17-b~ta-OIOL~ 16-HETHYL~ - ~ ~ ~ ~ P - E S T R A - ~ ~ ~ , ~ ~ ~ O ~ - T R I E N16-beta-PROPYLE - ~ . ~ ~ - ~ ~ ~ ~ - D I D L ~ ESTRA-1,3.5(

10 bTRIENE-3.17-beta-D10L~

17-1 3,313-TRIFLUORO-I-PROPYNYLJ- 2061-56-5

- ESTRA-lr3~5I10l~TRIENE-17-THIOL~ - EfTRA-lr3,5~10~-TRIENE-17-alpha-lNIOLl

3-METHOXY3-HETHDXY-

- ESTRA-1,3,5110l-TR1ENE-1~,5,17-be?m-TR101 - 16~17-0111CETATE ESTRA-l,3,5~10~-TRIENE-3.16-alpha~l7-betm-TRIOL, 3-BENZOATE,

-

2508-47-6

- E S T R A - 1 ~ 3 ~ 5 ~ 1 0 l - T R I E N E - l r J . 1 7 - T R I O L ~TRIACETATE

- ESTRA-l,3r5(101-TRIENE-l,3~17-b.ta-TRIOL~ --

TRIACETATE

ESTRA-lr3,5l lOI-TRlEN-3-OL 53-63-4

- ESTRA-lr3,5(10t-TRIEN-17-betm-OL~17-alpha-BUTMIYNYL-3-HElHOXY17-clphr-ETHWL-3-nETnOXI- ESTRA-lr3~5~10l-TRIEN-l7-b~t~-Ol~

- ESTRA-lr3,5110)-TRIEN-3-OLI - ESTRA-1~3~5l10I-TRIEN-17~OL~ -3 r5( ESTRA-1.3,SI

lO)-TRIEN-I-OL.

17-HERCAPTO17-alpha-HERCAPTO3-MElHOXY-

ESTRA-1,3$5( 10 '-TRIEN-17-betm-OL, 1035-77-4 ESTRA-1

t

3-Hi!THOXY-

10 t-TRIEN-17-OL s 3-HETHOXY-4-HETNY

L-

ESTRA-1~3,5~10I-TRIEN-ll-beta-OL~ 3-METHHW-4-METHrL-

3-HETHOXY-• - ESTRA~1~3~5110l-TRIEN~17~OL, 117-beta)-

-

43085-16-1

PHENYLCAR8AHATEr

101 1380 N1 1381 N1 1382 N1 RN 1383 N1 RN 1384 N1 RN

1385 N1 1386 N1 RN

- ESTRA-lr3,5f101-TRIEN-3-01, - ESTRA-Xr3~5~IOl-TRIEN-3-OL~

17-beta-lPILTHYLTHIO 117-b.ta-CTETRIHYDRO-2H-PYR~-Z-Y~Y)-

-- ESTRA-l~3r5~10l~TRIEN~17~ONE 53-45-2 ESTRA-4,9,ll-TRIEN-3-ONE, 17-alpha-ALLYL-17-HYOROXY-- 850-52-2 -- 20377-68-8 ESTRA-l,3,5~10l-TRIEN-17-ONE, 16-alpha-CHLORO- ESTRA-lv315f~OI-TRIEN-~~-ONEI DIHYDRO-3-HYDROXY-- 60966-54-3 E S T R A - ~ ~ ~ ~ ~ ( I O I - T R I E N - ~ ~1,3-DIHYOROXY-ONEI

1391 N1

- ESTRA-1~3~5~10l-TRIEN-17-ONE~ - ESTRA-1~3~51101-TRIEN-17-ONE~ - ESTRA-1~3~5(10l-TRIEN-l7-~Es - ESTRA-1~3~5~10l-TRIEN-17-ONE~ 1~3rl6-~lph~-TRIHYOROXY~,

1392 N1

- ESTR-5( 10 l-ENE-3e17-DIOL

1387 N1 1388 N1 1389 N1 1390 N1

3v4-DIHYDROXY-

Ir4-DIHYOROXT-* DIACETATE

4-HYDROXV-3-MElHDXY-

ESTRA-XvJ~5fIOl-TRIEN-I7-ONE. t-HYDRUXY-3-PIE(ETHYL1 9

1393 N1 1394 N1 1395 Nl RN

13%

N1

RN 1397 N1 1398 N1 1399 N1 1400 N1 1401 N1 1402 N1 1403 N1 1404 NI 1405 N1 1406 N1 1407 N1 1408 N1 RN 1409 N1 RN 1410 N1 1411 N1 1412 N1 RN

1413 N1 RN

1414 N1 RN

3-DIACETATE

- ESTR-5(10)-ENE-3,17-beta-DIOL

- E S T R - ~ - E N E - ~ , ~ ~ - ~ ~ ~DIPROPIONATE ~-OIOLI ESTR-4-ENE-S-beta,17-b~ta-DIOL. DIPROPIONATE -- 1986-53-4

--

ESTR-4-EN-17-bata-OL. 17-ALLYL432-60-0 LSTR-4-EN-3-ONE. 17-alpha-ALLVL-l7-HYOROXYESTR-4-EN-3-ONE, 17-alpha-ALLYL-17-beta-HYOROXYESTR-4-LN-I-ONE. 17-rl~ha-ALLYL-17-beTa-HmROXIESTR-4-EN-3-ONEv ~ ~ - ~ ~ P ~ ~ - B U T A D I Y N Y L - ~ ~ - ~ ~ ~ ~ - H Y O R O X Y -

- ESTR-5( 10 I-EN-3-ONE

-

I

17-alpha-BUTIDIYNYL-17-bcta-HYDROXY-

ESTR-4-EN-3-ONEs ~ ~ - ~ ~ P ~ ~ - ( ~ - B U T Y N Y L I - ~ ~ - ~ ~ ~ ~ - H Y D R O X Y ESTR-4-EN-J-QNEr ~ ~ - ~ ~ P ~ ~ - ( ~ - B U T E N Y L I - I ~ - H Y D R O X Y -

- ESTR-4-EN-3-ONEv 16-be~a~l7-DIHYDROXY-l6-M€THYL-

-

ESTR-4-EN-3-ONE. 16-b~~ar17-beT~-DINYOROXY-16-~ElHYL-

-

ESTR-4-EN-l-ONE* 16-bcta-ETNYL-17-beta-H~DROXY-

- ESTR-4-EN-I-ONE. 16-beta~l7-beta-DIHYDROXY-l6-PROPYL-, 17-ACETATE

-- ESTR-4-EN-3-ONEr 16-be~a-ETHYL-17-beta-HYOROXY-, ACETATE 33765-80-9 ESTR-4-EN-3-ONEt 17-beta-HYOROXY-’ -- 434-22-0 - ESTR-4-EN-I-ONEv 17-beta-HYDROXY-9 BROHOACETATE - ESTR-4-EN-3-ONE. 17-beta-HYDROXY-r 3-CYCLOPENTYLPROPIOTE (ester) 17-b~t~-HYOROXY-, DECANOATE -- ESTR-4-EN-3-WE, 360-70-3 - ESTR-4-EN-I-ONE. 17-beta-HYOROXT-7-alpha~17-OIHETNYL- 3704-09-4 -- ESTR-4-EN-3-ONEI 17-beta-HYDROXY-9 0-~2~4-DINITROPHENYLlOXIM 33514-81-7

1415

N1

1416

NI RN

1417 N 1

1416

Nl

1419 N1

1420

N1

1 4 2 1 N1 1422

N1

1423

N1 RN

1424

Nl RN

1425

N1 AN

1426

N1

RN 1427 N1 3428

N1 RN

1 4 2 9 MI

- ESTR-~-EN-~-ONEI 17-HYOROXY-l7-ETHYNYL-~ HEXINOATE. ESTR-S-EN-3-ONE, 17-beta-HYOROXY-r HYDROCIEDIIIIIATE -- 62-90-8 - ESlR-4-EN-3-ONEI 17-beta-HYDROXY-6-alpha-HETHYL-

ESTR-4-EN-S-ONE,

RN

RN 1432

N1

1433 N1 RN

--

ESTR-4-€N-I-ONE, 53224-67-2

- ESTR-4-ENE-3-ONEs -- ESTR-4-EN-3-ONE. 27984-91-4

--

1441 N1

RN

-

1435

N1

1436

N1

1437 N l RN 1438 N 1 RN 1439 N1 1440

N1 RN

1442

N1 RN

1443 N 1

RN

17-beta-HYDROXY-, 17-b4ta-HYDROXY-,

0-PHENYLOXIHE 3-PHENYLPROPIWTE

17-beta-HYOROXY-17-POPYL-

ESTR-IIlOl-EN-3-ONE~

~~-~~~P-HYDROXY-~~-PROPYL-

17-b@ta-HYDROXY-17-aIpha-ll-PROPYNYL)-

7359-79-7 ESTR-4-EN-I-ONE, 53290-01-0

- ESTR-4-EN-3-ONEl -- ESTRIOL 50-27-1

---

1434 N l

17-beta-HYDROXY-17-alphm-HETHYL-

- ESTR-I1 1 0 I-EN-3-ONE, 17-b~tir-HYOROXY-17-alph~-METMYL- ESTR-4-EN-3-ONE. 17-HYOROXY-7-nlpha-METnlL-, 17-ACETATE - ESTR-~-EN-~-ONEI l?-beta-HYDROXT-7-alph.-nE7HrL-r 17-ACETATE - ESTR-4-EN-3-ONE. 17-bet~-HYDROXY-17-alpha-(1-METHYULLYLl-- ESTR-4-EN-I-ONE. 17-beta-HYOROXY-l7-12-METHYLALLYL~2529-46-6 - ESTR-4-EN-S-ONE. 17-b@to-HYDROXY-r 0-1o-NITROPHENYL)OXInE - 64584-76-7 17-beta-HYDROXY-, 0-lp-NITROPHENYLtOXIME -- ESTR-4-EN-3-ONE. 33510-67-7

1430 N1 -.ESTR-4-EN-3-ONE9 1431 N l

OXIflE

17-bata-HYDROXY-,

O-(Z-PYRIDYLIOXIHE

17-beta-HETHOXY-17-HETHYL-

ESTRIOLI TRIACETATE ESTROGENS, extract f r o m plant RE0 CLOVER ESTROGENS, e x t r a c t f r o m p l a n t s RED CLOVER AN0 TIHOTNY ESTRONE 53-16-7 ESTRONE, HYDROGEN SULFATE. SOOIUM S A L l 438-67-5 ESTRONE, 0-METHYLOXIHE ETHANAHINEI ~-~~-~~I~-DIHYORO-~~~-DIMETHYL-~-HE~OXY~~~PHENYL-~N-~-BENZOPYR~-4-YLIPHENOXY I- N,N-OIETHYL-. HYOROCHLORIDE. trans84394-07-0 ETHANAHINE~ 2-( 4-1 3.4-DIHYDRO-2 Z-DIHETHY L-7-METHOXY~3~PNENYL-2H-l-BE~OPYRAN-4-YLtPHENOXYI- N,N-DIIIETHYL-, HYDROCHLORIDE, t r a n s 84394-08-1

,

- * 2 ~ l 4 ~ l 1 ~ 2 ~ O I P H E N Y L ~ l ~ B U TLATE EHTLlPHENOXYJ-N~N-OIRETYL-~ 1: - 1.5-NAPHTHALENEOISULFONATE ETHANAMINE, ( 2 I- 2-HYOROXY- 1.2 ~3-PROPANETRICARBOXY 54965-24-1

(

11

ETHANIIIINIIMr 2 ~ l 2 ~ l A C E T Y L O X Y ~ ~ 1 ~ 0 ~ ~ O ~ Y J ~ N ~ N ~ N ~ ~ I M € ~ Y 12:l) 55077-30-0

103 1444

N1

-

RN

-

ETHANAHINIUH, 2-f f BICYCLOf 2.2.1 lHEPT-5-EN-2-YLHYDRDXYPHENYLACETYLlOXY IWETHYL-, BROHIDE 58080-56-5

1-NvN.N-TR-

1445

N1 RN

1446

N1 RN

- ETHANE. AZO- 821-14-7 - ETHANE. AZO- 821-14-7

1447

N1 RN N1 RN

72-56-0 -- ETHANE. 2-BROHO-2-CHLORO-l~1,1-TRIFLWRO- 151-67-7

- ETHANE.

2~2-BIS~p-ETHYLPnENVLl-l~l-DICNLORO-

1449

N1 RN

ETHANE, -- 53-19-0

2-f~-CHLOROPHENYLl-2-~p-CHLOROPHENYLl-1~1-DICHLORO-

1450

N1 RN

1448

1451 N1 RN 1452

N1 RN

1453

Nl RN

1454

N1 RN

1455

N1 RN

14%

N1 RN

1457

N1

1458 N1 RN 1459 N l RN 1460

N1 RN

1461 N1 RN 1462

N1 RN

1463

N1 RN

1464

N1 RN

1465

Nl RN

1466

N1 RN

1467

N1

RN 1460

NI RN

1469

N1 RN

1470

N1

-

ETHANE, 2-~o-CHLOROPHENYLI-2-fp-CHLOROPHENYLl-l~1~l-TRICHLWO789- o 2 6

-

€THANE# 1,2-DIBROHO106-93-4 ETHANE * OICHLORO1300-21-6

-- ETHANE 1,l-OICHLORO75-34-3 -- ETHANE, 1.2-DICHLORO107-06-2 -- 629-14-1 ETHANE. i . 2 - o I E m o x r 1.2-DIHETHOXY-- ETHANE. 110-71-4 - ETHANEr 1,1-OIPHENYL-2-(o-FLUOROPHENYLl-- ETHANE, HEXACHLORO67-72-1 -- ETHANESULFONIC ACID ETHYL ESTER 1912-30-7 ETHANESULFONIC ACID. HETHYL ESTER -- 1912-28-3 t

--

ETHANE, TETRACHLORO25322-20-7

-- 60-23-1 ETHANETHIOLs 2-AHINO-- ETHANE, 1rl.l-TRICNLORO71-55-6 -- ETHANE, 1~1~1-TRICHLORO-2~2-~1Sfp-CHLOROPnENYLl50-29-3

---

ETHANE, 72-43-5

1~1~l-TRICHLMIO-2~2-BIS~p-HETHOXYPnENYLJ-

ETHANE. 1 ~ 1 ~ 1 - T R I C H L W O - 2 ~ 2 ~ 2 - T R I F L W R O ~ 354-58-5

- HYDROCHLORIOE 9rlO-ETHANOA~RACENE-9-~1OHl-METHYLAHINE~ N-HETHYL-,

-

10085-81-1

-- 9rlO-ETHANOANTHRACENE-9f10H)-PROPYLAMINE~ N-HETHYL-I 10347-81-6

-

HYDROCHLORIDE

7 r l 4 - E T H A N O D I B E N Z f ~ ~ b 1 A ~ H R A C E N E - 1 5 ~ 1 6 - D 1 C A R B 0 X Y LACIDS 1C 7,14-DIHYDRO9665-48-9

- 77~14-DIHETHYL~ 1 4 - E T H A N O D I B E N L f ~ ~ b ~ A N T H R A C E N E ~ l 5 ~ 1 6 - D I C ~ ~ACIDv DXYLIC

104 1471 N1 RN

1472 N1 RN 1473 N1 RN 1474

MI RN

1475 N l RN 1476

ETHANOLi Irl-BTSf4-CHLOROPHENYL)-r mixed With ~-CHLOROPHENTL-ZI~,~-TRTCNLOROPHENYLALO- SULFIDE 8072-20-6 ETHANOL, 2-BUTOXY111-76-2 ETHANOLB 2-CHLORO107-07-3 ETHANOLI 2-CHLORO-s METHANESULFOWTE 3570-58-9 ETHANOL,

2-~2-~4-~p-CHLWO-alph~-PHE"LrL~-l-PIPERAZINYL~ETHOXY~- 68-68-2

N1

1477 H1 RN 1478 N l RN

1479 N1 RN 1480 N1 RN

1482 N1 RN 1483 N1 RN

1464 N1 RN 1485 N1 RN 1484

----

N1 RN

1467 N l

RN 1488 N1 RN

1489 N1 1490 N1 RN 1491 N1 RN 1492 N1

RN 1493 N1 RN 1494 NX

RN

-

ETHANOL, 2-~2-~4-~p-CHLORO-aIpha-~ENYLBE~YL~-l-PIPERAZINYL~ETHOXY~-~ HONOHYDROCHLORIOE 1244-76-4

- Z-(p-CHLOROPHENYL EMANOLI 1-1-1 p-( 2-(DIETHYLAHIHO lETHaXY IPHENYL)-l-p-TOLYL- 78-41-1 -- ETHANOLs 2-CHLORO-, PHOSPHATE ( 3 : l ) 115-96-8 -- ETHANOLs 2-(CYCLOHEXYLAMINO)2842-38-8 -- ETHANOL, ~-(2-(4-~DIPHENYLMETYL)-l-PIPER~IMYL)ETHOXY~3733-63-9 -- ETHANOL. 2-ETHOXY110-80-5

---

--

-------

ETHANOL, 2-ETHOXY-, 111-15-9

ACETATE

ETHANOL, 2-( 2-ETHOXYETHOXY 111-90-0

)-

ETHANOLD 2 ~ 2 ' - ~ ~ ~ 2 - E T H O ~ - 5 - f f I T R O P H E N Y L ~ H E ~ Y L ~ I M 1 N O ~ 8 1 S ~ 58952-7a-6 ETHANOL, 2 D 2 '-( ( 3-( N-( 2-HYOROXYETHY L 1-N-OCTADECYLAHINO )PRoPYL)IMINO 101-t DIHYOROFW I O E 6818-37-7 ETHANOLr L-~ISOPROPYLAHIINOI109-56-8 ETHANOLs 2-( ISOPROPYLAMINO)-r NYDROCNLOt(I0E ETHANOL, 2-HETHOXY109-86-4 ETHAHOLI 2+ETHOXY-. ACETATE 110-49-6 ETHANOL, 2-(2-MF.TmnnETmmk 111-77-3 ETHANOL, TR1BRMK)1329-86-8 ETHANOL. Z,Z.i?-7RIFMO75-89-0

1496

1497

N1

-

RN

-,

N1

-

RN 1498

N1

RN

ETHANONEI 1-(7-12-HYOROXY-3-1 I 1-METHYLETHYLJAMINO)PROPOXY 1-2-BENZOFURANYLJ-HYDRDCHLORIOE 39543-79-8 6 r~ ~ - E T H E ~ P ~ I N A N - ~ - M E T H A N O L D 1 7 4 CYCLOPROPYLHETNYL I-alpha4 111-OIMETHYLETHYLl-4.5-EPOXI18r19-OIHYDRO-3-~YDROXY-6-METHOXY-dlph~-METHYL-~ HYDROCnLORIOE, 15-alpha,7-alphaISlJ53152-21-9

- 6,14-endo-ETHENOTETR*HYDR~IPAVINE 14521-96-1 - 7-alpha-11-HYOROXY-1-METHYLBUTYLJBISl2-EUTOXYETHYL) -- ETHER, 112-73-2 BIS(2-ETHOXYETHYLI -- ETHER, 112-36-7

1499

N1 RN

1500

N1 RN

1501

N1 RN

--

ETHER, EISl2-HETHOXYETHYLI 111-96-6

1502

N1 RN

--

ETHER, B I S I P E N T A B R ~ P H E H Y L I 1163-19-5

1503

N1 RN

1504

N1 RN

1505

N1 RN

1506

N1 RN

1507

N1 RN

1508

N1 RN

1509

N1 RN

1510

N1

1511

N1 RN

1512

N1 RN

1513

N1 RN

1514

N1

RN 1515

N1 RN

1516 N l RN

1517 N1 RN

--

s

ETHER, l-CHLORO-2r2.2-TRIFL~OETHYL OIFLUORWETHYL 26675-46-7

-- ETHERI 2-CHLORO-1~1.2-TRIFLWROETnlL 13838-16-9 2~2-DICHLOR0-1,l-DIFLWROETHYL -- ETHER, 76-38-0

--

OIFLUOROWETHYL HETHYL

ETHER, 2r4-DICHLOROPnENYL P-NITROPHENYL 1836-75-5

p-NITRORIENYL 2r4s5-TRICHLOROPHENYL -- ETHER, 22532-68-9 ETHERi 2,2~2-TRIFLVOROETHYL VINYL -- 406-90-6 -- ETHOOWMEEN 53127-17-6

-

ETHOO~BMEENDHYDROFLWRIOE

-- 64-17-5 ETHYL ALCOHOL

-

ETHYLAMINE, 2~l~~ll~~-EISI~~METHOXYPnENYLl~l~EUTENYLJPHENOXYL-~ HYOROCHLORIOE 42824-29-3 ETHYLAMINE, N ~ N - O I H E T H Y L - 2 - l p - l 1 ~ 2 - D I P H E N Y L - l - E U T E N Y L ~ ~ E ~ X Y l - ~ (€1-

- 13002-65-8 - ETHYLAMINEB N~N-DIMETHYL-2-lp-l1~2-OIPnENYL-l-EUTENYLl~E~XYl-~ (ZJ-

-

10540-29-1 €THY LAMINE t

2~2'-~l~2-OI~E~YLE~YLENEEIS~~~~ENYL~~OXY~lL)ISlN~N-OIMETHYL-~

- mcso15515-41-0

- L-.

€THYLANINE s ~ - ~ ~ - ~ O ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ O I M T ~ Y L - ~ ~ ~ E ~ Y R ( ~ ~ T H Y L I P ~ ~ Y ~ crythro15515-43-2

- ETHYLAMINEs NvI!-OIMTHYL-L-( HYDROCHLORIDE

-

341-69-5

(O-~ETHYL-.~~~.-R(ENYU)ENLILIOXII-D

106 1518 N 1

1519

N1

1520 N1 RN

1521 N 1 RN

1522 N1 RN

1523 N 1 RN

-

ETMYLAHINEi N.N-DIHETHYL-t-~p-~b~tm-NITRO-alph~-MENYLSTYRYLlMENOXYl-r CITRATE

- CITRATE, ETHYLAHINE, ~ ~ ~ ~ - ( 1 ~ 2 - D I r * I € N Y L ~ 1 - ~ T E N Y L l R l C N o X Y l ~ N ~ N - O L ~ E T H Y L - r (El-- ETHYLAPIINE, 2-Ip-(l~~-DI~ENYL~I-BUTEHYLlPHEHOXYl~N~HETHYL-i (2131750-48-8 -- ETHYLAHINE, 2-(DIPHENYLHE~OXYI-NiN-OI~ETHYL58-73-1 -- ETHYLNiINEi 2-(DIPHENYLHETHOXYI-NiN-DMETHYL-, NYOROCHLORIOE 147-24-0 - ETHYLAHINEv - 56-17-7

2~2'-OITHIOBIS-n OIHYDROCHLORIDE

1525

N1 RN

N-HETHYL-N-NITROSO-- ETHYLAHINEI 10595-95-6 -- 5370-01-4 ETHYLAPIINEi I-PIETHYL-~-I2~6-XYLYLOXVl-,

1526

Nl

-

1527

N1

1524 N1 RN

1528 N 1 1529 N1 1530

N1

1531

N1

1532 N1

ETHYLENE, 1-~p-~BENZYLOXYlPnENYLl-Z-BROtn-L-~m-FLWROPHENYLl-l-PHENYL-~

-

ETHYLENE, l-(p-(BENLYLOXY1PHENYL1-2-BR~-2-(o-FL~ROPHENYLl-l-PNENYL~~ 121-

- ETHYLENE, 1-tp-t BENZYLOXYIPHENYL I-2-BRM10-2-(p-FLUQROPHENYL)-I-PHENYL~~ ( 2 I- ETHYLENE, l - I p - ~ B E N Z Y L O X Y l P H E N Y L I ~ 2 - ~ ~ - F L M R O P H E N Y L l - l - r * I E ~ L -

-

ETHYLENE, l-BRat(O~l-~p-CHLOROPHENYLl-2~2~OIPHENYL-

N1

- ETHYLENE,

1534

N1

-

1535

N1

.. ETHYLENE, l-BROm)-l-(p-CHLOROPHENYL

N1 RN

1537

N1 RN

1538

Nl RN

1539 Nl 1540

N1

l-BROW-I-~p-CHLORO~ENYLI-2~l~~~ETMOXYPnENYLl~L~R1MYL-

ETHYLENE. ~ - ~ R Q ~ - ~ - ~ ~ ~ C H L O R O P H E N Y L I - ~ - ~ ~ - H E T H O X Y P H E N V L I - ~ - P H(E EN I- Y L - I )-Z-(p-METHOXYPHENYL I-2-PHENYL-r

-- 22393-62-0I-SROMO-l~Z-OIPHENYL-2-~~-ETHYLPHENYLl-r -l-BROMO-lrZ-OIPHENYL-2-(p-ETHYLPHENYLI~, ETHYLENEs

(El-

ETHYLENE. 22393-63-1

(21-

(21-

-- ETHVLENE, l~BROHO~2r2-DIPHENYL~l~~~~E~NYLPH€NYLI21141-45-7 - ETHYLENE, l - B R O ~ - 2 , 2 - O I P H E H Y L - l - ( ~ - F C ~ O P H E N Y C ~ - ETHYLENE, I ~ B R O P I O - Z ~ 2 - O I P H E N Y L ~ I - ( ~ - F L W R O ~ E N Y L l -

1542

N1

-

1543

N1

- ETHYLENE,

1544

N1

1541 N1

(El-

- ETHYLENE. 1-~p-~SENZYLOXYlPHENYLl-2-BRO~-2-~m-FLWROr*IENYLl-l-PnENYL-r (21- ETHYLENE. l - ( p - ( SENZYLOXY IPHENY

1533

1536

HYUROCNLMIIDE

-

ETHVLENE, l-BRQ1(0-2r2-OIPHENYL-l-(p-FLUOROPHENVL~ETHYLENE, l-BRO(W-~r~-OIPHENYL-l-~al~harelph~~~lpha-~IFL~O~-~LYLll-6ROMO-1-~m-FLUOROPHENYLI-2-~p-~ETMOXYPHENYLl-2-PHENYL-

ETHYLENE D l-BRO~O-l-~m-FLWROPHENYLl-2-~p-HETHOXYPHENYL)-L-PHENYL-~ (21-

107 1547

Nl

- ETHYLENE, l-BROm)-l-(p-FLMROPHENY

1548

N1

-

1549

N1

1550

N1 RN 1551 N1

L 1-2-( p-METHOXYPHENY L I-2-PHENYL-,

- ETHYLENE, -- ETHYLENE, 75-01-4

BRMIOTRIWENYLCHLORO-

1552

Nl

-

1553

Nl RN

-- ETHYLENE, CHLOROlRIS(p-METHOXYPHENYLI569-57-3

1554

N1

1555

N1

1556

N1 RN

1557 N 1 RN 1558

N1 RN

1559

N1 RN

1560

N1 RN

1561 N1

-

-

-

ETHYLENE, l-(p-CHLOROPHENYLl~2~2-0IW€NYLETHYLENE, 1-l~-CHLOROPHENYLl-2-~p-METHOXYPNENYLl-2-PNENYL-

ETNYLENEs 1-CYCLOHEXYL-2-~o-FLUOROPHENYLI-l-~p-METHOXYPHENYL)ETHYLENE, l-CYCLOHEXYL-2-(o-FLUOROPHENYLI-l-PHENYLETHYLENEOIAMINE, OIHYOROCHLORIOE 333-18-6 ETHYLENE, 1,l-OICHLORO75-35-4 ETHYLENE s 1m 1-OICHLORO-L IZ-BIS(p-CHLOR0PHENYL I72-55-9

-- ETHYLENE, 1~2-OIPHENYL-l-~p-ETHYLPHENYLl-2-NITRO-~ ( € 1 22393-64-2 -- 21141-47-9 ETHYLENEI 2~2-OIPHENYL~l-(p-ETHYLPHENYLl-l-NITRO~ - ETHYLEHE , 1,1-OIPHENYC-2-~n~-FCOPHENY L1-

1563

N1

-

1564

N1

- ETHYLENEi l ~ 2 - O I P H E N Y L - l - ~ p ~ M E T H O X Y W E N Y L l ~

1565

N1

-

1566

N1

- ETHYLENE.

1562

N1

1567

N1

1568

Nl RN

1569

N1 RN

1570

NI RN

-

ETHYLENEI ~ ~ ~ - O I P H E N Y L - ~ - ( O - F L U O R O P H E N Y L ~ ETHYLENE, l.l-DIPHENIL-2-(p-FLWROPHENYLI-

ETHYLENE, l-(m-FLWROPHENYLI-2-(p-METHOXYPHENYL)-2-PHENYL-

GLYCOL - ETHYLENE 107-21-1

- ETHYLENE CLYCOLt - 4672-49-5 - ETHYLENE OXIDE - 75-21-8

-- ETHYLENEI 127-18-4

1572

-

RN 1573

N1 RN

1574

N1 RN

1575

N1

1576

N1 RN

1577 N1 1578

N1

1579

N1

I-(o-FLUOROPHENYLI-~-(~-METHOXYPHENYLI~~-PHENYL-

ETHYLENE I 1-1 p-FLMROPHENY L )-2-(p-METHOXYPHENYL 1-2-PHENYL-

1571 N1 RN N1

OIMETHANEWLFONATE

TETRACHLORO-

ETHYLENE, TRICHLORO79-01-6

-- ETHYLENEi TRIPHENYL58-72-0 -- ETHYLENIMINE 151-56-4 -

E I-

ETHYLENer l-BRO~O-1-~p-FLWROPHENYLl-~-~p-~ETHOXYPHENYLl-Z-WENYL-~(Z1-

EUCAOINE EMESM-4-EN-12-01C 23522-05-6

ACID, 6-HYDROXY-I-OXO-,

EUPHORBIA LATNYRIS Llnn.,

crude extrect

- EVODIA RUTAECARPA, crude extract - EXOTOXIN, VIBRIO CHOLERAE

gamma-LACTONE

1581 N1 RN

--

FERASTRAL 73361-47-4

1582 N1 RN

--

FERRATE(Z-II 14402-89-2

1580 ~i FELSOL

1583 N1 RN 1584 N l

1585 N1

RN 1586

N1 RH

PENTACYANONITRWYL-r DISODIUI

-- FERRIC CHLORIDE 7701-08-0 - alpha-FETOPROTEIN, n e u t r a l i z e d -- 59536-65-1 FIREMASTER BP-6 -- 67774-32-7 FIRCMASTER FF-1

1587 N1

-

1588 N1 RN

-- f117-39-5 IAWN€t

FLAVANONEI 7- ( 14-0-(6-DEOXY-alpha- L-HANNOPYRANOSYL )-beta-O-SLUCOPIRLY L )OXY 1-4'-HETHOXY- 3',5,7-TRIOEOXY-r phorphorylated

3it',4'r5,7-PENTIHYDROXY-

1589 N1 RN

--

1590

-- FLW~!EN-~-AHINEI M-(Z-CHLOROETHYLI-N-ETHYL-r 13929-01-6

N1

RN 1591 N 1 RN 1592

N1 RN

1593 N1 RN 1594

NL RN

1595

N1

1596

Nl RN

1597 N1 1598 N1 RN 1599 N 1

1600 N I 1601 N1 RN

1602 N1 RN 1603

N1

--

FLAVONEI 6151-25-3

J~J'r4'~5~7-PEHTAHYOROXY-~ DIHYDRATE

FLUORESCEINi DISWIUn SALT 518-47-8 FLUORESCEINI 2'~4'r5'~7'-TETRABROr(O~4~7-DI~~O~r OIPOTASSIW SALT 6441-77-6

- OISOOIWl

FLUORESCEIN, ~ ' I ~ ' . ~ ' ~ ~ ' - T E T R A B R ~ - ~ , ~ ~ ~ I ~ - T E T R A C H L O R D - ~

- 18472-87-2SALT - FLUORESCEIN, 4r5,6r7-TETRACHLQRO-t' SALT

-

$4'r5' ,7'-TElRAIOM)-r OIsaDIW

63t-69-9

- FOIL ART ADHESIVE -- FOLSC ACID 59-30-3

---- N~~~4~AHINO~2~METHYL~5~PIRIHIDINYL~HETHYLl-N~I4~HYDROXY-1-HETHYL-FORHAHIOEt FOLIC

ACID,

nEmyL-

FOLLICLE-STIM)LATIN6 HORMONE 9002-68-0 FOLLICULAR FLUID, PORCINE

FOLLICULAR FLUID, PORCINE, r e t e n t a t e FORHALOEHYDE 50-00-0 FORHAHIDE 75-12-7

2 - I f TETRAHYDROFWFURYLlOITHIO~-1-BUTENYLl-t

1604 N1 RN 1605

N1 RN

1604

N1 RN

HYDROCHLORIDE

-- FORHAHIDE, --

HYDROCHLORIDE

N,N-OI-n-BUTYL-

741-65-9

FORHAHIDEI NiN-OIHETHYL68-12-2

FORHMIDEI M-f2~HYDAOXY-5~fl-HYOROXY-2-(I2-(4-EIETHOXYPHENYL)-l-1IETHYLETHYLJAH1NO)ETHYL) PHENILI-r (El-2-BUTEMLOIDATE (221) 1SALT)r DIHYDRATE 43229-80-7

1601 N l RN 1608

N1 RN

1609 N 1 RN 1610

N1 RN

1611 N 1 RN

1612

Nl RN

1613

N1

1614 N1 RN

1615

N1

RN 1616

Nl RN

1617 N 1 RN

1618

N1 RN

1619 N 1 RN 1620

N1 RN

1621 N1

-----

FORflAfl10E~ N-HETHYL123-39-7 FORPUIIIDE, N-I4-(5-NITRO-2-FURYL)-2-Tnl*ZOLrL)24554-26-5 FORMAMIDINE, N ' ~ ~ I ~ C N L W O ~ ~ ~ T O L Y L I - N ~ N - D I ~ T H ~ L 6164-984 FORMIYDROXAHIC ACID 4312-87-2

- FORMIC ACID, flETHYLHYDRALIDE 758-17-8 FREUND'S ADJUVAHT -- 9007-81-2 - FRUCTOSE, 6-CHLORO-6-DCOXY- 2-FUIALOENYDEI 5-NITRO-r 2-(2-HmROXYETnYLISEIIXC~ALO(L - 405-22-1 -- 2-FURALDWYDEs 5-NITRO-r SEHICARBAZONE 59-87-0 -- 53757-31-6 ~-FURANACRYLAHIDEI 5-NITRO-beta-PHENYL-- 2-FURA"lETHANElH1OL 98-02-2 -- 2f96-48-0 3HI-FURAWEv OIHYORO- 2-FMANPROPIOIIIC ACIDp TETRAHYDRO-~lpha-Il-N*PMTHYLHETHYLl-. 2 - f DIETHYLAMINOIETHYL ESTER, OXALATE 1 1 : 11 - 3200-06-4 - M-FURO( 392-9 I I 1 lBENZOPYRAN-7-ONE. 9-(2,3-OIHYOROXY-3-METHYLBUTOXY )-4-flETHOXY-, ( R 1- 482-25-7 - 5,893s. FUR013 ' ,4' :6,7 tNAPHTHO( 2,3-d I-l,3-DIOXOL-6(5aHl-ONE, 9-TETRANYORO-9-HYDROXY -53.4.5-TRI~ETHOXYPHENY L 1- 4354-76-1 - FWO( 3' 94' t6.7 t N A P H ~ O ~ 2 ~ 3 - d l - l r 3 - D I O X O L - 6 ~ 5 s H l - O N E ~ ~ , ~ ~ ~ ~ ~ ~ - T E T R A H Y D R O - ~ - H Y D R O X Y - ~ - TRIMETNOXYPMENYLI-. (~DQIS(5R-(5-alphs,5a-beto,8a-alphrr9-be~alI- 4375-07-9 - 6H-FUROlt' r3':4,5)OXA20LOf 3.2-a I-PYRIHIDJNE-2-flETNOL~ 2,3,3ot9a-TETRAHYDRO-3-HYDROXY6-IMINO-, MONOHYDROCHLORIDE. *

(

RN

1622

N1 RN

1623 N 1 RN

1624

N1 RN

1625

N1 RN

1626 N 1 AN 1627 N 1 RN

1628 N 1 RN 1629 N 1 1630

N1 RN

1631 N1 RN

-

sfereolromer 10212-25-6 4H-FUR01 312-c lPYRAN-2(6H I-WE, 4-HYDROXY149-29-1

- 0-6-OEOXY-rrlpha-L-flANNOPYRINOSYL-( beta-0-GALACTOPYRANOSIDE~ f3-bctsl-SOLANID-5-EN-3*YL 1-2 IO-lbats-O-GLUCOPYRAM)SYL-( 1-51 I-. HYOROCNLORIDE - 40816-40-8 -- GALACTOSEI 059-23-4 -- GALLIC ACID 149-91-7 -- GALLIC ACID. PROPYL ESTER 121-79-9 - GAR8HANIVARANA AUSHADAH -- GELATINS 9000-70-8 -- GENTAMICIN 1401-66-3

110 1632

N! RN

1633

N1 RN

1634 N1 RN

---

GENTISIC ACID 490-79-9 GERMANIUMs IL-CYSTEINE ITETRAHYDROXY51025-94-6

-- GERMANIW DIOXIDE 1310-53-8 - GEUtl ELATUn (Royle I Hook.

1635

Nl

1636

Nl

1637

N1 RN

--

1656

N1 RN

-- GLUCAGON, HONOHYOROCNLORIDE 28270-04-4

1659 N1 1640

N1 RN

1641 N1 RN 1642

N1 RN

1643 VI RN 1644 N1 RN

1645

N1 RN

1646 N1 RN 1647 N l RN 1646 N1 1649 N1 RN 1650

N1 RN

I 6 5 1 N1

-

f., wtract

GLEOITSCHIA HORRIOA nilklno. crude e x t r a c t GLUCACON 9007-92-5

GLOCITOL, 6-CHLORO-6-DEOXY-

1-DEOXY-1-IHETHYLAMINOI-, - 3~3'~~OXYBISl2rl-ETHANEDIYLOXYll~DXO~~rl-ETHANEDI~Ll 1BISl2~4r6-TRIIOOOBENZDATE1 -0-GLUCITOL~ 3,3'-1 ll,6-DIOXO-1 r6-NEXANEDIYL 1DIIMINOIBISI2e6.6TRIIODO-5-1 (~ETHYClt(INO1C~BONYL)BENLOATEI1 2 : l I ISALTI 54605-45-7 0-GLUCITOL, 1 ~ O E O X Y - l ~ l M E T H Y L A H I N O ~ - ~ IHINOI 72704-51-9

11:11 (SALT1

GLUCONIC ACID, I R O N I t t l SALT (2:11 299-29-6

-- GLUCOPYRANOSEi 2 ~ D E O X Y - 2 ~ ~ 3 ~ M E T H Y L ~ 3 ~ N I ~ O S0~EIOOl-~ 18883-66-4

-

SLUCOPYRANOSC, 1-THIO-n 1-~3-6UTENOHYDROXIMAlEl NO-( HIDROGENSULFATEI I MONOPOTASSIUM SALT. bcls-03952-98-5 GLUCOPYRANOSEt 1-THIO-,

I-( IS)-S-HYDROXY-4-PENTE~YDROXIMATE 1

HYDROGEN SULFATE D, beta-0- NO4 19237-18-4 -- alpha-0-GLUCOPYRMIOSIDE, 6-CHU)RO-6-DEOXY-betll-D-FRUCTQTURANOSrL50270-99-0

- alpha-0-GLUCOPYRANOSIOE,

- 6-CHLORO-6-DEOXY-beta-O-FRUCTOFURANOSYL-6-CHLM)O-6-DEOXY40984-16-5

--

~lph~-D-GLUCOPYRAW3SIDE, b.1~-D-FRUCTOFLRU(OSYL-6-CHLORO-6-DEOXY-

beta-D-GLUtOPYRAN031DE, lMETHYL-OE(N-AZOXY)METHYL14901-08-7

-- 0-GLUCOSE 50-99-7

-

0-GLUCOSE, 2-~3-ACETAMI00-2~4~6-TRIIODO-5-~N-METHYLICCTlnIDOlBENZAHIOD~-2-DE-

. - -.. 31112-62-6 - GLUCOSE, 6-CHLORO-6-DEOXYIIYY-

RN 1652

N1

1653 N 1 1654 N1 RN 1655 N1

- GLUCOSE, 6-DEOXY-6-FLWRO- SLUCOSE, 5-THIO-, D- 20408-97-3

- SLUTAMIC ACID, )AMINO IBENZOYL 1N-I p-I &!-t 2-AnINO-4-HmROXT-6-PTrRIOIHYLlETHYL - 3566-25-4 - SLUTAMIC ACID, N-lp-( l1-~2-MINO-4-HYDROXY-6~PTERIDINYLlETHYLlAMINOlBENZOYLJ~ L- 2179-16-0 (

RN

16%

N1 RN

111 1657

N1 RN

1658

1659

N1 RN

-

N l

- N-lp GLUTAMIC ACIO, -I I I2 ~ 4 - D I A M I ~ - 6 - P T E R I D I N Y LIMETHY L IHETHY LAMINO IBENZOYL I - ,

RN 1660

- GLUTAMIC ACID. - ( p - I I 12~4-OIAMINO-6-PTERIDINYLlMETHYL~AMINO~BENZOYL)-~ L- N54-62-6 - GLUTAMIC ACIDI N-lp-~ll2r4-DI*nINO-6-PTERIDINYL~MET~YL~HETHYLAMINOlBENZOYLI-~ L-

N1

-

59-05-2

OISOOIUM SALT, 7413-34-5

L-(+l-

- GLUTAMIC ACID, N-~p-lll2~4-OIAHINO-6-PTERIDINYLlMET~YL~METHYLAMINOlBENZOYL-~ SDDIUM S A L T

1661

N1 RN

1662 N1 RN 1663

N1

RN 1664

N1 RN

1665

N1 AN

1666

N1

1667 N 1 RN 1668

N1 RN

1669

N1

1670

N1 RN

1671 N 1 1672

N1 RN

1673 N1 RN

1674

N1

1675 N1 RN

1676

N1

1677

N1

1678

N1

-- GLUTAMIC A C I D t M O N O S O O I ~SALT, L - l + ) 142-47-2 -- 053678-77-6 - a l p h a - G L U T A H I N E i NlSup 21-(N-(N-ACETYLMIAIYLl-L-ALANYLl- GLUTAMINE, N,N'-l I S E L E N W I T H I D ) B I S ( 1-(f CARBOXYMETHYLICARBAMOYLIETHYLENEl l D I - L- 33944-90-0 -- GLUTARALDEHYOE 111-30-8 -- GLUTARAMIC ACID. 4-BENZAMIDO-N~N-DIPROPYL-~ DL6620-60-6 - GLUTARAMIC ACID, 2-11~3~OIOXO~2~ISOIM)OLYLl-~ OL-- QLUTARAMIC ACIDv 4-PHTHALII4IDO-. METHYL ESTER, DL19143-28-3 -- GLUTARAMIC ACID, 4-PHTHALYL69352-40-5 - GLUTARIC ACID, 2-PHTHALIMIOO-1 D L -- GLUTARIC ACID. 2-PHTHALIMIOO-, L340-90-9

.

-

GLUTARIC ANHYORIDEI

Z-PHTHALIMIDO-

-- GLUTARIMIDE, 2-lp-AMINOPHENYLI-2-ETHYL125-84-8 -- QLUTARIMIDE, Z - l p - ~ I N O P n E N Y L l - 2 - E ~ Y L - , W O S W A T E (1:lI 23734-aa-5 - SLUTARIHIDEI 2-l2-lDIETHYLAMINOlETHYL)-2-PHENYL-r HYOROCHLORIDE -- GLUTARIMIDE. 3-l2-l3~5-DItlETnYL-e-OXOCYCLOHEXYLI-2-HYDROXYETHYLI66-81-9 - SLUTARIMIDEB 3-11~3-DIOXO-2-METHYLIHDAN-2-YLI~ - GLUTARIMIOE. 3-lIr3-DIOXO-2-PHENYLIMAN-2-YLI- GLUTARIMIDE. S-~5~7-DIOXO-6-PHENYL-2~3~6~7-TETRAHYDRO-5H-CYCLOPENTA-~-OITHIIN-6-YLI-

1682 N1

-- GLUTARIMIOEI 2-ETHYL-2-PHENYL77-21-4 -- 42472-93-5 GLUTARIMIDEs N-METHYL-2-PHTHALIHIOO- GLUTARIMIDE, 2-11-OXD-2-ISOIhDOLINYLl~ - G L U T A R I M I D E ~ 2-SUCCINIHIOO-

1683 N1

- GLUTARONITRILE~2 - B R O t 4 0 - 2 - ( B R ~ E T H Y L I -

1679 N1 RN

1680 N1 RN 1681

1684

N1

N1 RN

--

QLYCEROL 56-81-5

112 1685 N1

- GLYCINAHIOEI

GLUTAMYL-O-PHENYLAL~YL-TRYPTOPHYL-SERYL-TIROSYL~O-ALANYL-LEUCYL~~ ARGINYL- PROLYL-

1686 N1 RN 1687 N l RN

I688 N I 1689

N1 RN

1690

N1

1691 N l 1692

N1

1693 N1

NnN-BISI Z - I B I S I CARBOXYIIETNYL)MINOIETHYL)- , CALCIW - GLYCINE TRTSODIUM SALT P

-

12111-24..9

N,N-BIS(CARBOXmETHYL)-, TRISOOIW SALT -- GLYCINE, 5064-31-3 - GLYCINE, N-CARBOXY-r ACETOMYL ESTER. N-BENZYL ESTER

--

GLYCINEi N-CARBOXY-. 1138-80-3

- GLYCINEa N-CARBOXY-I

-

N-BENZYL ESTER N-BENLYL ESTER, CYANOHETHYL ESTER

GLYCINEi N-CARBOXY-r N-BENZYL ESTER, Int-OIBROMDETHYL ESTER GLYCINE, N-CARBOXY-r N-BENLYL ESTER, ETHYL ESTER GLYCINEI N-CARBOXY-t N-BENZYL ESTER, coltlpd. w l t h ETHYL GLYCOLATE

16%

N1

- GLYCINE? N-CARBOXY-r

1695

N1

GLYCINE, N-CARBOXY-,

N-BENZYL PSTER, NETHOXYIIETHYL ESTER

1696

NI

GLYCINE, N-CARBOXY-,

N-BENZYL ESTER, canpd. uith METHYL GLYCOUTE

-

N-BENZYL ESTER, METHOXYETHYL ESTER

1698 N l RN

- SLYCINE, N-CARBOXY-I N-BENZYL ESTER, p-NITROPHENYL ESTER -- GLYCTNE, 212-DIPHENYL3060-50-2

1699 N1

- GLYCINE,

1697 N1

1700 N l RN 1701 NL 1702

Nl RN

1703 N l

1704 N1 RN 170s N l 1706 N1 1707

N1 RN

1708 N1 1709 N1

alpha-ESTER with O-threo-l+I-2~2-DICHLORO-N-lbeta-HYOROXY-~lpha-~HYOROXY~TH~L~p-(HETHYLSCILFONYL)PHENETHYL)ACETAIIIOE B NYOROCHLORIDE

-- GLYCINLB N-FORHYL-N-HYOROXY689-13-4 - 6LYCINEt N-FORNYL-N-HYOROXY-r SODLVn SALT -- GLYCINE, N-IN-L-gamma-GLUTAMYL-L-CYSTEINYLb 70-18-8

- N-l~~HYOROXYETHYL~~N~~5~ETHOXY~L~IIETnYL-6-OXO-1t6~OIHIDROPIRIOAZIGLYCIIlEs

--

N-4-YLIGLYCINE. N-~IPHENYLMETHOXY)CARBONYL)-i ETHENYL ESTER 64187-29-2

- GLYCINE,

--

N-IP-TOLYLWLFONYLJ-~ VINYL ESTER

OLYCINEI N-(TRIFLUOROACETYL)-, VINYL ESTER GLYCINONLTRILE, HONOHYORDCHLORIOE 6011-14-9

- GLYCOGEN. TYPE 1I:from OYSTER. heat doaggregated - GLYCOLIC A t 1 0 1 Of-2-THIENYL-r 6 9-TRIHETHYL-9-ALABICYCLOl3.3.1 MD”DH3-YL ESTER , HYOROCHLORIOE MONOHYDRATE - 32892-29-5 16

RN 1710

Nl

1711 N1 RN 1712 N1 RN

--

I

GLYCOLS, POLYETHYLENEm (ALKYLIII1NO)OIETHYLENE ETHER, )QMFATTY ACID ESTER OLYCOLS, POLYETHYLENES OIHETHYL ETHER 24991-55-7

- 6LYCOLSr POLYETHYLENE, ETHER

-

9002-93-1

1713 N1

- GLYCOPROTEINS,

1714

-- GLYCYRRHIZINIC AClO 1+05-a6-s

N1

RN

HONO~~-ll~lrJ~’,~TETRAHETHYWUIYLlPHLNTL~

frm CAMIIOA ALBICANS

113 1715

N1 RN

-

1716

N1

- GO-80

1717 N1 RN 1718 N1 RN

-

GLYOXYLONITRILEI PHENYL-r OXIME, 0~0-DIETHYLPHOSPHOROTHIOATE 14816-18-3

GOLD CHLORIDE 13453-07-1 GOLD, CHLORD(TRIETHYLPHOSPH1NEI15529-90-5

RN

~ l l ~ 2 - D I C A R B O X Y E T H Y L ) T H I O l -DISODIUM ~ SALT - GOLD, 12244-57-4

1720

N1 RN

-

1721

N1

- GOLD, ~l-THIO-beta-D-GLUCOPYRANOSATO-Sl~TRIETHYLPHDSPHINEl-, ~B~,~~~-TETRAACETATE

1719

N1

RN 1722 HI 1723 N1 1724 NI RN 1725 Nl RN 1726 N1 1727 N1 RN 1728 N1 RN I729 N1 1730 Nl RN 1731 N1 1732 N1 RN 1733 N1 1734 N1 RN 1735 N1 RN 1736

N1

GOLD, (1-THID-D-GLUCOPYRANOSATOJ12192-57-3

- 34031-32-8 - GONA-4rl2-DIEN-3-ONE, 17-METHYL-17-PROPYL- GONA-lr5~10I-DIEN-3-ONE~4~4,17-TRIHYDROXY-r 4,4-DIACETATE - GONADOTROPIN^ CHORIONIC - 9002-61-3

-- GONA-1,3,5~10J-TRIENE-3,16-alpha,17-beta-TRIOL~ 13-ETHYL19882-03-2 - GONA-1~3~5~10l-TRIEN-16-ONE~ 13-HYDROXY-3-METHDXY-- G4147-10-8 O N A - 1 ~ 3 ~ 5 ( 1 0 l - T R I E N - 1 7 - O N E ~3-HETHOXY-

13-a1pha-GONA-l~3~5~10l-TRIEN-17-ONE~ 3-METHOXY4248-04-8 GOSSYPILM H E R B A C E W L., extract GOSSYPOL ACETIC ACID 12542-36-8 GREWIA ASIATICA Linn., seed extract GUANIDINE, 1-AMINO-, HYDROGEN SULFATE 2834-84-6 GUANIDINE, 1-AZACYCLOOCT-2-YLMETHYLGUANIDINE, N-CYANO-N'-~ETHYL-N"-~2-~~~5-METHYL-1H-IMIDAZOL-4-YLlMETHYL~THIO-

IETHY L ) 51481-61-9

-- GUANIDINE, lv3-DIPHENYL102-06-7 - GUANIDINE, DODECYL-, ACETATE infxed wi th SODIUPI NITRITE

1737 N1 RN

-

1738 N1 RN

-- 60-02-6 GUANIOINE,

1739 N1 RN 1740

N1 RN

1741

N1

1742 N1 RN 1743 N1 RN

-

13:s)

GUANIOINE, ~2-~HEXAHYDRO-1(2Hl-AZOCINYLlETHYLl-~ HONOHYDROCHLORIDE 76487-49-5 (2-(HEXAHYDRO-l( 2H I-AZOCINYL)ETHILI-I SULFATE (2:l I

GUANIDINE, 1~L'-~~METHYLETHANEDIYLIDENElDINITRILDlBIS-~ DIHYDROCHLORIDE~DIHYDRATE 31959-87-2 GUANIDINE, 1,2,3-TRIAHINO-, HONONITRATE 4000-16-2 5'-GUANILIC ACID, DISODILM SALT, nixed wi th DISODIWI 5'-INOSINATE GUANINE 73-40-5 GUANINE-3-N-OXIDE 18905-29-8

114 1744

N1 RN

1745 N1 1746

N1

1747 N1 RN 1748

N1 RN

1749

N1

---

HAIR DYE FORI'TJLATIW 7402 HELIOTRINE 303-33-3 HELIOTRINEi ~I~-DIDERYORO23107-11-1

- 2,5-HEPTADIENOIC ACID, 7-1 2-14-13-CHLOROPHENOXY I-3-NYDROXY-l-EUTEHYL

-

RN

-

1751 N1

GUANOSINE 118-00-3

- 6V-525

Nl

RN 1750

--

1-3150IHYDROXYCYCLOPENTYL~-, I-. 11R-I I - a l p h a 1 2E,IZ I I & b e t a ( 1E ,3R* 1 .I-mlpha.5-alpha) 73275-754 2,5-HEPTAOIENOJC ACID, 7-1 2-16-1 3-CHLOROPHENOXY I-3-HYDROXY-l-BUTENYL)-Ir5DIHYDROXlCYCL0PEHTYL)-9 HLTHYL ESTER, ( 1 R - I l - a l p h a l 2 E ~ 5 E l ~ 2 - b e t a1E13R*1 l ,3-alpha,5-alphel)68399-12-2

- 2r5-HEPTADIENOIC ACIDS 7-1 2-144 3-CHLOROPHENOXY 1-3-HYDRDXY-l-BUTENYLI-3,5DIHYORO~YCYCLOPENTYLI-I METHYL ESTER.

1752

1753

1754

RN Nl

11R-I 1 - a l p h a 1 ZE,521,2-beTel lE,)R+) ,3-rlpha.5-alphol - 62524-99-6 - 2~5-HEPTAOIENOIC ACID, 7-( 2-1 4-(4-CHLOROPHENOXY I-3-HYDROXY-l-BUTENYL1-3~S-

RN

-

N1

- 2~5-HEPTADIENOIC ACID, 7-12-14~14~CHLORDPHENOXY~~S-HYDROXY-l-~UTENYL~-3~S-

RN

-

Nl

-

1755 N 1

-

Nl

RN 1757 N 1

RN

1758 N 1

OIHYDROYYCYCLOPENTYL I- I HETHY L ESTER, Il R - I l - a l p h a l 2 E , 5 E I , 2 - b a t a l lE13R* 1 , 3 - c I p h a ~ 5 - a l p h a l 162525-22-8

DIHYOROXYCYCLOPENTYLI-@ HETHYL ESTER. (1R-I l - m l ~ h a l Z E , 5 Z I .L-betallE,SR* I . 3 - a I p h a , 5 s l p h 1 1 -

62525-22-8

- 3,5-HEPTAOIENOIC ACID, 7-1 2-14-( 3-CHLOROPHENOXY 1-3-HYDROXY-l-BUTENYL)-3e5-

RN

1756

I-

DIHYDROX~CYCLOPENTYL)-. HETHYL ESTER, ( 1 R - I 1 - a l p h a 1 3E,5EI ,Z-betaIlE,3R* ),3-alpha.,5-alpha 64612-79-9

I I-

3~5-HEPTAOIENOIC ACID. 7-l2-l4-l3~CHLOROPHENOXY~-3-HYOROXY-l-~UTENYLl-3~5DIHYOROXYCYCLOPEMYL 1 - 1 HETHYL ESTER, 11R-11-alpha1 31SZ112-beTol 1E93R*) , 3 - a l p h a 1 5 - a l p h a ) 1-

- 3.5-HEPTADIENOIC ACID, 7-( 2 - 1 4 4 3-CHLOROPHENOXY ~-3-HYDROXY-l-BUTENL)-315-

DIliYOROXYCYCLOPENTYLl-B METHYL ESTER, I l R - I l - a l p h a ( 3E,521,2-beleI 1E13R+l~3-alphp.5-.lphal 64612-64-2

I-

395-HEPTADIENOIC ACID, 7- I 2- 14-1 3-CHLOROPHENOXY I-3-HYDROXY-1-WTENY L I-3,5OIHYDROXYCYCLOPENTYLI-B flETHYC ESTER, I l R - ( l - d l p h a l 32,521 ,2-aetirllE,3R* I ,3-alpha,5-alphal~64775-52-6

- 3.5-HEPTADIENOIC ACID, 7-1 2 - 1 4 4 4-CHLOROPHENOXY )-3-HYDROXY-l-BUTENYLl-3,5OIHYDROXYCYCLOPENTYL)-~ HETHYL ESTER, 11R-I 1 - a l p h a 1 3,521 , 2 - b t t a l 1E,3R*),3-.lphs15-alph.)

I-

1759

N1

-

1760

N1

-

RN

l1R-ll-alpha~2E,5ZI,2-batalIE~3R*l~3-~lpha~5-alphai~- 62524-94-1

215-HEPTAOIENOIC ACID, ~-~~~~-DIHYDROXY-~-~~-HYDRDXY-~-PHENOXY~~~~~ENYL~CYCLOPENTYLI~I METHYL ESTER t (1R-I 1 - a l p h a 1 2E.SE I .2-befaI lEs3R* 1 r3-alpha15-alphr) I2r5-HEPTADIENOIC ACTO, 7-1 3rS-DIHYOROXY-2-( 3-HYOROXY-4-PHENaXY-1-BUTENYL ICYCCOPENTYLb * HETHYL ESTER,

115 1761 N1

- 3,5+EPTIDIENOIC ACID. 7-l3~5-OIHYDROXY-2-l3~HYDROXY-4~PHENOXY-l~BUTENYLlCYCLOPEHTYLl~~ METHYL ESTER, l1R-ll-alpha~3~5ZI~2-beta~1E~SR*l~3-alphar5-alphalI-

RN 1762 N1

RN

1763 Hl

RN

1764 N1

- 73364-95-1 - 3r5-HEPTMIENOIC

ACIOD 7-1 3 ~ 5 - O I H m R O X Y - 2 - l 3 - H Y D R O X Y - 4 - P H E N O X Y - l - ~ E ~ L ) C Y C L O P E ~ L ~ - ~ METHYL ESTER, 11R-I 1-alpha1 3E.5E I ~2-betallEsSR* I ~3-alpha.5-aIphal164812-77-7

- 3.5-HEPTADIENOIC ACID. 7-1 395-DIHYDROXY-2-13-HYDROXY-4-MENOXI-l-BIITENTLICYCLOPEHTYL

I-

I

METHYL ESTER. 11R-1 1-alpha13E,5Ll .Z-bctal 1€*3R*),3-alpha,S-alpha 1 I64812-67-5

- 3t5-HEPTADIENOIC ACID, 7-13~5-DIHYDROXY-2-~3-HYDROXY-4-PHENOXY-l-~ENYLlCYCLOPEHTYL~-~ METHYL ESTER, 11R-I 1-alpha1 3 L 5 E 1,2-betaI 1E93R*l,3-alphar5-slphaI 1-

1765 N1

- 215-HEPTADIENOIC ACIDI

7-l3~5-OIHYDROXY-2-l3-HYOROXY-4-l3-~TRIFLMROMETnYLlPHENOXY1-1~

RN

1766 N1

BUTENYLICYCLOPENTYLI-s HETHYL ESTER, 11R-I l-alphaIZE,52I .Z-betir( 1E93R*1.3-alpha~5-alphaII62559-74-4

- 3~5-HEPTADIENOIC ACID, 7-1 3~5-OIHYDROXY-2-l3-HYDROXY-4-l3-llRIFLUOROMETHYLlPHENOXY

I-1-

BLUENYLICVCLOPENTYLI-. METHYL ESTER. (1R-I 1-alpha1 3,521,2-beta(1E13R*I ,3-alphat5-alpha1 ) 1767 N1 RN 1768 N1 1769 Nl RN 1770 N1 RN

1771 N1 RN

1772 N1 RN

1773 N1 RN

1774 N1 RN

1775 N1 RN

1776 Nl

- 3-HEPTANOL. 6 - l O I M E T H Y L A M I N O l ~ 4 r 4 ~ D I P H E N Y LACETATE ~~ Ieyter 1, (35,65)-1-1- 1477-40-3 - HYOROCHLORIDEI ~-HEPTANOLI6-lDI~ETHYLAMINO)-4~4-DIPHENIL-r ACETATE Icsterl. (35,6Sl-I-l-

3-HEPTANONEr 6-lDI~ETHYLIHINOI-4,4-~IPHENYL76-99-3

3-HEPTANONE, 6-IDInETHYUnINOI-4,4-DIPHENYL-r I+ I -- 247-88-1 -- 3-HEPTANONEr 6-lDIMETnYL*nINOI-4tQ-DIPHENYL-, L125-58-6 - ~-HEPTANONEI6 - I D I M E T n Y L ~ I N O l - 4 ~ 4 - O I P H E N Y L - ~ I S ) - 5653-80-5 -- 3-HEPTANONEr 5-DIF(ETHYLAMINO-4~4-OIPHENYL~~HYDROCHLORIDE 63834-33-3 -- 3-HEPTANONEi 6-lDIME7HYLAMINOI-4,4-DIPHENYL-~ HYDROCHLORIOEv ( * - I 125-56-4 -- 3-HEPTANONE, 6-(DIMETHYUMINOI-4,4-DIPHENYL-, HYDROCHLORIDE 1095-90-5

- 5-HEPTENAHIDEs 11R-11-alpha( - N-(METHYLSULFONYL)-, 60325-46-4

7-13-HYDROXY-2-~3-HYDROXY-4-PHEMXY-l-BUTENYLl-5-OXOCYCLOPEHTYL~2 ) ,t-betaIlE,3R*).3-slpha) 1-

RN

1777 N1

- 5-HEPTENOIC ACIO, 7-~2-O-l2-BENZOFW)ANYLI-3-HYDROXY-1-PROPENYLI-3~5-DIHYDROXYCYCLO~ PENTYL)-v METHYL ESTER.

RN

1778

N1

I lR-I l-alpha(2),Z-betaI1E ,3S*I ,S-alpha,5-alphaIi- 73285-87-7

- 5-HEPTEHOIC ACID,

7-l2-lS-BENZOlbITHIEN-2-YL-3-HYDROXY-l-~OPENYLl-3~5~

RN

-

DIHYDROXYCYCLOPEN1YL)-r BETHYL ESTER, ( 1R-( I-alpha12),2-betal 1E83S*)-3-alphat5-alphelImas-86-6

116 1779 N1

RN 1780 N1 RN 1781 N1

RN 1782

NI

RN

1783 N 1

RN

1784 N l

RN 1785

N1

RN 1786

-

5-HEPTENOIC ACID, ITFITRAH7-13,5-8IS( ITETRAHY~O-2H-PYR*N-2-YLlOXY )-?.-14-PHENOXY-S-I YORO2H-PYRAN-2-YL I O U I-1-BVIENYL ICYCLOPENTYL )-2-I PHENY LSELENOI-, METHYL ESTER 62524-93-0 5-HEPTEHOIC ACID, 7-1 2-1 4-1 3-CttLOROPHENoxY ~ - 3 - H T O R O X Y - l ~ ~ E N Y L ) - 3 ~ 5 - D I H Y O R W C Y C L O PENTYLI-, (1-rlphm-lL),2-beta-( lE,3R*) .3-olpha,S-alphm)It- 140665-92-7 5-HEPTEHOIC ACID, 7-1 2-1 4-t 3-CNLOROPHENOXY )-3-HYDROXY-l-WTENYL)-).5-DIHYDROXICrCLOPENTYLI-I METHYL ESTER, 1I l R - I 1-mlphml Zl,2-batallE~3R*l~3-alpha~5-rlpha~ 56687-85-5

- 5-HEPTENOIC ACIOs 7-I2-14-(3-CHLOROPHENOXY

-

1-3-1 lTETRAH1DRO-2H-PYRAN-2-YL)OXY 1-1-WENVLI3r5-BISllTETRAHYDRO-2H-PYRAN-2-YLlOXYlCYCLOP~~TL~-2-lPHENYlSELEN01-t METHYL ESTER 62559-75-5 5-HEPTENOIC ACIO. 7-1 2-1 2-1 2-1 4-CHLOROPHENYL 1-1~3-DIOXOUN-2-YL )ETHENYLI-3,5DIHYDROXYCYCLOPENTYLI-r HETHYL ESTER, l 1 R - I l-mlphm( 2 I , t - b e t m I E I ,3-alpha,5-alpha) 166176-10-1 5-HEPTENOIC ACID, 7- I2-( 5- ( 3-CHLOROPHENYL 1-3-HYDROXI-5-Om)-l-PENTENY L 1-3 6OIHYOROXYCYCLOPENTYLI-r METHYL ESTER, l1R-I 1-alpha12) . 2 - b ~ t a llE,SS* I ~ S - a l p h r , l - a l p h a ) I6242V-47-4 5-HEPTENOIC ACID, 7-1 2-1 5-1 4-CHLOROPHENYL 1-3-HYORW-5-Om)-l-PEHENYL DIHYOROXYCYCLOPENTYL1-. METHYL ESTER, l 1 R - I 1-mlphml 2 ).2-betm( 1EB3S@)r3-mlpha,5-alphml 162429-46-3

H1

- 5-HEPTENOIC ACID, 7-1 2-1 5-1 3-CHLOROPHENY LI-S-HVDROXY-l-PEHTEH~4-~L1-3.6-

RN

- 11R-I

1787 N 1

OIHYDROXYtYCLOPENTYLI-1 METHYL ESTER, 1-mlphal 21 ,2-betallEt3S*1,3-alpha,5-alpha) )73285-84-4

- 5-HEPTENOIC ACIOI 7-( 2-( 5~14-CHLOROPHENYL)~3-HYDROXY-1-PENTEN-4-YNYL)-lr5~ DIHYOROXYCYCLOPENTYLI-,

RN 1788 N 1

RN 1789

b-3~5-

Nl

RN

METHYL ESTER, I ,3-mlpha,5-alpha)

1 R - l l - a l p h a l Z l r 2 - b e t e l lEI3S* - l73285-85-5

-

1-

5-HEPTENOIC ACIOB 7-1 2-1 4-1 1-CYCLOHEXEN-1-YLTHIO 1-3-HYOROXY-l-BUTLNYL DIHYOROXYCYCLOPENTYLI-r METHYL ESTER. l 1 R - I 1-mlphml 2 ) $2-be to1 1E13S*)r3-alphr,5-alph~l 173285-92-4

1-3.5-

- 5-HEPTENOIC ACIDI 7-1 3 5-OIHVDROXY-2-12-12-114-F -

LUOROPHENOXY IrlETHYL 1-1 I3 - D I W L A N - 2 - Y L I ETHENYL)CYCLOPENlYLI-* METHYL ESTER. 11R-( l - a l p h a l L l ~ Z - b e t a l E l,3-alphmr5-alphal166i76-ai-z

1790 N 1

- 5-HEPTEHOIC CIDI 7-l3~5-DIHYOROXY-2-l3-HYDROXY-1-OECENYLlCYCLOPENTYLl-~

1791 N 1

-

RN

-

1792

N1

-

I 1R-I 1 - e l p h m l 21, 2 - b ~ t a LE l ,3R* 1,3-alpha ,J-alph. I )5-HEPTENOIC ACID, 7-1 3~5-OlH10ROXY-2-13-HYDROXY -1-DECENY L ICYCLOPENTYLI I 1R-( l-nl~hmlL1~2-betal1E~3S* I ,3-alah.5-alohl I36950-85-3 5-HEPTENOIC ACIDI 7-1 3.5-OIHVDROXY-L-I 8 METHYL ESTER

I

3-HYDROXY-31 S )-METHY L-l-OCTENYLICYCLOPENL>--

117 1793 N1

RN 1794 N1 RN 1795 N1

-

5-HEPTENOIC ACID, 7-l3~5-DIHYDRDXY-2-l3-HYDRDXY-3-METHYL-5-PHENTL-l-PEMEN-4-YNYL~

CYCLOPENTYLI-$ METHYL ESTER, l1R-I 1-olphaIZ1 ,Z-beta( 1E ,3S* I ,3-alpha.S-alpha I l62475-37-0 5-HEPTENOIC ACID. 7-l3~5-DIHYDRDXY-2-I3-HYDRDXY-1-OtTENYLlCYCLOPE~YLl-~

5-HEPTENDIC ACID, 7-l3~5-DIHYDRDXY-2-l3-HYDROXY-1-~TENYLlCYCLDPEHTYLl~r

1796 N1

-

5-HEPTENOIC ACIDI

RN

-

stereoiroiner 4510-16-1

1797 N1

dl-

23518-25-4 1-

7-l3~5-DIHYDRDXY-2-~3-HYDRDXY-1-OtTENYLlCYCLOPENTYLl~~

ACID, - 5-HEPTENOIC 7-l3~S-DIHYDRDXY-2-l3-HYDRDXY-1-OCTENYL)tYCLDPENTYLl-~ HETHOXAMINE SALT

1798 N1 RN 1799

N1

5-HEPTENDIC ACID, 7~l3~5-DIHYDROXY~2~l3~HYDRDXYOCTYLlCYCLOPENTYLl-- 27376-74-5 ACID, - 5-HEPTENOIC 7-l3~5-DIHYOROXY-2-l3-HYDROXY-5-OXD-5-PHENYL-l-PENTENYLlCYCLOPENTYLt-v METHYL ESTER,

RN 1800 N1

( 1 R - ( 1-alphat Zl .E-beta( 1E ,3S* -3-alpha,5-alpha) 1- 62429-44-1

-

3-HEPTENOIC ACID, 7-I3~5-DIHYDROXY-2-~J-HYDROXY-4-PHENDXY-l-B~ENYL~CYCLOPE~YLl-~ METHYL ESTER, l1R-11-alpha(€ or

Z I ,Z-betaI 1E,3R*l ,3-alpha,5-alphall1801 N1 RN 1802

N1 RN

1803 N1

RN 1804 N1

RN 1805

N1

1806

N1

RN

RN 1807 N1 RN 1808 N1

- 5-HEPTENOIC ACID, 7-l3~5-OIHYDROXY-2-l3-HYDRDXY-4-PHENOXY-l-BUTENYLlCYCLDPEHTYLl-~ ESTER, I1R-ll-alphalE1~2-betallE~3R~l~3-alph~,5-alpha~l73275-73-7 - METHYL ACID, - 5-HEPTENOIC 7-13~5-DIHYDROXY-2-13-HYDROXY-4-PHENDXY-l-BUTENYLlCYCLOPEHTYLl-~ -

METHYL ESTER, 11R-I 1-alpha1 21 ,Z-betal 1E , 3 R U l ,3-alpha,5-alphall54348-08-2 2-HEPTENOIC ACID, 7-1 3,5-DIHYDROXY-2-l3-HYDRDXY-4-l3-lTRIFLUOROnEYHYLlPHENOXY TENY Ll CYCLDPENTYLI-, I lR-ll-alpha( E I,Z-beta( 1E,3S*l,3-alpha,5-~lphall73307-37-6

2-HEPTENOIC ACID, - 7-1 3.5-DIHYDROXY-2-( 3-HYDROXY-4-13-1 TRIFLUOR0METHYL)PHENOXY I-1-BU-

-

TENYLI CYCLOPENTYLI-9 I 1 R - l 1-alphal2).t-betaIlE.3S* I ,3-alph~~5-alphall73307-38-7 5-HEPTENOIC ACIDI 7-1 3~5-DIHYOROXY-2-l3-HYDROXY-4-13-( TRIFLMRDMETHY LIPHENOXI I-1-BUTENYLI CYCLOPENTYLI-, METHYL ESTER, 11R-I 1-alpha12 I ,Z-betaI 1E ,3R*l,3-alpha,S-alpha I 173275-76-0

ACID, - 5-HEPTENOIC 7- I 3,5-D IHYDROXY-2 -

- 1 3-HYDRDXY-4- I 3- I TR IF LUDROMETHY L 1PHENOXY 1-1-BUTENYL) CYCLOPENTYLI-, MONOSODIUM SALTS I 1-alpha-I21 ,2-beta-l l E , 3 R * ).3-alpha.5-alpha 1-1 t - I 55028-71-2

ACID, - 5-HEPTENDIC 7-O~5-DIHYDROXY-2~l2~l2~lPHENOXYHETHYLl-l~3-DIDXDLAN-2-YLlETHENYLI CYCLOPENTYLI-, ~1R-ll-alphal2l,2-betal EI,J-alpha,5-alpha 11- 59619-81-7 - 5-HEPTENOIC ACID, 7-l3~5-DIHYDROXY-2-l2~l2-lPHENOXYMETnYLl-1~3-DIDXOLAN-2-YLlETnENYL) CYCLOPENTYLI-, BUTYL ESTER.

RN

I-1-BU-

l1R-ll-alphalZ~,2-betalEl~3-alph~,S-alph~ll- 66176-07-6

118 1809 N1

1810

- 7-l3~5-DIHrOROXY-2-l2-~2-1PHENOXYMETHYLl~l~3-DIOXOLAN-2-YLlETHENY5-HEPTENOIC ACID,

L I CYCLOPENTYLI-, METHYL ESTER, Il 1 R - l l-alpha~Ll.2-betaIEl~3-alpha.5-alph~l 59619-78-2

RN

-

Nl

-

5-HEPTENOIC ACIOv

-

CYCLOPENTYLJ-, METHYL ESTER, l 1 R - I 1 - a l p h a ( 21 12-beta,3-alpha,S-.lpha 66176-08-7

RN 1811 N 1

RN 1812 N1

RN

-

-

7-13~5-DIHYDROXY-2~l2~l2~~PHENOXYMETHYLl~1~3~DIDXOUN-2~YLlEMYLl

5-HEPTENDIC ACID, 7-l3r5-DIHYDROXY-2-l2-l2-~2-PHENYLE~YL~-l~1-DIOXDLAM-O-YLlETHENYL ) CYCLOPENTYLI-t METHYL ESTER, l l R - ( l - ~ l p h a l L l ~ 2 - b e t eE( ) r 3 - a l p h a , 5 - a l p h a l I66176-09-8 5-HEPTENOIC ACIDS 7-( 3 ,5-DIHYDROXY-2-( 2-1 2-( I3-TRIFLUOROMETHYLPHENOXY IMETHYL 1-1 3-DIOXOLAN- 2-YLlETHENYL)CYCLOPENTILl-. HETHYL ESTER. 11R-I l - d p h a t Z l , 2 - b ~ t a l E I ,3-alphs15-alpha b 166176-12-3

,

1814 N 1

-

1815 N1

- 5-HEPTENOIC

1816

N1

-

1817 N 1

-

1813 N 1

11-

5-HEPTENOIC ACID, ICYCLOPENTYL 17-1 5 t 5-OIMETHY L-3~HYOROXY-2-13~HYDROXY~1-DCTENYL 5-HEPTENOIC ACID, 7-l2-l6r7-DIMETHYL-3-HYDROXY-l-~NENYL)-5-HYDRDXY-5-OXMYCLOPEMY-

Ll-

RN 1818 N 1

1819 N l 1820

Nl RN

1821 N 1

1822

N1 RN

1823

N1

1824

N1 RN

1825

N1

RN 1826

Nl RN

1827

N1 RN

1828

N1 RN

-

-

ACID. 7-12-(4,4-DIHEMYL-3-HYDROXY-l-OCTENYLb-3-HIDROXY-5-ME~YLENECYCLDPENTYL 15-HEPTLNOIC ACID, 7-1 2-1 4 ,4-DIMETHY L-3-HYOROXY-l-OCTENY L 1-3-HYDRDXY-5-OXMYCLDPEMY L1-, HETHYL ESTER

-

5-HEPTENOIC ACID, 7-1 2-14-1 4-FLUOROPHENOXY 1-3-HYDROXY~l~BUTENILI-).5-DIHYDROXYCYCLDPENTYL I - ( 1 - a l p h a - I Z I ~ 2 - b e t a - I1E13S* I ,3-alpha,5-alpha 140666-04-4 5-HEPTENOIC ACID. 7-( 3-HYDRDXY-2-1 3-HYDROXY-3-HETHYL-1-DCTENYLl~5-OXMYCLDPEMYLlMETHYL ESTER

5

5-HEPTENOIC ACID, 7 - ~ 3 - H Y D R O X Y ~ 2 ~ ~ 3 ~ H Y D R O X Y ~ l ~ O C T E ~ L ~ ~ 5 ~ O X O C Y1CLOPEMYL~~~ 5-HEPTENOIC ACID, 7-~3-HVDROXY-2-l3-HYDRDXY~1-OCTENYL~-5-OXOCYCLDPEMYLl-~ METHYL ESTER, stereoisomer 31753-17-0 5-HEPTENOIC ACID, 7-1 3-tlYORDXY-2-( 3-NYDRDXY-1-OCTENY L I-5-DXOCYCLOPENTY LlMETHYLHESPERIDIN COMPLEX

P

- 5-HEPTENOIC ACID, 7-~5-HYORDXY-2-~3-HYOROXY-5~PHENYL~l-DCTENYLl~3~OXOCYCLDPEMYL~- 85280-91-7 - HERBAL “ S L I ~ I N GTABLETS“ -- 1-HEXADECANMINE 143-27-1 -- HEXADECYLAHINE, HYORDFLMRIDE 3151-59-5 -- 2r5-HEXADIEEfOIC ACID, 3-METHOXI-5-HETHYL-4-0~90-65-5 -- HEXWE 110-54-3

--

lr6-HEXANEDIAHINE 124-09-4

119 1829

N1 RN

1830

N1 RN

1851

N1 RN

-- ~33447-91-5 * ~ - H E X A N E O I O L I DIHETHANESULFONATEr I+-)-- ~33447-90-4 ~~-HEXANEDIOL DIHETHANESULFONATEr I neso-- 2.5-HEXANEDIONE 110-13-4

1832

N1

-

18x3 NI RN 1834 N 1 RN 1835

Nl RN

1836

N1

1837 N1

1838 N l 1839

N1

1840

N1

--

HEXANEI 3-lp-HETHOXIBENZYL1-4-lp-NETnOXYPHENYL~HEXANOIC 60-32-2

ACID.

~-AINO-

-- HEXANOIC ACID, 6-1(2-(1-DCTYNYL)CYCLOPENTYL)OXY)-, 27166-04-7 - 2-HEXANONE - 591-78-6 - 2-HEXANONE. 3,4-BIS(p-HYOROXYPHENYL)- 3-HEXENE. 3-lp-ETHOXY8ENZYL)-4-~p-ETHOXYPHENYL)- 2-HEXENE, 4-(p-METHOXYBENZYL)-3-(p-nETHOXYPH€NYL)- 3-HEXENE. 3-(p-METHOXYBENZYL)-4-(p-M€THOXYPHENYL)-

113-trans)-

--

HIBISCUS ROSA-SINENSIS,

-

HIPPOPHAE SALICIFOLIA 0. Don, bark e x t r a c t

1855 N 1

- HISTAGLOBIN -- H56-92-8 I S T A N I N E ~ DIHYOROCHLORIDE -- HISTIDINE, L71-00-1 -- L-HISTIDINE, N-beta-ALANYL305-84-0 - DL-HDHOCYSTEINEr S-ETHENYL- O-HOn0-19-NMI-17-alpha-PREGN-4-EN-3-ONE. 17,20.21-TRIHYDROXY- D-HOFIOPREGNA-4~16-OIENE-3r2O-DIONE - O-HOMOPREGNA-4~16-DIEN-3-OF1E -- D-HOMOPREGN-4-ENE-3~2O-DIONE 56722-93-1 - HCMAN CHORIONIC 6C+4ADOTROPIN, d e g l y c o s y l a t e d - HUtlIC ACID, J O O I W SALT

1856

N1

-

H W L U S LUPULUS, e x t r a c t

1857

N1 RN

1841 N l RN 1842

N1

1843

N1

1844

N1

1845

N1

1846

N1 RN 1847 N 1 RN 1848

N1 RN

1849

N1

1850

N1

1851 N 1 1852

Nl

1853 N l RN 1854

N1

1858 N 1 RN 1859 N l 1860

N1

1862

Nl

3-HEXENE, 3-lp-~ETHOXYBENZYL)-4-lp-METHOXYPHENYL~-, mixed w i t h 4-lp-HETHOXYBENZYL)-3lp-tlETHOXYPHENYL)-2-HEXENE (7:3) D-ermbino-NEXOSE, 154-17-6

2-DEOXY-

- HIBISCUS ROSA-SINENSIS,

flower extract

ROOT EXTRACT

-- HYDANTOIN 461-72-3 - HYDANTOIN~5.5-DIPHENYL- 57-41-0 - HYDANTOIN, 5.5-OIPHENYL-. and 5-ETHYLDInYDRO-5-PHENYL-4,6( l H ~ 5 H l - P Y R I N I O I N E D I O N E I1:21

-

HYOANTOIH, 5.5-DIPHENYL-, ACID ( 1 : Z I

- HYOANTOIN. ACID I 6 : l )

5r5-DIPHENYL-r

a n d 5-ETHYL-l-HETHYL-5-PHENYLB*RBITURIC m i x e d w i t h 5-ETHYL-5-PHENYLBARBITURIC

120 1862

Nl RN

1863

N1

1864 N1 RN 1865

N1

1866

N1 RN

3867

N1

1868

Nl RN

1869 N 1 RN

1870

Nl

1871 N 1 1872

RN N1 RN

1874

Nl RN

1875 N 1 RN 1876

N1 RN

1877

Nl RN

1878 N 1 1879 N 1 RN N1

RN 1881 N1 1862

N1 RN

1883 N 1 RN

I884 N 1 RN

1885 N 1 1886

Nl

1887 N 1 RN 1888 N1 RN 1889 N 1 RN 1890

-

--

HIDANTOIN, 5~5-DLPHENYL-t ~ S O O I L MSALT 630-93-3 HYDANTOINt I~C-DIPHENYL-B md (2-PHENYLIIU7YRYL)UIEA ( l : 2 l HYDANTOIN, 5-ETNYL-3-nETHYL-5-PHENYL50-12-4 NYDANTOIN, 5-ETHYL-3-nETHYL-5-PHENYL-t

(-

1-

HYDANTOINt 3-ETHYL-5-PHENYL86-35-1

- HYDANTOXN~5-ETHYL-5-PHENYL-r t-)-- HYDANTOINI 5-(p-HYDROXYPHENYLI-5-PHENYL2784-27-2 - HYDANTOIN. 1-((5-NITROFLIRFURYLIOENEIAHINOb - 67-20-9 - HYDANTOIN, 1-(~ 5 ~ I P ~ N I T R O P H E N Y L I F U I F U R Y L I O E N E ~ ~SODIlw NOI-~ SALT, HEMIHEPTAHYDRATE - HYDER6INE

Nl

1873

1880

---

N1 RN

1891 N1 RN

--------

14641-96-4 HYORATROPIC ACID, p-ISOBUTYL15687-27-1 HYDRATROPIC ACID, P-ISOBUTYL-s SODIUI SALT 31121-93-4 HYORATROPIC ACIDt p 4 2-THENOYLl40828-46-4 HYDRUINE 302-01-2 HYDRALINE t l-ACLTYL-2-PICOLINOYL17433-31-7 HYIIRAZINE, l-(p-*LLOPH*NOYLBENZYLI-2-nETHYL-,

HYDROBROIIIDE

HYDRAZINE, 2-BENZYL-1-METHYL10309-79-2 HYORALINE 1,2-BIS(DICNLOROMETYL)16054-41-4 NYORAZINE, (t!-BROm)PHENElHYLI-

-- HYDRALINEI l-(o-CHLOROPHENETHYL)-l SULFATE (1:ll 155-00-0 -- HYDRALINE, l-(p-CnLOROPHENElHYL)-, SULFATE (1:lI 2598-25-6 -- HYDRALIN€r 1-(2-(0-CHLOROPH€NOXY )€THYLl-, HYDROGEN SULFATE (1:lI 2598-73-4

-

HYDRAZINEe (P,6-DICHL~OPHENETHYL)-

- NYDRALINEt ~3t4-DICHLOROPHENElNYL)-- NYDRAZINE. li2-OIETHYL1615-80-1

-----

,

HYDRALINE t 1 2-DICTlIYL-. 7699-31-2

DIHYDROCNLORIDE

NYDRAZINE, 1,l-DLHEMYL57-14-7 HYDRALINEt 1,2-DIPIETHYL540-73-8 HYDRALINE, 1,2-DIHETHYL-. 306-37-6

DUIYDROCHUIRIDE

121

1893 NL RN

- HYDRALINE, - HYDRALINE, - 154-99-4

1894 Nl

- HYDRUINEr

1895 Nl

-

1896 N1

- 2656-72-6 - HYDRAZINE,1-lo-METHOXYPHENETHYLI-, - 2598-71-2 I-lp-HETHOXYPHENETHYLI-r -- HYDRALINE, 2771-13-3 - HYDRALINES METHYL- 60-34-4 - HYDRALINEI Is-HETHYLPHENETHYLI- HYDRALINE, lo-METHYLPHENETHYLI- 21085-56-3

1892 NI

RN

1897 ~1

RN 1898 Nl RN

1899 Nl RN 1900 NI 1901 N1

RN 1902 N1 1903 N1

RN 1904 N1 RN 1905 Nl RN

1906 Nl

RN 1907 N1 RN 1908 N1 RN

1909 N1 RN

1910 N1 RN

1911 Nl 1912 HI RN

1913 Nl RN 1914 Nl RN 1915 N1

RN 1916 Nl RN

1917 N1 RN

1918 N1 RN 1919 N1 RN

12r6-DIMETnYLPHENETnYLI-

1-1 ZrQ-DINETHYLPHENETHYL)-. SULFATE 1121 I l*l-DIPHENYL-r HYDROCHLORXDE

HYDRUINEr l2-FLUOROPHENElHYLl-

- HYDRALINEI HEPTYL-

SULFATE II:lI SULFATE (1:lI

- HYDRALINE, lp-METHYLPHENETHYLI- HYORALINE, I-(alphe-HETHYLPHENETHYLI-2-PHENETHYL- 2598-76-7 - HYDRALINEi l-lo-METHYLPHENETHILl-~SULFATE (1!11 - 2598-70-1 1-lp-METHYLPHENETHYLI-r SULFATE I1:lI -- HYDRALINE, 156-48-9 - HYDRUINEr 1-12-Io-HETHYLPHENOXY lETHYL)-, HYDROtEN SULFATE I1:l) - 2598-72-3

- HYDRAZINEI 11-METHYL-2-PnENOXYETHYLI-r - 3941-06-8 - HYDRALINEr MINOHYDRATE

HALEATE

- 7803-57-8

- HYDRALINEI PHENETHYL- 51-71-8 - HYDRALINE, PHENETHYL-r SULFATE l1:11

- 154-51-4 -

HYDRAZINEI l - I l ~ P H E N O X Y - 2 ~ W O P Y LMALEATE l~~

-- HYDRALINE, PHENYL100-63-0 l~l'-lp-PHENYLENEBISlDXYETHYLENEIIDI-~ DIHYDROCHLORIDE -- HYDRALINE, 13104-70-6 PHENYL-, HYDROCHLORIDE -- HYDRAZINEi 59-88-1 SULFATE l1:11 -- HYDRALINE, 10034-93-2

- HYORUOBENZENE

- 122-66-7

-- HYDROCHLORIC ACID 7647-01-0 - HYDROCINNUIALOEHmEr 2,4-BIS~PHENYLMETHOXYI-b~ta-l3~4-DIHETHOXYPHENYL~-g~mm~-OXO- 40321-74-2 - HYDROCINNAMALDEHYOE, 2.4-BISCPHEHY~TnOXYI-bet.-lp-nTTn~PHENTL)-gcrar.-OXO- 40321-70-8

122 1920 N1 RN

1921

N1 RN

1922 N1 1923 N1 1924 N1 1925 N1 RN

1926 N1 RN

1927 N1 RN

1928 N1 RN

1929 N1 RN

1930 N1 RN

1931 N1 1932 N1 AN

1933 N1 RN

1934 N1 RN

1935 N1

- HYDROCINNAMIC ACID, alpha-HYDRAZINO-3,4-DIHYDROXY-dlph.-~ETHYL-, L- 28860-95-9 - HYDROFLUORIC ACID - 7664-39-3 - HYOROGENATED COAL OIL FRACTION 1 - HYDROGENATED COAL OIL FRACTION 3

- HYOROGENATED COAL OIL FRACTION 9 - HYOROQUINONE - 123-31-9 - HYDROQUINDNEi CHLORO- 615-67-8 -- HYDROQUINONE, 2,6-DIMETHYL654-42-2 - HYDROQUINONEt 'IRIMETHYL- 700-13-0 - HYDROXILAMINE, NtN-DIETHYL-

- 3710-84-7 - HYPOCHLOROUS ACID - 7790-92-3 - HYPTIS SUAVEDLENS, leaf e x t r a c t -- IMFERON 9004-66-4 - IMIDAZD14~5-dll1~3)DIAZEPIN-8-DL~ 3-l2-DEOXY-bet~-O-PENTOFURANOSYLl-3~6r7r6-TETRAHYORD-, -

H - I M I D b Z O ~ 2 ~ l - C l ~ 1 ~ 2 ~ 4 - O I T H I A Z D L E ~ 3 -5s6-DIHYDRO~IONE~ -- 333813-20-6 - 5H-IMIDAZO( 2 ~ 1 - aIISOINOOLE~2-PHENYL-

1939 N1

-

1940 N1

- IMIDAZ012,1-alISDQUINOLINE~ 2-lp-CHLOROPHENYLI-

1936 N1 1937 N1 1938 N1

1941 N1 1942 N1 1943 N1 1944 N1 1945 N1 1946

N1

1947 N1 1948 N1 1949 N1 1950 H1 1951 N1

-

IMIDAZOl2~l-a)IS09UINOlINE~2-lm-IALLYLOXYIPHENYLIIMIOAZO( 2,l-a IISOQUINOLINE I 244-BIPHENYLYLIIMIOAZO( 2 ,l-a IISOQUINOLINE, 2-(p-BROMOPHENYL 1IMIOAZO( 2 ,l-a IISOQUINOLINE I 2-(m-CHLDIOPHENYLl-

IMIDAZ015,l-a1IS0QUINOLINE~ 2-ID-CHLOROPHENYLI2-( 3,4-DICHLOROPHENY L 1-

IMIOAZO( 2 I 1-a IISOQUINOLINE

- IMIDAZOI 2,l-a )ISOQUINOLINEI 5,6-DIHYDRD-2-1m-METHDXY~ENYL)- IMIDAZO( 2,l-a )ISOQUINOLINE 5.6-OIHYDRD-2-1 o-METHDXYPHENY L 1t

-

IMIDAZO~2,l-alIS0QUINOLINE, 5~6-DIHYDRO-2-lp-~ETHOXYPHENYLlIMIDAZ0(2,1-alIS09UINOLINE~ 5,6-DIHYDRD-2-PHENYL-

- IMIOAZ0~2,1-a)IS0QUINOLINE~5,6-DIHYDRO-2-p-TDLYL-

IMIDAZO(2,l-alIS0QUINOLINE~ 2-(m-ETHOXYPHENYLI-

IMIDAZD(2,1-alISOQUINOLINE, ~ - ( ~ - F L U O R O P H E N Y L I -

- IHIDAZO( 2,l-a )ISDOUINOLINEI 2-(iii-HETHOXYPHENYLI- IMIDAL0(2,1-alIS0QUINOLINE. 2-(o-METHOXYPHENYLI-

1953 N1

-

1954 N1

- IMIDAZD( 2 ~ 1 - IISOQUINOLINEI 8 3-METHYL-2-PHENYL-

1952 N1

1R)-

53910-25-1

IMIDAZ012,1-alIS0QUINOLINE~ 2-lp-METHOXYPHENYLI-

IMIDAZO(2~l-alISOQUINOLINE, 2-(3,4-(HETHYLENEDIOXYlPHENYLJ-

123

1963

N1 RN

-

1964

N1 RN

-- 64038-56-8 IHIDAZOLE-4-CARBOXAHIDE~ 5-(3,3-DIMETHYL-l-TRIAZENOl-,

1965

N1 RN

1966

N1 RN

1967

N1

1955

N1

1956

N1

1957

N1

1958

N1

1959

N1

1960

N1

1961

N1

1962

Nl RN

RN 1968 N l

1969

RN N1

1970

N1

1971

N1

RN

RN 1972

N1

IHIDAZO~2,1-aIISWUINOLINE,2-(p-NITROPHENYLlIHIDAZ0~2,1-alIS0QUINOLINE, 2-PHENYLIHIDAZOI 2 , l - a IISWUINOLINE, 2-(ni-PROPOXYPHENYL)IHIDAZOI 2.1-a IISOQUINOLINE, 2-p-TOLYLlH-IMIDALOLE,

5-AHINo-*

HYDROCHLORIDE

IHIDAZOLE v 1-( alpha-(4-BIPHENY LYL IBENZYLIIHIDAZDLE, 1-(alpha-(4-BIPHENYLY L IBENZYL l -

IHIDAZDLE-4-CARBOXAHIDE~ 5 - ~ 3 ~ 3 - B I S l 2 - C H L D R O E T H Y L l - 1 - T R I A Z E ~ l 5034-77-5 IHIDALOLE-4-CARBOXAHIDE~ 5-13,3-DIMETHYL-l-TRIAZENO)4342-03-4

CITRATE

-

IH-IHIOAZOLE-4-CARBOXAHIOE~ 5-HYOROXY-1-beta-D-RIBOFURANOSYL- 50924-49-7 -- IHIDAZOLE-4-CARBOXAHIDE~ 5-(3-METHYL-l-TRIAZENOl3413-72-7 - IMIDAZOLE, 1-Io-CHLORO-olpha,alpha-DIPHENYLBENZYLl- 23593-75-1

-

-

1H-IHIDAZOLE~ 1- ( 2- ( I 4-CH LOROPHENYL )HETllOXY I 2- ( 2 ~ 4 - DICHLDROPHENYL I ETHY L I NITRATE

-

9

28558-28-3 IH-IHIDAZOLE~ 1-(2-1 12-CHLORO-3-THIENYL )HETHOXY 1-2-1 2 .4-DICHLOROPHENYL IETHY L 165899-73-2 IHIDAZOLE, 1 - ( 2 - 1 ~ 2 ~ 4 - D I C H L O R O B E N Z Y L ) O X Y)OCTYLI-,

- IHIDAZOLE, 1-(2,4-DICHLORO-b@ta-( -

-

( 2 ,4-DICHLOROBENZY

OXALATE. d l -

L IOXY )PHENETHYL 1-

22916-47-8 IMIDAZOLEt

l-l2~4-DICHLORO-b@~~-l~2~4-DICHLOROBENZYLlOXYlPHENETHYL~-~

N1

-

RN

-

RN 1973

1974

N1 RN

1975

N1 RN

1976

N1 RN

1977

N1 RN

1978

N1 RN

1979

N1

1980

N1 RN

1981

N1 RN

1982

N1 RN

HONONITRATE 22832-87-7 IMIDAZOLE, 1 - 1 2.4-DICHLORO-b@fa-( MONONITRATE 24168-96-5

- 35554-44-0 1H-IHIDAZOLE,

-

2 s6-DICHLOROBENZYLIOXY IPHENETHYLI- s

1 ~ ~ 2 ~ I 2 ~ 4 ~ D I C H L O R O P H E N Y L ~ - 2 - ~ 2 - P R O P E N)ETHYL)YLOXY ~lPh~-(CHLORONETHYLI-2-HETHYL-5-NITRO-

IHIDAZOLE-1-ETHANOL. 16773-42-5

- IHIDAZOLE-1-ETHANOL. 13551-87-6

-

(

olpha-lHETHOXYMETHYL)-2-NITRO-

IMIOAZOLE-1-ETHANOL, 443-48-1

2-METHYL-5-NITRO-

IHIDAZOLE, 1-12-~ETHYLSULFONYLIETHYLI-2-HETHYL-5-NITRO19387-91-8 IHIDAZOLE-4-PROPIONIC IMIDAZOLE-2-THIOL. 60-56-0

ACID, alphe-AMINO-alpha-(FLWROHETHYLl-

1-METHYL-

- 2-IHIDAZOLIDINETHIONE 96-45-7 -

2-IHIDAZOLIDINETHIONE~ 4-METHYL2122-19-2

124 1983 N1 RN 1964 N1 1985 Nl RN

1986 Nl RN 1987 N1 RN 1988 N1 RN 1989 RN 1990 N1 1991 Nl 1992 Nl

-- IHIOAZOLIDINETHIONE~ N-NITROSO3715-92-2 - 2-IMI3AZOLIOINETHIONE ui th SWILM NITRITE -- 2-1HIDAZOLIDI"E 120-93-4 nlwed

-- 61-57-4 2-IHIDAZOLIDINWE

s

1 4 5-NITRO-2-THIUOLYL )-

4-A~INO-2,2~5,5-TETRAKIS( TRIFLUORWlETHYLl-- ~-IMIDAZDLIMI 23757-42-8 -- 4205-91-a 2-IMIOAZOLINE, 2-( 2~6-OICHLOROAN1LINO)-, MW4MYOROCNLORIOE

- 21498-08-8

- 2-IHIOUOLINE,

L~~4-IM)ANYLAMINOl~~ HYDROCHLORIDE

- 2-IMIDAZOCINE, HYDROCHLORIDE - MONOHYDROCHLORIDEI IHIDAZO(2,l-blTHIUOLE~ 2.3r5r6-TETRIHYDRO-6-~ENYL-. L-(- 16595-80-5 -- 1-INDANCARBOXVLIC ACID, ~-CHLORO-~-CYCLOHEXYL-I za96e.-07-z -- 1~3-1hDANDIONE 606-23-5 -- 1~3-INOANDIONE, 5-BROHO-2-PHENYL1470-35-5 -- 693az-20-3 1.3-1WAWIONE, 3-ETHOXY-1-INDANYLIDL"I-- 876-a3-5 1 ~-I~DU(DIONEI Z-HETHYL-

~ - I ~ ~ ~ . ~ ~ Q - T E T R U ~ ~ D R O - ~ - ~ T H Y ~ ~ I H O ) - I

)-

RN

1993 N1

RN 19%

N1 RN

1995 Nl RN 19%

N1 RN

1997 N1

RN 1998 N1 RN 1999 Nl 2000 N1

2001 N1 RN 2002

N1

RN 2003 Nl W 2004

N1 RN

2005

Nl RN

2006

N1 RN

2007 N1 RN 2008

N1 RN

2009 N1 RN

(+)-

Z-I

s

1 B~-INDAWIONE,I - ( 3-0x0-1-INDANYLIDENE1- 1707-95-5

- 1,3-1NDANDIONE, 2-(3-PYRIDYLHETHYLENE

1-

- 5-INDANDLs 6-I2-)IETHYLPIPERIDINO)-, HYDROCHLORIOE~ OL- I N D W O L I6-((2-HETHYLPIPERIDINOlMETHYL)-, MALEATE -- ~53305-31-0

-- 58586-10-0 lH-IWAZOLE-3-ACETIC ACID -

I

l-(p-CHLOROBENZY L)-

1H-INDAZOLE. l-B€HZIC-~-(3--(OXMETHYC~~WO)PROWXY b s

- HONOHYDROCHLORIDE 132-69-4 - ~H-INDAZOLE-~-CARBOXAHIDEPl-(p-CHLOROBENZYL)- 50265-05-9 -- 50264-62-5 1H-INLlAZOLE-3-CARBOXYLIC ACID, l-(p-BROHOBENZYL)ACID, l-(m-CHLOROBENZYL)-- lH-INLlAZOLE-3-CAR8OXYLIC 50264-61-4

-- 50264-60-3

lH-INDAZOLE-3-CARBOXYLIC

ACID, l-(o-CHLOROBENZYLl-

- 2,3-DIHYOROXVPROPYL 1H-INDAZOLE-3-CARBOXYLIC ACID, l-(O-CHLOROBENZYL)-r ESTER - 50264-95-4 - lH-IWAZOLE-3-CARBOXYLIC ACIO, l-(p-CHLOROBENZYL)-e 1~3-DIHYDROXY-2-PROPYLESTER

- 50264-96-5

126 2010

Nl RN

2011

Nl

2012

RN N1 RN

2013

N1 RN

2014

N1 RN

2015

N1 RN

2016 N1 RN 2017

N1 RN

2018

N1 RN

2019

N1 RN

2020

Nl RN

2021

N1 RN

2022

H1 RN

2023

N1

-

lH-INDAZOLE-3-CARLRBLIC

ACID, 1-lp-CHLOROBEWYLI-r

~s~-OIHYOROXYPROPYLESTER - 50264-93-2 - 2-HYDROXYETHYL lH-INOAZOLE-3-CARBOXYLIC ACID. l-(p-CHLDROBENZYLI-r ESTER - 50264-99-8 - lH-INDAZOLE-3-CIRBOXYLIC ACID, 1-14-~L(IRO-2-~ETHYLBENZrL)- 50454-68-7 -- 50264-86-3 lH-IMAZOLE-3-C*RBOXVLIC ACIDS I-( (4-CHtOROPHENYL)flETllrLI-

-

lH-INOAZOLE-3-CARBOXYLIC ACID. - 50264-75-0

1-(2,4-DIBROnOBENZYL1-

---

1H-INDAZOLE-3-CARBOXYLIC 50264-69-2

ACID, 1-12r4-DICHLM)OBENLYL)-

lH-INDAZOLE-3-CARWXYLIC 50264-68-1

ACID, 1-(3r4-DICHLOROBENZYLl-

-

50264-83-0

- lH-INDAZOLE-3-CARBDXYLIC ACIDS 1~12~4-DICHLWZOBLNLYLl-~ 2.3-OIHYOROXYPROPYL ESTER lH-IM)AZOLE-3-CARBVLIC ACIDI 1-(2r4-DIHETHYLBENZYL)-- 60264-78-3 -- 50264-63-6 lH-INDAZOLE-3-CMBOXYLIC ACIDI l-(p-FLVOROBENLYLI-- lH-INDAZOLE-3-CAR8OXYLIC ACIDS I-Cp-mOOBMZYLI58585-99-2 -- 58586-04-2 lH-INDAMLE-3-CARBOXYLIC ACID, 1-(2-HETHYLBENZYLI1H-INDAZOLE-3-CARWXYLIC ACID, 1-(2r4.5-TRICHLWZaBENZYL)-- 50264-76-1 - 1H-INDMOLE-3-CARBOXYLIC ACIDt l-I2,4,5-TRICHLOROBENZYLI-~ 2 3-OIHYDROXYPROPY L ESTER - 50264-85-2 -- 443-30-1 INDENE, 1-14-DIMETHYLI)1INOBENZYLIDENE I- 6-INOENOL, 3-I P - I 2-1 OIETHYLAMINOIETHOXY IPHENYL I-L-PHENYL- 1H-INOENOI 1.2-C )PYRIOINEs 2,3,4,4a~5,9b-HEXAHYDRO-2-ETHYL-7-nETHLYL-~ HYDROCnLORIOE. (4aRs.5RS.PbRSJ- INDIGOFERA SPICATA, seed e x t r a c t -- nunun NITRATE 13770-61-1 -- 87-51-4 1H-INOOLE-3-ACETIC ACID -- 53-86-1 INOOLE-3-ACETIC ACID. l-~p-CHLM)OBEHZOYLI-5-XETHOXY-2-~THVL3

RN 2024

N1 RN

2025

Nl

2026

N1

2027

N1

2028

N1 RN

2029

N1 RN

2030

N1 RN

2031

N1

PO32

N1

2033

N1 RN

2034

N1

2035

Hi

RN

RN

-

1H-INDOLE-3-ACETIC ACID. 1-(4-CHLOROBENZOYL)-5-METHOXY-2-HETHYL-~ CARBOXYHETHYL ESTER 53164-05-9

- INDOLE,

3-l2-A~UNDETHYLI-l-BENZVL-5-~ETHOm-2-~ETHYL-~ HONOHYOROCHLORIDE 525-02-0

INOOLE, 3-(2-AHINOPROPYLl-- 299-26-3 - 4-INDOLE-3-CARBOXALDEHYDE~ L-(m-AMINOPHENYLI-. III-TOLY L -3-THIOSEHICIRBAZONE )

-

IWOLE-3-CARBOXALDEHYDE~ 2-PHENYL-s 4-l~-METHOXYPHENYLl-3-THIOSE~ICARBAZME

126 2036

Nl

2037

N1

2038

N1

2039

N1

2040

N1

2041 N1

RN 2042

N1

2043

N1 RN

2044 N1 RN 2045

N1

2046

N1 RN

2047

N1

2048

N1

2049

N1

2050

N1

RN

- 4-lp-METHOXYPHENYL)-3-THIOSEWICAREAZONE -2~S-DIPHENYL-1-l2-l1-PYRROLIDINYL~ETHYL)---, 3-PHENYL-2-lp-I2-ll-PYRROLIOINYLlETHOXY)PHENYL~INDOLE-3-CARBOXALDEHYDEr e-PHENYL-. IWOLE e 5-.CHLORO-3-HETHYL-2-(p-(

IMOLE s 5-CHLORO-3- PNENYL-2-1 p-I 2-1 1-PYRROLIOINYL JETHOXY J PNENYL 1-

INOOLE 0 Z-lp-l2-lOIETHYLWINO~ETNOXY )PHENYLl-3-PHENYL-

IWOLE P 3-(p-I 2-1 DIETHYLAMINOIETHOXYIPHENYLl-2-PHENYL-, HYDROCHLORIDE INOOLE-2r3-DIONE 91-56-5 INDOLE.

INOOLE-~-ETHANOLB5-HYOROXY154-02-9 INDOLE-3-ETHANOL, 712-09-4

5-HETHOXY-

IWOLE v 5-FLUORO-3-PnENYL-2-(p-(

IMOLE

3-HETHYL-2-lp-I

2-(1-PYRROLIDINYL JETHOXY IPHENYLI-

INDOLE,

1H-INDOLE-2-SULFONIC ACID, 5 - l I A H I E I O C A R 8 O N Y L ) H Y O R A Z ~ ~ ~ 2 ~ 3 . 5 r 6 - T E T R - ~ tION0SODIUW SALT, TRIHYORATE

-- INDOLINIWr S-CHLORO-l.l-DIHETHYL-, 32179-45-6

--

INOOL-5-OL, 50-67-9

N1

--

INDOL-5-OLt 3-lP-AMINOETHYL)-, 971-74-4

RN 2053

N1 RN

2054 N1 RN 2055

N1 RN

2056

N1 RN

2057

Nl RN

2058

N1 RN

2059

N1 RN

2060

Nl

2061

N1 RN

206Z

N1 RN

2063

Nl RN

2064

N1 RN

2-1 1-PYRROLIDINYL JETHOXY JPHENYLI-

INDOLE-3-HETHANDL 700-06-1

2051 N1 RN 2052

2-1 1-PYRROLIOINYLJETHOXY JPHENYLJ-

BROMIDE

3-12-AMINOETHYL)conipd. with CREATININE SULFATE

-- 83364-03-8 INDOL-6-OL, 4 - C N L ~ O - 2 - O ~ 5 - D I C H L O R O ~ 4 - H Y D R O X Y P H E ~ Y L ~ ~ l ~ E T H Y L -- 83364-02-7 J-l-HETHYLINOOL-6-OLs 4-uILOR0-2-I3,5-DICHLORO-4-NYOROXYPHENYL -- 57285-09-3 INHIBIN -- 58-63-9 INOSIHE -- 4691-65-0 5'-INOSINIC ACID, DISWIUn SALT - 4~AHINO~l~Il*nINO*CETYLlHETHYLAHINO~~lr4~DIDEOXY-3~O-lP~6-DIISWNOL-chlro-INOSITOL, - ~~~~~~~~~~PENTADEOXY-~~T~-L-~~XO~HEPTOPYRA~SYLJ~~-O~HETH - 55779-06-1 -- 9004-17-5 INSULIN PROTAMINE ZINC INSULINI ULTRA LENTE

- IODINE - 7553-56-2

--

IOMEX 57285-10-6

-- I12645-95-3 R I D I W CNLaRIDL -- IRONIIII SULFATE 11:ll 7720-78-7

127

2071 N1 RN

TRIS~OIHETNYL0ITHIOCIRBIPTO~-- IRON, 14484-64-1 7-12-IDI~ETHYLA~INO)ETHOXYI~4'-nETHOXY-2-NETHYL~ 13004-41-6 -- ISOFLAVONE, 4'.5,7-TRIHYDROXY-- ISOFLAVONE, 446-72-0 - 2-ISOINOOLEACETAHIOE~alpha-ETHYL-2-0x02-ISOINDOLINEACETIC ACID. 1.3-0IOXO-- 4702-13-0 - 2-ISOINDOLINEACETIC ACID, 1~3-OIOXO-sVINYL ESTER ACID, 1n3-010x0-- 2-ISOINOOLINEBUTYRIC 3130-75-4

2072 N1

-

2065 N1 RN 2066 N1 RN 2067 N1 RN 2068 N1 2069 N1 RN '

2070 N1

2073 N1 RN 2074 N1 RN 2075 N1 RN 2076 Nl RN 2077 N1 RN 2078 N1 RN 2079 N1 2080 N1 RN 2081 N1 RN

2082 N1 2083 N1 2084 N1 RN 2085 N1

ISOLEUCINE, N-TRYPTOPHYL-r L-

ISONICOTINAHIOE~ 2-ETHYLTHIO-- 536-33-4 ISONICOTINIC ACID, 2-(2-(BENZYLCARBA~YLIETHYL~NYORAZIOE -- 51-12-7 ISONICOTINIC ACID HYDRAZIOE -- 54-85-3 ISONICOTINIC ACIOI 2-ISOPROPYLHYORAZIOE -- 54-92-2 ISONICOTINIC ACID. 2-ISOPROPYLHYORAZIOE, OIHYDROCHLDRIOE -- 6011-62-7 ISONIPECOTIC ACID, l-HETHYL-4-PHENYL-, ETHYL ESTER -- 57-42-1 - 10-~3-lDIHETHYLAHINO)PROPYL) ISONIPECOTIC ACIOI 1-HETHYL-4-PHENYL-, ETHYL ESTER and PHENOTHIAZINE 12:l)

-- 50-13-5 ISONIPECOTIC ACID, 1-HETHYL-4-PHENYL-r ETHYL ESTER. HYDROCHLORIOE

-- 67-63-0 IMPROPYL ALCMOL - ISOWINOLINE~5-( (0-CHLOROBENZYLIOENEIAH1NO)- ISOWINOLINE~J-CHLORO-l-I4-NETHYL-l-PIPERAZINYLI-5-N1TRO-

- HYDROCHLORIDE ISWINOLINES - 61-25-6

1-~~3,Q-OIMETHOXYPHENYLInEnlYL)-6r7-DIWETHD-~

- 6*7-ISWUIHDLINEDIOL, 1 ~ 2 ~ 3 ~ 4 - T E T R A H Y O R O ~ 1 ~ ~ 3 ~ Q ~ 5 ~ T R I ~ E T HHYOROCHLORIOEt OXYBENLIL~~~

- 18559-59-6 - 6~7-ISWUINOLINEOIOL~ (+-I- 18559-63-2 (-1-

RN 2086 N1

1 ~ 2 ~ 3 ~ 4 - T E T R A H Y D R 0 ~ 1 - ~ 3 ~ 4 ~ 5 - T R I H E T H O X Y B EHYDROCHLORIDE, NZYL~~~

RN 2087 N1 RN 2088 N1 RN 2089 N1 RN 2090 N1 RN 2091 N1 RN

- HALEATE ISOQUINOLINEI lr2r3,Q-TETRIHYDRO-L)-MINO-2-NETHYL-4-PHE~L-~ - 32795-57-4 -- 57-06-7 ISOTHIOCYANIC ACID. ALLYL ESTER ISOTHIOCYANIC ACID, ETHYLENE ESTER -- 3688-08-2

-- ISOTHIOCYANIC ACIOv -- ISOTHIOCYISIIC ACID, PHENYL ESTER 103-7&?-0

3-(HETHYLSULFINYL)PROPYL ESTER

501-44-2

-

JATROPHA CURCUSS f r u i t o r reeds

2092

N1

2093

N1 RN

2094

N1 RN

2095

Nl RN

-- 62765-90-6 JECTOFER -- 14788-78-4 JERVINE, 3-ACETATE -- 66409-97-0 JERVINEI N-BVlYL-12-b~t~.13-~Iphr-DIHYDRO-,

2096

Nl RN

- JERVINE, ll-OEOXO-l2-b~t~~l3-~lph~-DIHYDRO-ll-~lph~-HYDROXY- 73825-59-9

2097

N1 RN

2098

N1 RN

2099

N1 RN

2100

N1

RN 2101 N1 RN 2102

N1 RN

2103

N1

2104

N1

2105

Nl

2106

N1

RN

RN 2107

N1 RN

2108

NX RN

2109

N1

2110

N1

2111 N1 2112

N1 RN

2115

N1

2114

N1 RN

2115

N1 RN

2116

N1

2117

N1 RN

2118 N1

RN 2119

Nl RN

zieo

~1 RN

3-ACETATE

-- JERVINE, ll-DEOm)-l2-b~t~~13~~lph~-DIHYDRO-1l-b~~~-HYDROXY51340-26-2 -- JERVINE, 12-betr,l3-rlpha-OIH'mRO21842-58-0 JERVINE, N-FORHYL-- 66409-98-1 -- JERVINE. N-HETHYL64552-25-6 -- KANAHYCIN, SULFATE (1:l) lS.ltl 25389-94-0

------

KARHIWMCIN 39472-31-6 KETONE,

2-AMINO-5-BENZIHIDALOLYL PHENYL

KETONE, 5-CHLORO-2-THIENYL HETHYL KETONE, 3 ~4-OIHYDRO-2-(p~HEI)IOXYPHENY L )-l-NAPHlMY L-p-( 2 4 1-PYRROLIDINYL 1ETHOXYlPHENYL. HETHANESULFONATE 68307-81-3 KINASE tENZYHE-ACTIVATING)r URO9039-53-6 LACTIC ACID, cotnpd. d t h 1837-57-6

LACTIC ACID, 306-23-0

- LACTIC ACID,

------

p-HYDROXYPHENYL-

ZINC SALT t 2 : l l r DL-

LACTIC OEHYDRObENASE C(sub 4 ) LACTIC DEHYDRSENASE X LACTOSE 63-42-3 LAHIIM ALBW Lfnn.,

extrect

L A N T H W CHLORIDE 10099-58-8

LANTHANLM NITRATE 10099-59-9 LASHIOSPHAERA FENZLI Rdch, crude wtracf LAURIC ACID, 1984-77-6

~I~-EPOXYPRDPYLESTER

LEAD 7439-92-1

-- 6080-56-4 LEAD ACETATE t 1 I ) s

--

6,9-DIUUW-2-ElHOXYACRIDINE (,1:1)

TRItlYDRATE

LEAD.' BIS(ACETATDITETRAHWRDXITRI1336-32-6

129 2121

Nl RN

2122

N1 RN

2123

N1 RN

2124

N1

2125

N1

2126

N1 RN

2127

Nl RN

2128

N1 RN

2129

N1

2130

N1 RN

2131 N1

-- 598-63-0 LEAD CARBONATE -- 7758-95-4 LEAD CHLORIDE -- 10099-74-8 LEADIII) NITRATE 1122) - LECITHIN, IODIDE - LEMMATOXIN-C-C' -- LENTINAN 37339-90-5 -- 61-90-5 LEUCINE. L-

L-LEUCIMs N-(3-AnINO-2-HYDRaXY-l-DX0-4-PHtNrLBUlrL)-r I S - I R * , S * ) 158970-76-6 LEUCINE. N-CARBOXY-. N-BENZYL 1-(1,2-DIBRDHDETHYL) ESTER, L-

-- 2018-66-8 LEUCINE, N-CARBOXY-r N-BENZYL ESTER. L- LEVCINE. N-CARBOXY-, N-BENZYL 1-VINYL ESTER -- 35457-80-8 LEUCWCIN VP 3 ~ 4 f s u pBl-DIPROPANOATE -- 57-22-7 LEUROCRISTINE -- LEURMRISTINE SULFATE (1:l) 2068-78-2

2132

N1 RN

2133

N1 RN

2134

N1 RN

2135

N1 RN

2136

N1 RN

L-HPC - 78214-41-2

2137

Nl

-

2138

N1

- LIQUIPRDN

2139

2140

Nl RN N1

- LITHIUl CARBOHITE - 554-13-2 - LITHIUM CHLORIDE

2141

N1

2142

N1

2143

N1

2144

N1 RN

2145

N1

2146

N1

2147

Nl RN

2148

N1

2149

N1

2150

N1

RN

2161

Nl

2152

N1 RN

-

LEVORIN 11014-70-3

LINDLEIC ACXD loxidired)

12:l)

- 7447-41-8 - LITHOSPERnIC ACID, owi dl zed - LITHOSPERHIC ACID. oxidized and lyophilired - LITHOSPER)(U( RUOERALE, root extract

--

LIVIDWYCIN 11111-23-2

- LOCOUEED - LONICERA CILIOSI, leaf extract -- 9002-67-9 LUTEINILIN6 HORMONE

--

LUTEINIZING

AN'TISERUn

LUTEINIZIN6 H O R W E s 6oNIDocRAPNoN RELEASINS HORtWE LUTEINIZING ItCWWE, WINE, bet.-subunit LUTEINIZINC HORHDNEI RAIPI)IT ANTIBWINE SERW LUTEINIZING HDRIIONE-RELEASING HORWONE 9034-40-6

130 2153

N1

2154

N1

2155

N1

2156

N1

2157

N1

2158

N1

2159

N1

2160

N1

2161

N1

- Ll )Up pT-ECI Nl - IOZ-IPNHGE HORHDNE-RELEASING HORMDNEr (rup Z),D-TRPlSup 3 # 6 1 - ZL Ul -T DE I~NlI ZRIPN Gl r ~HORMONE-RELEASING HORMONE, 3~61)p

-

RN N1

2163

N1

2164

N1 RN

IAC-D-ALAlrup

11-0-PHEI.up

L U T E I N I Z I N G HORMONE-RELEASING HORMONEI I N - A C - D - p - C l - P H E ( r u p l,Zt-D-TRP(sup 3 ) - 0 - P H E l ~ u p 61- 0 - A L A I W p 1 0 1 1 -

- 1LUTl!INIZING HORMONE-RELEASING HORMONEr IN - A C - 0 - p - C l - P H E I l u p - 2 I - 0 - T R P l r u p I ) - D - P H E l S u p 6 I - 0 - S E R l S u p 1011- 1L Ul -T~E- CI N1I-ZOI N- PGH EHORMONE-RELEASING HORMONE, IAC-OEHYDRO-PROlSup l r u p 2 ) - 0 - T R P ( s u p 3,6))-NIrup a l p h a ) - M e - L E U I r u p 7)- lL)U- OT-EpI-NCIlZ- PI NHGE (HORMONE-RELEASING HORMONE, ( N - A C - D - P - F - R I E I r u p sup 2)- D-TRPIrup 3r6)-0-ALA(rup 1 0 1 ) - 2L Ul-D-TRP( T E I N I Z I N G HORMONE-RELEASING HORHONE, I A C - H Y P l r u p l ) - D - P H E ( r u p 3 1 - 0-TRPI 6 )1- lL)U- DT-EpI-NCI lZ-IPNHGE lHORMONE-RELEASING HORMONE, IN-AC-OL-5-ME-TRPlrup sup 2)- D-TRP(sUp 3 l - O - P H E ( S u p 6 ) - O - A L A l % u p 1 0 ) ) SUP

SUP

2162

N-AC-L-AUlrup

-

L U T E I N I Z I N G HORMONE-RELEASING l)-p-F-O-PHE(rup ZI-D-TRP(rUp 86855-16-5

HORMONE, l A C - O - N A L l 2 l l r u p 3 ) - 0 - A R G l l u p 6))-

- lL)U- OT-EpI-NCIlZ- IPNHGE (HORMONE-RELEASING HORMONE, I N - A t - D - P H E l r u p sup 2 ) - D - T R P l s u p 3 ~ 6 ) -D - A L A f r u p 1 0 1 1 - 2L 1U-T0E- TI NRIPZlIsNuGp HORMONE-RELEASING HORMONE. 1 A C - 0 - P H E l r u p 1 ) - D - P H E l r u p 3,611- lLlU- pT-ECI Nl -IOZ I-NPGH EHORMONE-RELEASING HORMONE, ( A t - d e l t a l s u p 3 ) - P R O I r u p l ~ u p 21- D - T R P ( s u p 3,611- 80152-22-3 - 1L 1U-TpE- CI Nl -I0Z-IPNHGEHORHONE-RELEASING HORMONE, ( A C - d c l t a l i u p 3 ) - P R O ( r u p lsup 2)- D - T R P ( r u p 3 , 6 1 - N l s u p a l p h a l - M c L E U l r u p 7 ) ) -

2165

N1

2166

N1

2167

N1

2168

N1

2169

N1

-

2170

N1

- 1L U, 3Tl -EDI -NpI-ZCI Nl - GP HHORMONE-RELEASING HORMONEI I N - A C - D - T R P l l U p EIsup Z ) - O - P H E I s u p 61- 0 - A L A l t u p 1 0 ) 1-

2171

N1

-

2172

N1

2173

N1

- 2L U)-O-TRP( T E I N I Z I N G HORMONE-RELEASING 3 ~ 16 - L U T E I N I Z I N G HORMONE-RELEASING

2174

N1

-

2175

Nl

-

L U T E I N I Z I N G HORMONE-RELEASING HORMONE, 11-p-F-0-PHElSup 2 ) - 0 - T R P l s u p 3,611-

- EL UI - TDE- TI NR PI Z(ISNuGp HORMONE-RELEASING HORMONE, 31- O - T R P ( s u p 61)- EL UI - TDE- TI NR IPZI ISNUGp HORMONE-RELEASING HORMONE, 3,611-

IAC-delta(sup 3bPROInup IAC-PROlrup l l - O - P H E l ~ u p l A C - O - T H I ( ~ u p 1) - D - P H E l l u p

L U T E I N I Z I N G HORMONE-RELEASING HORMONE, ( N - A C - O - T R P l r u p 1 0 ) 11 ~ 3 ) - O - p - C l - P H E l s u p 2 )-D-ARG(Sup 6)- O-ALA(.up

L U T E I N I Z I N G HORMONE-RELEASING HORMONE P I N-AC-DL-TRPI Sup l)-D-p-Cl-PHElsup 2 ) - 0 - T R P l s u p 3)- 0 - P H e l s u p 6 l - D - A L A l r u p

Sup

HORMONEi I A C - D - T R P ( l u p

)-

L U T E I N I Z I N G HORMONE-RELEASING l O ) ) - , ETHVLAMIOE

HORMONE, I D - A L A l r u p 611HORMONEi I D - A L A I ~ u p 6 ) - D E S - G L Y I r u p

- 6)-DES-GLY-EMZ(sup L U T E I N I Z I N G HORMONE-RELEASING HORMONEI 1 0 - A L A l r u p ETHYLAMIDE - 52435-06-0 - 1L 0U1T-EPIRNOI ZI rI uNpG HORHONE-RELEASING HORMONEI O - A L A ( s u p 6 1 - D E S - G L Y I s u p 9 ) - P ETHYLAMIOE - 7L 1U-T0EEISN-I GZ ILNYGl ~HORMONE-RELEASING HORMONEt D - A L A l l u p 6 ) - I N ) M E - L E U ( r u p u p 1 0 ) - P R O I S u p 9 1 - ~ETHYLAMIOE - 91L U 1-T E I N I Z I N G HORMONE-RELEASING HORMONE, I D - A L A I l u p 6 l - P R O - E b l E t l ~ ~ p l O ) ) - p

RN 2176

N1

2177

N1

2178

N1

2179

N1

10))-

1I-D-PHEllup

-

L U T E I N I Z I N G HORMONE-RELEASING

HORMONE, I D - A N A l r u p 61 1-

131 2180 N1 2181 N1

- 9))LUTEINIZING HORWNE-RELEASING H O R W E , - LUTEINIZING HORHONE-RELEASING HORMONEt

ID-BHAlSup 6)-PRO-H1Etl~up ID-BIAIs~p6))-

2182 N1

- 9)-NHEt LLITEINIZING HORMONE-RELEASING NORMONEr

ID-BIAlSup 6 ) ~ P R D l s u p

2185 N1

- LUTEINIZING HORMONE-RELEASING HOWHONE,

ID-BNMSUP 6))-

)-

2184 Nl 2185 N1

2186 N1

- LUTEINIZING HORNONE-RELEASING HORI(OWE, ID-BOAISUP

- LUTEINIZING HORMONE-RELEASING BOC-ISERIBZL)Isup 2 )-D-TRPl ACETATEe TRIHYDRATE - l)-DES-HISlsup LUTEINIZING HORHDHE-RELEASING H O R M E r BOC-ISERIBZL)Isup 21-D-TRPllup GLY-OCH3(Sup HORMONE, sup 6 1 )-s

1 )-DES-HISI sup

2187 N1

61)-

- 1LLITEINIZING HORMONE-RELEASING H O R M E , BOt-lSERlBZL)lSup )-DES-HISlsup Z)-D-TRP(sUp 6)I - . ACETATE 10))-~

6)-

HYDROCHLORIDE, HYDRATE l2:3:81 2168 N1

- LUTEINIZING HORMONE-RELEASING HORMONE, BOC-ISERIBZLIl~up 1 I-DES-HISlrup 2)-D-TRP(rup 6 ) HYDROCHLORIOE - l)-DES-HISl~up LUTEINIZING HDRHDHE-RELEASING HORMONE. BOC-ISERIBZL)(rup ~)-D-TRPI~uP6)I-v HYDROCHLORIDE. HYDRATE l2:3:8) - ALBUnIN LUTEINIZING HOWMONE-RELEASING HORMONE conjugated t o BOVINE SERLRl - LUTEINIZING HORHONE-RELEASING NORMONE. ID-BTAlsup 6 ) ) - LUTEINIZING HORHONE-RELEASING HORMONE 10-CHAIsup 6 1)- LUTEINIZING HOWHDNE-RELEASING HORMONEr ID-DAAIsup 6)))-,

2189 N1 2190 N1 2191 N1 2192 N1 2193 Nl 2194 Nl 2195 N1 2196 N1 2197 N1

-

LUTEINIZING HORHMJE-RELEASING HORMONE, (D-DCAISU~6))LUTEINIZING NORHDNE-RELEASING HORMONEr ID-DCBlsup

6 1)-

LUTEINIZING HOAHONE-RELEASING HORMONE, IDES-GLYIrup ETHYLAMIDE

- lO)-lO-LEUlsup LUTEINIZING HORMONE-RELEASING HORHONE* IDES-GLYfsup 6 )INISUP alpha)-ME LEUISUP 71, PROISU~9)-NHEt 1 1

2198 N1

-

LUTEINIZING HORMONE-RELEASING HORMONEn IDES-NISIsup 21-DES-GLYIrup lO))-a ETHYLAHIOE LUTEINIZING HORMONE-RELEASING HORMONES DIACETATE, TETRAHYDRATE

)-

2199 N1

-

2200 N1

- LUTEINIZING HORMDNE-RELEASING HORMONEI fD-DHBB(sup 6 ) ) -

2201 N1

-

LUTEINIZING HORMONE-RELEASING HORMONE. ID-p-F-PHElsup 2 )-D-ALAlsup 6 1 )-

N1

-

LUTEINIZING HOR"!E-RELEASlNG HORMONE, 2-1 GLNlsup 1 1-DES-HIS1aup 2)-D-HEllsup 6)- DES-GLYIsup lo))-* ETHYLAMIDEv HYDROCHLORIDE. HYDRATE l1:1:2)

2202

2203 N1

- Z)-D-PROlsup LUTEINIZING HORMONE-RELEASING HORmbJEr Z-IGLNISU~ l)-DES-HISlr~p 6)- DES-GLYlsup 10))-r ETHYUHIDEv ACETATE, HYDRATE 12:7:5)

22OQ N1

- LUTEINIZING HORr(OWE-RELEASING H O R W E t Z - l G W l S ~ p1 )-DES-HIS(sup l)-D-PSEIsup 61- OES-GLYlsup 10) ETHYLAMIDE~ ACETATE - 2LUTEINIZING HORMONE-RELEASING HORMONEr 2-IGLNI sup 1 )-DES-HISlsup )-D-PSElSup 6)- DES-GLYISUP 10 1 I - , ETHYLAMIDE, ACETATE, 1-0

2205 N1

TETRAHYORATE

2206 N1

- 21-0-PSEIrup LUTEINIZING HORWNE-RELEASING HORHONE 2-IGLNI 1 )-DES-HIS1 DES-GLYIsup l o ) ) - , ETHYLAMIDE. HYDROCHLORIDE v

*Up

sup

6)-

2207 Nl

- 2LUTEINIZING HORMONE-RELEASING HORMDNEr Z-lGLNlriup 11-DES-HISl~Up ETHYLAHIOE. HYDROCHLORIDE. I-D-PSElsup 6 DES-GLYI sup 1 0 ) 1-

1-0

HYDRATE l10:17:30 1 2208 NX

- 1)-DES-HISlrup LUTEINIZING HORHONE-RELEASING HORHONEI Z-lGLNlNH-BZL)lSUP HYDROCHLORIDEI 2)l-r

HYDRATE (2:3:61

132

-

LUTEINIZING HORMONE-RELEASING HORMONE. Z)-PROlsUp S)-D-PHEIsUp 6))-

(L-GLU(sup

l)-D-PHE(rup

2209

N1

2210

N1

2211

N1

2212

N1

2213

N1

-

2214

N1

- 1LUTEINIZING HORMONE-RELEASING HORMONE, IL-GLU-PROISUP ) - D - P H E l r u p 2)-D-TRP(SUp 3)- D-TRPltUp 6))-

2215

N1

2216

N1

2217

N1

2218

N1

2219

N1

2220

N1

2221

N1

2222

N1

- L)-PROlsUp LUTEINIZING HORMONE-RELEASING HORHONEr 3)-D-TRPlSUp 6))- LUTEINILING HORMONE-RELEASING HORMONE. 2),0-TRP(¶up 3~6))- P)-D-TRPIsup LUTEINIZING HORMONE-RELEASING HORHONEI 3)- 0-PHEIsup 6))-

-

11-GLUIsup l)-D-PHEl,up ID-pGLUU(rup 1I rD-PHE( Sup (D-GLUIsup l ) - D - R I E I s u p

LUTEINIZING HORMONE-RELEASING HORMONEv (D-p-GLUlBup 2)-D-TRPIsup 3)- D-PHElsUp 6))-

LUTEXNXLXNG HORMONE-RELEASING NORMONE, (D-SLU(rup Z)-D-TRP(sUp 3.6) )-

l)-D-PHE(.W

1 )-O-THI(SUP

LUTEINILING HORMONE-RELEASING HORMONE, I D - H I S I S u b

6 )IIN-BZL )-PRO1 s u p 9 I - N E t

)-

- LUTEINIZING HORNONE-RELEASING HORMONE, 2-L-HlSTIOINE-6-L~6LYCSNE~ - LUTEINILING HORMONE-RELEASING HORMONE, I l l m B z L ) - D - H I S (sup 6 )-PRO( 9)-NET)- LUTEINIZING HORMONE-RELEASING HORMONE, ID-LEUISup 611- LUTEINILING HORMONE-RELEASING HORMONE I D - L E U I s u p 1 0 ) ) - 9 ETHYLAMIDE - 6)pDES-GLY-NHZLsup LUTEINIZING HORMONE-RELEASING HORMONEi ID-LEU(¶up l o ) ) - # ETHYLAMIOE Sup

LUTEINIZING HORMONE-RELEASING HORMONE, ID-LEUIsup

6 1 I OES-GLY-EM2 ISUP 1 0 1 p PRO- ETHY LAMIDE I s u p 9 1 1 2223

N1

2224

N1

LUTEINILING HORMONE-RELEASING HORMONE P lO)-PROlSup 9 ) ) - ~ ETHYLAMIOE

2225

N1

2226

N1

2227

N1 RN

- 2LUTEINILING HORMONE-RELEASING HORMONE, ) ) - r HYDROCHLORIDE, HYDRATE l 2 : 3 : 6 ) - LUTEINIZING HORMONE-RELEASING HORMONE, - rLUTEINIZING HORMONE-RELEASING H O R W E , lpha)-nE)LEUlsup 7 ) ) -- 60452-40-6 LUTEINIZING HORMONE-RELEASING HORMONE,

2228

N1

-

2229

Nl

2230

N1

2231

N1

2232

N1

2233

N1

LUTEINIZING HORMONE-RELEASING

-

( D-LEU(tup

6 )-DES-GLI( s u p

Z - l L E U ( r u p 1)-DES-HISlsup ID-LEUIsUp 6))-# ETHYLAMIDE (9-LEUlrup 6)(N(rup 6-(2-METHYULANINE)

HORMONE, IIONDACETATE, TETRAHYDRATE

- LUTEINIZING HORMONE-RELEASING HORMONE, - LUTEINILING HORMONE-RELEASING HORMONE, - LUTEINIZING HORMNE-RELEASING HORMONEI - 3LUTEINIZING HORMONE-RELEASING HORMONE, ) - D - N A L I 2 ) l s u p b)-PRO-NHEtIsup 9 ) - 6LUTEINIZING HORMONE-RELEASING HORMONEI l-W-LEU(sup 7) - 6)-NMe-LEUIsup LUTEINIZING HORMONE-RELEASING HORMONE, 7)-PRO-NHEt(sup 9 ) ) - 6)-PRO-NHEt(sup LUTEINIZING HORMONE-RELEASING HORMONE, 9))- LUTEINIZING HORMONE-RELEASING HORMONE, 9 ) - W E t 1- LUTEINIZING HORMONE-RELEASING HORMONE, - LUTEINIZING HORMONE-RELEASING HORMONE,

I D - M T F l r u p 6))l D - N A L I l ) l s u p 6))lD-HAL(2)fsup

6))-

I N A L I 1) I s u p

)-

lD-NAL(2)lsup

)-

2234

N1

2235

N1

2236

N1

2237

N1

2238

N1

lD-NALl2)Irup ID-NALI 2 ) I s u p ID-NIAIsuP

6)rPRDISvp

I D - P F P l s u p 6))ID-PHEISUP 2))-

133 2239

N1 RN

2240

N1

2241 N 1 2242

N1

2243

N1

2244

N1

2245

Nl

2246

N1

2247

Nl

2246

N1

2249

N1

2250

N1

2251

N1

2252

N1

- LUTEINILING HORl"E-RELEASING 1- 654784-64-0

-

LUTEINILING HORMONE-RELEASING HORHONE. ID-PHEIaup 2)-ALAIsup 3l-AUl.up QI-D-PHEIsu~ 6 ) ) LUTEINILIN6 HORlW4E-RELEASIN6 H O R W E , ID-PHEIrup Z)-D-ARiROIrup

6))LUTEINIZING HORHCNE-RELEASING HORHONE, ID-PHElsup Z)-U)Ol1up 3bD-PHElsup 6 ) ) -

- 6))LUTEINILING HORWE-RELEASING

-

NORMONE, ID-PHElSUp i?))-ID-AUlSuP

HORHONEr ID-BlEIsup ZB-D-LEUIsup

LUTEINILING HORME-RELEASING HORHONE, ID-PHEIrup P)-LEUIsup 3 l - D - P H E l r ~ p 611LUTEINIZING HORMONE-RELEASING HORMONE, ID-PHEIrup 2 ) - L E U l ~ u p 3)-D-TRPlsup 6))LUTEINILING HORMONE-RELEASING HORMONEr ID-PHElsvp L)-LEUIsup 3l-D-TRPlrup 6)-ME-LEUISUp 7 ) ) -

- 2LUTEINIZING HORHONE-RELEASING HORHDNEt I O - P H E I S ~ ~ ) )-I2-HE-ALAl sup 6 1 )-

-

LUTEINILING HORIUNE-RELEASING HORHDNEr l D - B l E ( ~ u p ZI-NE-LEUlsw 3)-D-PHEl$up 6))LUTEINILING HORHONE-RELEASING HORHONE, IPHElsup P)-NVA(sup 3 1 - D - A L A l s w 6)- DES-GLYlsup 1011-r ETHYLAMIDE LUTEINILING HORMONE-RELEASING HDRHONE, ID-PHEIlup 2)-NVIlsUp 3)-D-PHEIsup 61 1-

- 6))LUTEINIZING HORMONE-RELEASING HORMONE,

(0-PHElSup 2 ) - D - R l E l ~ u p

- 3l-D-PHElsup 611-

LUTEINILING HORMONE-RELEASING HDRMONE, ID-PHElrup Z)-D-PHEIsup

6))-t HYDROCHLORIDE, HYDRATE, l 2 : 2 : 7 1

2253

N1

2254

N1

2255

N1

LUTEINILING HORMONE-RELEASING HORMONE, ID-PHElrup Z)-PHElsup

- S)-D-PHElsup LUTEINIZING HORMONE-RELEASING HORHDNEI 6))- LUTEINILING HORMONE-RELEASIN6 H O R m E r L)-D-IPH)GLYIsup 6) - I)-D-PHEISup LUTEINILING HORKWE-RELEASING HORMONE, 6))-

ID-PHElrup 2)-PHElsup ID-PHEl Supl

)-

2256

N1

2257

N1

2258

N1

-

ID-PHEIS~~

2)-mo1i~

LUTEINILING HORWE-RELEASIN6 HORIIONE. ID-PnElsup Z)-PROlSUP S)-D-TRP(sup 61)-

- LUTEINILING HORHONE-RELEASING HORMONE, 3I-D-PHEl s u p 6 1

ID-PHElSUp Z)-SARlSUp

)-

2259

N1

2260

N1

2261 N 1 2262

N1

-

LUTEINIZING HORMONE-RELEASING HORMONE, ID-PHEI s u p 2 )-TRP(Sup 3)-D-ALAlsup 6))LUTEINILING HORMONE-RELEASING HORMONE B ID-PHEI S u p 2 J-D-TRPI SUP 3 ) - N I r u p mpsilon)-lGLU-D-PH- D-TRP-SER-TYR)-D-LYSlsup 61)-

- S)-D-PHElSup LUTEINIZING NORHONE-RELEISING'HORHONEr 6))- S)-D-TRPI LUTEINILING NORHONE-RELEASING H O R m E r 61 Sup

2263

N1 RN

2264

N1 RN

-

ID-PHEllup 21-D-TRPllUp

ID-PHE1.w

2bVILlrup

)-

LUTEINIZING HORWE-RELEASING HORHCNE IP I 6 ) e

6-10-1 1pl-DIMETHY LETHY L )-0-SERINE 1-9-IN-ETHYL-

L-PROLINA~IDE)-10-DESLYCIN*HIDE- 57982-77-1 - 6-D-LEUCINE-9-lN-ETNYL-L-PROLINAMIDE)LUTEINIZING HORMONE-RELEASING HORMONE ( P I G ) , 10-DEGLYCINAMIDE- 53714-56-0

134 2265

N1

2266

N1

2267

N1

-

2268

N1

-

2269 N 1

-

2270

N1

-

2271

N1

-

2272

N1

-

2273

N1

2274

Nl

2275

N1

2276

N1

LUTEINIZING NORHONE-RELEASING HORHONEi ID-PfFISup 6))LUTEINIZING NORMONE-RELEASING HORMONE, ID-SER-IBUlsup T ) l l l u p 6I-OES-GLY 1 - e ETHYLAHIDE LUTEINIZING NORHONE-RELEASING HORMONE, Z-lSERlBZL)lsup l)-DES-HIS(Sup 2)-D-PHEIrup 61- OES-GLYCSW l o ) ) - , OIHETHYUI(IDEI ACETATE, HONOHYDRATE LUTEINIZlNG HORHONE-RELEASING HORMONES Z-lSERlSZL)lrup l)-DES-HISlSUp 2)-0-PHEl~up 6)- OES-GLYISW l o ) ) - , ETHYUHIOEi HYDROCNLORIDE. HYDRATE 12:3:4) LUTEINIZING Hnm(ME-RELEASING HORMONE, 2-lSERIBZL)lsup 1)-OES-HISlsup 2)- DL-PHElH*lsub 5 ) )Isup 6)-DES-GLYl sup 101 I-. ETHYLAHIOE~ ACETATE, DINYORATE LUTEINIZING HORMONE-RELEASING HORMONE. Z-lSERlBZL)lS+ ~ p l)-DES-HISlsup 2)- 0 - P H E l k l t u b 5 ) ) l ~ 6)-DES-GLYlsup ETHYLAMIDEI ACETATEi MONOHYDRATE

lo))->

LUTEINIZING HORMONE-RELEASING HORMONEr Z-lSERlBZL)lSUP l)-OES-HISlsup Z)-O-PHEIsup 6 ) j - v HYDRDCHLDRIDE, HYDRATE l2:3:81 LUTEINIZING HORMONE-RELEASING NORHONEo Z-(SERIBZL)lsUP 11-DES-HIS1 sup 2)-D-TYRlHa 11 sup 6)- DES-GLYls+ 10) ) - v ETHYLAHIDEv ACETATEi DIHYDRATE

-6

LUTEINIZING HORHONE-RELEASING HORMONES ID-SERINE-t-BWTYLls~ 6)rDES-GLYCINE-NH2l¶up 1 0 ) )-B ETHYLAHIDE LUTEINIZING HORMONE-RELEASING HORHONEi lD-lSER-TBU)lsUI, )-DES-GLY I sup 10 )-PRO1 sup 9 1 1 - p ETNYLAHIDE

- LUTEINIZING HORMONE-RELEASING NORHONEI ID-TBAISW - LUTEINIZING HORIIDNE-RELEASING HORHONEs lD-TBAl¶UP 9)-NnEt - LUTEINIZING HORHDNE-RELEASING HORMONE, ID-TMOISup - LUIEINIZING NORHONE-RELEASING HORHONEi lO-THP(Sup

6))OtPROIlW

)-

2277

N1

2278

N1

2279

N1

2280

N1

2281

N1

2282

N1 RN

2283

N1 RN

22w

N1

2285

N1

2206

N1

2287

N1

2268

N1 RN

2289

N1 RN

2290

N1 RN

2291 N1 RN

-

-

6))6))-

LUTEINIZIN6 HORHONE-RELEASING HORHONEi 0-TRPISUP 6)LUTEINIZING HORl"E-RELEASING 10).PRO(sup 9)-r ETHYLAHIDE

HORMONE, D-TRPlsup 6),DES-GLYl¶up

LUTEINIZING HDRMONE-RELEASING HORHDNEr ITRPlsup 2)rLEUIIUp 3)rD-ALAlSup 6), DES-GLYlsup l o ) ) - # ETHYLMIDE LUTEINIZING HORHDNE-RELEASING HOR~*KIEBD-TRPI Wp 6 )-lN)HE-LEUlWP 7)-DES-GLYISup 10)- PROISUP 9)-, ETHYUnIDE 66866-63-5 LUTEINIZING HORKNE-RELEASING HORHONE, ID-TRPIsup 6)-PROlr~p 9 ) ) - r ETHYLAHIDE 57773-65-6 LUTEINIZING WORmE-RELEASIN6 9)-NEt )-

ID-1RPlrup 6 )-PRO1 sup

LUTEINIZING HORMONE-RELEASING HORIIONLI ID-TRYPI~up 6).DES-GLY-Wllub 2 1 ) - * ETHYLAHIOE

- LYCOWS LUCIDUS, crude exlract - LY6001Wl FLEXISUI. axtract -- 56-87-1 LYSINE, LLYSINE, Hlrrrp ~)-I~-AHIHO-~-CARBOXYETHYL)-I - 18810-04-3 -- HAGNESIW SULFATE I1:1) ~w-e8-9 -- HALEIHIDE 541-59-3

L-

135 2292

N1 RN

2293

Nl RN

2294

N1 RN

2295

N1

RN

- MALEIHIDE, DISROMO- 1122-10-7 - HALEIHIDEv DISROMO-N-HETHYL- 3005-27-4 - MALEIMIOE, DICHLORO-

1193-54-0

- HALEIHIDEt - 20198-77-0 - MALEIHIDEI

2,3-DICHLORO-N-ElHVL-

2296

N1 RN

2297

N1

-

2298

N1

- MALLOTUS PHILIPPINENSIS h e l l .

2299

N1

-

RN

-

2300 N 1 RN 2301

N1 RN

2302

N1

2303

N1 RN

2304

N1 RN

2305

Nl

2306

N1 RN

2307

N1 AN

2308

N1 RN

2309

N1 RN

2310

N1

2311

N1 RN

2312

N1

2313

N1 RN

2314

Nl

RN

2315

N1

2316

N1 RN

2317

N1

2318

N1 RN

2319

Nl

2320

N1

2321

Nl RN

- 1123-61-1

---

2.3-OICMLORO-M-METHYL-

MALLOTUS PHILIPPINENSIS b e l l . Arg., Arg.,

c a p s u l e hairs extract

MALONIC ACID, BUTYL-r MON011~2-DIPHENYLHYORAZIDE)r CALCIW SALT (2:l) 34461-73-9 HALONIC ACID 156-80-9

ION12-I

MALTOSE 69-79-4

- HALVAVISCUS CONUTTJ keemn.. f l o w e r e x t r a c t -- Dl29883-15-6 - )-HA~ELONITRILE-beta-O-6ENTIOBIOSIDE WELD NIT RILE^ betm-0-GENTIOBIOSIDE -- 0.L-MA 51371-34-7 CHLORIDE 11:2) -- HANGANESErII) 7773-01-5 -- MANGANESEIII) CHLORIDE TETRAHYDRATE 13446-36-9 DIOXIDE -- MANGANESE 1313-13-9 fElHVLENEBISlDITnIOCARSAHAT0))-- MANGANESE, 12427-38-2 - MAUNGANESEp IETHYLENEBISIDITMIOCARB~T0)- and ZINC ACETATE ( 5 0 : l ) -- MANGANESE OXIDE 1317-35-7 - MANNITOL, 1~6-BISll2-CHLOROETHVL~A~NO~-l~6-DIOEOX~-~ DIHYDROCHLDRIOEBD- 551-74-6 -- MANNITOL. 1.6-DJBROMO-1.6-DIDEOXY-r D488-41-5 - MANNOSE, 6-CHLORO-6-DEOXV-

-

MASWIN

--

HENTHA ARVENSIS Linn..

-- MAVTANSINE 35846-53-8 - HEDICAGO SATIVA -- HELAHINEt HEXMETHYL645-05-6 MENTHA ARVENSIS. e x t r a c t

p-HENTHANE e 1.8-EPOXY470-82-6

l e a f extract

136 2322

N1 RN

2323

N1 RN

2324

N1 RN

2325 N1 RN 2326

N1 RN

2327

N1 RN

2321)

N1 RN

2329 N1 RN

2330 N1 RN 2331 N 1 RN

2332 Nl RN

2333 N1 RN 2334

N1 RN

2335 Hl RN 2336

N1 RN

2337

N1 RN

2338 N1 RN

2339 N1 RN

2340

N1 RN

2341

N1 RN

2342 N 1 RN

2343 N 1 RN 2344

N1 RN

2345

Nl RN

2346

Nl RN

2347 N1 RN 2340 N l RN

-----

NERCURY 7439-97-6 NERCWY. IACETAT0)PHENYL62-38-4 MERCURY, IlO-CUIB0XYPHENYL)THlO)ETHrL-r 54-64-8

SOOIW SALT

MERCURYIII) CHLORIDE 7487-94-7

-- MERCURY, CHLORDETHYL107-27-7 -- HERCURY. CHLORWETHYL115-09-3 -- BERCURYp I3-CYAmKiUINIDINO)METHYL502-39-6 -- 627-44-1 ttERCURYv DIETHYL-

-

PIEREVRYs IDIHYDRDGEN 7r12-81Sll-HYDRDXYETHYL~-3rUrlf~17~TETR*WETnYL~2rl1)~ PORPNINEDlPROPIONATEL2-) 1-t DISODIUDl SALT 15375-94-7

--

BERCURYr IHYDRDGEN PHOSPHAT0)BISlETHYL2440-45-1

-- MERCIRY, IDXHVDROGEN PHOSPHATO)METHYL* 92787-44.3 -- BERCURY. ETHYLlPHOSPHATOIl-))2235-25-8 -- MERCURY HYDROXYBETHYL1184-57-e - HERCURYtII) IODIDE - 7774-29-0 -- MERCURYs (METHANETH1OUTD)METHYL25310-48-9 -- H22967-92-6 E R C U R Y I ~ ~ )METHYL-r B IDN -- WERCURYIII) OXIDE 21906-53-2 -- BETANILAtlIDEt 6-SULFANILYL17615-73-5 ACIDS BUTYL ESTER -- PIETHACRYLIC 97-80-1 9

---

-----

--

BETHACRYLIC ACIDS ETHYL ESTER 97-63-2 BETHACRYLIC ACID, ISOBUIYL ESTER 97-86-9 METHARCYLIC ACIDS 2-ISCCYANATOETHYL'EITER 30674-10-7 MTHACRVLIC ACID, 29964-84-9

ISODECYL ESTER

METHACRYLIC ACID, HETHYL ESTER

80-62-6 HETHANEARSWIC ACID, DISODIIM U L l 144-81-8 HETHANE, M X Y 25843-45-2 METHANE, CHLORO74-17-3

137 2349

Nl RN

2350

N1 RN

2351 N l RN

2352

N1

RN 2353

N1

2354

Nl

2355

N1

-- METHANE, CHLORODIFLWRO75-45-6 -- HETHANEv DICHLORO75-09-2

--

METHANEI DICHLOROFLUORO75-43-4

-- METHWEDIOLs DIMETHANEWLFWTE 156-72-9 - HYDROCHLORIDE HETHANESULFONANILIDE, 4'-II-IDIMETHYLAHINO)PROPIWYL)-, - METHANEWLFONANILIDEr

~ ' ~ ~ ~ - I H E X A H Y D R O - ~ H ~ A Z E P I N ~ ~ ~ Y L ~HYDROCHLORIDE PROPI~YL~~D

2356 N l 2357

N1 RN

2358

Nl

2359

N1 RN

2360

N1 RN

2361

N1 RN

2362

N1

RN 2363 N 1 RN

2364 N 1 RN 2365

N1

2366

N1 RN

2367

N1

2368

N1

RN

RN

2369

N1 RN

2370

N1

- METHANESULFONANILIDEI HYDROCHLORIDE - HETHANESULFONANILIDEs HYDROCHLORIDE

---

METHANEWLFONIC ACID,

-

-

4'4

3-Il-PYRROLIDINYL)PROPIWYL)~~

( A N l I P Y R I N Y L N E T H Y l M D ) ~ ~narrSWIUl

METHANESULFONIC ACID.

ETHYLENE ESTER

METHANESULFONIC ACID. 926-06-7

ISOPROPYL ESTER

PROPYL ESTER

2~6-HETHANO-3-BENTALOCIN-~-OL~ ~~~~~~~~~~~-HEXAHYDRO-~-~CYCLOPRDPYLNE~YL~~D~~-DI~ET~YL3572-80-3 2~6-HETHANO-3-BENZAZOCIN-8-OL~

1~2~3~4r5~6-HEXAHYDRO-6~ll-DIMETHYL-)-(SENYL~- 359-83-1

2,6-nETHAND-3-BENZlIN-8-DL~ 1~2~3~4~5~6~HEXAHYDRO~6~ll~DIME~YL~3~l3-ME~YL-2-B~ENYL~-~ HYDROCHLORIDE 2276-52-0

- 2~6-METHIU30-5-BENZAZOCOCIH-b-OLr ~ I ~ ~ ~ ~ ~ ~ ~ ~ ~ - H E X I H Y D R O - ~ ~ ~ ~ ~ DHYDROBROnIDE I M E ~ Y L ~ ~ ~ ~ E N E T H Y L - ~

-

1239-04-9 1,6-~ETH*NO-lH-4-BENZILONIN-lO-OL~ 2 , 3 , 4 ~ 5 , 6 ~ 7 - H E ~ H Y D R O - l ~ ~ - D I M E T H Y L -HYDRWOMIDEr r t-)72150-17-5

HEWHYDRO-, -- 4~7-llETH*NOIH)ANr 2825-82-3 - .~~~-METHANOINDANI ~Ph~-1,2~4~5.6rlr6~8-~1~~O-kr9.7.70- ~D~-METHANOINDAN, l-alpha~2-alpha,4-b~ta~51617-b~t~~~~8-~TACHL~O-~-~lph~,4~7~7~-RXO-

-

alpha- TETRAHYDRO5103-71-9

RN

2371 N l

RH 2372

N1 RN

2373 N1 RN

SALT

68-89-3

-- METHANEWLFONIC ACID, 1912-31-8

-

4'-13~IPHENETHYLAIIINO)PROPIWIYL)-~

--

METHANOL1 IfETHYL-oH(-MD(I)-. 592-62-1

ACETATE I n t e r )

138 2374

Nl RN

2380

N1 RN

2381

N1 RN

2382

N1 RN

2383 N1 RN

2384 N I RN

2385 N1 RN 2386

N1

2387

N1 RN

2380

N1 RN

2389

N1 RN

2390

N1

2391 N1 2392

Nl

2393

N1

2394

N1

2395

N1

2396

N1

2397

N1

2398

N1

2399

N1 RN

2400

N1

RN

RN

RN

--

NETHANOL, 53532-37-9

1~3,4~THIADIIZOL-2-YLIMI~I-

-- METHIDNINE. DL59-51-8 -- WETHIDNINED 163-68-3 -- METHYL SULFOXIDE 67-68-5

--

METIRAM, METHYL8064-35-5

-- MINERAL OIL 8012-95-1 -- NITHRAMYCIN 18378-89-7

--

WILA1 HDLYBDENUN 7439-98-7

ACID, DISOaIUn SALT -- MOLYBDIC 7631-95-0 -- MOLYBOIC ACID, D1SW)IUH SALT, 10102-40-6 - alpha-MOWORCHARIN

-

DIHYDRATE

beto-HOMORCttARIN MONTANOA TOMENTOSA, l e a f e x t r a c t MONTANOA TOMENTOSIB leaf extrmct. crude I"TANOA

TOnENTOSA, leaf e x t r a c t . r m i - p u r i f i e d

- m)RINGA OLEIFERA Lamk., e x t r a c t e x c l u d i n g r o o t r - MORINGA PTERYGOSPERMIJH, ROOT EXTRACT - M0RPHININ-3~6-alpha-010L. 17-ALCVL-7r8-OIOEHIORO-4~5-a~pha-EWIXY-~ HYDROCHLORIDE - 57-29-4 - HORPHINAN-~,~~-DIOLI 17-ICYCLWUTYLVETHYL)-, ~S-fR*~R*~~~2~3-DIHTDROXYBUTANEO I1:l) I T E (SALT) - 58786-99-5 -- MDRPHIWN-3r6-a~phm-DIOLr 7~8-DIDEHYDRO-4,5-mlpha-EPOXY-l7-METHYL57-27-2 - MDRPnINAN-3~6-alpha-DIOL~ 7.8-DIDEHYDRO-4,5-alphm-E~XY-l7-ME~YL-~ DIACETATE I e r t r )

-

561-27-3

139 2401 N1

-

MORPHINAN-3,b-alpha-DIOL, 7~8-DIDEHYDRO-4,5-alpha-EPOXY-l7-METHYL-,

RN 2402 N1 RN 2403 N1 RN 2404 N1

- MORPHINAN-~I~-DIDL, ~.~-DIDEHYDRO-~,~-EPOXY-~~-~ET~~L-I (5-olphil,6-olpha)- HYDROCHLORIDE, 52-26-6 -

- VDRPHINAN-3,6-alpha-DIOL, 7s8-DIDEHYDRO-4.

-

-

2406 Nl

-

RN

RN 2408

N1 RN

2409 Nl RN 2410 N1 RN 2411 N1 RN 2412’ N1 RN 2413 N1 RN 2414 N1 RN 2415 N1 RN 2416 N1

VDRPHINAN-~B~-DIOL, ~~~-DIDENYDRO-~B~-EPOXY-~~-HE~HYLHONOHYDRATE

f S-irlpba,b-alpha)-. - 6009-81-0

RN 2405 N1

2407 N1

-

SULFATE 64-31-3 MDRPHINAN-3,17-DIOL. TARTRATE 12:l)P 15-slpha-EPOXY-17-METHYL-,

MORPHINAN-6-~lpha-OL, 7,8-OIOEHYDRO-4.5-alpha-EPOXY-3-ElHOXY-l7-METNYL-~ HYDROCHLORIDEI OIHYDRATE 6746-59-4 MORPHINAN-6-alpha-OL~ 7,8-DIDEHYDRO-4.5-alpha-EPOXY-3-MElHOXY-l7-METHYL76-57-3

- MORPHINAN-6-alpha-OL~ 7,8-DIDEHYDRO-4.5-alpha-EPOXY-3-METHOXY-l7-METNYL-~ -

2417 N1 RN 2418 N1

PHOSPHATE

r1:11 52-28-8 MORPHINAN-6-alpha-OL. 7,8-DIDEHYDRO-Q.5-alph.-EPOXY-3-METHOXY-l7-MElHYL-, I SALT 1

SULFATE 12:11

- HORPHINAN-3-OLs 17-METHYL-, I - 1 - 77-07-6 17-METHYL- 9-alpha~13-alpha114-alpha-MDRPHINAN-3-OL~ - 125-73-5 - MORPHINAN-~-OLI17-METHYL-, TARTRATE 11:l) (SALT), 1-1- 125-72-4 - MORPHINAN-6-ONEI 4s5-alpha-EPOXY-3,14-DIHYOROXY-17-METHYL-~ HYDROCHLORIDE - 357-07-3 1420-53-7

4~5-alpha-EPOXY-3114-DIHYDROXY-17-~Z-PROPENYL~-- MORPHINAN-6-ONE, 465-65-6

-

MORPHINAN-6-ONEB 4~5-EPOXY-3~14-DIHYDROXY-l7-lZ-PROPENYL)-~ HYOROCHLDRIDE, 15-alpha 1357-08-4 MORPHINAN-6-ONE. 4,5-alpha-EPOXY-3-HYDROXY-l7-MElHYL-~

IS’-alpha - HYOROCHLDRIDE 71-68-1 - MDRPHINAN-6-ONE1 4~5-alpha-EPOXY-3-~ETHOXY-l7-METNYL-, TARTRATE 11:11 1-

I

RN

DIACETATE fmrtmrl

HYDROCHLORIDE 1502-95-0

- 34195-34-1 - MORPHINAN,

6,7.8,14-TETRADEHYDRO-4,5-alpha-EWXY-3~6-DIMETHDXY-l7-MElHYL-,

RN 2419 N1 RN 2420 N1 RN 2421 N1

HYDROCHLORIDE HYDRATE 850-57-7

- VORPHOLINE 4-IN-I 1 4-BENZODIOXAN-2-Y LMETHYL 1GLYCYL 1- 3562-90-1 - MORPHOLINE 2-CHLDROETHYL- HYDROCHLORIDE - 3647-69-6 - MORPHOLINE, 9

I

n

4-~2-lp-lalph~,bcts-DIMETHYL-p-METHOXYSTYRYL1PHENOXYlE~YLl-,

RN

I E 1- HYDROCHLORIDE, 15542-14-0

140 2422 N1 RN 2423 N1 RN 2424 N1

6,5-0IHEMYL-2-RlENYL-, HYDROCHLORIDE -- MORPHOLINEt 36981-93-8 -- HORPHOLIHE, 2,6-DI~ETHYL-N-TRIOECYL24602-b6-6 - MPHOLINE, E - 0IHYDROUIU)RIDE 21853-06-5

4~4'-tDIHETHYLVIMLENE)8IS(p-PHENTLENliOm)DI-~ I t )-

RN 2425 H1

2426 N1 2427 N1

RN 2428 N1 RN 2429 N1 RN 2430 Nl RN 2431 Nl 2432 N1 RN 2433 Nl

RN 2434 N1 2435 Nl 2436 Nl AN 2437 N1

RN 2438 N1

--

HORPHOLINE, 4-1 2-1 p - l 6 - ~ E M O X T ~ 2 ~ R l E N I L ~ 3 r 4 - D I H I D R O ~ l ~ N * R)I TPHHYEL W )ETHYL)-I HYDROCHLORIOE HORPHOLINEI 4-(2-lp-(6-HETHOXY-2-PHENYL-2-I~ENYL)PHENDXY

)ETHYL)-

MPHOLINE, 3-HLTHYL-Z-PHENYL-, HYDROCHLORIDE 1707-14-8

-- MORPHOLINEe 4~~2~l5~NITROIHIDALOL~l-YL)ETHYL~6506-31-2 N-NITRWO-- MDRPHOLINE, 59-w-z -- IIORPHOLINE, 4-1 35619-65-9 MONOSPERHA axcludlng -- MLLDAHINE 36069-45-1 -- WLDAHINE DEACETYL36069-46-2 3,4r5-TRIHETHOXYTHIOE~OYL)-

DC. 4x Wlght, e x t r a c t

HUCUNA

roots

I

-

MUSTARD, protein cmcmtratm

- HYCOTOXIH F-2 -- 9004-99-3 52 nvRJ

- 2-NAPHTHACENECARBOXAIlIDE 7-CHLORO-4-~DIHEYHYLA~I~l~l~4~48~5~5~~6~ll~l28~~TAHYDRO~ s

- 2-NAPHTHACENECARB~IDEr 3 r 6 ~ 1 O ~ l Z ~ l 2 ~ ~ P E N T A H Y D R O X Y ~ l ~ l l -~ONOHYDROCHLORIDE DIOXO-~ - 64-73-3 - 2-NAPHTHACENECARBOXAMIOE~ 7-CNLORO-4-lDIHETHYL~I~~-lr4148,5rS.rbYDRO3r6.10~12r12a-PENTAHYOROXY-6-nETHYL-l~ll-DIOXO- 57-62-5 - ~-NAPHTHACENECARBOXAHIOEI 7-CHLORO-4-~DIHETHY~I~~-1r4.4~.5~5ar6~llr12a-OCTIHIDRO3 ~ 6 ~ 1 0 ~ 1 2 ~ l ~ ~ - P E N T A H Y D R O X Y ~ 6 ~ M E T H Y L ~ l MONOnYDROCnLORIDE ~ll-DIaYO~~ - 64-72-2 3~6r10~12~128~PEHTIHYDR~Y~l~ll~DIOW)~ 127-33-3

7-CHLORO-4-fDIHETHYLA~I~~-l~40,5rlalTAHYDRO-

RN 2439 N1

RN 2440

N1 RN

2441 N1 RN 2442 N1 RN 2443 N1 RN

- 42-NAPnTHACENECARBOXAHIDE. -iDI~ETHYLUIlNO~-l~4,4~~5~58~6~ll~l2~~OCT~YDRO~3~5~6~lO~l2

- HEXAHYDROXY-6-HETHYL-1~ll-DIOXD79-57-2 - 2-NAPHTHACENEC*RBOXAHIDE. 4-1DI~ETHYLAHINO~-1~414~,5,5a~6~11~12a-OCTAHYDRO-3~5~6~lO~l2~12~HEXAHYOROXY-6-~ETHYL-l~1l-OIOXO-~ MONOHYOROCHLORIDE - 2058-46-0 - 4-fDIHETHY )-1 r4 ,595. ,I1 121-OCTAHYDRO-3r6~ 1 120 ,lea-

-

2-NAPHTHACENECARBOXAnJDE. LAHINO &I 96 PENTAHYDROXY-b-HETHY~-la Il-OIaYO-

60-54-8

I

v

141 N1

-

RN

-

2445 N 1

-

2444

RN

2446 N1

2-NAPHTHACENECARBOXAMIDEt 4-lDIMETHYLAMINO~-1.4,~,5,5ar6,11~12a-OCTAHYDRO-3r6~1O~l2~l2~PENTAHYDROXY-6-METHYL-l~ll-DIDXD-~MONOWYDROCHLORIDE 64-75-5

2-NIPHTHACENECARBOXAMIDE~

4-lDIMETHYLAMINO~-1,4,4a.5.5a~6,11.12a-~TAH~R~-3~6~lO,l~~12aPENTAHYDROXY-6-METNYL-l~ll-DIDXD-N-ll-PYRROLIDIHILnETHYL~~

N1

-

RN

PENTAHYDROXY-6-METHYL-9-lM~PHOLINDnETnY~ll-DIDXO- 67238-91-9

RN 2447

-

2-NARITHACENECARBOXMIDEr 4-lDI~ETHYWIINO~-1~4~4a~5~5a~b~ll~12a-OCTAH~RD3,5.10,12r12a-PENTAHYDRDXY-6-METHYL-l,ll-DIDXD-, MONOHYDROCHLORIDE 10592-13-9

2448 N 1

-

751-97-3

2-HAPHTHACENECARBOXAMIDE~ 4-1DIMETHYLAM1NO~-1~4~4~~5rkr6r11~12a-~1AH~R0-3~6~10~12~12~-

1-NAPHTNACENECARBOXYLIC ACID,

2-ETHYL-1~2~3~4rb~ll-HEXAHYDRD-2~5~7-TRIHYDROXY-b~ll-DIOXD-4~ Il2.1.6-TRIDEOXY-4-0-l2~6-DIDEOXY-4-0-~lZR-tr~n~~-TETRAHYDRO-6-METH~LXDXD-ZH-PYRAN-Z-YL)

~Ipha-L-lyxo-HEXOPYRANOSYL~-3-lDIMETHYLAMINO~-~lpha-L-ly~o-NEXDPYRN 2449

N1 RN

2450

N1 RN

2451

N1 RN

METHYL ESTER, (1R-ll-alpham2-beta,4-beta)1- RANOSYL)DXY)-l 57576-44-0 -- NAPHTHALENE 91-20-3 -- 81-NAPHTHALENEACETIC ACID 6-87-3 - 2-NAPHTHALENEACETIC ACID, 6-METHOXY-aloha-METHYL-* SWIW S*LTe L - I - 1-

-

26159-34-2

- 1,5-NAPHTHALENEDIAMINE

2452

N1 RN

2453

N1 RN

- 2243-62-1 - NAPHTHALENEI - 6240-55-7

2454

N1

- NAPHTHALENE,

2455

Nl

-

2456

N1

2457

N1

2458

Nl

1,2-DICHLORD-3-NITRO-

1,2-DIHYDRO-S~4-DIPHENYL-7-ME~OXY-

NAPHTHALENE, 1~2-DIHYDRO-4-lp-l2~3-EPOXYPROPDXY)PHENYL)-7-METHDXY-3-R1ENYL-

- NAPHTHALENE

1,2-DIHYDRO-4-1 p-FLWOPHENYL )-7-METHOXY-3-PHENYL-

RN

- NAPHTHALENES 1,2-DIHYDRO-7-METHOXY-3-PHENYL-Q-(p-TOLYL)- 52,3-NAPHTNALENEDIOL, -l3-l11~1-DIMETHYLETHYL~AMINO1-2-HYDROXY~O~XY~-l~2~3~4-TETRAHYDRO- 42200-33-9

2459

Nl RN

-

2460

N1 RN

8-AMINO-7-HYDROXY-,

MDILM SALT

- 2,7-NAPHTHALENEDISULFONIC ACIDn 3~3'-ll4~4'-BIPHENYLYLENE~BISlAZO~~BISl5-MINO-4-HYDROXT-~ SALT - TETRASWIUM 2602-46-2

2461

N1 RN

2462

N1

-

RN

-

N1

-

RN

-

2463

3*6-NAPHTHALENEDISULFONIC ACID, 2007-20-7

3.6-NAPHTHALENEDIWLFONIC ACID, 3545-86-8

1~7-DIAMIN0-8-HYDROXY-

2.7-NAPHTHALENEDISULFONIC ACID. 3 p 3 ' - I I 3 t 3' -DICHLORO-4,4 ' -BIPHENY LY LENE ) - B I S l A20 1 ) B I S I 5-AMINO-4-HYDROXY-, TETRASODIUM SALT 47897-65-4 2,7-NAPHTHALENEDISULFMIC ACIDI 3.3'4 I 3,3'-DIMETHOXY-4.4'-BIPHENYLY LENE ) B I S I AZ0)BISI 5-AMINO-4-HYDROXY-s TETRASODIUn SALT 2429-74-5

142 2464

2465

N1

- 6,8-NAPHTHALENEDISULFDNIC ACID, 3~3'-1l3~3'-DIMETHOXY-4~4'-BIPHENYLENE~BISlAZO~BISl

RN

-

N1

RN 2466

N1 RN

2467

N1 RN

2468

N1

2469

Nl

RN

2470

~ - A M I N O - ~ - H Y O R O X Y - B TETRASOOIUM SALT 2610-05-1

- 61,3-NAPHTHALENEDISULFONIF ACID, .6l-1 I3*3'-DIHETHYL-4,4 -8IPHENYLYLENE ) B I S I A Z O ) 1 B I S I4-AHINO-L-HYDROXY-, TETRASODIUM SALT - 314-13-6 - 2,7-NAPHTHALENEOISULFONIC ACID, 3 ~ '3 - 1 I3 ~ ' 3 -DIMETHY L - 4 ~ 4-8IPHENY LY LENE ) B I S l A20 1 ) B I B 1 5-

AMINO-4-HYDROXY-p 72-57-1

TETRASOOIUM SALT

2,7-NAPHTHALENEDISULFONIC ACID, 3-HYDROXY-I

DISODIUM SALT

135-51-3

- D1*3-NAPHTHALENEOISULFONIC ACID, 7-HYDROXY-d-IPHENYLAZO)-, I S O D I U H SALT - 1936-15-8 - 2,7-NAPHTHALENEDISULFONIC ACID, 3-HYDROXY-4-ll4-SULFO-l-NAPHTHYL)AZO)-~ TRISODIUM SALT

RN

-

N1

AICDn - 1-NAPHTHALENEHEPTANOIC 1.2,6.7~8,8a-HEXAHYORO-be~a~del~m-DIHYDROXY-2~6-DIHETHVL-8-

915-67-3

12-METHYL-1-OXOBUTOXY

1-p

AHMONIUM SALT,

llS-ll-alphalbete-S*,delta-S*~~2-mlphm,6-b~ta, RN 2471

N1

1- 8-betalR*),8a-betm) 75225-51-3 1-NAPHTHALENEHEPTANOIC ACID, - 1~2~4~,5.6,7,8,8a-OCTAHYDRO-bet~~deltm-DIHYDROXY-2,6-OIMETHYL8-l2-HETHYL-l-OXO8UTOXY1-,

AMHONIL!PI SALT,

l1S-ll-alphall-be~a-Sr.delta-S*),2-alpha~6-beta, &beta1 Re) ,8m-beta 1)2472 2473

RN

-- 54-80-8 2-NAPHTHALENEt4ETHANOL,

N1

-

N1

RN 2474

N1

RN 2475

Nl RN

2476

Nl

RN 2477

2478

2479

N1

2-NAPHTHALENEPROPIONIC ACID, 3~4-DIHYORO-~lpha~mlphm-DIMETHYL-bet~-ETNYL-6-HElHOXY55620-96-7

- 2-NAPHTHALENEPROPIONIC ACID, 5620-97-8 - 53~4-DIHYORO-alphm,alph~-DIHETHYL-6-t4ElHOXY-b~t~-PROPYL2-NAPHTHALENEPROPIONIC ACID, - b~ta-ETHYL-6-METH0XY-mlpha.alphr-D1tiETHYL-

517-18-0 2-NAPHTHALENESULFONIC ACID, 28907-84-8

5-AMINO-,

S W I U H SALT

ACID, - 1-NAPHTHALENESULFONIC 3,3'-14,4'-BIPHENYLENEB1SlAZO1~BISl4-*nINO-r DISODIUW SALT

RN

-

N1

ACID, coinpd. w i t h - 2-NAPHTHALENESULFONIC l+1-alphm-l2-DIMETHYLAHINO1-1-METHYLElHYL-

RN

-

N1 RN

2480 N1

2481

~lpha-llISOPROPVLAt4IND~HETHYLl-

573-58-0

ACID, - 41-NAPHTHALENESULFONIC -HYOROXY-3-ll4'-Il1-HYDROXY-5-SULFO~2~NA~~ALENYL~UO)~ DISOOIUn SALT 420-06-0 - 63~3'-DIMETHYLllrl'-BIPHENYL~~4-YL~AZO1-~ 2-NAPHTHALENESULFDNIC ACID, - 6-HYDROXY-5-116-METHDXY-4-SULFD-rn-TOLYL)AZO)-~ D I S O D I W SALT

RN

-

N1

- NAPHTHALENE 1 2 3,4-TETRAHYDRO-2-(

25956-17-6 v

I

p-CHLORDPHENY L b l - l p - I

YL)-

2482 N 1

alpha-PHENYLPHENETHVL

PROPIONATE 11: 1) 17140-78-2

-

2-NAPHTHALENEVALERIC

ACID,

5.6,7,8-TETRAHYORD-mlpha,alpha-DIHElHYL-

e 8 3-EPOXYPRDPOXY

IPHEN-

143 2483 N1 RN

- 112H)-NAPHTHALENONE, 7 - C H L O R O - 3 ~ 4 - D I H Y O R O - Z - l 3 - P Y R I O Y L ~ ~ - 786-97-0

2484 N1 RN

-

2485 N1

11 2 1 )-NAPHTHALENONEr 7-CHLORO-3~4-0IHVORO-2-13-PYRIOYL 1786-97-0

- O11C2HT)-NAPMTHALENONE A H I D R O - ~ - ~ ~ ~ ~ - I S O P R O P ~ L - ~ ~ - ~ ~ ~ ~ ~ ~ ~ ~ - ~ ~ P ~ ~ - O I M E T H Y L - ~ SEHICARBAZONE I - 1 - NAPHTHOl2rl-b)FURAN~ 2-PHENYL-1-1p-12-11-PYRROLIOINYL)ETHOXY )PHENYLl- 2-NAPHTHOIC ACID, 4r4'-METHYLENEB1S13-HYOROXY-, e s t e r uith 2-1 2-1 4-1 p-CHLORO-alphaI

9

24.36

N1

2487 N1 RN 2488 N1

RN 2489 N1 RN

2490 N1

2491 N1 RN 2492 N1

2493 N1 2494 N1 2495 N1 24%

N1

2497 N1 2498 N1 2499 N1 RN

2500 N1 RN

2501 N1

RN 2502 N1 RN 2503 N1 RN 2504 N1 RN 2505 Nl RN 2506 N1 RN

2507 H1 RN

-

PHENYLBENZYL)-l-PIPERA~INYL)-ETHOXY)ETHANOL 5978-92-7

- 2-NAPHTHOIC ACID, 4,4'-METHYLENEBISl3-HYDROXY-r compd. uith IE1-1~4~5~6-TETRAHYORO-l-METHYL2-l2-12-7HIENYL)VINYLlPYRIHIOINE -

11:11 22204-24-6 1-NAPHTHOL

- 90-15-3

-

2-NAPHTHOLI 7~8-DIHYDRO-6-PHENYL-5-lp-l2-PIPERIOINOETHOXY~PHENYLl-~ HYOROCHLORIOE

-

2-NITROSO- 1-NAPHMOLe 132-53-6

-

1-NAPHTHOL, 192 t 3~4-TETRANYDRO~l~lp-I 2-1 DIETHYLAMINOIETHOXY IPHENYL )-L-PHENYL-, HYOROCHLORIDE

- 1-NAPHTHOL. 1.2.3.4-TETRIHYDRO-1;2-DIPHENY 1-(-METHOXI- 11-NAPHTHOL, ~2~3~4-TETRAHYORO-1-(p-FLU~OPHENYL~-6-METHOXY-2-~ENYL- 1-NAPHJHOL. 1 ~ 2 ~ 3 r 4 - T E T R A H Y O R O - 6 - ~ E T H ~ X Y - l - ~ E N Y L - 2 - l 3 - P Y R L O Y L ~ -

I-NAPHTHOL, 1~2~3~4-TETRAHYORO-6~METHOXY-2-PHENYL-l-~L-PYRIDYLl-

- 1-NAPHTHOL, 1~2~3~4-TETRAHYORO-6-METHOXY-2-PHENYL-l-l4-PYRIOYL~- 1-NAPHTHOL. 1~2~3~4-TETRAHYORO-6-METHOXY-2-PHENYL-l-l~-TOLYL~- lH-NAPHTHOl2~1-b)PYRAN-l-ONE~ 3-PHENYL- 6051-87-2 - 1~4-NAPHTMOQUINONE - 130-15-4

-- 6954-48-9 I I ~ - N A P H T M W I J I ~ 6-BROHOWE~ - 1 , 4 - N A P H T H O W I ~ E v5-HYDROXY-2-METHYL- 481-42-5

- lr4-NAPHTHOWINONE, 2-METHYL-

- 58-27-5 - ~B~-NAPH~HWUINONE, 2-METHYL-3-~3~7~11~15-~ETRAMETHYL-2~6r~O~l4~HEXADECATETRAE~L~~ - 863-61-6 - 2-NAPMTHYLAMINE - 91-59-8

- 2-NAPHTHYLAMINE. 13115-28-1

-

3-NITRO-

lp2,3,+TETRAMYDRO- 2-NAPHTHYLAMINE, 2954-50-9

2508 N1

-

RN

-

1.3rS-N*PnTHYLENEIRIWLFaSIC ACID, 8.8'-IUREYLENEBISIm-PHE~LENECARB~LI~I~l~-METHYL-

111-PHENYLENE)CARBONYLIHINOl)DI145-63-1

144 2509 Nl RN 2510 N1 RN 2511 N1 2512 N1 RN 2513 N1 RN 2514 N1 RN 2515 Nl RN 2516 N1 RN 2517 N1 RN 2518 Nl RN 2519 N1 RN 2520 N1 RN 2521 N1 RN 2522 N1 RN 2523 N1

RN 2524 N1 RN 2525 N1 2526 N1 IN

2527 Nl RN 2528

N1 RN

2529 N1 RN 2530 N1 RN 2531 H1 RN 2532 N1 RN 2533 Nl RN

2534 Nl RN

-

1~8-NAPHTHYRIDINE-3-CARBOXYLICACID,

-

NEOPROSERINE

- 389-08-2 -- NEOCARZIND¶TATIN 9014-02-2

l-ETHYL-1~4-DIHYDRO-7-~TNYL~4~OXO-

-- NEURAMINIDASE 9001-67-6 -- NICKEL 7440-02-0

-- NICKEL(I1) ACETATE 11:2) 373-02-4

--

NICKEL CAR8DNYL 13463-39-3

-- NICKELIII) CHLORIDE ll:2) 7718-44-9 NITRATE (l:2) -- NICKEL(I1) 13138-45-9 -- NICKEL(f1) SULFATE HEXIHYDRATE 11:1:6) 10101-97-0 -- NICKEL SULFIDE l3:2l 12035-72-2 -- NICOTINE 54-11-5

-- NICOTINE, TARTRATE 11:Z) 65-31-6 -- NICOTINIC ACID, 2-1 3-CHLDRO-o-TOLUIDINO)17737-65-4 - NICOTINIC ACIOI eoavpd. uith 3s 7-DINYDRO-7-( 2-HYDROXY-3-( 4 2-HYDROXYETNYL 3 ETHYLIEIINO~PROPYL~-~~~~DI~ETHYL~~H~~INE-~D~~DIM~E - ~437-74-1 -- NICOTINIC ACID, NEOPENTANETETRAVL ESTER 5668-04-3 - NICDTINIC ACIDS 3-PYRIDYLHETHYL ESTER, FUrURATE - NICOTINIC ACID, l,lt3r3-TETRAESTER wlth L-~ROXY-~,~D~.~-CYCLOHEXINETETRA~ETN~L - 21959-26-0 ACID, 2-1olphm~mlpha~a~phm-TRIFLUORO-m-TOLUIOI~~-- NICOTINIC 4394-00-7 ).(oHwoOIu( S*L1 -- NIGERICIN. 2M43-80-3 -- NITRIC ACID 7697-17-2 -- NITROGEN DIOXIDE 10102-44-0

-- NITRDOEN OXIDE 10024-97-2 -- NITRDOLYCERIN 55-63-0 ACID, SODIlM -- NITROUS 7632-00-0 -- 4248-77-5 lr9-"ANEDIOL. DIHETHANESULFWATE SALT

146 2535 N1 RN

- 2r4m6r8-NONANETETRAENOIC ACIDS 9-14-NETHOXY-2.3.6-TRIHETHYLR(ENYL)-3r7-DIMETHYL-r - trans- a11 54350-48-0

2536 N1

-

2537 N1

-

RN

-

7-NONENOIC ACID, 9-f 5-HYDROXY-2-l3-HYDROXY-1-DCTENY f lR-(l-alphmlZ)~2-beta(1E13S*).5-alpha))64072-63-5

m

-

~-NDNEN-~-ON€I

2536

ETHYL ESTER,

2r4~6i8-NONATETRAEN-l-INI~, N~3~7-TRIMElHYL-9-12~6~6-TRIMETHYL-l-CYCL~EXEN-l-YL~-r N-OXIDE, mll-trons-

9~f3~HYDROXY-6~l2-HYOROXYETHYLIDENE~~2~NETHYL~2~DXEPAEL~-2~6-DI~-

125-12-alpha-l5*),3-beti.6E I - ETHYL-. 71117-51-6 -- "OXYNOL-9 26027-38-3 - A-NOR-5-slph~-A~DSTANE-2-alph.~17-b~ta-DIOLr 2-ETNWL)-

RN 2539 N1 RN 2540 N1 2541 N1 2542 N1

-

A-NOR-5-mlpha-*H)ROE-2-b~ta~l7-beta-DIOLe

2-ETHYNYL-

- A-WOR-S-alpha-~ROST~E-2-beta~l7-beta-DIOLe 2-mlpha-ETHWL-

2543 N1

- 17-ACETATE

2544 N1

- A-NDR-5-mlph.-~ROSl~E-2-~lpha~l7-beta-DIOL-~ 2-ETHYNYL-s DIACETATE

2545 Nl 2546 N1 2547 N1 2548 N1 2549 N1 2550 N1 RN 2551 N1

RN 2552 Nl RN 2553 N1 RN 2554 N1 2555 N1 2556 N1

A-NOR-5-alpha-A,M)ROST*NE-2-beta,l7-betm-DIOL~

- OIACETATE

A-KXI-5-mlph.-*H)~T~E-2-betmtl7-beta-DIOL, Iester 1

2-ETHYNYL-8

2-alpha-ElNYNYL-.

- A-NORIH)ROSTANE-2-b~ta,l7-beta-DIOL. 2-rlpha-ETHYNYL-l7-.lpha-NETHYL- 1-NOR-5-.lpha-A~WAN-l7-~E, 2-alpha-ETHYNIL-2-HmR~-

-

A - N O R - 5 - a l p h a - ~ O T ~ - 1 7 - a 3 E r 2-beta-ETHYNYL-2-HYOXY-

- A-FIOR-5-alpha-ANDROSl~-l7-betm-~E. 2-alpha-ETHYNYL-2-beta-HYDROXY-- B-NDRAH)ROST-4-EN-3-ONEl 17-b.t.-HIDROXY-II-BElNYL3570-10-3 -- 7-NORBORNANECIRBOXIU)EnrDL. ls7-DIFlElHYL-2-OD(O-r t r m s 20231-45-2 -- ~113-48-4 - N O R B M I N E N E - ~ ~ ~ - D I C A R ~ O X Z NN-f2-ETHYWEXYL)IDEI

- SULFITE 5-NDRBORNENE-Lr3-DINETHANOLr 1.415,6r7,7-HEXICHLO0-1 - 115-29-7

CYCLIC

- 19-NORC*RDA-l~1~511O~-~IENOLIDE~ 3-IlElHOXY- 19-NORC*ROA-I~3~5~lO~-TRIENOLIDE~ 9-HETHOXY-11-OXO-

- 20-NORCROTALAN*N-Il~lS-DI~E~ 14~19-DI~YDR0-13-HYOROXY-~ fl2-xi~13-xi - 6029-87-4 )-

RN 2557

m RN

2558 N1 2559 N1 RN 2560 N1

- 29-NORD*rmRA-17f20)~24-01EN-21-01C ACID, 16-fACETYLOXY)-3~11-DIHYOROXr-1 f3-alphat4-alpha,

- 6-alphr.9-beta.ll-alpha.l3-rlphm,l4-beta.~6-b.t~6990-06-3 - 1 8 - ~ E S T R A - 1 ~ 4 - D I E N - 3 ~ 1 7 - D I O N Z IlO-NYDROXY-.

ACETATE (ester)

- 19-NW-9-b~tarlO-m1ph~-~NOST-5-ENE-3~ll.22-TRIONE~ 9-BETHYL- 2-mlpha.16-alph..20125-TE~~Y~~990-83-0 - NORLEWINE. 6-MIDIND-, MONOMYDROCHLMIIDE~HYDRATE

2561

N1 RN

2562

N1

2563 2564

-- NORLEUCINEm 6-DIALO-5-OXD, 157-03-9

L-

-

19-NOR-17-alpha-PREG-4-EN-17-OL,

N1

- 19-NOR-17-mlpha-PREGNA-4~20-DIENE-3~17-DIDL~DIACETATE

Nl

-

19~NORPREGNA-4~6-0IENE-3~2O-DIONE~

19-NORPREGNA-4~6-DIENE-3~11~2O-TRIONE

21-HETHYLENE-

2565

N1

2566

N1 RN

ACETATE - 6,11-beta-DICHLORO-l7-HYOROXY-,' 24832-00-6 - ACETATE lP~NORPREGNA-4,6-DIENE-3,ZO-DIONE, 17-mlphm-HYDROXY-6-HETHYL-r -- 619-NORPREGNA-4,9-DIENE-2l-NITRILE, 17-HYDROXY-3-0XO-, 117-mlphm)5928-58-7

C567

Nl

-

2508

N1 RN

2569

N1

2570

N1 RN

2571

N1

2572

N1

2573

N1

RN

RN 2574

N1

2575

N1

-- 6795-60-4 19-NOR-17-alphm-PREGNA-4,2O-DIEN-3-ONE~ 17-HYDROXY- 19-NORPREGNA-3,5-OIEN-2O-YNE-3-beTd,l7-b~Tm-DIOL~ OIACETATE - 19-NOR-17-mlpha-PREGNA-3,5-OIEH-eO-YNE-3~17-DIOL~ DIACETATE - 2205-78-9 - 19-NOR-17-mlpha-PREGNA-4,4-DIEN-2O-YNE-3,17-DIOL~ DIACETATE - 19-NOR-17-alpha-PREGNA-4,6-OIEN-2O-YNE-3,l7-beTa-DIOL~ DIACETATE - 19-NOR-17-alphm-PREGNA-3,5-DIEN-2O-YN-l7-OL, 3-lCYCLOPENTYLOXY)-, ACETATE -

3000-39-3

19-NOR-17-alpha-PREGNA-4,6-OIEN-2O-YN-3-ON€, 17-HYDROXY-,

N1 RN

- SUCCINATE, 19-NOR-5-beta-PREGNANE-3~20-DIONE~ el-HYDROXY-, - 5758-81-6 SODIUM SALT -- 19-NOR-17-mlphd-PREGNA-l,3,5(10~-TRIENE-3~l7-DIOL 2553-34-6

2577

N1

-

2578

N1

- 19-NOR-17-alpha-PREGNA-l,3,5l10~-TRIEN-20-YNE~ 21-BROM0-3~17-DIMETHOXY-

RN 2576

2579

-

N1

- 19-NOR-17-alpha-PREGNA-l,3,5llO)-TRIEN-2O-YNE~ 21-CHLORO-3~17-DIMETHOXY-

2580

N1 RN

-

HYDROGEN

19-NOR-17-alpha-PREG~-l,3,5~10~-TRIENE-3~17-beta-OIOL

RN

RN

ACETATE

7548-46-1

7548-44-9

19-NOR-17-mlpha-PREGNA-l,3,5llO~-TRI€N-2O-YN€-3~l7-DIOL 57-63-6

2581

N1

- 19-NOR-17-~lpha-PREGNA-l,3,5(10~-TRIEN-2O-YNE-3,l7-OIoL, 3-13-lDIMETHYLAMINO~PROPIONATE 1 , c o i u p l c x w i th ALUnINUM TANNATE

2582

N1

-

2583

N1

-

19-NOR-l7-olpha-PREGNA-l~3~5llO~-TRIEN-2O-YNE-3~l7-DIOL, 3-1 3-(OIMETHYLAMINO)PROPIONATE), c o m p l e x w i t h Z I N t TANNATE 19-NORPREGNA-1,3.5~10~-TRIEN-2O-YNE-3~17-DIOL,and 13-ETHYL-17-HYOROXY-18,19-DINOR-l7-alpha- PREGN-4-EN-20-YN-3-ONE 17-ACETATE 3-OXIME

2584

N1 RN

2585

N1

2586

N1

2587

N1 RN

-

1 9 - N O R P R E G N A - 1 ~ 3 ~ 5 1 1 O ~ - T R I € N - 2 O - Y N E - 3 , 1 7 - O I O L ~ ll-METHOXY-, lll-alpha,l7-~lph~l61665-15-4

- 13-METHOXY9-NOR-17-~lph~-PREGNA-l~3~5~lO~-TRIEN-2O-Y~€-2~l7-DIOL~ - 19-NOR-17-~lph~-PREGNA-l~3~5llO~-TRIEN-2O-YNE-3~l7-DIOL~ 11-alpha-METHOXY- 19-NOR-17-alpha-PREGNA-l~3~5llO~-TRIEN-2O-YNE-3,l7-DIOL, 11-beta-METHOXY-

34816-55-2

147 2588

N1

2589 N1 2590 N1 2591

N1 RN

2592

N1 RN

2593 N1 RN

2594 N1

-

19-NOR-17-mlpha-PREGNA-l,3,5110~-TRIEN-20-YNE-4~17-DIOL~ 3-HETHOXY-

- 19-NOR-8-alpha,17-a1ph~-PREGNA-l~3~5llOl-TRIEN-2O-YN€-3~l7-DIOL~ 2-HETHYL- 19-NOR-8-alpha,17-a1pha-PREGNA-l~3~5~lOl-TRIEN-2O-YNE-3~l7-OIOL~ 16-beta-HETHYL-

19-NORPREGNA-l,3,5(10)-TRIEN-20-YNE-3,17-OIOL. ll7-alphm)-, m f x t . with (3-beta,l7-alphal-19-NORPREGN-4-EN-20-YNE-3.17-OIYL OIACETATE 8075-78-3 19-N0RPREGNA-1,3,51101-TR1EN-20-YNE-3.17-D10L,

l17-alphrl-~mtxt.

wlth 117-alpha)- 19-NORPREGN-4-EN-2O-YN-17-OL 8064-76-4

- 19-NOR-17-alpha-PREGNA-l,3,5llOl-TRIEN-2O-YN-l7-OL~ 3-(CYCLOPENTYLOXYl-

- 152-43-2 - 19-NORPREGNA-1~3~5(101-TRIEN-20-YN-17-0L~ 3-1 CYCLOPEHTYLOXY )-ll-HETHYL- I ll-beta,l7-olphel- 55648-36-7 - 17-alpha-19-NORPREGNA-l,3~5llOl-TRIEN-2O-YN-l7-OL~3-HETHOXY- 72-33-3 - 19-NOR-17-alpha-PREGNA-l,3,5llOl-TRIEN-2O-YN-l7-OL, 3-HETHOXY-, 9

RN

2595 N1 RN

2596

N1

and 6-CHLORO- 17-HYOROXYPREGNA-4.6-OI€NE-3,2O-OIONE

2597 N 1 RN 2598 N1 2599 N1 2600

N1

2601

N1

2602

N1

-

19-NOR-17-alpha-PREGNA-4~9,ll-lRIEN-2O-YN-3-ONE~17-HYDROXY848-21-5 19-NOR-17-alpha-PREGNA-4~9~ll-TRIEN-20-YN-3-ONE~17-HYOROXY-, and TESTOSTERONE 19-NOR-17-alpha-PREGN-4-ENE-3,17-beta-OIOL, 3-ACETATE

19-NOR-17-olpho-PREGN-~-ENE-3,17-0IOL, 3-PROPIONATE A-NOR-17-alpha-PREGN-2O-ENE-2-beta,17-bcta-DIOL,

2-alpha-ETHYNYL-20~21~21-TRIFLUORORN

2603

Nl

2604

N1 RN

2605

N1

2606

N1 RN

2607 N1 RN 2608

N1 RN

-

19-NORPREGN-4-ENE-3,ZO-OIONE 472-54-8 ~ ~ - N O R P R E G N - ~ - E N E - ~ I ~ O - O I 4-CHLOROONE, 19-NORPREGN-Q-ENE-3~20-DIONE~1 6 - E T H Y L - 2 1 - I I l - O X W M ) E C Y L ) O X Y ) - r (16-alpha167490-00-0 19-NORPREGN-4-ENE-3.2O-OIONE,

17-alpha-HY0ROXY-~ACETATE

19-NORPREGN-4-ENE-3,20-0IONE~ 17-HYOROXY-, HEXANOATE 1253-28-7

17-HYOROXY-16-HETHYLENE-, - 19-NORPREGN-4-ENE-3~20-DIONE~ 7759-35-5 - 19-NOR-17-alpha-PREGN-4-EH-17-0L - 965-90-2

2610 N1

-

19-NORPREGN-17(20 I-EN-+ONE

2611

N1

-

19-NOR-17-alpha-PREGH-Q-EN-3-~E,

2612

N1

-- 52-78-8 19-NOR-17-alpha-PREGN-4-EN-3-ONE,

2609 N1 RN

RN

2613 N1 RN

2614

N1

19-NOR-17-alpha-PREGN-5-EN-20-YN-17-OL 16915-71-2

17,21-DIHYOROXY17-HYDROXY-

- 19-NOR-17-alpha-PREGN-5(101-EN-3-ONEs - 6318-07-6 - 19-NOR-17-alpha-PREGN-50-EN-3-ONE,

17-HYOROXY17-beta-HYOROXY-

ACETATE

148 2615

N1 RN

2616

N1

2617

Nl

2618

N1 RN

2619

N1 RN

2620 N1 RN 2621 N l RN 2622

Nl RN

2623

N1 RN

2624

N1

2625

N1

2626

N1

2627

N1

RN 2628

Nl

2629

Nl

2630

N1

-- 19-NOR-17-~1pha-PRE6-4-EN-3-fflEr 17-NYDROXY-. 18063-30-4 - I ~ - N O R - J ~ - M ~ ~ ~ ~ - P R E G N - ~ - E N17-HYDROXI-r -~-ONEI

- 19-NOR-17-alpha-PREffl-4-EN-3-ONE.

ACETATE

and TESlO!lTEWNE

1 7 ~ 2 0 t o r2 1 I,i!l-IRIHYOROXY-

-- 19-NOR-17-alphe-PREGN-4-EN-2O-Y~-3-be~a~l7-0101 1231-93-2 9-NOR-17-~lpha-PREGN~5~10~~EN~20-YNE~3~~l~ha~17~DJOL -- 121466-08-0

-- 19-NOR-l7-alpha-PREGN-5l10~-EN-20-YNE-3-betarl7-OIOL -- 19-NOR-17-alph.-PRE6-4-EN-2O-YNE-3-b.t~, 2307-97-3

17-01OL,

17-ACETATE

2061-46-3

-- 6785-71-3 19-NOR-17-alpha-PREGN-4-EN-2O-~E-3r17~OIOLrOIACETATE -- 297-74-7 19-NOR-17-alpha-PREGN-4-EN-2O-~E-3-beta~l7-OIOLDIACETATE - 19-NOR-17-alpha-PREffl-4-EN-2O-YNE-3~l7-beta-OIOL~OIACETATE

- 19-NDR-l7-~lph~-PREG~5(1Q~~EN~2O~Y~~3~17~b~~~~OIOL~ OIACETATL:

- ~3-BETHOXY-17-alphM~ - N O R P R E G N - ~ - E N - ~ O - Y N E - ~ - ~ ~ ? DIACETATE, ~ ~ ~ ~ - O I Omixt. LI with ~ ~ - N O R P R E ~ ~ ~ A - ~ I ~ ~ ~ ~ ~ O ~ - ~ R( ISCi N ll- ~ O ~ Y N - ~ ~ ~ O L

-- 19-NOR-17-alpha-PREGN-5llOl-EN-2O-YN-l7-OL, 19-NOR-17-alph~-PREfflN-rr-EN-PO~YN~17-0L 52-76-6

21-CHLORO-

- ACETATE 19-NOR-17-a1pha-~EGN-4-EN-2O~YN-17-b~t~-OLr 3-ICYCLOPENTYLOXY 1-s es t e r t - 19-NOR-17-nlpha-PRE6N-4-EN-2O-YN-17-OL mlxad w i t h 3-HElHOXY-19-NDR-17-alpha-~EfflA-1~3r5(10)-TRIEN-LO-YN~17~01 (

RN 2631 N l 2632

Nl

RN 2633

N1

2634

N1 RN

2635

N1

RN 2636

N1 RN

2637

N1 RN

2638

NI RH

2639

N1

2640

N1

2641

N1

- 19-NOR-17-alpha-PREGN-5f -- ~ ~ - N O R - I ~ - ~ ~ ~ ~ M - P R L ~ N - ~ - E N - ~ O - Y N - ~ - O N E ~ -- 19-NOR-17-a1pha-PREGN-4-EN-2O-YN-3-ONE. -- 19-NOR-l7-alpha-PRLGNEN-2O-YNONE, 8015-14-3

LO l-EN-2O-YN-3-fflE

17-ACETOXY-

51-98-9

~ ~ - N O R - ~ ~ - ~ ~ ~ ~ ~ - P R E G N - ~ - E N - Z O 4-CHLORO-YN-~~ONE~

21-CHLORO-17-HYOROXY-

3124-70-7

17-beta-HEPTANOYLOXY-

3836-23-5

-- I1238-54-6 ~ - N M I * ~ ~ - M ~ P ~ M - P R E G N - ~ - E N - ~ ~ - Y N - ~ -10-HYOROPEROXY-17-HYOR~YOP(E.

--- 19-NOR-l7-aIpha-PREffl-5IlO)-EN-2O-YN-3-OF(E~ - 19-NOR-17-aIphm-PREGN-4-EN-t0-~-3-~~ - 19-NOR-17-aIpha-PREGN-4-EN-20-YN-3-ONEr -

I ~ - N O R - ~ ~ - ~ ~ ~ ~ ~ - P R E G N - ~ - E N - ~ O - Y 17-HYDROXTN-~-ONE, 66-22-4

I7-HYDROXI-

66-23-5

17-alpha-19-~PREGN-4-EN-20-YN-3-ONE~

17-beta-HYOROXI-I

ACETATE

~ ~ - N O R - ~ ~ - M ~ ~ ~ . - P R E G N N - ~ - E N - ~ O - Y H - I -17-HYOROXY-* ONE~ ACETATE ( e s t e r ) , 0-AtETYLOXIHE

17-NYDROXY-r ACETATE

Ie s t e r I I O-(CARBOXYHETHYL IOXIHE

2642

N1

17-HYDROXY-r ACETATE

( e s t e r ) * 0-HEXANOYLOXIHE

2643

Nl

~ ~ - N O R - ~ ~ - ~ P ~ ~ ~ ~ - P R E G N - ~ - E N - ~17-HYOROXT-r O - Y N - ~ ~ N EACETATE ~ ( e s t e r ) , 0-ISOBUTYRYLOXIBE

149 2644

N1 RN

2645

Nl

2646

N1

2647

N1

2648

N1

2649

N1

2650 N 1

- mixed - PRE6N*-l~3r5~l10~-TRIEN~2O-YNE~3.17-DIOL

~ ~ - N O R - ~ ~ - ~ ~ ~ ~ ~ - P R E ~ N - ~ - E N - ~ 17-HYDROXY-I O - Y N - ~ - O N ACETATE E, w i t h 19-NOR-17-alpha-

8015-12-1

- OXIHE 19-NOP-17-4lph.-PRE6-4-EN-2O-YN-3-ONE.

17-HYDROXY-~ ACETATE,

- tester).

19-NOR-l7-4lphrrPRESN-4-EN-2O-YN-3-ONE, 0-PROPIONILOXIHE

17-HYDROXY-,

ACETATE

- ~tester) ~ - N O R - ~ ~ - M I ~ ~ ~ - P R E C N - ~ - E N - Z O - Y N 17-HYDROXY-s -~-ONE, ACETATE 0-ITETRANYDRO- PH-PYRAN-2-YL)OXIHE - 1-MAMANTANECARBOXYLATE ~ ~ - N O R - ~ ~ - ~ I ~ ~ ~ - P R E ~ N - ~ - E N - ~ O -17-HYDROXI-, YN-I-ONES ( e s t e r ) , OXIHE

- 19-NOR-17-mlpha-PREGN-4-EN-20-YN-3-ONE~ tranr-mlphm~alpha'-DIElHYL-4.4'-

17-HYOROXY-, STILBENEDIOL

- 19-NOR-17-alphm-PREGN-4-EN-2O-YN-3-ONE~ ( e s t e r I , 0-ACETYLOXIHE

17-HYDROXI-.

and HEXMOATE

,

2651 N1

-

2652 N1

- 17-HYDROXYPRESN-4-ENE-3,eD-DIONE 19-NOR-17-rlpha-PRE6-4-EN-2O-YN-3-ONE~ 17-HYDROXY-, HEXINOATE

2653

N1 RN

2654 N1 RN 2655

N1

2656

N1

2657

N1 RN

17-HYDROXY-

-

8015-30-3 19-NOR-17-mlpha-PRE6-4-EN-2O-YN-3-a3E,

17-HYDROXY-7-mIphm-HETHYL-

- 19-NOR-17-~lph~-PREGN-4-EN-2O-YN-3-ONE, 17-HYDROXY-, - 0-lp-NITROPHENYLIOXIME 19-NOR-17-alpha-PREGN-4-EN-20-YN-3-ONEr 17-HYDROXY-1

-

N1

2660

Nl

2661

N1

RN

with

5-HETHOXY-19-NOR-l7-.lph.- 8015-29-0 - w19-NOR-17-alphr-PRE~-5l1O)-EN-2O-VN-3-ONE~ 17-HYOROXY- mtxed i th 3-HETHOXY-19-NOR- ~ ~ ~ ~ I P ~ ~ - P R E ~ ~ ~ ~ ~ ~ ~ ~ I ~ ~ ~ ~ T R I E N - ~ O

2659

Nl

and

- 19-NOR-17-mlphm-PREGN-4-EN-20-YN-3-ONE~ mixed PRESNA-l~3r5tlO)-TRIEN-2O-YN-l7-OL

-

2658

~ ~ - N O R - ~ ~ - ~ ~ ~ ~ . - P R E ~ N - ~ - E N - ~ O - 17-HYDROXI-. Y N - ~ - O N E ~ HEMNOATE ( e s t e r ) , OXIME

0-HETHYLOXIME

64584-79-6

19-NOR-17-4lph~-PREGN-4-EN-20-YN-3-ONEm ~~-HYDROXY-I mixcd w i t h 1~3~5~lO)-TRIEN-2-YNE-3~17-DIOL (60:l)

19-NOR-17-alpha-PREGNA37270-71-6

19-NM1-17-alpha-PREGN-4-EN-20-YN-3-ONE, 17-HYDROXY-,

and PREHARIN

17-HYDROXY-*

PROPICMATE

- 19-NOR-17-mlpha-PREGN-4-EN-20-YN-3-ONEr

17-HYDROXY-,

4nd

- 19-NOR-17-alpha-PREGN-4-EN-2O-YN-3-ONEr

17-HETHOXY-

19-NOR-17-dpha-PRE6N-Q-EN-20-YN-3-ONE~ Ie s t e r 1 s OXIHE

TESTOSTERONE

2662

N1

2663 N 1 2664

N1

RN 2665

N1

2666 N 1 2667

Nl

2668 N 1

RN 2669

N1

2670

N1 RN

2671 N 1 RN

-

19-NOR-17-4lphe-PREGN-4-EN-20-YN-3-ONE~ 17-HETHOXI-I-aIpha-HETnYL-

L-ETHYNYL-- I-NOR-5-alphm.17-mlpha-PREGN-20-YNE-2-betmpl7-DIOL~ 1045- 2 9-0

- h-NDR-17-alpha-PRE6N-20-YNE-2r17-DIOL~

2-ETUYNYL-

- h-NDR-17-mlphm-PRE6N-2O-YNE-2-beta,l7-beta-DIOL. 2-alpha-METHYL2-ETHYNYL-I DIPROPANOATE. - A-NORPREGN-20-YNE-2,17-DIOL, I 2-brta.5-~lph~.17-alph.)-

&-NOR-17-alpha-PREGN-2O-YNE-2-beta,l7-beta-DIOL, 2-alpha-ETHYNYL-

---

56470-64-5 NORVALINE, 5-1lr3-DIOXO-2-ISOINDOLINYL)-5-OXD-~ DLNYSTATIN 1400-61-9 OCHRATOXIN 37203-43-3

150 2672

Nl

2673

N1

2674

N1 RN

2675

N1 RN

2676

N1 RN

2677

MI RN

2678

N1 RN

2679

N1

2680

N1

2681 N l RN

2682

N1 RN

2683

N1 RN

2684 N1

---

OCIHUH SANCTUl Llnn.. OCInVn SANCTW L.,

leaf e x t r a c t

leover

~-OCTADECENYLAHINEP( 2 ) 112-90-3 9-OCTADECENYLAHINE. HYDROFLWRXOEs ( 2 ) 7333-84-8

-- 5392-40-5 2*6-OCTADIENAL~ 3~7-OIHETHYL-

--- 3825-26-1 - of --

OCTANOIC ACID, II,2-DIETnYLETnYLENE)DI-p-PnENILENE ESTER 20305-51-5 OCTANOIC ACIOI

AHHONIuI SALT

PENTAOECAFLUORO-r

OIL of ARBUS PRECATORIUS OIL

PISLM SATIWn Llnn.

OILS, NUTMEG 8008-45-5

-- OILS, PAM 8002-75-3 - OLEAN-l2-EN-P8-OIC ACIDi 3-(~O-bmta-O-GALACTOPYRA~SYL-~1-3)-0-~b~t~-D-SLUCOPYRINOSYL(1-4))-betm-O-GLUCOPYRANOSYL)OXY)-, 13-bctab - 53043-29-1 - OLEAN-12-EN-28-OIC

ACIDI

3-1 O-botc-D-SLUCOPYRUK)SYL-(1-2 1-04 bct&-D-GLUCDPYRANOSYL-( b~ta-O-GLWAPIRANOSYL )OXY t 3-bet. - -50657-29-9 - OLEAN-12-EN-30-DIC ACID, ~-~R~M-HYOROXY-II-OX~-I HYDROGEN SUCCINATE, DISODIUn SALT (

)-

RN

2685 N 1 RN

2666

N1

2687

N1

2688 N 1 RN 2689

N1

2690

MI RN

2691

N1 RN

2692

N1 RN

2693

~1

RN 2694 2695

N1 N1 RN

2696 2697

N1 RN N1

-

7422-40-1

- OLEORESIN of - ORACON -- ORGOTEXNS 9016-01-7

---

MM W66UL. exudate from COmIPHORA W U L

ORNITHIME, N(rup 5)-CARBAtfOYL-l

L-I

and SODIUM NITRITE ( 2 : l )

ORNITHINEi 2-lDIFLUOROHEMYL)70062-12-9 DL-ORNITHINE, 2-1OIPLUOROnETHYL)67037-37-0

-- gan~na-ORYZAMJL 11042-64-1

-- osniwi -- 2-OX*-5-.lph.-*NDR0STIN-S-ONE, - 4-OXA-l-AZABICYCLOl3.2.0IHEPTANE-2-CARBOXYLIC - lZR-l2-alpha,3Z,5-aluho~)TETROXIDE 20816-32-0

OVARIAN FOLLICULAR EXTRACT, SWINE

4-OX1-5-alpha-AWROSTAN-3-ONE~ 6-alpha-BROWO-17-b~t&-~YOROXY-l7-~~YLP4543-59-7

~~-~R~.-NYDROXY-I~-~E~~)YL-

53-39-4

3-1 2-NYOROXYETHYLIOENE )-7-OXO-,

RN

1-41 I-

)-

%

61177-45-5

ACID, "OWTASSZUM SALT,

151 2698

N1

2699

N1 RN

2700

N1

RN

RN 2701

N1

2702 N1

-

4-OXA-1-AZAB1CYCLOl3.2.O)HEPTANE-2-CARBOXYLIC ACID, ~-(~-HYDROXYETHYLIDENEI-~-OXO-I HONOPOTASSIUH SALT, (2R-(Z-alpha.3Z,5-alpha))-. 111ixt. wlth ( 2 5 - ( 2 - a l p h a , 5 - a l p h a . 6 - b e t a ( S * ) ) ) - 6 - ( ~AHIN014-HYDRDXYPHENYL~ACETYL~AHINOl-3,3-DIHETHYL-7-0x0-4-THIAl-AZABICYCLO(3.2.0)HEPTANE-Z-CIRBOXYLIC ACID ( 1 : 2 1 74469-00-4

6-DXABICYCLD(3.1.0lHEXANE~ 2,2'-OXYBIS2386-90-5

2H-OXACYCLOTETRAOECI2~3-d~ISOINOOLE-2~18~5H~-DIGNE~ 16-BENZYL-6~7~8~9~10t12p,13~14~15~15~~ 16~17-DODECAHYDRO~5~13-DIHYOROXY-9~15-DI~ETHYL-l4-~ETHYLENE-~ I E I - ( 5s. 9R,l2aS,135,155, 15a5, 1 6 a S ~ 1 8 d S I14930-96-2

4H-1~3~5-DXADIAZINE-4-lHIONE~ TETRAHYDRO-3,5-DIHETHYL-

- 1,2.4-OXADIAZOLE.

3-1 2-1 DIETHY1AHINO)ETHYL )-3-PHENYL-s

2705

N1

-

2706

N1 RN

- 1 5 - O X A E S T R A - 1 ~ 3 ~ 5 ( 1 0 l - T R I E N - l 7 - O N E ~3-HYDROXY- 40715-31-9

2707

N1 RN

2708

N1

2709

N1 RN

2710

Nl

2i03

N1

2704

N1 RN

l-OXA-2,5-DISILACYCLOPENTANE,

CITRATE

2,5-DIHETHYL-2,5-DIPENYL-

15-OXAE5TRA-1.3.5(10l-TRIENE-3.17-DIOL, 49849-01-6

(17-betal-

15-OXAESTRA-1~3~5(10l-TRIEN-l7-ONE~ 3-(CYCLOPENTYLDXYl-

- OXALIC ACID, BIS(CYCLOHEXYLIDENEHYDRAZIDE1 - 370-81-0 - 15-OXA-19-NM1-17-alpha-PREGNA-l,3.5~lOl-TRIEN-2O-YN-l7-OL~ 3-HETHOXY-

-

11-OXAPREGN-4-ENE-3~20-OIONE iaaa2-77-4 8-OXA-5-THIA-1-AZABICYCLO~4.2.0)OCT-2-ENE-2-CARBDXYLIC ( 6 R I 7R 1 - 7 4 2 - ( 315-DICHLDRO-

ACID,

4-OXO-1~4Hl-PYRIOYLlACETAHIDOl-3-~~f5-METHYL-lr3~4-THIADIAZOL-2-YL ITHIO IHETHYLI2711

N1 RN

2712

N1 RN

2713

N1

2,2-OIOXIDE - Ir2-OXATHIANEt 1633-83-6 2.2-DIOXIDE -- 1,2-OXATHIOLANE 1120-71-4

N1

-

RN

2-CHLOROETHIL)-2-( - 3-( 3778-73-2

RN 2714

-

OXAZAPHOSPHMIINE~ 2-~BIS~2-CHLOROETHYLlAMINOlTETRAHYDRO-r CYCLOHEXYLAHINE SALT 4465-94-5 1~3~2-OXAZAPHOSPHORINE~ (2-CHLOROETHYLIAMINOITETRAHYDRO-,

2719

N1

2720

N1

- 2-OXAZOLEPROPIONIC ACID. 4v5-DIPHENYL- 21256-18-8 - 2~4-OXAZOLIDINEDIONE, 5,541HETHYL- 695-53-4 - ~,~-OXAZOLIDINEOIONEI 5-ETHYL-3.5-DIHETHYL- 115-67-3 - ~ ~ ~ - O X A Z D L I D I N E D I O N E3,5,5-TRIHETHYLI - 127-48-0 - 2-OXAZOLIDINETHIONE, 5-((n-tert-BUTYLF?tENOXYlHETHYL)- 2-OXAZOLIDINETHIONE, 5-((p-CHLOROPHEHOXYlHE~HYLl-

2721

N1

- 2-OXAZOLIDINETHIONE.

2722

N1

2715

N1 RN

2716

N1 RN

2717

N1 RN

2718

N1 RN

RN

-

2-OXIDE

5-(RIENOXYHETHYLl-

2-OXAZOLIDINETHIONE,

5-~~~~lpha,alpha.alpha-TRIFLWRO-m-TOLYLlOXYlMETHYLl3414-47-9

152 2732

N1 RN

2733

Nl

RN 2734

N1 RN

2735

NX RN

2736

Nl

RN 2737 N! 2738 N1 RN 2739 N1 RN 2740

N1 RN

2741 N1 2742

Nl

RN 2743

N1 RN

2744 Nl 2745

N1

2746

N1

2747 N1 RN 2723

N1 RN

2724

N1

RN 2725

HI RN

2726

N1

2727

N1 RN

2728

N1 RN

2729

Nl RN

2730

N1 RN

2731 N l RN P740

N!

RN

----

OXYTOCIN 50-56-6 OXYTOCINt 8-L-ARGININE113-80-4 OXYTOCIN. 1-BUTYRIC A C I D 4 4 L-2-AHIEK)BUTYRIC ACID 1-7-GLYCINE33605-67-3

-- OZONE 10028-15-6

--

PALLMIUn(2+1 CHLORIDE 7647-10-1

-

PALHITAHIOED N-JSOBUTYL-

- O-thr.04 PALHITIC ACIDI 8lpha-ESTER with - 1-2 #2-OICHLORO-N-( be ta-HYOROXY-alphafHYOROXYHETHYL1-D-NITROPHENETHYLIACETAMIOE - 530-43-8 -- 53025-21-1 PANrqCRIN -- PAPAIN 9001-73-4

---

PAPAYA, r e e d PARATHORMONE 9002-64-6

,

PASSIONFLOWER EXTRACT 8057-62-3 PAXITOL PE-043

- PEFFLAN

--- 5~fWORPnOLINOHETHYLl~E~~5~NITRO~1~~ETHYL~2~IHIDAMLYLIWETHYLWEA-3~(5-NITROFVRICLIRYLIOINe-AnIM)~PENICILLIN 1406-05-9

2~OXAZOLIOINETHIONE~ 5-VINYL-, 107P-93-1

IRI-

2-OXAMLIDINONE.

H I N O I - ~ HYOROCNLORIDE 52279-59-1 t-OXALOLIDINONEr 67-45-8

2-OXALOLINEr 5 ~ ( C n L O R O n E ~ Y L l - 2 - ( p - N I l R O ~ E N Y L l -

- .OXAZOLO( 312-dIC 114 IBENLODIALEPIN~6~5Hl-ONE, 1 0 ~ ~ L O R O ~ l l b ~ ~ 0 ~ t H L O R O P n E ~ L l ~TETRAHYDRO2~3r~7rllb~

- lO-UILORO-llb-~~-FLUOROPHENYLl3r2~d1~1~418ENZODIUEPIN~6~5N1-~E~ - 1 ---24166-13-0

OXAZOLO(

2 P 3 D 7 D l b -TETRAHYORO- 7- ( 2-NYORUXY €THYL 187060-91-9

OXAMLO( ~ D ~ ~ ~ ~ ~ ~ D ~ ~ B E N Z O D ~ ~ E P I N ~ ~ ~ M ~ - ~ E D ~ ~ ~ ~ ~ D ~ ~ ~ ~ T E T R A H Y D R ORlENYLI~ ~ O ~ ~ ~ ~ ~ ~ ~ ~ ~ L ~ F L U M 59128-97-1 OXONIC ACIOI POTASSIW SALT 2207-75-E

OXYGEN 7782-44-7

PENITREH A 12627-35-9

153 2749 N 1

- 1,5-DIHYDRO-5-HETHYL-l-l5-O-PHOSPHONO-beta-Dlr4,5,6r8-PENTAUlACEN*PHTnTLEN-3-AHINE~

RIBOFURANOSYLI-,

HONOHYORATE

2750 N l

RN 2751 Nl

RN 2752 N1

RN 2753 N 1 2 754

N1

2 755

N1

RN 2 756

N1

2757 N l RN 2 758

N1

2 759 N 1

RN 2760 N 1 '2761

NI

I-PENTANOLs 5-( 3-CHLORO-Z-HYDROXYpRO~XY 1-- 18485-61-5 -- 2.5,6.11r14-PEHTAOXAPENTMECANE 143-24-8 -- 53-64-5 2-PENTENENITRILE. 2,3-6IS(p-HETHOXYPHENYLl- ?-PENTENONITRILE. 2 ~ 3 ~ B I S l ~ ~ M E T H O X Y P H E N Y L ~ ~

--

4-PEHIENONITRILEs I-NYOROXY-I l-PENTEN-4-YN-3-OLt 113-18-8

RN 2763 N 1 RN

2764 N1

RN 2765 N1

RN 2 766 NI RN

2767 N 1

RN 2766 N 1

RN 2769 N 1

l-CHLORO-3-ETHYL-

- PEPTIDE, PINEAL ACID, WTASSIUH SALT (1:l) -- PERCHLORIC 7778-74-7 - PERILLA FRUTESCENS (Linn.) B r i t t . , extract ACID, POTASSIW SALT -- PERHANGANIC 7722-64-7 - PHELLOBERIN A

- 4b~5~6~7r8~&r9~10-OtTIHIORO-O-CIRBOXY-3-~~OXY-b~t~~4b~8PHENANTHRENE-2-ACRYLIC ACIDt

TRIHETHYL-,

2762 NL

S-

2-ETHYL ESTER, 6-HETHYL ESTER

- 2-PHENANTHRENECARBOXYLIC ACID. 1-ETHYL-1~2,3.4-TETRAHYDRO-7-HETHOXY-2-HETHYL-~

-

cls-t+-l-

5684-13-9

- 1.3-D1CHLOR0-alpha-1 9-PHENANTHRENEHETHANL. L-(DIBUTYLAHIM )ETHYL 1-64 TRIFLWROIIETHYL 8 - . HYDROCHLORIDE - 36167-63-2

-- PHENINTHRO~3r4~d~-lr3-OIOXOLE-5~CARBOXYLIC

ACIDS 8-HETHOXY-

35142-05-3

- HETHYL PHENA~R013t4~dI-l~3-0IOXOLE-5~C*RBOXYLIC ACID, 8-HETHOXY-. ESTER - 35142-06-4 1.10-PHENANTHROLIHE -- 66-71-7 5-OXIDE -- PHENAZINE, 304-81-4 -- 60-12-8 PHENETHYL ALCOHOL - 4-AHINO-alpha-I PHENETHYL ALCOHOLI t e r t - W T Y LAHINO1-3-tHLORO-I-( TRIFLWROHETHYL I-, HONOHYOROUILORIDEI ( + - I -

2770 N 1 RN

2771 N 1

RN 27t2 N 1

RN

- p-( PHENETHYL ALCOHOL, 2 4 D I E T H Y L A H I MI E M X Y l-alph~-(p-HETHOXIPHENILl-rlph-PHEmL- 35623-89-3

- mlpha-~p-(2-~DIETHYLAMINO)ETHOXY)PHENYL)-beta-ETHYL-alph~PHENETHYL ALCOHOLt

Ip-HYDROXYWENYLI-p-METH0XY-t - 35263-96-8

-

CITRATE

PHENETHYL ALCOHOL. a l p h a - l p - ( 2-(DIElHYlAHINO)ETm)XY IPHENYLI-beta-ETHYL-p-HETHOXY-alpha- PHENYL-. CIlRATE (1:ll 35263-93-5

154 2773 N1

-- 462-78-9 ------- 458-24-2 -

PHENETHYL ALCOHOL,

rlph~-Ip-(2-(DIHETnYLAMINOlETnM(YlRIENILI-bet~-ETHnOm-p-nETHO-a-

RN 2774

N1 RN

2775

N1 RN

2776 N1 RN

2777 N1 RN 2778

N1 RN

2779

N1 RN

2780

N1 RN

2781 N1 RN

2782 NL RN 2783

N1 RN

2764

N1 RN

2785

Nl RN

Ipha- lp-HETHOXYPHENYLI-, HYDROCHLORIDE 42824-30-6 PNENETNYLAMINE, p-CHLORO-alphr,alpha-DIRETNYlPHENETHYLAHINEr p-CHLORO-alpha.mlpha-DIHETNYL-, 151-06-4

PHENETHYLAHINEl Ndpha-OIHETHYL-. 300-42-5

HYDROCHLORIDE

PHENETHYLAHINE, Ndpha-DINETHYL-. 826-10-8

HYDROCHLORIDEt 1-1-

PHENETHYLAHINE, N,alpha-DIHETHYL-, 51-57-0

HYDROCHLORIDEI I + ] -

PHENETnYLAHINE. N-(3rS~DI~ENYLPROPYLl-~lph~-HETHYL~ 390-64-7 PHENETHYLAtIINE, N - E ~ Y L - a l p h a - f l E T H Y L - m - ( T R I ~ L ~ ~ E T H Y L ~ -

-

--

PNENETHYLAHINE, N-ETHYL-alpha-HETHYL-n-( HYDROCHLORIDE 404-82-0

PHENETHYLAHINEi alpha-flETHYL-i -- 51-64-9 -- PHENETHYLANINE, alphs-HETHYL, 300-62-9 -- PHENETHYLAHINE, olpha-HETNYL-, 1462-73-3

2768

N1 RN

2789

N1 RN

-- PHENOL 108-95-2

2790

NI

-

N1 RN

2787 N1 RN

RN 2791

N1 RN

2792

N1 RN

2793

N1 RN

2794 N1 RN

2795

N1

-

TRIFLVOROnETHYLI-,

PHENETHYL~HINEIp-HETHOXY-N-NETHY L4091-50-3

----

2786

HYDROCHLORIDE

PHENETHYLAHINE, alpha-HETHYL-r

I + 1(4-1-

HYDROCHLORIDE. SULFATE (2:111 ( + I -

51-63-8 PNENETHYLAHINE, alpha-NETnYL-. 60-13-9

SULFATE ( 2 : l l n ( + - I -

PHENETHYLAMINE, 3,4,5-TRIPIETHOXY54-04-6

PtiEtmL, 4-1 l4-lACETYLDXYlRIENYLll3~4-DIHYDRO-1~2Hl~NAPHTHALENYLIOENElHEIH~ Y L I- P ACETATE 36415-57-3

PHENOL, 4-((4-( ACETY LOXY WHENTL)( 2-HETHYL-4-HETnYLENECYCL~EXYLIDENE )BETHYLI-r ACETATE 36415-56-2

PHENOL, p-(7-1 ALLYLDXYI-ll-ETNYLDIBENZO(brf ITHIEPIN-IO-YLI- 05850-06-8 - HEflIHYORATE PHENOL, 3-I ALLYLOXY l-ll-ETHYL-6H-DIBENLO~b~f lTHIOCIN-12-YLI-~ - 85850-88-0 -- PHENOL, p-1 7-(ALLYLOXY I-ll-ETHYLDIBENZlb~fIOXEPIN-10-YLb 85850-85-7 - p-I PHENOL, 2-1 ALLYLOXY l~6-ETHYL-l1~12-OIHYDRODIBENZO( ICYCLOOCTEN-5-YL I- 85850-87-9 -- PHENOL, m-AllINO591-27-5 p-I

MI.

RN 2796

N1

RN

155 2797

N1

Rh 2 798

N1 RN

2799

N1 RN

2800

N1

2801

N1

2802

N1

2803

N1 RN

2804 N 1 RN

2805 N 1 RN 2806

N1 RN

2807

N1 RN

2808

N1 RN

2809

N1

2810

N1 RN

2811 . N l RN 2812

N1

RN 2813

N1

2814 N l RN 2815

N1

2816

N1

RN

-- PHENOL. 0-MINO95-55-6 -- PHENOL, p-AnINO123-30-8 -- 56537-91-8 PHENOL, 2-( (BIS~2-CHLOROETHYLIA~IM,lHETnYLI~4-NITRO- PHENOL, p-(b.ta-BR#Q-2-FLUORO-rlpha-PHENYLSTYRYLl-

-

PHENOL, ~ - ( ~ R ~ ~ - B R ~ ~ O - ~ - F L U O - ~ I ~ ~ ~ - P H E N Y L S ~ Y R Y L I -

- PHENOL, p-(bata-BR~-4-FLVORO-alpha-PHENYLSlYRYLlPHENOL, 2-~ec-BLITYL-4.6-DINITRO-- 88-85-7 -- 1491-59-4 PHENOL, 6 - t - B U T Y L - 3 - ~ 2 ~ I H I O A Z O L I N - 2 ~ Y L n E ~ Y L I - 2 ~ 4 - O I H E T n Y L - PHENOLI 6-t-BUTYL-3-~2-IMIDAZOLIN~2~YL~ETHYLl-2~4-DIMETHYL-~ - HYDROCHLORIOE 2315-02-8 -- PHENOL, 0-CHLORO95-57-8 -- 56538-00-2 PHENOL, 2-( I ~2-CHLOROETNYL~A~INO~~ETHYLl-4-NITRO- PHOSPHATE1 PHENOL. 4.4'-(CYCLOnEXYLIDENEHETHYLENE I O I - . BIS(OIHYOR0GEN - 15480-76-9 TETRAMDIWI SALT - PHENOL, 4 1 4 ' - ( C Y C L O H E X Y L I O E N E ~ E ~ Y L E N E 1 0 1OIPROPIWATE -~ fester1 -- PHENOL, 2.4-DICHLORO120-83-2 - p-(p-( PHENOL, 2 4 DIETHYLAHINO IETHOXYI-alpha ,beta-DIHETHYLPHENETHYL I-. - erythro15624-00-7 - p-(p-( PHENOL, 2-1 OIETHYLAHINO IETHOXY l-alpha,bata-OIHETHYLPHENETHYL I - ,

-

HYOROCHLORIOE~threo15542-21-9

.

PHENOL, p - ~ p - ~ 2 - ~ D I E T n Y L A H I N O ~ E T H O X Y l - a l p h a , b e t ; l - O T Y L S T Y R Y L l -

- PHENOL. p-(p-( 2-(DI€THY L W I M IETHOXY I-alpha-HETHY LPHENETHYLIr x :1I - CITRATE 15624-37-0 - HYOROCHLDRIOE PHENOL, p-lp-~2-lDIETHYLWINO1ETHOXY I-beta-HETHYLPHENETHYLI-, - 15624-38-1 - PHENOL, 1- 1 p-( 2- 0 IETHY LAHINO I ETHOXY IPHENYL I- 2-( p-nElliOXY PHENYL I -1-BUTE N I L I - , HYDROCHLORIOE - 42576-23-8 - PHENOL, 2-(P-( 2-( DIETHYLAHINO IETHOXY lPHENYL I-1-HETHYLVINY L HYDROCHLORIDE -- 66877-41-6 PHENOL, 4 ~ 4 ' - ~ 1 ~ 2 - O I E T H Y L E T n Y L E N E I B I S ~ 2 - W I N O - PHENOL, 4 ~ ' - lm2-DIETHYLETHYLENE l I B I S ( 2-FLUORO- 74536-61-1 -- 85720-49-6 PHENOL, 4 9 4 I - t 1,2-OIETHYLETHYLENE )BISI3-FLUOROp- (

RN 2817

N1

2818

N1 RN

2819

N1 RN

2820

N1 RN

2821

N1 RN

2822

N1 RN

(

p-(

-

4.4'-( - PHENOL, 5776-72-7

--

1- B

1,2-0IETHY LETHYLENE101- I C +- I -

PHENOL, 4r4'-~1~2-DIETHYLETNYLENElDI-r meso-

84-16-2

156 2823 N1 RN 2824

N1 RN

2825

N1

2826

N1

RN

RN

2827 N l 2828

HI

4~4'~fOILTHYLIOENEETHYLENElOI~ -- PHENOL, 84-17-3 -- 84-19-5 PHENOL, 4 ~ 4 ' ~ l O I E T H Y L I O E N E E T H Y L E N E I DOIACETATE I~~ - pPHENOLr -l3~4-OINYORO~2~2-OIHETHYL~7~NETrmXY~-~E~L-~-l-BE~P~~~Y L I-. trans- 84394-35-4 - p-I PHENOL. p-( 2-f 0IHETHYLAHINO)ETHOXY )-olpha,betr-OIHEMILA(ENE~YL b, thro- cry 15515-42-1

- -,

PHENOL. p-lp-( 2-lOIHETHYLAMINOlETHOXY )-.lph.,b*t.-OInETHILSTIRYL)PHENOLi

p-I 7-f 2-IOIHETHILIWINO JETHOXY I-11-ETHYLOIBENLOfb,f

RN 2829

N1

-

RN

-

2830 N1 RN 2831

Nl

RN 2632 N1

ITHIEPIN-lO-YL)-

coined. uIth ETHYL ACETATE 1 5 : l ) 85850-14-4 PHENOL, p-13-( 2-(OIHETHYLAHINO ) E T H O X T ) - l 1 - E T H Y L - ~ n - D I B E f b ~ f) M W X N - 1 2 -YL)-* HYDRATE (Q:1) 85850-81-3

- pPHENOL. - 1 7 4 2 - f OIMETNYLAHINOIETHOXY 1~11-ETHYLOIBENZfL~f )OXEPIN-lO-YLb

--

85850-80-2 PHENOL, OIHETHILAHINO)ETHOXY I ~ 1 2 - E T H Y L - 5 ~ 6 - O I H W ) R ~ 1CII~E~l~~~ CLOOCTEN-11-YL I85850-75-5 PHENOL, 4-1 b t 4 - f 2-f OI~ETHYLIWINOIETHOXYIPHENYL1-2-PnENIL-l-BUTENIL)-r D-f 8-f 2-f

ICI-

RN 28J3

Nl RN

2854 N l RN 2835

N1 RN

2836

N1 RN

2837 N1 2838 N l RN 2839

Nl

RN 2840

~1

- 6k7-06-3

---

PHENOL, 4 ~ 4 ' - l l ~ Z - O I H E ~ Y L E T H Y L E N E ~ O ( - 1I - ~ 17808-24-1 PHENOL, 4~4'~~1~2-OIMETnYLETHYLENE101-~ (il15542-16-2

-- 5776-76-1 PHENOL, ~ ~ ~ ' - ( ~ ~ Z - O I R E T ~ Y L E T H Y L E N EI It -O1 ~- - I -- PHENOL, 4~4'-ll~Z-OIMETHYLETHYLENE101-rmeso2962-14-3 - PHENOL, 4 , 4 ' - ~ l ~ 2 - O I H E T H Y L E T Y L E N E ) O I - , racemls-- PHENOL, I1~1-OIHETHYLETHYL)-4-nETnOXY25015-16-5

-p-lalph~,bet~-OIHETHYL-p-l2-PIPERIOINOETHOXIlPENETHYLl-, - p-l~lph~.b~tr-OInETHIL-p-l2-fl-PYRROLIOINYLIETHOXY~PnENETHYL~-, PHENOL, ~ ~ l 2 r 2 - O I H E T H Y L - 7 ~ H E T H O X Y ~ 4 ~ P H E N Y L ~ 2 H - 1 - N - S - Y L ~ 84394-22-9 PHENOL,

erythro-

RN 2841

Nf

2842

N1

15515-47-6

PHENOL, p-lalpha,beta-OIMETHYL-p-~2-PIPERIOINOETHOXY~ST~YLJPHENOL,

c r y thro-

RN 2843

N1

2844

N1 RN

2845

N1

RN

15622-17-0

PHENOL, p-lolph~,bct~-0IHEMYL-p-l2-~I-PYRROLIOINYL~ETHOXT)ST~IL~-

--

PHENOL, 2*4-DINITRO51-28-5

214-0INITRO-, -- PHENOL, 1011-73-0

SOOILM SALT

157

2846

N1

RN 2847 N l

RN 2848 N1 RN 2349

N1

RN 2850

N1

RN 2851

Nl

2852

N1

2853

NL

2854

N1

RN 2855

N1

2856

N1

RN 2857

N1 RN

2858

Nl

RN 2859

N1

RN 2860 N1 2861

N1

RN 2862

N1

RN 2863 N1 RN

2664

N1 RN

2865

N1

2866

N1 RN

2867

HI

2868

N1

2869

N1

2870

N1

RN 2871 N1 RN 2872

N1 RN

2873

N1

2874

N1

RN RN

----

PHENOL. p-12r4-DIPHENTL-3-FURYL)54756-50-2 PHENOL. p-13~Q-DIPHENYL-2-FURYL)54756-49-9 PHENOL. ~ - ~ ~ D ~ - D I P H E N Y L - ~ - F U Y L I 54756-51-3

-- PHENOL. 4~4'-Il-ETHYL-2-METHYLETHHrLEHElDI-r aythro20576-52-7 -- PHENOL. 4,4'-Il-ETHYL-~-METHYLETHYLENE)OI-r threo20576-53-8 - PHENOL, p-lm-~LUaRO-~lpha-PENYLSTYRYLl- PHENOL. p-lo-FLUaRO-alph~-PHENTlST~Yll- PHENOL. p-(p-fLUORO-.lph.-PHENYLS~Yl)-- PHENOL, ~ - I ~ - H Y D R O X Y - ~ ~ ~ ~ I - N E T H Y L E T H Y L ~ ~ I M ) ~ P R O P('3)OXY~-D 57526-81-5

--

PHENOL. m-CIMIDA~l2.l-oIISWUINOLIN-2-YLlPHENOL, 80-05-7

4~4'-ISOPROPYLIDENEDI-~polymer - PHENOL, 1-CHLORO-2~3-EPOXYPROPANE

---

W l th

25068-38-6 PHENOL. m-METHOXV150-19-6 PHENOL. 4-16-METHOXT-2-PHENIlBENLO(bITHIEN-3-YL)21382-73-0

- PHENOL, p-16-flETHOXY~2-PHENYL-3~4-DIHrORO~l-NAPHTHYL)~ -- PHENOLi 2-tIETHOXY~4-VINYl7786-61-0 -- 88-24-4 PHENOL, 2~2'-flETHYLENEBI416-tert-BUTIL-4-ETHYL-

~,~'-WETHYLENEBIS~~.~I~-TRICHL~O-- PHENOL, 70-30-4 -- 87-86-5 PHENOL. PENTACHLORO- PHENOL. 4-13-PHENYL-2~IM)OLYLl-2-l1-PYRROLIDINYLMElliYLl-- PHENOL. p-I 2-PHENYLNAPnTtW 2 .I-b IFWAN-I-YLI-~ ACETATE 25433-81-2

-

PHENOL, m - l P Y R A Z O L O ~ J r 5 - ~ ~ W I N O l I N - 2 - Y l ~ -

- PHENOL. 4.4'-12-PYRIDYLM~THYLENEIOI-. BISlN.IDRaOEN SULFATE) ( e s t e r ) , DISOOILM SALT, OIHYDRATE - PHENOL, 4~4'~fP-PYRIOYLH~THYLENElOI~~ BIS(HYDROGEN SULFATE) lestrrlr DISWIUn SALT, HYDRATE

PHENOL, 2r3,416-TETRACHLQRO-- 58-90-2, - PHENOL. P - ~ ~ ~ ~ ~ ~ ~ ~ - T E T R ~ E ~ polymr Y U U I Twith Y L )ETHYLENE - ~ OXIDE and FORWALDEHYDE - 25301-02-4 PHENOL, 2,4,5-TRICHLORO-- 95-95-4 -- PHENOL. 2s4,5-TRICHLORO-. Sw)IUn SALT 136-32-3 -- PHENOL, p-VINYL2628-17-3

158 2675

Nl RN

2876 N1 RN 2877

N1 RN

2678 N 1 RN

2679 N1 RN

2880 N1 RN

-- PHENOTHIAZINE 92-84-2 - 10H-WENOTHIAZINE-2-ACETLt (*-I- 54323-85-2

--

--

RN

RN

2885 N 1 RN

2886 N 1 RN 2887 N 1 RN 2888

Nl

RN

2889 N l RN

2890 N1 RN 2891 N 1 RN

2892 N 1

2893 N 1 RN

2894 N 1 RN

2896 N 1 RN

2896

N1 RN

La97 N1 RN

P-CHLORO~IO-(N~N~DI~THYL-b~t~-A~YLI-

PHENOTHIAZINE, 2-CHLOR0-10-( 3-(OIMETHYLA~IWlPROPYLl-

50-53-3 PHENOTHIAZINE, Z-CHLORO-lO-( 3-fDIMETHYLALnINalPROPYLl-~ ~YOROCHLORIDE

- 69-09-0

2882 N1

2684 N l

13993-65-2

--

2883 N1

PHEWTHIAZINE-2-ACETIC ACID, lO-tlETHYL-

-- 800-22-6 PHENOTHLUINEI

Zeal N 1

RN

ACID, ~ - ~ E T H O X Y - . ~ ~ ~ . D ~ O - D I I ( E T H Y L - D

PHENOTHIAZINE, L-CHL(IRO-10-l3-~OIHETHYLA~INOlPROPYLl-, LITHIUM CARBONATE I 1:36 I

and

PHENOTHIAZINEI 2-CHLORO-lO-l3-~4-HETnYL-l-PIPERAZI~LlPROPYLl58-38-8

- WENOTHIAZINE~ Z-CHLORO-lO-( 3-1 l ~ ~ E T H Y L ~ 4 ~ P I P E R A Z I N Y L l ~ O P Y L l - ~ ETHANEOISULFONATE

-

1257-78-9 PHENOTHIAZINEB lO~DIETnYLAMINOPROPIONYL-3-TR~FLWR~ETHYL9 HYDROCHLORIDE

30223-48-4 JH-PHENOTHIAZINEr 7 ~ ~ O I M E T H Y L A ~ I N O l ~ 3 ~ ~ ~ E T H Y L I M I N O l ~ ~

3-METHOCHLORIOE - 62-73-4 -- PHENOTHIUINED 10-(2-OI~ElMYLMINOPROPYLl60-87-7

--lO~~2~IDIMETHYLAHINOlPROFYLl-~ - 10-l3~l4~METHYL~l-PIPERAZINYLlPROPYLl-2-lTRIFWOROnETHYLI- 440-17-5 I-2-O(ElMYLlMIO -- 50-52-2 - l o - ( 2-( and PHENOTHIAZINE~1 0 ~ l 3 ~ ~ O I ~ E T H Y ' L l ~ I N O ~ P R O P Y L l -

58-40-2

PMENOTHIAZINE~

r(ONOHY0ROCHLORIDE

58-33-3

PHENOTHIAZINE.

117-89-5

PHENOTHIAZINEn 1 0 4 3-( Q-METHY L-1-PIPERAZINYL IPROPYLI-?.-( D IHYOROCHLORIOE PHENOTHWINE

TRIF LWROnETHYL I-

10-( C l-H€THY L-2-PTPERIOYLlEWYL

D

I-

PHENOTHIAZINE, l-METHYl-2-PIPERIDYL IETHYL l-2-lM~THYLltlIOl-, 1 0 4 344-HETHYL-1PIPERAZINY L~PROPYL~-2-1lRIfLUM)O~ETnYL~PHENOTHIAZINE

-- 84-06-2 -- 522-25-8 --

PHENOTHIAZINE, 1 0 - l l l - ~ E l M Y L - 3 - P Y R R O L I D I N Y L l 1 I E ~ Y L l ~ ~ HY0ROCHLORIDE

1229-35-2 PHENOTHIAZINE,

lO~l2~ll-PIRROLIOINYLlETHYLl~

PHENOTHIUINED 10-~2-Il-PYRROLIDINYLJETHYLI~~ PIWJOnYOROCHLORIDE PHENDTHIAZINE, 10-(3-POIF(VeLIDINYU(ETHYLl-

29216-28-2 FNENOTHIAZINE-~-SULFON~~ZDED

2-lDIHETHY~INOlPROPYLl-N~N-DI~ETHYL~ - 10-1 1456-24-8

159 2898 N1 RN 2699

N1 RN

2900

N1 RN

2901

N1 RN

2902

N1 RN

2903

N1 RN

2904

N1 RN

2905

N1 RN

2906

N1 RH

2907

N1 RN

2908

N1 RN

2909

N1

RN 2910

N1 RN

2911

W1 RN

2912

N1 RN

291s

N1 RN

2914

N1 RN

2915

N1

2916

N1 RN

2917

N1

2918

N1 RN

2919

MI

2920

N1 RN

2921

N1 RN

2922

N1 RN

29t3 N1 RN

2924 N1 RN

-

-

---

PHENOTHIAZINE-2-WLFfflAHIDE~ 10-l2-lDIHETHYLAHINO~PROPYLl-N~N-OIHETHYL-~ IWWlETHANESULFONITE 13115-40-7 PHENOTHIALINE-2-SULFONAMIDE~ N~N-OIHETHYL-lO-l3-l4-MEWYL-1-PIPERAZINYLl~OPYLl316-81-4 m-PHENYLENEDIARINE 108-45-2 p-PHENYLENEOIAMINEv 2067-58-5

N~N-EISl2-CHLOROETHYL~-

-- n~-PHENYLENEDIAHINE~ 4-CHLORO5131-60-2 -- p-PHENYLENEOIAMINE. 2-CHLORO615-66-7

-----

p-PHENYLENEOIAMINEm NBN'-DIPHENYL74-31-7 0-PHENYLENEDIAHINE~ 4-NITRO99-56-9 p-PHENYLENEOIAMINE~ Z-NITRO5307-14-2 PHLOROGLWCINOL 108-73-6

PHOHOPSIN A -- 64925-80-0

------

---

PHOSPHINE OXIDEi 64693-33-0

PHOSPHINE OXIDE, T R I S ( 1 - U I R I D I N Y L I 545-55-1 PHOSPHINE OXIDE. TRISl1-l2-HEWYLlAZIRIDINYL~57-39-6 PHOSPHINE SULFIDE, T R I S ( 1 - A Z I R I D I N Y L I 52-24-4 PNOSPHINIC AMIDEs P ~ P ~ B I S l l - A Z I R f D I N Y L ~ ~ N - l l - A D A W N T Y L ~ 53743-43-4 PHOSPHINOMIOIC M I D E I 14465-96-4 PHOSPHONIC ACID,

-

P~P-BISll-AZIRIOINYL~-

Ip-~2-EENZOTHIAZOLYL)BENZYL~-,D I E W Y L ESTER

PHOSPHONIC ACIDS (LI~-EPOXYPROPYL)-~ C A L C I U l SALT ( 1 : l ) p I lRtZS)-(-I26016-98-8 PHOSPHONIC ACID,

(1st-EPOXYPROPYLt-r

CALCIUM SALT, HYDRATES

I1 :1 :I t I (IRBLS )-(- I-

* PHOSPHONIC ACIOI

--

P~P~BISll-AZIRIDINYL~~P~l1-AOAHANTYL~-

26016-99-9 PHOSPHONIC

(lrZ-EWXYPRDPYL)-n

DISOOIUM SALT t l R s Z S 1 ( - ) -

ACID, l-HIDROXY-1~1-ETHANEDIYL ESTER

PHOSPHONIC ACIOp l l - H Y D R O X Y - 2 ~ 2 r 2 - T R I C L ~ O E M Y L l - ~D I E M Y L ESTER 993-66-2 PHOSPHONIC ACID, METHYL-v DIHETHYL ESTER 756-79-6 PHOSRMNIC ACIDS 12~tr2-TRICHLORO-I-HYDROXTETnrL)-. 52-68-6 PHOSPHONIC ACID, SODIUM SALT 55869-01-7

(2~Oit-TRICWU#O-I-HYOOROXrETHrL)-r

D I M E M Y 1 ESTER M E M I L ESTER.

PHMPHWIC DIMIOE. p-~5-AMINO-3-PHENYL-lH-l~2~4-TRIIML~I~YL~-NrN,N'~N'-TETR~~YL1031-47-6

160 2925

N1 RN

2926

N1 RN

2927

N1 RN

2928

N1 RN

2929

N1 RN

2930

N1 RN

2931

Nl

RN 2932

N1 RN

2933

N1 RN

2934

N1

RN 2935

Nl RN

2936

N1

2937

N1 RN

2938

Nl

2939

NI RN

2990 N1

-

PHOSPHOWTHIOIC ACID, o - n m Y L ESTER 21609-90-5

- INNER -

PHOSPHORAHIOIC ACIOI SALT 3308-51-6

- PHOSPHORAMDIC ACID, ESTER

2942

Nl RN

2943 N1

RN 2 W

N1 RN

2945 N I RN

2946 N1

RN 2947

N1 RN

2948

N1

RN I949

Nl RN

0-(4-~Om)-2,5-DICHLORORIENYL)

N~N~BIS~2~CHLOROETHYLl~O~~3~~INOPROPYLl~r

METHYL-, 4-tert-BVTYL-2-CHLOROPHENYL

METHYL

.. 299-86-5

---

PHOSPHORIC ACIDi 8 I S ~ 2 ~ 3 ~ O I E R W O f R O P YESTERI L) HA6NESIUl SALT 36711-31-6 PHOSPHORIC ACID, 2,2-OfCHLOROVINYL 62-73-7

-- PHOSPHORIC ACIOp 126-73-8 -- PHOSPHORIC ACIOI 78-40-0 PHOSPHORIC ACID, -- 512-56-1

---

TRIBUTYL ESTER TRIETHYL ESTER TRIMETHYL ESTER

PHOSPHORIC TRIAMIOE, HEXAHETHYL680-31-9

- PHOSPHOROOIAtlIOIC - SALT 11566-15-0

-

-

O I M T H Y L ESTER

PHOSPHORIC ACID, TRITOLYL ESTER 1350-78-5

K I O . NIN-BIS(L-CHLOROETHYC~-,

PHOSPHOROOITHIOIC ACID, 8.C-BUTYL

CYCLWEXTLAHINE

and ISOOCYTL ESTERS, ZINC SALT

RlOSPHOROOITHIOIC ACID, S-~2-CHLORO~1-~I~3~OIHYRO-l~5~DIOXO~2H-ISO~OL-2-YL)EMrL) 0,O-OICTHYL ESTER 10311-84-9

-- 296-02-2 -- 60-51-5 -

PHOSPHORODITnIOIC ACID, DIALKYL ESTER, ZINC SALT PHOSPNOROOITHIOIC

S-(ETHYLTHIOIMETHVL

ACID, O.O-DIETHYL

ESTER

PHOS~ORODITHIOIC ACIOV O~O-OIISOAU(YL~C6-ClO nixad) ESTER

2991 ~iPHOSPHORWITHIOIC RN

PHENYL-I

ACID.

o,o-oInEmyL

S-(~-ACETAHIDOETHYL)

ESTER

13265-60-6

PHOSPHORWITHIOIC ACID, 0,O-DIHETHYL 2-MERCAP~-N-~EMYLACET~IDE

-

ESTER, S-ESTER wlth

PNDSPNORWTTnIOIC ACID, 0,O-DIMETHYL E?ITER* S-ESTER ulth 3-lMERCAP?UMETHYLl- 1~Zr3-BENmfRIAZLN-4(~1-~€ 86-50-0 PHOSR(0ROOITHIOIC ACIOI O.O-OINETHY1 ESTER, S-ESTER 4 t h

---- 56-38-2

N-(MERCAPTOnETHYL)PHTHALIHIOE 732-11-6

PHOSPNOROFWORIDIC ACIOI BIS(I~METHYLETH).L) ESTER J5-91-4 PHOSPHOROTHIOIC ACIDn S ~ ~ 2 - l 3 ~ M I N O P R O P Y U ) ( I M l E T H Y LESTER l 20537-88-6

PNOSPHOROTHIOIC ACID, OBO-OIETHYL O-(2-~ETHYLTHIOIETHYLl ESTER, nixed wlth 0.0-DLETHYL S424ETHILTHIO)ETHYL) ESTER l 7 I J l 8065-40-3 PHOSPHOROTHIOIC ACID, O.O-DlETHYL 0-(2-1SOPROPYL-6-~ETnYL-4-PYRIMIDINILI 333-41;s PHOSPHOROTHIOIC ACID,

0.0-DIETHYL

ESTER

O-(p-NIIRmENIL)

ESTER

161 2950 2951

2952

N1 RN

PHOSPHOROMIOIC ACID. 13593-03-6

RN

- PHOSPHOROTHIOIC ACID, - ESTER 2921-68-2

Nl

-

ti1

RN 2953

-

ti1

RN

ESTER

OvO-DIETHYL O-13~5~6-TRICHLORO-2-PYRIDYLI

PHOSPHOROTHIOIC ACID,

0.0-OIMETHYL

PHOSPHOROTHIOIC ACIO. ESTER 55-36-9

O,O-DIMETHYL-,

$4' -THIM)IPHENOL - 45383-96-6

-

010-DIETHYL 0-(2-QUIMOXALINYLl

ESTER, 010-DIESTER

with

0-(4-METHYLTHIOI-m-TOLYL~

2954

N1 RN

2955

N1 RN

2956

N1 RN

2957

N1 RN

ACIOI 0 ~ 0 - D I M E T H Y L 0-(p-NITROPHENYL) ESTER - PHOSPHOROTHIOIC 296-00-0 -- PHOSPHOROTHIOIC ACID, 010-OIMETHYL 0-(2,4,5-TRICHLOROPHENYLl ESTER 299-84-3 - PHOSPHOROTHIOIC ACID, O - 1 2 - I E M Y L M I O ~ E T H Y L ~0,O-OIMEMYL ESTER - 867-27-6 -- PHOSPHOROTRITHIOIC ACID, SBSSS-TRIEUTYL ESTER 76-48-6

2958

N1 RN

ACIDI -- PHOSPHOROUS 121-45-9

2959

N l RN

-

2960

MI

PHOSPHORUS ( w h i t e l 7723-14-0

- PHTHALAMIC ACIO, N-(2,6-OIOXO-3-PIPERIOYLl-~OL- 6-PHTHALAZINECAREOXYLIC ACIDt 3 ~ 4 - D I H Y O R O ~ 1 ~ l H Y D R O X Y M E T H Y L l ~ 5 ~ 7 ~ D I M E ~ Y L - 4ETHYL - O X O - ESTER ~

2961

N1

2962

N1 RN

2963

N1 RN

-- 4PHTHALALINEt 64-23-1 -- PHTHALAZINE, 36798-79-5

2964

N1 RN

PHTHALALINE, -- 66-54-4

2965

N1

-

RN

TRItlETHYL ESTER

-

56611-65-5 1~4-DIHYDRUINO-

1-~2-~lr3-OIMETHYL~2~BUTENYLIDENEIHYDRUINOl1-HYORAZINO-

1(ZHI-PHTHALAZINONE, 4-ll4-CHLOROPHENYLlHETHYLl-2-~HEXIHYDRO-1~MEMYL-lH-AZEPIN-4-YLl-~ B HYOROCHLORIDE 79307-93-0

RN

-

2966

Nl RN

-- 8PHTHALIC ACID. 5-66-7

2967

N1 RN

2968

N1 RN

2969

N1 RN

2970

N1 RN

-- 8PHTHALIC ACID, 5-70-1 -- 66587-56-2 PHTHALIC ACID,

2971

N1 RN

-

2972

N1 RH

2973

N1 RN

2974

N1 RN

-

BENZYL BUTYL ESTER

PHTHALIC ACID, 117-61-7

EISIL-ETHYLHEXYL) ESTER

PHTHALIC ACID, 117-81-7

BISl2-ETHYLHEXYLI

PHTHALIC ACID, 64-74-2

ESTER

BUTYL ESTER, ESTER w i t h BUTYL OLYCOLATE DIALKYLlC7-91 ESTER DIBUTYL ESTER

PHTHALIC ACIDS DIETHYL ESTER -- 64-66-2 -- 0PHTHALIC ACID, DIHEXYL ESTER 4-75-3 - PHTHALIC ACID, DIISOBUTYL ESTER - 64-69-5

162 2975

N1 RN

2976

Nl

RN 2977

N1 RN

2978

N1 RN

2979

N1 RN

2980

N1

2981 N l 2982

N1

2983

N1

2984

Nl RN

2985

N1 RN

2986

N1 RN

2987

Nl

2988

N1 RN

2989

N1 RN

2990

Nl

2991

N1 RN

2992

N1 RN

2993

N1 RN

2994

N1 RN

2995

N1

P996

N1

2997

N1

2998

N1 RN

2999

N1 RH

3000

N1 RN

3001 N1 3002

N1 RN

3003 N1 RN 3004

N1 RN

3005

N1 RN

---

PHTHALIC ACID, 117-82-8

DIIMETHOXIETHYL) ESTER

PHTHALIC ACID, 131-11-3

DIHETHYL ESTER

-- PHTHALIC ACIOI 117-84-0

---

OIOCTYL ESTER

PHWALIC ACID, 131-18-0

DIPENTYL ESTER.

PHTHALIC ACID, 131-70-4

!iDNDBvTrL ESTER

- PHTHALIC ACID, - PHTHALIC ACID,

HMJO-rec-BUTYL

ESTER

WNDBUlYL ESTER, A I M N I I M SALT

-

PHTHALIC ACID, HONO-rec-BUTYL

--

PHTHALIC ACID, HONDCYCLDHEXYL ESTER 7517-36-4

- PHTHALIC ACID,

-----

ESTER, WlloNIUl SALT

PHTHALLC ACID, WNO-(2-ETHYLHEXYL1 4376-20-9 PNTHALIC ACID, 30833-53-5

HONOISWWYL ESTER

PHTHALIC

nomsmmn

ACID,

ESTER

ESTER, AMMONIUM

SALT

PHTHALIC ANHYDRIDE 85-44-9 PHTHALIHIOE 85-41-6 PHTHALIHIDEv N-( 3,5-DIMETHYL-4-ISOXUOLrUIETHrL)~

PNTHALIHIDE, -- 50-35-1 - PHTHALIHIDE. 731-40-8 -- PHTHALINIDE, 2614-06-4 -- 841-67-8 PHTHALIMIOE. - PHTHALINIDEI

-

"0-t.rt-BUTYL

ESTER, ArmONIUn SALT

PNTHALIf'lIOEs

N-l2,6-DIOXO~3-PIPERIDYL~N ~ l 2 ~ 6 ~ 0 1 0 X O ~ 3 ~ P I P E R I D IVt L- ~I-r

N-l2~6-DIOXO-3-PIPERIDYLl-,D-f+)N-~~,~-DIOXO-~-PIPERIDYL)-I L-C-1N-~2~6-DIOXO~3~PlPERlDYLl~3~NITRON - I 2-0x0-I-PIPERIOYLI-

- PHTHALInIDE 4 . 5 A 7-TETRAHYDRO-N-I 2.6-OIOXO-3-PIPERIOY L -- PNTHALIHIOE, N-I(TRICHLOROMETHYL)THIOI133-07-3 -- PHTHALIHIOINE~ Z-I2~6-DIOXOPIPERIOEN-3-yl)26581-81-7 -- PHTHALIHIOINE. 2~ETHYL~3~lb~~~~PIPERIDIND-~-PHENETIDI~~21590-92-1 B

-

PHTHALINIOINE~N-12-OXO-3-PIPERIDYL)-

-- 5388-42-1 PHTHALInIDINE~ 2-PHENYL-

- PHTHALDNITRILE 91-15-6 - PNYSALIN-X - 72497-31-5 PHYSOSTIGHINE -- 57-47-6

)-

163 3006

N1 RN

3007

N1 RN

---

3008

N1

- PHYTOLACCA OOOECANORA~ e x t r a c t

3009

N1

-

RN

-

N1

-

RN

-

N1

-

3010

3011

RN

-

3012

Nl RN

3013

N1 RN

3014

N1 RN

--

3015

N1 RN

-

3016

Nl RN

,

PHYSOSTIGMINE SALICY LATE I 1:1I 57-64-7 RIYTOHEMASGLUTININ 9008-97-3

PICOLINIC ACID, 5-AMINO-6-17-AMINO-5~8-OIHYORO-6~METHOXY-5~8-OIOXO-2-WIHOLYL1-4-(2- H~OROXY-3~4-OI~ETHOXYPHENYL~-3-~ETHYL3930-19-6 PICOLINIC ACID. 5-AMINO-6-~7-A~IHO-6-METHOXY-5~8-OIOXO-2-WINOLYL~-4-12-HYOROXY-3,4- OIMETHOXYPHENILI-~-METHYL-B METHYL ESTER 3398-48-9 PICOLINIC ACID. S-MINO-4-~2~3-DIHYDRO-3~4-OI~ETHOXY-2-HYOROXYPHENTLI-6-~2~2~OI~E~ THYL-4- ~ E T H O X Y - 5 - O m ) - H I - I ~ I O A Z O l 4 r 5 - h I W I N O L I N ~ 8 ~ Y L ~ - 3 - H E T H Y L ~ 15964-31-5 PICOLINIC ACIO. 1918-02-1

PICOLINIC ACID 9 5-BUTY L21813-99-0

PILOCARPINEe HONOHYOROCHLORIDE 54-71-7

-- PILOCARPINE, EONONITRATE 148-72-1 - PINEAL GLANO, BOVINE, extract

3017

N1 N1

3019

N1

3020

N1

3021

N1

3022

N1

3023

Nl RN

3024

N1 RN

3025

N1 RN

3026

N1

-

RN

IwoRocnmIoE, - o30484-77-6

N1 RN

CALCIW SALT s HYORATE

PICOLINIC A C I O P 3*6-OICHLORO1702-17-6

3018

3027

~-AMINO-~,~B~-TRICHLORO-

-

PINUS LCS(BERT1ANA P I N W WNOEROSA.

needle extract

PINUS PONOEROSA, n m d l e extract, acetone-soluble f r a c t i o n

- PINUS WNOEROSA. needle extract, volatlle f r a c t i o n - PINUS WNOEROSA. needle extract, water-soluble f r a c t i o n - 2',6'-PIPECOLOXYLIOIOE, 1-METHYL- 96-88-8 -

2'r6'-PIPECOLOXYLIOIOEr 1722-62-9

- PIPERAZINEp 54-91-1 -

PIPERAZINE,

1-METHYL - v

MONOHYDROCHLORIOE

l~4~BIS~3~BRo(opROPIoNYL~l-(BIS(p-FLVOROPHENYL)METNYLI-4-CIEDIAMYL-, ( E I-

PIPERALINEI l-lp-tert-BUTYLBENLYLI-4-(p-CHLORO-alpha-RIE~LBE~YLI82-95-1

N1

- ~PIPERAZINE, -~~-~~~~-BUTYLBENLYLI-~-IP-CHLORO-~~~~~-RIENY~BENLYLI-~

RN

-

3029

N1 RN

-- PIPERALINE, 17730-82-4

3030

Nl RN

3028

3031

N1 RN

-

oItiYo~ocnLmmE 129-74-8

~ - ~ - B U T Y R Y L - ~ - C I E D I A M Y L - BKYOROCHLORIOE

1-PIPERAZINECARBOXA~IOE~NmN-OIETHYL-4-tlETHYL-,

CITRATE ( 1 : l t

1642-54-2 PIPERAZINEr

1-18-CHLORO~lO~ll-OIHYOR00IBENZO~b~flTNIEPIN~lO-YLI~4-METHYL13448-22-1

164 3032 N 1 RN

-- PIPERMINE. 303-26-4

3033 N l

-

3034 N1

-

RN 3035

N1 RN

3036 N 1 RN 3037

N1 RN

3038

3039

RN

-

N1

RN 3040

N1 RN

3041

3042 N1 RN

3043 N1 RN

----

PIPERALINE, l - ( p - C H L ~ O - e l p h a - P H E N Y L B E N Z Y L ) - 4 - 1 m - n E T L ~ - , HYDRUCHLORIOE 36236-67-6 PIPERAZINE, l - l p - C H ~ O - a l p h a - P H E ” L I I I - 4 - M E ~ Y L - , HYDROCHLORIDE 14362-31-3 PIPERAZINE v 1-1 p-CHLORO-~lphc-PHENY LBENZYL )-4-tlETHY L- s MONOHYOROCHIBRIDE 894-56-4 PIPERALINE, l-(m-CHLOROPHENYL )-6-( 2-1 5-METHYLPYRAZOL-3-YLlE~YL)-~ DIHYDRDCHLORIDE 20344-15-4 PIPERAZINE, 1~4-OINITROSO140-79-4 2r6~PIPERAZINEDIONE~ 4.4’-PROPYLENEDI-, 21416-87-5

Nl RN

3045

N1 RN

3046

N1

-

3047

N1

- 4-1 1-PIPERAZINEETHANOL, (5-CHLORO-2-OXO-3(

3048

N1 RN

3049

N1

3050 N1 RN 3051

Nl RN

3052

N1 RN

3053 N l RN 3054

N1

-- PIPERUINE, 303-25-3

--

(+-I-

PIPERAZINE, l-lDIPHENYLMETHYL)-Q-~ETHYL82-92-8

3044

RN

DIWDROCHLORIDE

9

N1

RN

PIPERALINE 8 l-(p-CHLORO-elphe-PHENTLI)EHZrL)-r

PIPERAZINEI l ~ l ~ ~ C H L O R O ~ . ~ l ~ ~ P H E HYDROCHUWIIDE N Y ~ E ~ Y L l ~ ~ 18719-22-7

-- 82-93-9 PIPERALINE l-(p-CHLORO-alpha-PHENYLBENZTL 1-4-METHYL-- 569-65-3 PIPERAZINE. l - l p - C H L O R O - e l p h ~ - P H E N Y ~ E ~ Y L ) - ~ - ~ m - M E ~ Y L B E ~ Y L i - OIHYDROCHLORIDE PIPERALINE. l-Ip-CHLORO-elphe-PENYLBE“ILl-4-lm-METHYLBENZYL~-, - 1104-22-9

-

N1

l-(p-CHU1RO-~lph.-PH€NYLBENZYLl-

l-IDXPHENYU(ETHYLI-4-MElHYL-~ HYDROCHLORIDE

1-PIPERALINEETHANOLr 4-13-16-CHLMIO~3~4~DIHYDRO~2H~1r4~BENmTHIAZ~~4~YLlPROPIL)-r MALEATE

2H~-BENZOlNIAZOLYLlACETYL)-~ HYDROCHLORIOE

35941-71-0 1-PIPERUINEETHANOLs 4-1 3 4 2~~LOROPHENOTHIUIN-lO-YLIPROPYL)58-39-9 I-PIPERAZINEETHANOL, 4 ~ ~ 3 ~ ~ 2 ~ C H L O R O P H E N O T H I U I N ~ l O ~ Y L l P R W Y L ~ - ~ end lO~l1-OIHYORO-N,NDIMETHYL-5H-DIBENZOI a,d )CYCL~EPTENE-delte(rup 5 .gamma I-PROPY LAMINE 1-PIPERAZINEETHANOL~ 4~~3~12~CHLOROPHENOTnIALIN-lO-YL~PROPYLI-~ MONOHYDROCHLORIDE 3111-71-5 1-PIPERAZINEETHANOL,

3-1 2-( TRIF LUOROMETHYL )PHENOTHIUIN-lO-YL - 4-69-23-8 1-NI7R050-- PIPERAZINE. 5632-47-3

-

(

)PROPY L )-

1-PIPERAZINEPROPANOL, Q-lb.ta-METHOXYWENETHYL)-alphe-PHENTL-.

- OIHYDROCHLORIDE 27588-43-8

- 4-16-1

1-PIPERALINEPROPANOL~ ~ 6 - ~ E T H O X Y ~ 8 - 9 U I N O L Y L l ~ I N O t H E ~ L ) - ~ l pMALEATE htYL~~ 11:21

165 3055

N1

RN 3056

N1 RN

3057

N1 RN

3058 N 1 3059

N1 RN

3060 N 1 RN 3061

N1

3062

N1 RN

RN

- PIPERALINEI 1-~l1-PYRRDLIDINYLCARBYL1HETHYL~~4-~S'~4'~5'-TRIHETHD~CI~Y~ 1)-, HALEATE - 26328-04-1 - ~PIPERAZINIUni - ( ~ ~ ~ P - C Y C L O ~ E X Y L - ~ ~ ~ ~ - H Y D R ~ Y P H E NHETHYL E T H ~ L Y L - ~

-

SULFATE 115-63-9

- PIPERIDINE - 110-89-4 - PIPERIDINE 1-1 N-( (1.4-BENZOOIDXAN-2-1 L1HETHYL)GLYCYL )- PIPERIDINE, l - l l r Q - B E N Z O D X O X A N - 2 - Y ~ E T H Y L 1 - r HYDROCHLORIDE - 135-67-5 - 1-PIPERIDINEBUTANAHIDE~ B

-

~-14-CHLOROPHENYL1-4-HYDROXY-N,N-DIHETNYL-~lpha,~lph~-DIRIEHIL-~ HYDROCHLORIDE 34552-83-5

-

1-PIPERIDINEBUTANOL, a l p h a - I 4-1 1rl-DItlETHY LETHY L IPHENY L 1-4-1HYORDXYDIPHENYLHETHYL I50679-08-8

RN

-- 1-PIPERIDINEBUTANOL~ olphodpha-DIPHENYL-, 3254-89-5 - PIPERIDINEI 1-CHLORO- 2156-71-0

3064

N1 RN

-

3065

N1

3063 N 1

3066

3067

PIPERIDINEI 129-03-3

HYDROCHLORIDE

4-(5H-DIBENZO(a~dlCYCLOnEPTEN-5-YLIDENE~-l-HETHYL-

RN

- HYDROCHLORIDE PIPERIDINE, 4-(5H-DIBENZO(a~d)CYCLOHEPTEN-5-VLIDENE)-l-HETnYL-, - 969-33-5

N1

-

RN

-

N1

- PIPERIDINE, 1-(2 - ( p - ( alpharb~ta-DIHETHYL-p-HETHOXYSTYRYL 1PHENOXY)ETHYL I - ,

RN 3068

N1 RN

3069

N1 RN

3070

Nl RN

3071

N1

3072

N1

-

PIPERIOINE, 1-(2 - Ip-( alpha, beta-DIMETHYL-p-HETHDXY PHENETHYL 1PHENOXYIETHY L 1erythro15515-48-7

HYDRDCHLORIDEI 15542-09-3

- PIPERIDINE, 15542-07-1 -

,

(El-

l B l ' - l

lOIHETHYLVINYLENElBISlp-PHENYLENEOXY1lDI-~I € ) -

1-PIPERIDINEETHANOLt 4-8ENZYL-alpha-(p-HYDROXYPHENYL1-b~ta-HETHYL-~ 12:11 23210-58-4

TARTRATE (SALT1

-- 1-PIPERIDINEETHANDL, alpha-l5-PHENYL-3-ISOXALDLYL1-. CITRATE 14838-45-0 - PIPERIDINE. 2-(6-HETHOXY-2-PHENYL-3~4-DIHYDRD-l-NAPHTHYL1-l-HETHYL-~

(1:lI

HYORIODIDE

-

PIPERIDINE,

4-l6-HETHOXY-2-PHENYL-3~4-OIHYDRO-l-NAPHTHYLI-1-HETHYL-r HYDROCHLORIDE

3073

N1

- 1-( PIPERIDINE. 2-Cp-f 6-flETHOXY-Z-PHENYL-3~4-DIHYDRO-~-~A~THYL PPNENOXY JETHYL J-

3074

N1

-

- 9

3075

N1

3076

N1 RN

HYDROCHLORIDE

PIPERIDINE, 1-12-lp-~6-HETHDXY-2-PHENYL~2-11.mENYLlPH€NOXY1ETHYL1-~ HYDROCHLORIDE

- PIPERIDINEI -- PIPERIDINE, 16509-35-6

1-(1-HETHYL-Z-((alpha-PHENYL-o-TDLYLlOXY)ETHYL1-

l-HETHYL-4-1N-2-THENYLANILINO1-~ TARTRATE

166

3081 N1 RN

-- PIPERTDINES 1-NITROSO100-75-4 -- PIPERIDINEt l-Il-PHENYLCYCLM(EXYLI77-10-1 - PIPERIDINEs 1-1 1-PHENYLCYCLOHEXYL i - 8 - 956-90-1 -- PIPERIDINE. 1-PIPEROYL-r I € , € ) 94-62-2 PIPERIDINEi 2-PROPYL-r ISI-- 458-88-8

3082 N1

-

3077 N1 RN 3078 N1 RN 3079 N1 RN 3080 N1

RN

RW

3083 N1 RN

3084 N1

HYDROCHLORIDE

PIPERIDINE, l-l2-lN-12-PYRIDYL~ETHYLIANILINO1ETHYLI-r

- HYDROCHLORIDE 24699-40-9 - PIPERIDINIUI, l-lI2-CYCLOHEXYL~2~PHENYL~l~3~DIOXO~N~4~YLlMETnYLl~l~METHYL-~ IODIDE - 6577-41-9 - PIPFRIDINIUMv 1.1 -~3-alphar17-beta-OIHYOROXY-5-al~ha-~ROST-2-beta~l6-betr-YLENEIBISIl- NETHYL-B DIBROMIDE, DIACETATE, HYDRATE

3085 N1 RN

3086 N1

3007 Nl

- BRDHIDE PIPERIDINIIA(~ - 35035-05-3

3-lDI~2~THIENYLMETHYLENEl-5~~ETHOXY~1~1~DI~E~YL~~

.. PIPERIDINIUMi ~ - E T H Y L - I - I ~ - H Y O R O X Y E ~ Y L ) - IBROMIDE, BENLILATE l e ster I - 4-PIPERIDINOL, 4-14-CHU1RO-alpha~alph~~~lph~-TRIFLUM(Om-TOLYLl-l-lQ.4-BISlp-FWPHENYL)BUTYL)- 26864-56-2 -- 4-PIPERIDINOL, 1,3-DInETnYL-4-PHENYL-, PROPIONATE 77-20-3 OR0

RN

3088 Nl RN

3089 N1 3090 N1 3091 Nl 3092 N1 3093 Nl

- PIPER LON6UM

BENZENE EXTRACT - PIPER - PIPER LQNbUni CHLDROFORN EXTRACT LONGUM,

- PIPER LONCUPI. f r u l t extract - PIPER LONGUM, METHANOL EXTRACT

- PIPER LONGUM, PETROLEUM EXTRACT 3095 Nl - PIPER OFFICINARLRI, - PIPER PEEPULOIDES, leaf extract 3097 N1 - PIROMEN - 9008-99-5 3098 Nl - PITUITARY HORMONE - 9002-72-6 3099 N1 - PIVALIC ACIDi ESTER with 2-HYDROXYACElOWENONE - 2522-81-8 3100 N1 - PIVALOPHENONE, 4'-METHYL- 30314-44-4 3101 N1 - PLATIMM I I V ) CHLORIDE - 13454-96-1 3102 - PLATIMMIIIl SULFATE 3103 Nl - P L A T I M THWlINE BLUE - 63748-54-9 3104 - PLUMBAGO INDXCA, root ETHER

3094 N1

fruit axtract

30%

N1

RN

GROWTH

RN RN

RN

RN

N1 RN

N1

extract

167 3105

N1 RN

3106

N1 RN

-

3107

N1 RN

TETRAETHYL-- PLUHBANEB 78-00-2

3108

N1 RN

3109

N1

-

PLUHBANE, CHLOROTRIETHYL1067-14-7 PLUMBANE. CHLOEOTRIHETHYL:1520-78-1

PLUMBANE, TETRAHETHYL75-74-1

POOOCARPA-8~11~13-TRIEN-l~-OIC ACID, 12-METHOXY-, 2-IDIETHYLAMINOIETHYL ESTER

- PODOCARPUS BREVIFDLIUS S t o p f , l e a f e x t r a c t - PODOPHYLLIN - 9000-55-9 - POLYALKYLARYLSULFDNIC ACID, SODIUM SALT - POLYCHLORINATED BIPHENYLS - 1336-36-3 - POLYCHLORINATEO BIPHENYL IAROCLOR 1 0 1 6 1 - 12674-11-2 - POLYCHLORINATED BIPHENYL IAROCLOR 1 2 2 1 1 - 11104-28-2

3110

N1

3111

N1 RN

3112

N1

3113

N1 RN

3114

N1 RN

3115

N1 RN

3116

N1 RN

-

-

POLYCHLORINATED BIPHENYL I AROCLOR 1242 I 53469-21-9

3117

N1 RN

-

POLYCHLORINATED BIPHENYL (AROCLOR 1 2 4 8 I 12672-29-6

3118

N1 RN

3119

N1 RN

3120

N1 RN

3121

N1 RN

3122

N1 RN N1

3123 3124

Nl RN

3125

Nl RN

3126

N1

-

POLYCHLORINATED BIPHENYL I AROCLOR 1 2 5 4 1 11097-69-1

BIPHENYL (AROCLOR 1 2 6 0 I - POLYCHLORINATED 11096-82-5

-

POLYCHLORINATEO BIPHENYL (KANECHLOR 300 I 37353-63-2 POLYCHLORINATED BIPHENYL (KANECHLOR 4 0 0 ) 12737-87-0

BIPHENYL IKANECHLOR 5 0 0 1 - POLYCHLORINATED 37317-41-2 - POLYCHLORI NATE0 TR IPHENYL - POLYETHYLENE GLYCOL 111000 - 25322-68-3

-

-

POLYETHYLENE GLYCOL MONOSTEARATE 9004-99-3 POLYGONUn HYDROPIPER L.,

d r y powdered w h o l e plant

3127

N1

3128

N1 RN

3129

N1

- P O L Y G M HYDROPIPER L l n n . , r o o t e x t r a c t ACID COPOLYMER - WLYINOSINIC:WLYCYTIDYLIC 24939-03-5 - WLYOXYETNYLENENONYLPHENYLETHER, PVA, a n d GLYCERIN

3130

N1

-

3131

N1

-- PDLYf 1-VINYL-2-PYRRDLIDINONE 1 H u e p e r ' s 9003-39-8

Polymer H 0 . l

-

P o l y m e r No.2

RN 3132

N1 RN

3133

N1 RN

3134

N1 RN

-

POLY~1-PHENYLETHYLENEl2~5-DIOXO-3~4-FVRYLENE~l

Hueper's - POLY(1-VINYL-2-PYRROLIOINONEl 9003-39-8 - POLY~1-VINYL-2-PYRROLIDINONEl H u e p e r ' s - 9003-39-8 -- POLU 1-VINYL-2-PYRROLIDIWE I Hueper's 9003-39-8

P o l y m e r No.3 Polymer

No.4

168 3135

N1 RN

3136

N1 RN

3137 N1 3138 N1 3139 N1 RN 3140

Nl RN

3141 N1 RN 3142

N1 RN

3143

N1 RN

3144 N1 RN 3145

Nl RN

3146

N1

3147 N1 3148 N l

-- POLY(l-VINYL-2-PYRROLIOINE1 Hueper's Polymer No.5 9003-39-8 -- POLY~l-VINYl-2-PYRROLIOINONEb th~eper's Polymer No.6 9003-39-8 -

PORCINE SROUTn HORNONE

- PORTULACA OLERACEA. -- POTASSIUII CYANIDE 151-50-8 -- POTASSIUn FLUORIDE 7789-23-3

---

---

reed extract

POTASSIW IWIOE 7681-11-0 POTASSIlM NITRATE 7757-79-1 POTASSIUM NITRITE ( 1 x 1 ) 7758-09-0 WTASSIW PYROSULFITE 16731-55-8

-- WTASSIUn TRIIWIOE 12298-68-9

-

POTATO BLOSSOIISt GLYCOAU(ALOI0 EXTRACT

- POTATOt GREEN PARTS

- PREbNA-4~17~20~-DIENE~2O~CARBONIlRILE, - 17-alpha-PRE6NA-4r6-OIENE-21-CARBOXY~IC -- PREGNA-lt4-OIEN~-3t2O-OIONE~ 2l-~ACETYLOXY~~9-~LuoRO~ll~17~OIH~ROXY~l6~~ETHrL-t 21-HYOROXY-3-OXO-,

PROPIONATE

3149 N l

RN 3150 N l RN 3151 N l

ACIO,

17-NVOROXY-3-OXO-

HONOPOTASSIW SALT 2181-04-6

9-betr,lO-elpha-WEbN*-4t6-01ENE-3t20-DIONE 152-62-5

(ll-betarl6-betal-,

niwt. with

~1l-b~t~~rl6~b~t~l~9~FLUORO~11~17~OIHYOROXY~16~~ETHY~~

- 8064-08-2 - PRE~NI-~~~~DIENE-~~~O-OIONEV -

2l-~PHOSPHONOOXY)PREW-lt4-DIENE-3~20-01ONE 0150OIUn SALT

RN 3152

Nl RN

3153

N1

RN 3154 N1 RN 3155 31%

Nl RN N1 RN

3157 N1 RN 3158 N l RN

22-(ACETYLOXY )-ll-HYOROXY-l7-( 72064-79-0

-

(1-OXOPENIYLJOXY) - #

(11-beta)-

PREGNA-lt9-DIEHE-3~2O-OIM~ 17,21-BIS( ACETY LOXY )-2-BRMYI-6 ~~-OIFLWRO-~~-NYDRWYKI@ (6-betarll-beta)57781-14-3

PREGNA-1~4~0IENE~3r2O~OIONC~ 17~21-BIS~ACETYLOXY~-6~9~0IFLVORO~ll~NY~WY-l6~nEYL~~ t 6-rlpha , l l - b e t a ,M-betm)33569-32-7

-- PRECNL-4r6-0IENE-3tLO-OI~E~

6-CHLORO-17-ETHYL-

802-81-3

- P21-CHLMIO-9-F RL6NI-lr4~OIENE~3~20~01~~ LUWIO-11-bet a.17-0IHYOROXY-16-het 17-PROPIONATE - P5122-46-7 -- W1961-77-9 E ~ ~ 9 r 6 - O L E N E ~ 3 t L O6-CHLORO-17-HYOROXY~OI~~~

b-RKTH'(L- v

-

WE~A-4,6-DIENZ-3,20-DIONfr 302-22-7

6-CHLORO-17-NYDROXY-r

ACETATE

169 3159

N1 RN

3160

N1

RN 3161

Nl

3162

N1 RN

3163

N1 RN

3164

Nl

RN 3165

N1

3166

RN N1

RN 3167

N1 RN

3160

N1

3169

N1

RN

RN 3170

N1 RN

3171

N1

-

PREGNA-1,4-DIENE-3,20-DIONE, KETATE (ester1 151-69-9

6-alpha-CHLORO-17-alpha-HYDROXY-,

PREGNA-4,6-DIENE-3~2O-DIONE~ 6-CHLORO-17-HYDROXY-, ACETATE mlxed w i t h 3-METHOXY- 17-elpha-19-NORPREGNA-l~3~5110)-TRIEN-20-YN-l7-0L 8065-91-6

PREGNA-Q,6-DIENE-3,2O-DIOWE, - 6-CHLORO-17-alpha-HYDROXY-l6-~lpha-METHYL-

-

PREGNA-4,6-DIENE-3,2O-DIOWE,

6-CHLDRO-17-HYDRDXY-l6-METHYLENE-.

ACETATE 6799-23-1

- PREGNA-1-4-DIENE-3rLO-DIONE, 9-CHLORO-16-beta-HETHYL-ll-be~a~l7~Pl-~IHYDROXY-~ -

17,2l-OIPROPIONATE 5534-09-8

PREGNA-1,4-DIENE-3,20-DIONE, 6~9-DIFLUORO-11~12-DIHYDROXY-16~l7-lll-METHYLETHYLIDENEl 6191OXY I ] - ,

(6-alpha,ll-b~t~.16-alpha1-

67-73-2

-

59198-70-8

-

PREGNA-4,6-DIENE-3~2O-DIONE~6v17-DIMETHYL-

- 6-ulpha,9-DIFLUORO-ll-beta~l7~2l-TRIHYDROXY-l6-~lpha-ME~YLPREGNA-1,4-DIENE-3,2O-DIONE, 2135-17-3

- 977-79-7 -

PREGNA-1~4-DIENE-3~20-DIONE~ 6-alpha-FLWRO-ll-be~a,21-DIHYDROXY-l6-a1pha-METHYL152-97-6

PREGNA-1~4-DIENE-3~2O-OIONE~

- 9-FLUORO-11-beta,21-DIHYDROXY-l6-alpha-HETtlYL382-67-2 REGNA-~~~-DIENE-~~~O-DIONEB - P9-FLUORO-11~21-DIHYDROXY-16-METHYL-l7-~ll-OXOPENTYLlOXYI-~ Il l - b e t a , l 6 - b e t a I - 2152-44-5 - PREGNA-1~4-DIENE-3~2O-DIONE~ 9-FLUORO-11~17-DIHYDROXY-16-~ETHYL-2l-~l-OXO-3-PHENYLPROWXI-r mixt. w l t h (ll-beta,l6-alphal-, I ~ ~ - ~ ~ ~ P , ~ ~ - ~ ~ ~ ~ ~ I - ~ - F L U O R O - ~ ~ , ~ ~ - D I H Y D R O X Y - ~ ~ - M E ~ Y L -

RN 3172

RN N1

-

PREGNA-lr4-01ENE-3~2O-OI~E~

-

PREGNA-1~4-DIENE-3,ZO-DIONE,

-

PREGNA-1,4-DIENE-3.2O-DIONEI

-

16.17-ACETAL 3385-03-3

3173

N1

3174

N1

3176

N1 RN

3177

60593-91-1

6-FLMRO-17-HYDROXY-. ACETATE -- PREGNA-4,6-DIENE-3r2O-DIONE~ 2162-49-4 - PREGNA-4,6-DIENE-3,2O-DIONE~ 21-FLUORO-17-alpha-NYDROXY-l6-METHYL-~ ACETATE lorter) - PREGNA-1.4-DIENE-3,2O-DIONE~ 9-alpha-FLUORO-16-~lph.,17-alphr-ISOPROPYLIDENEDIOXY-ll-b~t~HYDROXY- 2135-14-0

N1

RN

3175

-

2l-lPHOSPHO~OXYlPREGNA-1~4-DIENE-3~20-DIONE DISODILRI SALT

N1 RN

9-FLUM)O-16-alpha-METHYL-ll-beta~l7,21-DROXY-~ PHOSPHATE

- 9-FLUORO-ll-beta. 124-94-7

21- DISODIlM

16-elpha. 17,Pl-TETRAHYDROXI-

6-~lpha-FLUOR0-ll-be~a,l6-alph~~l7~2l-lE~AHYDROXY-~ CYCLIC w i t h ACETONE

170 3178

N1 RN

3179

N1 RN

3180

Nl

RH

with - PREGNA-lr4-DIE~-3r20-DIOm~

PRE~~NA-~.~-DIENE-~~~O-DIONEI 9-FLUORO-ll-betar16-rlpharl7rel-TETR~YDROXY-~ CYCLIC 16rl7-ACETAL ACETONE 76-25-5

-

-

9-FLUaRO-ll-beta~16-alpha~l~~2l-TETRAHYDROXY-~ CYCLIC 16.17-ACETAL with ACETONE, 21-13,3~DIMETHYLB~YRATEI 5611-51-8 PRE~NA-LI~-DIENE-~,~D-OI~E,

9-~LWRO-ll-beta,16-aIphrrl7~2l-TETR~YDROXY-~ 16~21-DIACLTATL - 67-78-7

,

,

3181 N1 * PR EGNA-1 B 4-0 IENE-3 20-0IONE P 9- FLVORO- 11-bet a B 17 21-TRIHIDROXY* 21-ACETATE 338-98-7 RN 3182

N1

RN 3183

N1 RN

3184

N1 RN

3185

N1 RN

3186

N1

- PREGNA-1~4-DIENE-3r2O-DIONE, - 9-FLUORO-ll-beta~l7.2l-TRIHYDROXY-16-alpha-METHYL-

,

50-02-2

- PREGNA-l.4-DIENE-3,20-DIONE, 9-FLUORO-1l-beta~17~2l-TRIHYDROXY-16-b~ta-MElHYL-

-

378-44-9

- 6P R- E~tlNpAh~a1-~F4 L- DU IOERNOE-~lSl~-2bO ~e OtIaO~NlE7~~ 2 l - ~ I H Y D R O X V - Y L - ~ - 21-ACETATE 1597-82-6 - PREGNA-~s~-DIENE-~,~O-DIONEI ACETATE - 9-FLUORO-ll-bet~~17r21-TRIHYOR~-16-alpha-~E~YL-~ 1177-87-3 - PREGNA-1~4-DIENE-3~2O-OIONE, 9-FLUORO-ll-beta~l7~2l-TRIHYDROXY-l6-beta-METHYL-~ 21-ACETATE and 9-FLUORO-ll-brto~l7~2l-TRIHYDROXY-16-beta-NETHYL-PREGNA-1~4-DIENE-3120-DIONE 21-IDIHYDROGEN PHOSPHATE)

3187

N1 RN

3188

N1 RN

3189

N1 RN

3190

N1

- PREGNA-lr4-OIENE-3,2O-DIONE~ 9-FLUW)O-11-beta~l7ri?l-TRIHYOROXY-l6-alpha-METHYL-, PHOSPHATE1 - 21-IDMYOROGEN 312-93-6 - PREGNA-~,~-DIENE-S,~O-DIONEI 9-FLUORO-ll-bata,l7~2l-TRIHYDROXY-l6-~lpha-MElHYL-, 21-1 DIHYDROGEN PHOSPHATE) D I S W I u ( SALT. - 2392-39-4

- PREGNA~1,4-DIENE-3,2O-DIONE~ - PREGNA-l~Q~DIENE-3~2O-DIONE~ 9-FLUORO-ll-b~ta~l712l-TRIHYDROXY-l6-alpha-METHYL-,

~ - F L W R O - ~ ~ - ~ C ~ ~ , ~ ~ , ~ ~ - T R I H Y D R O ~ 21-IDIHYDROGEN - ~ ~ - ~ ~ ~ ~ - M E ~ H Y ~ - , PHOSPHATE1 I OISOOIlM SALT 151-73-5

17t21-OIPROPIONATE

PREGNA~1~4~OIENE~3r2O~DIONE~

3191 N1

9-FLUORO-ll-beta~17,21-TRIHYOROXY-16-beta-METHYL-,

RN 3192

N1 RN

3193

N1 RN

3194

N1

3195

N1

3196

N1 RN

3197

N1

17.21-DIPROPIONATE - 5593-20-4

- PREGNA-1~4-DIEWE-3r2O-DIONEr 9-FLUORO-ll-beta.l7r2l-TRIHYDROXY-l6-a~pha-MElHYL-, 21-ISONICOTINATE 2265-64-7

- PREGNA~l~4~DIENE-3rZO-OIONE~ 9-FLUORO-ll-beta~l7~2l-TRIHYDROXY-16-alpha-METHYL-~ 17-VALERATE

-

33755-46-3 P R E G N A - 1 ~ 4 ~ O I E N E - 3 ~ 2 O ~ O I O17-HYDROXYNE~

- PREOWA-lr4~DIENE~3~2O-OIONE~ ~~-HIDROXY-D ACETATE

-- PREGNA-1.4-DIENE-3,2O-DIONE,

PREGNA-~I~-DIENE-~~~O-DIONE 17-HYDROXY-, , 425-51-4

ACETATE Ierterl

17-HYDRO%Y-6-alpho-MElHYl-,

ACETATE

171 3198 N1 RN 3199 N1 RN 3200 N1 3201 N1 RN 3202 N1 3203 N1 3204 N1 RN 3205 N1 RN 5206 N1 RN 3207 N1 RN 3208 N1

PREGNA-4~6-DIENE-3r2O-DIONE~17-HYDROXY-6-tlEMYL-. ACETATE -- 595-33-5 - PREGNA-4,6-DIENE-3,2O-D1ONEI 17-HYDROXY-6-nETHYL-. ACETATE mixed 19-NOR-17-alph~-P R E G N A - 1 ~ 3 ~ 5 ~ 1 0 ~ - T R I E N ~ 2 ~ Y N E - 3 ~ 1 7 - D I O L ith - w8064-66-2 17-HYDROXY-6-METHYL-, ACETATE, and - PREGNA-4,6-DIENE-3,2O-DIONE, TESTOSTERONE - PREGNA-4~6-DIENE-3,2O-DIONE, 17-HYDROXY-6-METnYL-16-nETHYLENE-, 2919-66-6 - ACETATE

and - 9-bctnr10-nlpha-PREGNA-4,6-DIENE-3,20-DIONE 17-HYOROXYPREGN-4-ENE-3~2O-DIONE HEXANOATE OM~ PROPIONATE - P R E G N A - ~ , ~ - O I E N E - ~ I ~ O - D I17-HYDROXY-r

PREGNA-1.4-OIENE-3~2O-DIONE~ll-beta.l7,21-TRI~YDROXY-- 50-24-8

P R E G N A - ~ , ~ - D I E N E - ~ I ~ O - D I Oll-beta,l7121-TR1HYDROXY-. NE~ -- 52-21-1

22-ACETATL

ll-betas17,21-TRIHYOROXY-, - PREGNA-1,4-DIENE-3,20-DIONEs 21-(HYOROGEN SUCCINATE), ~ N O S O D I U nSALT - 1715-33-9 - ll-bcta,l7,21-TRIHYDROXY-6-alph.-~ETHYL-~ PREGNA-1~4-DIENE-3~2O-DIONE~ 21-ACETATE

- 53-36-1

- PREGEIA-1,4-OIENE-3,20-DIONE. ll-betar17r21-TRIHYDROXY-6-~lpha-~ETHYL-~ 2l-(HYDROGEN

- SUCCINATE 2375-03-3

t D H0llMM)IUn SALT

RN -3209 N1 3210 N1 3211 N1 RN 3212 N1 RN 3213 N1 RN

3214 Nl RN 3215 N1 3216 N1 3217 N1 RN 3218 N1

- PRECNA-3.6-DIENE-3.17~20-TRIOL,

TRIACETATE

- PREGNA-4~6-DIENE-3rll~2O-TRIONE

- PREGNA-lr4-DIENE~3~1l~ZO-TRIONE~ ~ - C H L O R O - ~ - F L U O R O - ~ ~ - H Y D R O X Y - ~ ~ - ~ ~BUTYRATE ~~-~E~HYL-S - ~25122-57-0 17*21-DIHYDROXY-n 21-ACETATE -- PREGNA-1s4-OIENE-3~11~20-TRIONE~ 125-10-0 R E ~ A - 1 . 4 - D I E N E - 3 r l l ~ 2 0 - ~ 117~21-DIHYDROXY-16-b~ta-nETnYL~E~ -- P1247-42-3 -- P53-03-2 R E C N A - l ~ Q - D I E N E - 3 ~ l l r 2 0 - 7 R I O N E I 17.21-HYDROXY- PREGNA-4~17-DIEN-21-OICACID. 20-CYAND-3-OXO-~ ETHYL ESTER - PREGNA-4,6-DIEN-20-ONEn6-CHLORO-17-clpha-ETHYL-3-beta-HYDROXY-- 17-alpha-PREGNA-2~4-OIEN-20-YNO~2.3-dlISOXA7.OL-17-OL 17230-88-5 and - l7-alpha-PREGNA-214-DIEN-20-YNO~2.3-d~ISOXAZOl-17-OL, 4-EN-3-ONE - TESTOSTERONE 17-~lphrr-PREGNA-2~4-DIEN-2O-YNO~2~3-d~ISOXA~OL-17-OL, and NEPTANOATE 1 7 - c l p h ~ - P R E G N A - 2 ~ 4 - D I E N - 2 O - Y ~ l 2 ~ 3 - d ~ I S O ~ O L - l 7and -DL, - TESTOSTERONE PROPIONATE ~~-~~~II-HYDROXY-~~-~ETHYLINDROST-

3219 N1 3220 N1 3221 N1 3222 N1 3223

N1

3224 Nl

ACID, - 17-~lph~-PREGNANE-2l-CARBOXYLIC 1.3~5,14.17r19-HEXAHYOROXY-, gamma-LACTONE - PREGNANE-3-alphs~20-alpha-DIOL~and PREGNANEOIONE I4:ll

- PREGNANE-3rZO-DIONE

- 5-~lph~-PREGNANNE-11~tO-DIONE~ 16-beta-BROllO-3-b~ta,l7-alpha-DIHYDROXY-

172 3225 N1 3226 N1 3227 N1 3228 H1 3229 N1 3230 N1 3231 N1 3232 NL 3233 Nl

3234 N1 3235 N1 3236 N1 3237 N1

- PREGNANE-3,S O - O I W 6-beta. 16-alpha-OIHE~YL-B-.lpha-HYOR~2O-(N-AtETYWYDRUIM1- 5-alph.-PREGNAN-5-beta-OLI 20~~N~NICOTINILnrt)RALINlD

5-.lph.-PI1EWIN-l-b.t.-OL.

-

PRE6"-20-W,

3-dphaa17-0IHYDROXY-

- 5-alpha-PREGNAN-20-OE~ 3-beta~17-beta-OIHYDROXY- ~ - ~ ~ P ~ M - P R E G " - ~ O - O N3-beta-HmROXY-. ENEI 2O-ISONICOTINYUIYORALONe - PREGNAN-2O-ONE, - ~ - ~ ~ ~ M - P R E G N A N - ~ O -3-HYOROXY-1-HETHOXYONE, - 5-alpha-PREG~N-2O-OE,3-beta-HYOROXY-2l-I~E~YLENEPIPERIOI~l- 5-alph~-PREGNAN-20-ONE. 3-beta-HYOROXY-. 20-NICOTIHYLHYORUONE - PREGNAHT HARE SERUM GONADOTROPIN - ACETATE PRE6NA-l,4,6-IRfENE-3~~O~OI~E, (ester) - HeN-DIETHY ~~-~~P~~\-PREGN-~~ENE~~~-~~~~~CARB~AHIDE, - ~ ~ - ~ ~ ~ ~ ~ - P R E G N - ~ - E N E - ~ ~ - ~ ~ ~ ~3~20-01OXO-CARSOXAHIOEI - 17-alphe-PREGN-b-ENE-16-bata-CAR~IDE, 3-beta-HYOROXY-PO-O-, ACETATE (ester) - 17-alph~-PREGH-4-EHE-2l-CARBOXYLIC ACID, ~ - F L U O R O - ~ ~ - ~ ~ ~ ~ ~ ~ ~ - O I H YHONOPOTASSILM D R O X Y - ~ - ~W -L ST - 595-57-3 - 17-HYDROXY-7-alph~-HERCA~O-3-OXO-~ 17-alph~-PREGN-4-ENE-21-CARBOXYLIC ACID, gamma-LACTONE ACETATE - 52-01-7 ~-HYOROXY-~~-~~~~M-HETHOXY-

~-CHLORO-~~-M~~~.-HYOROXY-,

L-3-b.ta-HYDROXY-LO-OXO-

3238 N1 3239 N1 3240 N1 RN 3241 N1

RN 3242 Nl 3243 N1 3244 Nl

RN 3245 HI

-

PREGN-5-ENE-3,20-OIONE

- PRE6N-ll-EHE-3s20-DIME -- 71-58-9 ('6-alphaI -PREGN-+ENE -3 20-0IONE, 17- ACETY LOXY I-6-HETHY - miPRECN-4-ENL-lr20-OI~Er 17-(ACETYWXY )-6-HETHYL-, tb-alphal-, xt . w i t h 17-beta1-3E3TRA-1 .lr5(10 I-TRIEN-17-YL

3246

L-

HYOROXY

(

RN

I

s

- CYCLOPENTANEPROPANATE 71615-27-5

HI

- niixt. PREGN-~-ENE-~,~O-OIONEB with (17-alphal-

RN

*

~ ~ - I A C E T Y L O X Y I - ~ - ~ E T H Y LI6-~lphaI-, -I

l9-NMIPREGNA-lt3~5(10I-TRIEN-20-YNE~3~17~DIOL 8003-08-5

3247 Nl 3248 N1 RN

- PREGN-4-ENE-3,20-DIONE 16-BROm)-- PREGN-4-ENE-3~20-OlONE~II-~(BRO(IOACETYLIOXY)-~fll-alphab

3249 H1

-- PREW-4-ENE-3r20-OIONE, 16-(ISRO~ACETYL)OXYI-~(16-alphaI51541-48-1

RN 3250

N1

I

36049-50-0

'-

PRE6N-4-ENE-3.20-OIONE,

9-alpha-BROEIO-11-beta-HYOROXY-

3252 N1

- PRE6N-4-ENE-3,20-OIOE, 12-alpha-BRO~-ll-beta-HmROXY- PRE6N-4-ENE-3rZO-OIONE, 6-alph.-BROm)-17-.lph~-HYOROXY-.

3253 Nl

-

3251 Nl

ACETATE

P R E G N - ~ - E N E - ~ I ~ ~ - O I 4-CHLOROONEI

3256 N1

-- PREGN-4-ENE-3r20-OIONE, 16-alpha-MUIRO1816-80-4 - PREGN-Q-ENE-3rIO-DIONE, 16-CHLORO-11~17-OJHYDRWY-~11-ACETATE - PRECIH-~-WE-~,~O-DIONEI 4-CHLOR0-17-alpha-HYDROXY-

3257 N1

-

3254 N1

RN 3255 N1

PREGN-4-ENE-3r20-OIONE,9-alpha-CHLORO-ll-beta-Hrt)ROXT-

173 3258

N1

3259

N1

3260

N1.

3261

N1

3262

N1

3263

N1

3264

N1 RN

3265 N1 RN 3266

N1

- PREGN-~-EHE-~DZO-OIME,12-alpha-CHLORO-11-beta-HYOROXY-

-

PREGN-4-ENE-3r20-OIONE~ 4-CHLORO-17-slpha-HYOR~Y-r

- PREGN-4-ENE-3.20-OIONEr 6-alpha-CHLORO-ll-HWOXY-, - PREGN-~-ENE-~.~O-OIONES6-alpha-CHLORO-17-HmROXT-,

-

PREGN-4-ENE-3.2O-DUE,

- PREGN-4-ENE-3.20-OIONE, - PREW-4-ENE-3.20-DIMIEl ACETONE - wlth 4968-09-6

-

N1 N1

PREGN-4-ENE-3, PO-DIONE

3270

N1

327s

N1 RN

3274

Nl

3275 N1 3276

N1

3277

N1

3278

N1 RN

3279

N1

3280 N1 3281 N1 RN 3282

N1

3L83

Nl RN

3284

N1

3285 N1 3286

N1

3287

N1

3288

N1

3289

N1

ACETATE

CYCLIC ACETAL

3269

RN

16-beta-CHLORO-17-alphe-HYDROXY-,

1 6 - ~ ~ ~ ~ ~ . ~ ~ - D I H Y D RCYCLIC O X Y X ~KETAL -~

PREGN-~-ENE-~.~O-OIONES16-alpha.l7-OIHYOROXY-,

3268

N1

ACETATE

wlth 2-FURYL METHYL KETONE

-- PREGN-4-ENE-Sr20-DIONEr 1807-15-4 - PREGN-5-ENE-7~20-DIONE,

3272

ACETATE

6-alpha-CHL~O-l7-.Iph.-H~R~Y-,

cyclic ACETAL

Nl RN

3271 N1

ACETATE

PREGN-4-ENE-3r20-OIONE~ 16-plph.,l7-DIHrr)ROXY-r wlth ACETOPHENWEB (RI24356-94-3

3267

-

ACETATE

17.21-DIHYDROXY-e 3.17-OIHYOROXY-e

OIACETATE DIACETATE

, 1 1 - b e t i , 17-0IHYOROXY-9-alpha-FLWRO-

- PREGN-4-ENE-3.20-DIME~ 11,17-DIHYOROXY-9-alpha-FLUORO-l~-METHYLENE-~17-ACETATE - PREGN-Q-ENE-~B~O-DIMIEI 17.2l-OIHYDROXY-l-~RCA~-, 1.21-OIACETATE - PRE6N-4-ENE-3s20-DIO"EI l1-bet~.17-OIHYOROXY-21-~ll~l-PHENYLMETHYL~-lH-IMAZOL-J-YLIOXV)

--

ACETY LOXY I 53716-43-1 PREGN-4-ENE-3~2O-OIONE~6-alphr~I6-alpha-OI~THYI.1816-78-0

- PREGN-4-ENE-3.20-DIONEI 6-beto.16-alpha-DIHETHYL- PREGN-Y-ENE-3,20-DIONEa 6-alpha.l6-alpha-OlMETHYL-l7-alphe-HrDRO-, ACETATE - PREGN-4-ENE-3,20-DIONE, 16.17-EPOXY- PREGN-4-ENE-3.20-OIONE~ 16-olpha.17-EWXY-- PREGN-4-ENE-3r20-01ONE, ll-beta~18-EPOXY-l8r21-DIHYDROXY6251-69-0 - PREGN-4-ENE-3r20-OIONE~ 16-alpha,l7-EPOXY-6-HYDROXY- P R E ~ N - Q - E N E - ~ ~ ~ O Q I O26.17-EPOXY-6-beT.-HYDROXrS -- PREGN-~-ENE-~.~O-DIDNEI 6-alpha-FLUORO2300-03-0 - PREGN-~-ENE-~,~O-OIONEB21-FLUORO-- PREGN-~-ENE-~~~O-OIONENEI 9-fL~O-ll-beta.l7-OIHYDROXY-, 17-ACETATE 2529-45-5 - PREGN-4-ENE-3.20-DIONE~ ~ - P ~ ~ ~ ~ - F L U O R O - ~ ~ - ~ ~ ~ ~ - H Y D R O X Y - PREGN-~-ENE-~,~O-OIONEB12-alpha-FLUORO-11-alpha-HYDROXY- PREGN-4-ENE-3.2O-DIONE* 6-alpho-FLVORO-17-alpha-HYDROXY-~ ACETATE - 6-alpha-FWOR0-17-alpho-HY0ROXY-l6-~lpha-ME~YL-, PREGN-4-ENE-3,20-DIDE, ACETATE

-

PREGN-~-ENE-~,~~-DIONEI ~7-alpha-HYOROXY-l6-alpha-METHYL-~ ACETATE PREGN-4-ENE-3.20-OIME. 17-ACETATE ( e a t e r )

21-FLUORO-17-HYDROXY-6-al~a-ME~YL-,

174 3290 N1

- PREGN-4-ENE-3,20-DIONE, tl-~LUORO-l7-mlpha-HYOROXY-6-.lph.-nEIHrL-~

ACETATE (ester)

ACETATE -- PREGN-4-ENE-3,20-OIOE, 1818-56-0 3293 Nl - PREW-4-ENE-3r20-DIONE~6-bet.-FLUORO-16-mlpha-METHYL3294 N1 - PREGN-4-ENE-3,2O-OIONE, 9-FLUORO-ll-betn~17s21-TRIHYDROXYRN - 127-31-1 3295 N1 - PREGN-4-ENE-3,2D-OIONE, 4-HYDROXY6-b.ta-HYDROXY3296 N1 - PREGN-~-ENE-~B~O-DIONEV 3297 Nl - PREGN-4-ENE-3.2O-DIONEr 11-beta-HYDROXY3298 17-HYOROXYRN - 68-96-2 3299 N1 - PREGN-5-ENE-7.20-OIOE, 3-beta-HYOROXYNl - 5-alpha-PREON-l-ENE-3~20-D10NE1 17-dpha-HYDROXY3301 N1 - PREGN-4-ENE-IvLO-DIONEt 17-HYOROXY-P ACETATE RN - 302-23-8 21-HYDROXY-, NE, ACETATE (ester1 3302 N1 - P R E G N - ~ - E N E - ~ B ~ ~ - D I O N1 - PREGN-4-ENE-3~2O-DIONE~ll-alPh~-HYOROXY-~ HEMISUCCINATE, conipd. with BOVINE SERUM ALBUMIN

3291 N1

PltEtrN-4-ENE-3r20-DIfflE~ ~ ~ - F L ~ ~ R O - ~ ~ - H Y D R ~ ~ Y - ~ - ~ E T H ~ L E N E - I 6-alpha-FLUORO-16-al~a-METHYL-

3292 NI RN

N1

PREGN-4-ENE-3.20-OIfflEr

3300

3303

3300 Nl

RN 3305 N1 3306 N1

3307 N1 3308 Nl

--

PRE6N-4-INE-3v20-DIMr 17-HYDROXY-, HEXANOATE 630-56-8

- PREGN-4-ENE-3.2O-OIONE. ll-betm-H~ROXY-9-al~ha-IODO- PREW-4-ENE-3.20-DIOm. - PREGN-4-ENE-3s20-010NEr 2l-HYOROXI~T-MERCAPm~r21-ACETATE 7-PROPIONATE - PREGN-Q-ENE-3.20-OIONE. THIOACETATE tar - P R E G N ~ 4 ~ E N E ~ 3 ~ L D - D I17-HYOROXY-6-METHYLONE~ -- PREGN-4-EN~-3,2O-DIONE. 17-HYDROXY-6-nlph.-METHYL520-85-4 - PRESN-4-ENE-3~20-DIONE~17-HYDROXY-I-METHYL-, ACETATE - PREGN-~-EWE-S,~O-DIONEV ACETATE, ESTRAOIOL POLYESTER with PHOSPHORIC ACID - TESTOSTERONE PREGN-4-ENE-3r20-DIWEr 17-HIDROXY-6-alpha-METHYL-~ ACCCTITE. and HEPTANOATE - PREGN-4-ENE-3~ZO-DI0NEv ACETATE, and TESTOSTERONE PROPIONATE - PREGN-~-ENE-~,~O-DIONEB ACETATE - PREGN-4-ENE-3sLO-DIWEr 1-HERCAFTO-, ACETATE - PRESN-4-ENE-5~2O-DIWE, I-alpha-HERCAPTO-, THIOACETATE Iertcrl 6-alpha-METHYL-- PREGN-~-ENE-~,~O-DIONEI 903-71-9 - PREGN-4-ENE-3.2D-DIWEr 17-METHYL- PREGN-4-ENE-3~2O-OIONE~17rl9~21-TRINYOROXY11-beta-HIDROXI-12-mlpha-IWO-

17-HYOROXY-l-alpha-MERCAPTO-,

fee

3309 N1 3310 N1 RN

3311 N1 3312 Nl 3313 N1 3314 Nl 3315 N1 3316 N1 3317 N1 3310 N1 RN 3319 N1 3320 Nl

1

17-HYDROXY-6-alpha-METHYL-,

and

17-HYDROXY-6-alph.-METHYL-,

~~-HYOROXY-~-M~~~M-ME~YL-~~~METHYLENE-,

175 3323 N 1 RN

-- 516-15-4 PREGN-4-ENE-3~11.2O-TRIONE - PREGN-~-ENE-~.II~~O-TRIMSEI 9-6Rom)-

3324

N1

3325

N1

-

PREGN-4-ENE-3.11.20-TRIONE.

9-alpha-CHLORO-

3326

N1

-

PREGN-4-ENE-3.11.20-TRI~E,

12-alpha-CHLORO-

3327

N1

3328

N1

3329

N1

3330

Nl

- PREGN-4-ENE-3,11,20-TRIUNE, 9-alpha-FLUMIO- PREGN-4-ENE-3~1ls20-TRIONE~9-FLUORO-17-HYOROXY-r

-

ACETATE

PREGN-4-ENE-3~11~2O-TRIONE~9-alpha-FLUORO-17-HYOROXY-, ACETATE

3332

N1

3333

N1

3334

N1

3335

N1

- PREGN-4-ENE-3,11,20-TRI~E, 12-alpha-IODO- 17-alpha-PREGN-5-EN-3-b*ta-OL~ 16-beta-METHYL- PREGN-5-EN-20-ONE. 3-beta-CNLORO- PREGN-5-EN-ZO-ONE. S-beta-tHLOR0-17-alpha-HYDROXY-~ ACETATE l e s ter - PREGN-5-EN-20-ONEI 3-beta-CHLORO-16-alpha-METHYL- 17-olpha-PRE~-5-EN-2O-ONE, 3-beta-CHLORO-16-beta-MElHYL-

3336

N1 RN

-

3337

N1

3338

N1 RN

- PREGN-5-EN-7-ONE. -- PREGN-4-EN-20-CNE. 57-16-9

3339

N1

-

3331 N 1

)

RN 3340

N1 RN

3341

N1

3342

N1

3343

N1

3344

N1

3345

N1

3346 N 1 3347

Nl

3348

N1

3349

N1

3350

N1

3351

N1

3352

N1 RN

-

PREGN-5-EN-20-ME, 387-79-1

3-beta,l7-OIHYDROXY3 ~ 1 7 - 0 I H Y D R O X Y - ~DIACETATE

3-beta.17-DIHYDROXY-6-.lpha-nETHYL-.

17-ACETATE

PREGN-~-EN-~-ONEB 20-alpha-HYDROXY145-14-2

-- PREGN-~-EN-~-ONEB 20-beta-HYDROXY145-15-3 - PREGN-5-EN-LO-ONE. 3-beta-HYOROXY- PREGN-4-EN-20-ONE. 17-HYOROXY-. ACETATE - PREGN-5-EN-20-ONEV 3-beta-HYDROXY-16-bet.-nETHYL- PREGN-Q-EN-S-ONE. 20-MERCAPTO- PREGN-4-EN-3-ONEn 20-THIOXO- PREGN-5-ENO( 16.17-c )PYRAZOL-2O-ONE 3-beta-HYDROXY-,

- 17-alpha-PREGN-5-EN-2O-YNE-3-beta,l7-OIOL, -

ACETATE

3-1 3-CYCLOHEXYLPROPIONATE I

3353 N 1 3354

N1

3355

N1 RN

3356

N1 RN

5-alpha-PREGN-2-EN-2O-YN-17-beta-OL

- 17-alpha-PREMS-4-EN-ZO-YN-3-~E. 6-alpha-CHLORO-lI-b.ta-HIDROXT- ~ ~ - ~ ~ ~ ~ P - P R E W I - ~ - E N - Z O - Y N - ~ -lOl - bNcEt a~~ 1 7 - D I H Y D R O X Y - , 17-ACETATE - 17-alpha-PREtN-4-EN-ZO-YN-3-ONE, 6-alpha.2l-OIMETHYL-17-HYOROXY-- 434-03-7 ~ ~ - ~ ~ P ~ ~ - P R E G N - ~ - E N - ~ O - Y N - ~17-HYOROXY-ONE, - 17-alpha-Fl8EGN-4-EN-ZO-YN-3-ONE~ 17-HYOROXY-9 and tranr-;llpha,alpha'-DIETHYL-4,4'STILBENEDIOL - 17-alpha-PREGN-4-EN-20-YN-3-ONE~ 17-HYOROXY-. and 1 7 - H Y O R O X Y P R E G N - 4 - E N ~ 3 ~ 2 O ~ D I O NHEXANDATE E - 19-NOR-17-alpha-PREGNA-lr3r5~10)-TRIEN17-alpha-PREMS-Q-EN-20-~-3-ONE, 17-HYDROXY-. end 20-YNE-3.17-DIOL 11:lOOO) - 53568-84-6

--

17-alpha-PREGN-20-YN-3-0NE~ 64584-52-7

17-HYOROXY-~ 0-lp-NITROPHENYLIOXIME

176 3357

N1

3358 N1 RN 3359 N1 RN

3360 N1 RN 3361 N1 RN 3362 N1

3363 N1

RN 3364 N1 RN 3365 N1 RN

3366 N1 RN 3367 N l RN

3368 N1 RN 3369 N l RN 3370 N1 RN 3371 N l RN

3372 N l RN 3373 N1 RN 3374 N1 RN 3375 N l RN 3376

N1 RN

3377 N l RN

3378 N1 3379 N1 RN

3380 N l RN 3381 N l RN

3382 N l RN

- PREMRIN

----

PRIMEX 8041-44-9 PRO6ESTERONE 57-83-0 PROLACTIN 9002-62-4

L-PROLINAHIDE , 5-0x0-L-PROLY L-L-HISTIDY L-- 24305-27-9

-

L-PROLINAHIOEP 5-0x0-L-PROLYL-L-HISTIDYL-I TARTRATE

1-PROLINE I 1-11fl4-01HETHYLW1NO~~1~4~4~~5~5~~6~11~12~~~T~YDR0~3~6~1 2n-PENTAHYDROXY-

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--

I14-)10RPHOLINY UIETHYLJAHINO )CARSO-

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PROPANE 1-BRW-- 106-94-5 l-WTOXY-2,3-EPOXY-- PROPANE, 2426-08-6 v

---

PROPANE, l-CHLORO-2r3-EPOXY106-89-8 lr3~PROPANEOIWINE 109-76-2

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-- 52340-46-2

~I~-PROPANEDIOL~ ~-CHLORO-B 14-1-

-- 60827-45-4 1~2-PROPINEDIOL. 3-CNLORO-r

-----

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1~2-PROPANEOIOl~ I-CHLMIO-. 1-ACETATE 24573-30-6 1,Z-PROPANEDIOL. 3477-94-9

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l*t-PROPANEDIOL* 3-CNLORO-n DIACETATE 869-50-1 ~~~-PROPANEOIOLI DIMETHANESULFONATE 15886-84-7 ~~~-PROPANE~IOLI 3-1 f l O - E ~ Y L - l l - l ~ ~ H Y D R D m P H E N Y L ~ D I B E M Z O)THIEPIN-3-YL)OXY lb~f 85850-94-8

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- 1.2-PROPANEDIOL~ 3-1 ~10-ETHYL-ll-PHENYLDIBENZO~b~f ITHIEPIN-3-YLIOXY I - , ISOPROPY L ALCOhOL f 2: 1I - 85850-90-4 -

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- 83-ll10-ETHYL-11-PHENYLDI8ENZlb~f~OXEPIN-3-YL~OXYI5850-89-1

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3389

N1 RN

3390

N1

3391

N1 RN

3392

N1 RN

3393

N1 RN

3394

N1 RN

3395

N l RN

3396

N1

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85850-92-6 lv2-PROPANED1OLs

1.2-PROPAHEDIOL, 3-( 6-€THY L-5-PHENY L - l l ~ l 2 - D I H Y D R O D I B E N Z O ( a I a ICYCLOOCTEN-2-Y L )OXY-

I85850-91-5

3-MERCAPTO- l,Z-PROPANEDIOL, 96-27-5 - 3-lp-l6-METHOXY-2-PHENYL-3~4-DIHYDRO-l-NAPHTHYL~PHE~XYl1.2-PROPANEDIOLe

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1,3-PROPANEDIOL. 57-53-4

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DICARBABATE

PROPANE, 1.2-EPOXY75-56-9 PROPANE, l.Z-EPOXY-3-PHENOXY122-60-1 PROPANENITRILE, 2-lbeta-D-GLUCOPYRANOSYLOXY)-2-METHYL554-35-8

3397

N1 RN

Z-NITRO- PROPANE, 79-46-9 -- 41-PROPANESULFONIC ACID, 076-02-2 - PROPANE, 1,2r3-TRIBROMO- 96-11-7

3398

N1

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with

3-((11-ETHYL-lZ-PHENYL-6H-DIBENZOlb~flTHIOCIN-3-YL~OXY~-~ HYDRATE

RN

RN

sompd.

1,2-PROPANEDIOLv

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RN 3387

1,2-PROPANEDIOL, 3-1 I10-ETHYL-11~lp-HYDROXYPHENYLlDIBENZlb~f )OXEPIN-3-YL)OXYl-o HYDRATE 1 4 : l ) 85850-93-7

2s3-DIMERCAPTO-.

P(ONOSOD1W SALT

1~2.3-PROPANETRICARBOXYLIC ACID, 2-HYDROXI-,

T R I L I T H I U n SALT,

HYDRATE 3399

N1 RN

3400

N1

-- PROPANE, 96-18-4

1~2.3-TRICHLORO-

- PROPANIBIDABIDE,

3-l112-llAMINOIMINMIETHYL~AMINoI-4-THIAZOLYL~METHYLlTHIOI-N-

RN 3401

N l RN

3402

N1

-

1AMINOSULFONYL)76824-35-6 PROPANOIC ACID, 2-14-CHLDROPHENOXY)-2-METHYL-~ 3.4-DIHYDRO-2.5,7,8-TETRAMETHrL-2-l4r8~12TRIMETHYLTRIDECYLI-2H-l-BENZOPYRAN-6-YL ESTER, 50465-39-9

12Rl4R~8RI) - PRDPANOIC ACID, 2-HYDROXY-, compd. w i t h 3-( CYCLOBUTY LMETHY L l-6-ETHY L - 1 1 2 3 1 4 p 6 - H E W Y D R O I

RN 3403

Nl RN

3404

N1 RN

-

9 5

11~11-DIMETHYL-2~6-METHA~-3-BENZ*ZMIN-B-OL (1:l) 75639-72-4

- 62-PROPWOL, 452-73-9 -- 1-PROPANOLv 156-87-6

l-lo-ALLYLOXYPHENOXY~-3-IS0PROPYLIIIINO-r 3-AMINO-

HYDROCHLORIDE

178 3405

Nl

3406

N1 RN

3407

N1

3408 N l RN 3409

Nl RN

3410

Nl

1411 N1 RN 3412

N1

3413

N1

3414

N1 RN

3415

N1 RN

3416

N1 RN

3417

N1 RN

3418

N1

RN

RN

- 2-PROPINOLO 1-AMINO-3-CHLORO-a -- 59348-49-1 2-PROPAWL, 1-AMINO-3-CHLORO-t - 2-PROPANOL. 1-AHINO-3-CHLORO-l -- 2-PROPAWL, 1-AHIW-3-CHLORO-r 34839-13-9

--

2-PROPAWL, 34839-12-8

1-AMINO-3-CNLORO-r

I- ) -

I+-)BENZOATE ( e s t e r ) ,

HYDROCHLORIDE

HYOROCNLORIDEI I-)HYDROCHLORIDE, I +-b

2-PROPANOLt 1-AMINO-3-1 p-1 6-METHOXY-P-PHENY L-3 p4-OXHYDRO-l-NAPHTHY L IPHENOXY)-I HYOROCHLORIDE

- I-( ----

t-PROPANOL, l-Itert-BUTYLAMINOl-3-l16-CHLORO-m-TOLYL)OXY HYDROCHLORIDE 15148-80-8

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2-PROPAWL, 14tert-6UTYLAHINO)-3-Il6-CHU)RO-m-TOLYLIOXY)-~ HYDROCHLORIDE 15148-80-8 2-PROPANOLi t e r t -6uTYLAMINOl-3-I 0 - 1 ITETRAHYDROPWFWYL )OXY )PHENOXY )-, HYDROCHLORIDE 35108-88-4 2-PROPANOL, l~l'~I2-BUTYNYLENEOIOXY~61SI3-CHLORO1606-83-3 2-PROPANOL, l-CHLORO-3-IL-H'IDROXYETHYLI18371-74-9 2-PROPANOLs 1-CHLORO-3-IMPROPOXY4288-84-0

-- 2-PROPANOLe l-CHLORO-3-IPENTYLOXY 125401-93-8 - 2-PROPANOL. 1 -1 11,4-CYCLOHEXYLENE IBIS( HETNYLENEOXY IBIS( 3-CHLMIOs l '

3419

Nl RN

3420

N1

RN 3421 N1 RN 3422

N1 RN

3423

Nl RN

3424 ti1 RN 3425

N1 RN

3426 3427

N1 RN N1 RN

3428

N1

3429

N1 RN

3430

N1 RN

---

2-PROPANOL, 1~1'-lDECAHETHYLENEOIOXY~BISl3-CNLORO24765-68-2 1-PROPANOLI 213-01BROtlO-~ PHOSPHATE 0:l) 126-72-7

-

- 2-PROPANOL, 13674-87-8 - 1-PROPAWL, - 59-52-9 - 1-PROPANOL. - 556-52-5

1,3-DICHLORO-r

PHOSPHATE I 3 : l )

Zv3-DIHERCAPTO2r3-EPOXY-

-- Z-PROPANOLI l~l'-~ETHYCE~~IOXY~BISI3~CHLORO~ 13078-45-0 - p-TOLUENESULFONATE 1-PROPAWL. 3,3'-IHINODI-. OLMETHANESULFONATE l e n t e r l , - 32784-82-0 2-PROPANOL, 1-(IH-INDOL-4-YLOXYI-3-1 fl-HETHYLETHYL)AMINO)--- 2-PROPANOLv 13523-86-9 l-ISOPROPYLAHINO-3-IP-I2~NETHOXYETHYL)pHENOXY I - ,

--

TARTRATE 74220-04-5

~-PROPANOLI l~lISOPROPYLAMINO~-3-lp-l2-HETHOXYETHYL~PHENOXY~-~ TARTRATE I2 :1) 2-PROPANOLs 1 ~ I I S O P R O P Y L A M I N O ~ - 3 - I l - ~ P H l H Y L O X Y ~ 525-66-6

-- 13013-17-7 2-PROPANOLt

l~IISOPROPYLAMINOl~3-I 1-NAPHTHYLOXY ) - t

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179 3431

N1 RN

3432

Nl

RN 3433

N1 RN

3434

Nl RN

3435

N1

3436

Nl

3437 N 1 3438

N1 RN

3439

N1 RN

3440 N 1 RN 3441

N1 RN

3442

N1 RN

3443

Nl RN

3444

Nl

3445

N1 RN

3446

Nl

--

2-PROPANOL, 1-1 ISOPROPYLAMINOl-3-l1-NAPtlTHYLOXY 1 - v 318-98-9

HYDROCHLORIDE

- 2-PROPANOL. 1 - t b - i ~-~ETHOXYETHYLIPIKN~XY 1-3-11 ~-~ETHYLETHYLIAIIINOI-. - 37350-58-6 -- 2-PROPANOL. 1~l'-lPENTA~ETHYLENEDIOXTlBISl3~CHLORD24771-52-6

--

2-PROPANOL, 18371-82-9

1,l'-IPROPYLENEOIOXY )BISO-CHLORO-

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1~1'-lTRIMETHYLENEOIOXY lBISl3-CHLORO-

i+- I-

- 1-PROPINONEr 1-15-BROna-2-THIENYL)-. 3-THIOSEllICARBAMNE - 2-PROPANONE, 1-l4-lC~LOROnETHYLl-l~3-DIOXOLIN~2-YLl- 1-PROPANONE. 1-(2- Ibeta-0-GLUCOPYRANOSYLOXY 1-4 ,b-OIHYDROXY PHENYL )-3-t 4-HYOROXYPHENY L 1- 60-81-1 -- 684-16-2 2-PROPANONE, 1,1,1,3,3t3-HEXAFLUORO-- 2-PROPANONE HEXAFLWRO-. SESWIHYORATE 13098-39-0 -- 2-PROPANONE. HEXAFLUORO-9 TRIHYORATE 34202-69-2 -- 54-36-4 1-PROPANONE, 2-METHYL-l~Z-DI-3-PYRIDYL2-METHYL-l~Z-O1-3-PYRIDYL-~ TARTRATE 11:21 -- 1-PROPANONE, 908-35-0 - 2-PROPINONE. TETRACHLORO-- 632-21-3 2-PROPANONE. lrl.3~3-TETRACHLORD- 2-PROPEN-l-MINE, 3-1 4-BROMOPHENY L I-NIN-DIMETHYL-~-I 3-PYRIDINY L OIHYOROCHLORIDE 12)- 60525-15-7 -- PROPENE. 3-CHLORO107-05-1 - PROPIONAllIOE~ 3 ~ 1 l 1 1 ~ 4 ~ B E N L M ) I O X I N ~ 2 ~ Y L ~ l l E T H Y L ~ A l l I N O l - N - l l E T H Y L -- 63762-75-4 PROPIONAMIDE~ N-l2-l6-CHLORO-5-METHOXY-3-INDOLYLlETHYLI- PROPIONAMIDE 3-~ETHYLAMINOl-N-METHYL-N-ll~Z~3~4-TETRAHYORO-l-NAPHTHYLl- N-l1-~ETHYL-2-Il-PIPERIDIHYLlETHYLI-N-l2-PYRIOINILl-~ PROPIONAIIIDE FUWRATE - 13717-04-9 -- 65792-56-5 PROPIONAMIDE. N-NITROSO-H-PROPY LACIO, 2-13-BENZOYLPHENYLI-- PROPIONIC 22071-15-4 -- PROPIONIC ACIOI 3-1 3-CNLORO-4-CYCLOHEXYLBENZOYL 132808-51-8 e

)- P

RN 3447

Nl RN

3448

N1

3449

N1 RN

3450

N1

3451

Nl RN

3452

N1 RN

3453

N1 RN

3454

Nl RN

3455

N l

3456

N1

RN

RN

B

I

-

PROPIONIC ACID, 2-lp-CHLOROPHENOXYl-2-METHYL-. 4-HYOROXY-N.N-DIl'lETHYLBUlYRAllIOE 26717-47-5

-- 637-07-0 PROPIONIC ACIO,

2-lp-CHLOROPHENOXY I-2-HETHYL-1

ESTER w i t h

ETHYL ESTER

s

180 3457 Nl RN 3458 N1 3459 Nl RN

3460 Nl RN

3461 N1 RN 3462 N1 RN

3463

Nl

3464 Nl RN

- PROPIMIC ACID. 2-(1~2,Sr6-TETRUIYDRO-lr3~DIHETHYL~2,6~DIOXO7H-PWIH-7-YL) ETHYL ESTER - 54504-70-0 2-14-CHU#OPHLW)XY)-2-nETHYL-r

- PROPIONIC ACID, 2-CHUW(O-e SaDIUI SALT -- PROPIONIC ACIDv e-lI4-CHLoRO-o-TOLYL)oXY)93-65-2 -- PROPIONIC ACIDv 2-1 14-CMLDRO-o-TOLYL)WY 1-v 16484-77-8 -- 52214-84-3 PROPIONIC ACID, Z~14~12~2~OICHLORDfYCLOPROPYL~PHENOXY~~2-HETnYL-- PROPIONIC ACID 8-( 2,4-DIUILOROPHENOXT 120-36-5 - PROPIONIC ACID, Z-12~4-DICHLOROPHLNY1-1 I* 1-- ,27031-31-8 PROPIONIC ACID. 3 ~ 3 ' ~ ~ l r 3 - D I O X O - 1 ~ 3 ~ D I 6 E R ~ ~ L E ~ ~ O I ~ It)-

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r

3465 N1 RN

-- PROPIONIC ACIDV 2-1p-4 IMIDUOI ~I~-M)PYRIDIN-L-YL)PHHENYL)55843-86-2

3466 N1 RN

-- PROPIONIC ACID, Z-IMETnOXY-2-NAPHTHYL)-, 22204-53-1

3467 N1

It)-

- PROPIONIC ACID,

3 - I p - 1 6 - H E T H O X Y - 2 ~ P H E N Y L ~ 3 ~ 4 - D I H Y D R O ~ 1 - N ~ ETHYL ~~

ESTER 3468 N1 RN

3469 N1 RN 3470 N1 RN

3471 N1 RN 3472 Nl RN 3473 N1

-- PROPIONIC ACID, Z-lS-RIEHM(YPHENYLbr CALCIUM SALT, dl34597-40-5 -- PROPIONIC ACID, 2-12,4,5-TAICHLMIOPHENOXY)93-72-1 -- PROPIONITRILE 307-12-0 -- PROPIONITRILEr 3-MINO-- PROPIONITRILEI 3-MINO-r FUHARATE I2:l) 2079-89-2 - PROPIONITRILE, 14-CHLORO-6-1ETHYLIHINO )-a-TRIMIN-Z-YLAHINO )-2-Ml?THYL- 21725-46-2 ION IT RILE^ 3~3'-IllINOOI-- PROP 111-94-4 151-18-8

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2-1

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3474 N1

RN 3475 H1 3476 N1

-

PROPIONITRILE. 3-1 3-~ETHOXYESTRA-l~3r5110 I-TRIEN-17-b.t.-YL)OY

- PROPIONITRILE. 3-(lslpha-~ETHYLPHENETHYL)I~~~~-, MONOHYOROCHLORIOE~ - 18305-29-8 -- PROPIONITRILEe TRICHLORO12408-07-0 - m-PROPIONOTOLUIDIDE~ - 2-~ETHYL-4'-NITRO-slpharalpha,a1ph&-TRIFLOUIO13311-84-7 - PROPIOPHENONE. 3-(P-CHLOROPHENYL)-2-PHENYL-4'-1 2-1 1-PYRROLID1NYL)ETHOXYl(*-

RN 3477 Nl RN 3478 Nl RN 3479 N1 RN 3480

N1

3481 Nl RN

1-

- 31349-74-3

- PROPIOPHENONEi 2~3-DIPHENYL~4'~12-~1-PYRROLIDINYL~ETHOXY~- PROPIOPHENONE. , POLYESTERS - PHOSPHITE 9014-72-6 ~'~~'I~'-TRIHYOROXY-~-IP-HYORDXYPME~L)-I

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181 3482 N1 RN 3483 N1 RN 3484 N1 RN 3485 N1 RN

3486 N1 RN

- NPROPYLAVINE, ~N-OIETHYL-3-lp-~6-METHOXY-2-PHENYL-3-BENlOrllRANYLlP~E~~~-~ - HYOROCHLORIOE 25433-67-4 - PROPYLAMINE, ~N-OIMETHYL-3-~DIBE~O~b~~lTNIEPIN-d~lta-rupl11~6H~.g~mm~l~- N113-53-1 -- PROPYLAMINE, N-l2-HYOROXYPROPYLl-N-NITROSO39603-53-7

-

PROPYLAMINE. N-METHYL-N-NITROSO924-46-9

N-~2-OXOPROPYLI-N-NITROSO- PROPILAVINE, 39603-54-8

3487 N1

-

RN

-

N1

- PROSTA-5~13-DIEN-l-OIC ACID, 9,15-OIHYOROXY-16.16-OIMETHYL-ll-OXO-,

3488

RN 3489 Nl RN 3490 N1 RN 3491 N1 RN 3492 N1

-

PROSTA-5.13-OIEN-1-OIC ACID, 2,2-0IFLUORO-9~11,15-TRIHYDROXY-l5-METHYL-~theta-LACTONE. ~5Z,9-alpha.ll-alph~,l3E,l5Sl62443-67-8

- PROSTA-5~13-0IEN-l-OIC ACID, 11,15-OIHYOROXY-l6.16-OIMETHYL-9-OXO-, -

-

(5Z.9-alpha,13E115S)-

85235-22-9 ~52,11-alpha,13E~15R)-

39746-25-3 PROSTA-2~13-01EN-l-OICACID, 11~15-OIHYDROXY-16~16-01METHYL-9-OXO-~ METHYL ESTER,

12E.11-a1pha.l3E~15Rl64318-79-2 PROSTA-5~13-OIEN-1-OICACID, 9~15-OIHYOROXY-15-ME~YL-ll-OXO-~ 152,9-alpha.l3E ,155)85280-90-6

- PROSTA-5~13-OIEN-l-OIC ACID, 11~15-OIHYOROXY-15-METHYL-9-OXO-~ 5Z.11-alphaBl3E.15R l (

RN 3493 N1 RN 3494 N1 RN 3495 Nl

- 55028-70-1 - PROSTA-5~11I-OIEN-1-OICACID,

11.15-DIHYDROXY-15-METHYL-9-0x0-r

-

52,11-alphat13E I 15S.172 I35700-27-7

-

PROSTA-5112-OIEN-1-01CACID, 9~15-OIHYDROXY-11-OXO-~ 15Z,9-elphe,12E,15Sl64072-89-5

- PROSTA-5~13-OIEN-1-OIC ACIOp I 52,9-a1pha,13E 15s I -

9~15-OIHYOROXY-11-OXO-~

I

RN

3496

N1 RN

3497 N1 RN

3498 N1

- 41598-07-6 - PROSTA-5~13-OIEN-1-OICACID, 152,11-alpha,l3E.15S)-ll,15-OIHYDROXY-9-OXO- 363-24-6 - PROSTA-5~13-OIEN-l-OICACID, 9~15-OIHYOROXY-11-OXO-~ laoIbda-LACTONE, (5Z19-a1pha,13E.15S)- 62410-98-4

- PROSTA-5~13-OIEN-1-OIC ACID, 9v15-OIHYOROXY-11-0x0-r t het a-LACTONE, 5Z,9-alphaV13E-15s 1-

I

RN 3499 N1 RN 3500 N1 RN 3501 N1

- 62410-77-9 - PROSTA-5~13-OIEN-1-OICACID, 11~15-OIHYOROXY-9-OXO-~ lambda-LACTONE, 152,ll-alpha. 13E ,15S1- 62410-93-9 - PROSTA-5~13-OIEN-1-OICACID. 11~15-OIHYOROXY-9-OXO-~MONOSOOIUn SALT. IIZ,ll-alpha,11E ,15SI- 53697-17-9

- METHYL PROSTA-5~13-OIEN-1-OICACIOI 12-FLUORO-9r11~15-TRIHYDROXI-, ESTER. + l52,9-alpha,ll.alpha,l3E,15-alphal(

3502

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PROSTA-5~13-OIEN-1-OICACID, 1 2 - F L U O R O - 9 ~ 1 1 ~ 1 5 - T R I H Y D R O X Y - ~ METHYL ESTER. I + I - , 15Z,9-olphs,ll-alpha,13E,l5-beta ) -

3503 N1 RN 3504

N1 RN

3505 N1 RN 3506

N1 RN

3507 N1 RN 3508 N1 RN 3509 N1 RN 3510 N1 RN 3511 N1 RN 5512

m RN

3513 N1 RN

3514 N1 RN 3515 Nl

- PROSTA-5~13-OIEN-l-OIC ACIOi iota-LACTONE, 5Zs9-alpha, 11-alpha,13E ,155I

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[

- 80029-za-3

- PROSTA-5.13-OIEN-1-OIC ACID, 15-METMYL-9~11,15-TRIHYDROXY-~ theta-LACTONE, 152,9-alpha, ll-alpha,l3E,l5S) - 62411-08-9 - PROSTA-5~13-DIEN-l-OIC ACID, ~5Z19-elphar11-alphar13E,15sI-9r11,15-~IHYDROXY- 551-11-1

- PROSTA-5~13-0IEN-1-OIC ACID, ~ ~ ~ ~ P ~ ~ - T R I H Y D R~OtO-UCTOHE, OXY-* 15Z.P-alpha~ll-alphar 13E-1551- 62410-84-8

- PRWTA-5.13-DIEN-1-OIC ACID, 9,11,15-~IHYDROXY-t lanbda-UClOM€i 1Sz.P-alpha, 11-alpha, 13E 155I-

- 55314-49-3

B

- PROSTA-5~13-DIEN-l-OIC ACIO, 9 ~ 1 1 ~ 1 5 - T R I H Y O R O X Y ~ 1 5 - M E ~ Y L ~ ~ ~5Z~9-alph~~ll-olph~,l3E~l5Sl~ - 35700-23-3

- PR05TA-5~13-DIEN-l-OIC ACID. 911lt15-TR1HYOR0XY-r METHYL ESTER, 15L19-~lph~111-~lph4, 13E115SI-

- 33854-16-9 - Platnbda-LACTONEI R O S T A ~ 5 ~ 1 3 ~ 0 I E N ~ lACID, ~ O I C 9111rlS-TRIHYDROXY-15-METH~L-r IbZ~P-alpha. ll-alpha,13E115S)

- 62411-21-6

- PROSTI-5~13-OIEN-l-OIC ACID. I5Z~9-a~~ha~ll-alphs~l3E~l5S~-9tll~l5-TRIHYOROXYeompd. with TRIMETHYLOLAMINOnETHWE - 38562-01-5 - P~5Z,9-alpha~ll-alpha~13E.l5S~R O S T A ~ 5 ~ 1 3 ~ O I E N ~ lACID. ~ O I C 9~llrl5~TRIHYOROXY-15-METHYL-, somnpd. with 2 - A M I N O ~ 2 ~ ~ H Y D R O X Y ~ E ~ Y L ) - l t 3 - P R O P A N E D(181 IOL I - 58551-69-2 - PROSTAGLANDIN Atsup 21 - 13345-50-1 - PROSTA-5,9,13-TRIEN-l-OIC ACIDt ~ ~ - H Y D R O X Y - L S - ~ E T H Y L - ~ ~ - ~ O - I 15Z19-alpha113E115S)-

- 85235-20-7 - PROST-5-EN-1-OIC ACID, l t ~ F L U O R O ~ 9 ~ 1 1 r l 5 ~ T R I N Y D R O X Y ~ ~ (5Z,9-alphar ll-alpha~l5-olpbl- ESTER, PROST-I-EN-1-OIC ACID, 12-FLVORO-9.11rl5-TRIHYDROXY-, METHYL 5Z,9-alphal 11-alphatlS-bcta nETHYL

ESTER. It)-,

3516 N1

( t I-,

3517 N1

I

)-

- PROST-13-EN-I-OIC ACXD. Ptll.15-TRIHYDROXI-~ larnbda-LICTONE, (9-elpha~ll-alpharl3E,155)-

- 62411-18-1 - PROST-5-EN-1-OIC ACID, 9~llrl5-TRIHYDROXY-, 15Z~9-~1ph~~ll-~lph~~15S*~~ 3519 N1 - PROTEINASEs AGKISTRODON RN - 9046-56-4 3520 N1 - PROTEINASE, BACILLUS SPHAERICW ALKALINE RN - 63551-77-9 3521 N1 - PROTEINAS€* RN - 9039-61-6 3522 N1 - PRUNASIN RN - 99-18-3 ARtlENIACA kernels 3523 N1 EMARGIWATAt uood 3524 Nl CORYLIFOLIA dry seeds 3525 N1 RN

HETHYL ESTER. ( + b e

3518 N1

RHMIOSTWA VENOM

BOTHROPS VEHOM

P R W

1.. whole

PRUNVS

PSORALEA

3526 Nl

extrect

L..

- PTERYCIOTA ALATA (Roxb.)

powdered

R. EW., extract excluding roots

183 3527 Nl 3528 N1 RN 3529 N1 RN 3530 N1 RN 3531 N1 RN 3532 N1 RN 3533 N1 3534 N1 RN

3535 N1 3536 N1

RN 3537 Nl 3538 N1 RN 3539 N1 RN 3540 Nl RN

3541 N1 RN 3542 N1 RN 3543 N1 RN 3544 N1 RN 3545 N1 RN 3546

Nl RN

3547 N1 RN 3548 N1 3549 N1 RN

3550 N1

- PUNICA GRANATUM Linn.. f r u i t skin -- PURINE. 2-AMINO-6-lBENZYLTHIOl1874-58-4 - PURINE, 2-AMINO-6-(ll-METHYL-4-NITROIMIOAZOL-5-YLlTHIOl- 5581-52-2 -- 9H-PURINE. 6-6ENTYLAHINO-9-TETRU(YDROPYRIN-2-YL2312-73-4 -- W724-34-5 I N E . 6-IBENZYLTHIOI-- 87-42-3 PURINE, 6-CHLORO- PURINE. 6-(~2.4-DINITROPHENYLlTHIOlPURINE, 6-~I1-METHYL-4-NITROIMIDAZOL~5-YLlTNIOI~ -- 446-86-6 - PURINE, 6-Il1-METHYL-4-NITROIMIOAZOL-5-YLlTHIO)-~and 17~Zl-OIHYOROXYPREGNA-1~4-01ENE-3,llr20-TRIONE -- 9H-PURINEv 6-lMETHYLTNIOl-9-beta-O-RI6OFURANOSYL342-69-8

-

PURINE. 6-(PENTYLTHIOl-

-- PURINE. 6-IPROPYLTHIOI6288-93-3 PURINE-6-THIOL -- 50-44-2 -- 892-49-9 9H-PURINE-6-THIOL, 9-beta-O-ARA6INOFURANOSYL-- 6112-76-1 PURINE-6-THIOLr m W m Y D R A T E - PURIN-6-THIOL. 3-N-OXIDE - 145-95-9 - 9H-PURINE-6-THIOL, 9-RIBOFU)ANOSYL- 4988-64-1 -- 9H-PURINE-6-THIOL8 9-b.ta-D-RIBOFURANOSYL574-25-4 -- PURINE-6(lH)-THIONE, 2-AHINO154-42-7 -- 68-94-0 6H-PWIN-6-ONEs 1,7-DIHYORO-- 79485-03-3 PV-123 - 2H-PYRAN, 2e2' -(3-tHLOROPROPYLENEDIOXY IBISITETRAHYORO- LH-PYRIN-~.~(~HI-DIONEI3-ACETYL-6-METHYL-, M D I W SALT - 4418-26-2 - 5r6-DIHYORO-4-METHO%Y2H-PYRAN-2-ONEr 5.6-DIHYDRO-4-HETHOXY-6-STYRYL-. IRI-. nixt. 6-PHENETHYL-ZH-PYRAN-2-ONE and 4-METHOXY-6-lp-METHOXYSTYRYLI-ZH-PYRAN-2-ONE

3551 N1 RN 3552 N1 RN

-

54708-51-9

-

PYRAZOLE-3-CARBOXYLIC ACID.

3554 N1

(2:2:11

-- PYRAZOLE 288-13-1 - lH-PYRAZOL€-3-CAR,RBOXMIDE. l-f3-CHLOROPHENYL)-5-METHOXY-N~N-DIMETHYL-

3553 N1 RN

uith

- 5-HYDROXY-1-lp-SULFOPHENICI-4-lp-SULFOPHENYLlAZO-~ 1934-21-0 - PYRAZOLE, 3-PHENYL-S-(o-TOLYLI-

TRIJODIM SALT

3555

N1 RN

3556

N1 RN

3557

N1 RN

3558

N1

RN 3559

N1

3560

N1

RN

-- 3,5-PYRAZOLIOINEDIONE~ 4-BUTYL-lr2-DIPHENYL50-33-9 -- 3r5-PYRAZOLIDINEDIONEs 4-BUTYL-l-lp-HYDROXYPHENYLl-2-PHENYL129-20-4 -- ~30748-29-9 ~~-PYRAZOLIDINEDION lrZ-DIPHENYL-4-13-HETHYL-2-BUTENYL)EI

-

2-PYRAZOLINE-l-CARBOX*nIOE~ QnS-DIOXO-3-HETHIL-~ ~-((o-ETHOXYPHENYLIHYDRAZOFIE) 22948-48-7

- 4-1 2-PYRA~OLINE-l-CARBOX4HJDE~ ~.S-DIOXO-~-HETHYL-D 215-XYLYLHYDRAZONE - 22948-54-5 - 4-2-PYRAZOLINE-l-CARBOXAHIDE. ~B~-OIOXO-~-HETHYL-, 13 5-XY LYLHYORAZONE - 34388-24-4 - 4H-PYRUOLOI 115-a IINOOLEI 2-1 3-HETHOXYPHENYLI9

RN 3561 N1 3562

N1

3563

N1 RN

3564

N1

)

- 4H-PYRAZOLOll~5-a)INDOLE,2-PHENYL- 8H-PYRAZOL0~5~l-m~ISOINOOLE2-PHENYL- 61001-42-1 I

3573

N1

3574

N1

-- 61001-30-7 PYRAZOL0~5rl-alISOQUINOLINE~ 5,6-OINYDRO-2-13-llETHOXYPHENTL)- PYRAZOLOI5~1-a~ISWUINOLINE,Sr6-OIHVDRO-l-METHYL-2-PHENYL-- 61001-31-8 PYRAZOLOl5,l-MlISOQUINDLINEt 5,6-DIHYDRO-2-PHENYL- PYRAZOLOl5,l-a~ISMWINOLINE-l-HETHANOL. 5.6-DIHYDRO-2-PHENYL- PYRA~OL015,l-a~ISOQUINOLINE~2-lm-HETHOXYPHENYLI-- PYRAZOLOl5.1-a~ISOQUINOLINE~ 2-PHLNYL61001-36-3 - lH-PYRIZOL013~4-d)PYRIHIDINE,4-AHINO-l-HETHYL-- H-PYRMLDI 3.4-d IPYRIHIDIN-4-OL 315-30-0 - PYRAZOLO(1.5-a IQUINOLINE, 2-lm-l BENZYLOXYIPHENYLI- PYRAZOLOll.5-a~QUINOLINEr4rS-01NYDRO-2-(3-ETHOXYPHENYLl- PYRAZOLOIlrS-al~INOLINE~4,5-DIHYORO-2-(3-HETHOXIPHENYLl-

3575

N1

-

RN

3565 3566

N1 N1

RN 3567

N1

3568 N1 3569

N1

RN 3570

N1

3571 N 1

RN 3572 N 1

PYRAZOLO~1,S-alPUINOLINE~4,5-DIHYDRO-2-PHENYL-

3576

N1

- P Y R A Z O L O I ~ ~ ~ ~ M I Q U I N O L4rSi-DIHYDRO-2-(3-PROPOXYPWENYL~INE~

3577

N1

-

3578

N1

3579

N1 RN

3581 N 1 3582

N1 RN

3583 N 1

3584

N1 RN

3585

Nl RN

P Y R A Z O L O I ~ ~ ~ ~ M ~ Q U I N O2-13-HETHOXYPHENYLb LINE~

- PYRAZOLOI~~S-M)WINOLINED2-PHENYL-- 8003-34-7 PYRETHRW

---

-

3s6-PYRIOAZINEDIONE~ 1.2-OIHYDRO-s

31 2N)-PYRIDAZI"E,

cot&.

ulth ZL-MINOETHAHOL

5-u(rw)-4-CHLoRO-2-PENYL-

1698-60-8 312H);PYRIDUINOEIEs

4r5-DINYDRO-6-I~-~INOPHENYL)-5-)ILTHYL-

~(~H)-PYRIDAZINONEI 38957-41-4

Q-ETHM(Y-2-HEnlYL-5-~~OLINO-

~-PYRIDIWIN€B N-( 1 2 - C H L O R O - 1 - ~ P H T H A L E ~ l ~ H E ~ Y L E N ~ I ~ Z ~ 6 ~ D I H E T H Y L ~ 38641-70-2

185 3586

N1 RN

3587

N1 RN

351313 N1 RN 3589

N1

3590

N1

RN 3591 N1

RN 3592

N1

RN 3593

N1 RN

3594

N1 RN

3595

Nl RN

3596

N1 RN

3597

N1

- alpha-l ~-PYRIOINEACETAHIOEI 2-~OIISOPROPYLAHINOlETHYL)-~lph~-PHENYL~ - 3737-09-5 - 2-PYRIDINEACETAHIOE, PHOSPHATE - alpha-l2-lOIISOPROPYLAMINO)ElHYL)-alpha-~ENYL-~ 22059-60-5 -- PYRIDINE, AMINO26445-05-6 -

PYRIDINE. 2 - l 2 32-SISlp-l 2-lOIETHYLAMINO )ETHOXY )PHENYL)-l-PHENYLVINYLl-

-- ~-PYRIDINECARBOXWIOEI 6-AMINO329-89-5 -- 57021-61-1 3-PYRIDINECARBOXAMIOEs 1~2-DIHYORO-2-OXO-N-l2p6-XYLYL)- MALEATE PYRIDINEr 2-~p-CHLOR0-~1pha-l2-1D1nE~YLAM1NO~ETHYL~~ENZYL~-, (1:l)

-

113-92-8

-- PYRIOINE, 3-(6-CHLORO-3-METHYLINOEN-2-YLl2126-63-8 2,3-PYRIOINEDICARSOXIMIDE -- 4664-00-0

-- 3,4-PYRIDINEDICARSOXIMIOE 4664-01-1

-- 2,3-PYRIOINEDICARSOXIMIOE~ N-l2~6-OIOXO-3-PIPERIDYL)31804-66-7

- 3~5-PYRIOINEOICARBOXYLIC 1,4-OIHYDRO-2~6-OIMETHYL-4-la-NITROPHENYL1-~ ACID.

2-(BENLYWETHYL

RN 3598

N1

RN 3599

N1

RN 3600

N1 RN

3601

N1 RN

3602

N1

-

AMINO )€THY L HETHYL ESTER, Mf)NDHYOROCHLORIOE 54527-84-3

- 3.5-PYRIDINEDICARSOXYLIC

ACID. lr4-DIHYDRD-2,6-OIMElHYL-V-(m-NITROPHENYL~-~ ESTER 22609-73-0

SISl2-PROPOXYETHYLI

- 395-PYRIDINEDICARBOXYLIC ACID, OIHETHYL ESTER - l~C-DIHIDRO-2~6-DIHETNYL-4-(2-NITROPHENYL~-~ 21829-25-4 - 62r6-PYRIOINEOIMETHANOLI alpha-(sup ~ - ~ ~ ~ 1 ~ 1 - D I M E T H Y L E T H Y L ~ A M I N O ~ H E T H Y L ~ - 3 - HDIHYDROCHLORIDE YOROXY-~ - 38029-10-6

3603

N1

- HALEATE PYRIOINE, 2 - ~ 1 2 ~ l D I M E T H Y L A ~ I N O I E T H Y L ~ l p - M E T H O X Y S E N Z Y L l A M I ~ ~ - ~ - 59-33-6 (181) - PYRIOINE. 2,2'-01THIODI-. lsl'-DIOXIDE

3604

N1

-

RN

3605

N1

RN 3606

N1 RN

3603

N1

RN 3608

N1

3609

N1

2-PYRIDINEETHANOL, alpha.alpha-BIS(p-( 2-(OIETHYLAMINOIETHOXY )PHENYL)-b.ta-WENYL-

-- PYRIDINEI ETHENYL-. 1-OXIDE. HMX)WLYtiER 9045-81-2 -- 61-67-6 ~-PYRIOIHEMETHANDLI 4~6-OIHETHYL-5-HYDROXY-- 3-PYRIDINEllETNANOL~ 4,6-OIHETHYL-5-HYDROXI-) 148-51-6

-

HYDROCHLORIDE

3-PYRIDINEMETHANOL and SALICYLIC ACID PYRIDINEi 3-l6-METHOXY~1~~~~METHOXY~ENYL~-3~4~OIHYORO-2~N*PHTHYLl-~ HYDROCHLORIDE

3610 N1 3611 N1 3612 N1 3613 N1 RN 3614 N1 RN 3615 N1

- PYRIDINE, 2 - 1 6 - M E T H O X Y ~ 2 ~ P H E N L ~ 3 , 4 - D I H m R O - I ~ N A ~ T H Y L l ~ - PYRIOINE, 4-16-METHOXY-2-PHENYL-3,4-DIHYDRO-l-NAWTHYL)-

- PYRIDINE-1-OXIDE~2r2'-OITHIOBIS-, NAGNESIUN SULFATE. TRIHYDRATE -- 53912-89-1 PYRIDINE, 3-(2-PIPERIOINYLl-r MOEIOHYDROCHLORIDE~ -- l(4HI-PYRIDINEPROPIDNIC ACIDB ~~~~.-AMINOD-~-HYDROXI-Q-OXO10182-82-8 - PYRIOINIMs 1-( (7-(((~-AMINO-4-THIAZOLYLl~ IIHINOIACE(9)-

(l-CARBM(Y-1-METHYLETHOXl

TYLlAHINO)-2CARBOXY-8~OXO-5-THIA-l-~ABICYCLO~4.2.0lOCT~2-EN-3-YLlHETHYLl-~ HYOROXIOE. inner s a l t . 16R-I6-irlpha.7-bettrlT1))-, PENTAHYORATE

RN

3616 Nl

- 72558-82-8

- PYRIOINIUn* 2-CARBOXY-8-0XO-7-(

RN

-

3617 N1

-

RN 3618 N1 RN 3619 Nl

1-I I 2-( 2~THIENYL~ACET~IDOl-5-THIA-1-AZABICYCLO(4.2.01OCT- 2-EN-3-YL)METHYLl-, HYDROXIDE, Inner salt 50-59-9

21 1H I-PYRIOINONED 6-CYCLOHEXYL*l-HYDROXY-4-METMYL-t compd. 2-AMINOETHANOL 11:l.l 41621-49-2

N1 RN

3621 H1 RN 3622 N1

- 29868-97-1 - ~5~11-DIHYDRO-11-~l4-METHYL-l-PIPERAZIN~LlACElYLl-~ H-PYRIDOIZI~-~~~~~QIBENZ~I~EPI"~-M~EI -- 6H-PYRIOOI 4 ~ 3 - b)CARBAZOL-9-OL. 5,ll-DItlETHYL51131-85-2 -- 9244-63-3 ~-PY~IDOl3~4~blI~DLE - 9H-PYRIDO~3,4-bl1NDOLEp7-METHDXY-l-METHYL-. th PYRIDO(3r4-bIIllDOLE nixed ui

~-METHOXY-~-METHYL-~~~-DIHYORO-~HHHYDROCHLORIDE (2:l I

3623 N1 RN

3624 N1 RN 3625 N1 RN

-- lH-PYRID0(3,4-bIINDOLE, 20315-68-8 I

- PYRID012~3-dlPYRIMIDINE-6-CARBDXYLIC ACIO, 1-PIPERALINYLl- Ir8-OIH~DRO-8-tlH~L-5-DXO-2-I 51940-44-4 -- 58-56-0 PYRIDOXOL HYDROCHLORIDE

3627 N1

-

3628

Nl RN

3629 N1 3630 N1 RN 3631 N1 RN 3632

N1 RN

3633 N1

2~3~4,9-TETRAHYDRO-6~METHDXY~

- MONOHYDROCHLORIDE 2f1H I-PYRIDONE 1-(2-(4-o-TOLYL-l-PIPERAZINY L)ETHYLI-I - 4949-11-5

3626 N1 RN

RN

th

- 65~11-DIHYDRO-l1-l14-MElHYL~l~PIPERAZINYLlACETYLl~~ H-PYRID0~2~3-bll1~4lBENZ~I~EPIN~6-ONE~ DIHYDROCHLORIDE DIHYDROCHLORIDEI HYDRATE

3620

Ul

2-PYRIMIDINAHINE,

4-( 2-1 1-tlElHYL-5-NIT~D-1H-InIOAZOL-2-Y L1ETHENYLI- 9

< Ek

- 62973-76-6 -- PYRII4IDINE * 6-BUTY L-2.4-DIMINO-5-PHENYL27653-51-6 - 3r4-DIHYORO-2~4-DIOXO-5-FLWRD-N-HEXYL1~2Hl-PYRIMIDINECARBOXA~IOEt -- ~~~-PYRIHIOINEDIUIINED 5-(p-CHLOROPHENYLI-6-ETHYL58-14-0 -- PYRIMIDINE, 2,4-DIAMLNO-5-( 3~4-DICHLOROPHENYLl-6-HETHY L7761-45-7

-- PYRIMIDINE, 27653-49-2 - PYRIMIDINE

2,4-DIAUSNa-6-ETH'L-5-CHeHrL-

s Pt4-01A~INO-6-1SOPROPYL-5-PHENYL-

187 3634

N1 RN

- PYRIMIDINEr - 18588-50-6

3635

N1 RN

-- PYRIMIDINEi 2,4-DIAMINO-5-PHENYL18588-49-3

3636

N1 RN

2~4-DIUIINO-6-METHYL-5-PHENYL-

3638

N l RN

3639

N1

- PYRIMIDINEr 2A-DIMINO-5-PHENYL-6-PROPYL- 27653-50-5 - PYRIHIDINE, 2,4-DIAMIHO-5-(3,4r5-TRI~ETHOXYBENLYLl- 738-70-5 - PYRIMIDINE v 2-1 12-1DIMETHYWIINOIETHYL 11D-METHOXYBENZYL )AMINOI- 91-85-0 - 4~6l1H~5Hl-PTRIMIDINEDIONE~ OIHYORO-5-ETHYL-5-PHENYL-. md

3640

N1 RN

-- 4125-33-7 ~ 6 l 1 H ~ 5 H l ~ P Y R I M I O I N E D I O5-ETHYLDIHYDRD-5-PHENYLNE~

3641

N1

-

3637

N1 RN

5-ETHYL-5-PHENYLBIRBITURIC ACID

2,4-(1H.SH~-PYRIMIDINEDIONE. 1-(2 4 (2-HYDROXY-3-12-METHYLPHENOXY 5-METHYL-

3642

Nl RN

3643

3644

N1 RN N1 RN

3645

N1

3646

N1

RN

RN 3647

N1 RN

3648

N1 RN

3649

N1

RN 3650

N1 RN

3651

N1 RN

3652

Nl

3653

N1 RN

3654

N1 RN

3655

N1

3658

- 4-METHOXY-2-l5-r(ETHOXY-3-HETHYL-lH-PYRAZOL-l-YLl-6-METHYLPYRIMIDINE. -

18694-40-1

2 141S,6( 1H ,3H I-PYRIMIDINETETRONE

P

MONOHYDRATE

3237-50-1

- 4-(DIMETHYLAHINOI-l 2 . 4 . 6 l 1 H . 3 H ~ 5 H l - P Y R I M I D I N E T R I ~ E 5.5-DIETHYL-, ~ ,L-DIHYDRO-

mixed with

1,5-DIHETHYL-2-PHENYL-3H-PYRAZDL-3-ONE 8015-18-7

- 2 I l H ) - P Y R I ~ I D I N O N E ~4-AMINO-l-beta-D-IRABINOFWANOSYL-, MONOHEXADECANOATE I ESTER I - 41948-17-8 - PYROCATECHOL - 120-80-9 - PYROCATECHOL, 4-12-A~INOETHYLI- 51-61-6 - PYROCATECHOLI 4-( 2-ARINOETHYL I - , HYDROCHLORIDE - 62-31-7 - PYROCATECHOLD 4-(2-UIINOPROPYL)-. l S l - ( + l - 14513-20-3 - PYROCATECHOL, 4 ~ 4-I' 1,2-DIETHY LETHYLENE 101- 79199-51-2 - PYROGALLOL

- 87-66-1 -

PYROGEN PYROSULFWWS ACIDI DISOOIIM SALT ?681-57-4 PYRROLE-l-ACETAMIDE, 1435-07-0

- SALT, 1H-PYRROLE-2-ACETIC DIHYDRATE

N.N-OIETHYL-2,4-DINITROACID>

l-MElHYL-5-(4-HETHYLBENZOYLl-, SOOIUn

RN

-

PYRROLE-2-ACETIC ACID. 26171-23-3

N1 RN

-

2-PYRROLEACETIC ACID) ~ - H E T H Y L - ~ - I ~ - T O L U O Y L I - P SODIVPI SALT 35711-34-3

3656 N 1 3657

lPR0PYL)WINOlETHYLl-

HYDROCHLORIDE

N1 RN

-

1-HETHYL-5-p-TOLUOYL-

PYRROLIDINE,

2-1 4-1 1,2-BISI4-METHOXYPHENYL - 1-1 35386-89-1

1-1-BUTENYL)PHENOXY IETHYL 1-

188 3659

N1

- PYRROLIOINE, 1-1 2 4 p-I 1 Z-BISI p-I(ETHOXYPHENY L I-1-BUTCNY L IPHENOXY IETHYL 1HYOROCHLORIDEI ( E l - 35278-53-6 - PYRROLIDINEi l-l2-lp-ll~~-BISlp-~ETHOXYPHENYLl~3~METHYL-l~EVTENYLlPHENOXY~ETHYL1-, HYDROCHLORIDE - 42824-37-3 - 112-PYRROLIDINECA~XYLICACID, 1-BEHML-L-VINVL ESTER - 1-PYRROLIDINECARBOXYLIC ACID, 1 ~ l D r 3 ~ N E R C A P T O ~ 2 ~ N E ~ Y L ~ Ll ~ ~I SO&P) I ~ Y L ~ ~ - 62571-86-2 v

RN 3660

Nl RN

3661 NX 3662

Nl RN

3663 N l RN 3664

Nl RN

3665

N1

5666

N1 RN

3667

N1

3668 N l RN 3669 N1 RN 3670

N1

3671 N1 RN 5672

N1 RN

5673

N1

PYRROLIOINE, 1-1 2-14~13-l4~CnLOROPHENYL~~2~2~DIMElHYL~7-~THOXY-~H~1-BENZOPYRAN-4-YL) PHENOXY )ETHYLI-, HYDROCHLORIDE 57897-55-9

-- 1148-11-4 1~2-PYRROLIDINEDICARBOXYLIC ACID.

-

1-BENZYL ESTER, L-

1~2-PYRROLID1NEDICARBOXYLIC ACID. 1-BENZYL 2-(l,P-DIBROIK)ETHYLI ESTER PYRROLIDINE, 1-l2-l4-lZ~2-DIETHYL-7-NE~OXY-3-PHEEFTL~2H-l~BENZO~RAN-~-YLl~ENOXY )ETHYL 1 > HYDROCHLORIDE 57897-58-2

-

--

PYRROLIDINE, 1-(2-(4-(3~4-DIHrORO-2~2-DIETHYL-7-MEMOXY-3-PnENYL-2H-l-~EN~O~AN-4-YL) PHENOXY )ETHYL)-. HYDROCHLORIDE PYRROLIDIW. l~l2~l4~l3~4~DIHYDRO-2r2~DIMETHYL-7-METHOXY~3~PHENYL-2N-l-BE~OPYRAN-4-YL) PHENOXY )ETHYLI51423-20-2 PYRROLIDINE. l-l2-l4-(3r4-DIHY0RO-2r2-OI~~THYL-7-MET~~Y-4-PHCNYL-2H-l-BENZDPYRAN-3-YLI PHENOXYIETHYL)-r ( € 1 84394-37-6 PYRROLIOINE~ 1-1 2-1 4-1 3,4-OIHYDRO-2.2-OIMETHY L-7-llETHOXY -3-PHENYL-2H-l-BENZOPYRAN-Q-YL) PHLNOXY )ETHYLI-s HYOROCHLORIDE, ( E l PYRROLIOINE. 1-I 3-1 4-I 3 ,4-0IHYORO-2,2-OINETHY L-?-~ETHOXI-5-PHENYL-2N-l-BENZDPY RAN-4-YL) PHENOXYIPROPYL)-I HYOROCHLORIDEv ( E 184394-09-2

-

PYRROLIDINE, 1-l2-l4-l3~4-0IHYDRO-7-METHOXY-3-PHENYL-2H-l-BE~OPYRIN-4-YL~PnENOXYIETHYL)-B ( E l 33382-08-0 PYRROLIOINEI 1-12-l4-l3~4-DIHYDRO-7-METHOXY~3~~EHYL-2H~l~BE~PYRAN-4-YL~~EN~ 0XY)ETHYLl-r (2133382-06-8

RN

- PYRROLIOINEI -~2-~p-l3~4-DIHYORO-6-NETHOXY-2-~ENYL-l-NA~THYL~PHENOXY~ETHYL~~ - 11845-11-0 - PYRROLIDINEe 1-12-~p-l3~4-DIHYDRO-6-~ETHOXY-2-PHE~L-1-NA~THYL~PnE~XYlE~YLl~ HYOROCHLORIOE - 1847-63-8

N1

-

RN

- e543q-45-6

RN 3674 N1 RN 3675

-

B

N1

-9

3676

PYRROLIOINE, 1-1 2-1 p-I 6 I 7-DIHYDRO-2-WEHTL-5H-I"O( EIHYLI-. HYOROCHLORIOE

5 ~ 6 - b)FUIAN-3-Y L)PHENOXI1-

189 3677 N 1 RN 3676

N1

-

PYRROLIDINE. 1 - 1 2-1 p-( 5,6-DIMETHOXY-2-PHENY HYDROCNLORIDE 3333-83-3

L-3-BENZDFIIRWY L IPHENOXY IETHYL)-r

PYRROLIDINE, l,l'-l 11,2-OIMETHYLETHYLENElBISlp-PHENTLENEDXYETHYLENEI

- 15515-44-3 N1 - PYRROLIDINE, slpha.beta-DIllETHY 1-1 2-1

IDI-.

meso-

RN 3679

p-(

RN

3680

N1 RN

-

L-p-HETHOXYPHENETHYL )PHENOXY )ETHYL I - ,

HYDROCHLORIOE, e r y t h r o 15515-45-4 PYRROLIDINE, l-l2-l4-l2~2-DIMETHYL-7-METHDXY-3-PHENYL-2H-l-BENZOPYR~-4-YL~PHEM X Y )ETHYL)53996-41-1

3681

N1 RN

-

3682

N1

- PYRROLIDINE, 1-12-14-~2~2-DIMETHYL~7~~ETHOXY-3~PHENYL~2H-l-BENZO-4-YLlPHE-

RN

3683 N1

-

PYRROLIDINE, 1-~2-l3-l2r2-DIMETHYL-7-METHOXY-3-PHENYL~2H-l-BENZOPYRAN-4-YLl~ENOXY )ETHYLl-, HYDROCHLORIDE 84394-15-0

NOXY )ETHY L )-. 57897-49-1

HYDRDCHLORIDE

PYRROLIDINE, 2 B 2-DIMETHYL-1-1 2-1 p - I b-METHDXY-2-PHENYL-2-Ir(OENYLlPHENOXY 8 HYDROCHLORIDE

-

3684 N1

-

3685

3686

3687

RN

-

RN

-

N1

- PYRROLIDINEi 1 - 1 2 - ( 4-1 2 ,Z-DIMETHY L-3-PHENYL-2H-l-BENZOPYRAN-4-YL

RN

-

N1

- DIHYOROCHLORIOE, PYRROLIDINE, 1 ~ 1 ' - l l D I M E M Y L V I N Y L E N E ~ B I S l p - P H E N Y L E N E O X Y ~ ~ 0 1 - ~ (EI-

RN

-

RN

-

N1

-

3690

Nl

3691

N1

-

3692

N1

-

3693 3694

Nl

PYRROLIDINE. 1-12-~p-lslpha~bet~-DIMETHYL-p-METHOXYSTYRYLlPHE~XYlETHYL~-r HYDROCHLORIDE, IE 115542-06-0

21853-05-4 PYRROLIDINE, 1~l2~lP~l2~4-OIPHENYL-3-FURYL~PHENOXYlETHYLl54756-54-6 PYRROLIDINE v 1-( 2-1 p - I 4 *B-DIPHENY L-3-FURY L )PHENOXY IETHY L IOXALATE. HYDRATE PYRROLIOINEB 1-(2-(p-(Z,~-DIPHENYL-l-PROPENYL)PHENOXI

PYRROLIDINE, 1-(2-1 p - I 2-1 m-METHOXYBENZYL l-l-I4ETHYL-2-PNENY ETHYLI-

PYRROLIDINE, - 66839-98-3

N1

-

Nl RN

-

v

)ETHYL)-

PYRROLIDINE. 1-1 2-( p - I 3-1 m-FLUOROPHENY L I-2-PHENY L-1-PROPENYL IPHENOXY IETHYL 1-

-

-

IPHENOXY IETHYL-

I - , HYDROCHLORIDE 57897-51-5

RN

RN

3695

PYRROLIDINE, 1-1 2-1 I 2 B 2-DIMETHY L-4-I4-MElHOXY W E N Y L I-3-PHENY L-2H-l-BENZOPYRAN-7-YLIOXY 1 ETHYLI-, HYDROCHLORIDE 57897-53-7

N1

3688 N 1 3689

)ETHYL I -

L-1-BUTENYLIPHENOXY 1-

1-lI4-METHOXYl1~1'-BIPHENYLl-3-YL~METHYL~-

PYRROLIDINE.

1-~2-lp-l7-~ETHOXY-2~2-DIMETHYL-3-PHENYL-4-CHROMANYLlPHENOXYlETHYL)-, trans31477-60-8

PYRROLIDINE, 1-~2-~p-l6-METHDXY-2-PHE~YL-3-BEHZOFURANYLlPHE~XY~ETHYLl-~ HYDROCHLORIDE

3333-85-5

190 3696

N1 RN

3697

Nl

3698

N1

3699

N1

RN

RN 3700

N1

3701

N1

-

PYRROLIDINE~ 1-1 3-1 p-( 6-HETHOXY -2-PHENY L-3-BENZOFURANY L IPHENOXYIPROPYLI HY DROCHLOR I D € 25433-68-5

B

- PYRROLIOINE, 1-1 2-1 4-1 7-HETHOXY -3-PHENY L-2H-1-BENZOPYRAN-4-Y L )PHENOXY IETHYL I- PYRROLIOINE. 1-1 2-14-1 6-HETHOXY-2-PHENYLBENZDl b ITHIEN-3-YLIPHENOXY IETHYLI- HYDROCHLORIDE 34289-01-5 - PYRROLIDINE, 1-1 2-14-1 7~HETHOXY~3~PHENYL~1H~2-BENLOTHIOPYRAN-4~YLlPHENOXY IETHY-

L I - , HYDROCHLORIDE 36266-82-7 PYRROLIDINE, 1-f2-l4-17-HETHOXY-3-PHENYL-2H-l-BEEIZOTHIOPYRAN-4-YLl~ENOXYlETHYL l - i HYDROCHLORIDE PYRRDLIDINEI

- 1-~p-~6-HETHOXY-2-PHENYL-3~4-DIHYDRO-l-NAPHTHYLlPHENETHYLl-~ HYORMHLORIDE

3702

N1

- PYRROLIDINEI 2-1 p-l6-HETHOXY-2-PHENYL-3,4-DIHYORO-l-NAPHTHY L IPHENOXYIETHYLI-1-1 HYDROCHLORIDE P

3703

N1

-

PYRROLIDINE,

4-lp-16-HETHDXY-2-PHENYL-3~4-DIHYDRD-l-NAPHTHYLlPHENYLlBUTYLl~~ HYDROCHLORIDE

3704

3705 3706

3707

N1

N1 N1

N1 RN

3708

N1 RN

3709

Nl RN

3710

N1 RN

3711

N1 RN

3712

Nl

3713

N1

3714

N1

3715

N1

-

PYRROLIDINE, 1-1 3 - l p - I 6-HETHOXY-2-PHENYL-3,4-DIHYDRO-l-NAPHTHY -B HYDROCHLORIDE

L IPHENYL IPROPY L 1-

- PYRROLIDINE, 1-1 2-1 p-I 5-HETHOXY-2-PHEWL-l-INDANY L IPHENDXY)ETHYLl- PYRROLIOINE, 1-1 2-1 p-I 6-HETHDXY -2-PHENY L-2-INDENY L IPHENOXY)€THY L 1-

-

s I E 1-

B

HYDROCHLORIDE PYRROLIDINE. 1-(2-1 p-I 7-HETHOXY-2-PHENY LNAPHTHOI 2 el-b IFURAN-1-Y L IPHENOXYIETHY LI - , HYDROCHLORIDE 25433-87-8 PYRROLIDINE, 1-1 2-1 4-1 1-1 4-HETHOXYPHENY Ll-2-NITRO-2-PHENY LETHENYL IPHENOXY IETHYL)-9 I Z I 52235-18-4

- PYRROLIDINEi 1-1 2-1 4-1 1-1 4-METHOXYPHENY L I-2-NITRO-2-PHENY

-

LETHENYL IPHENOXY)€THYL I - 2-HYDROXY-1~2~3-PROPANETRICARBOXYLATE 1 1 : l ) 5863-35-4 PYRROLIOINE, 1-1 2-1 p-I alpha-( p-METHOXYPHENYL )-be ta-NITROSTYRYL 1PHENOXY IETHYL )10448-84-7 PYRROLIDINE, 1-1 2-1 I1-lp-HETHOXYPHENYLl-2-PHENYLNAPHTHOl THYLI-, HYDROCHLORIDE 25439-33-2

2 Bl-b IFURAN-8-YLIOXY IE-

- 1-l2-lp-l3-ln-METHOXYPHENYLl-2-PHENYL-1-PENTENYLIPHENOXYIETHYLl- 2-1 - 2PYRROLIDINE~

PYRROLIDINEi 1-( p-I 3-lm-METHDXYPHENY L I-2-PHENY L-1-PROPENY L IPHENOXY IETHY L I PYRROL~DINEI 1-1 Ip- I 3- Ip-HETHOXYPHENYL I-2-PHENY L-1-PROPENY L IPHENOXYIETHY L 1-

- PYRRDLIOLNEI

1-13,4-lHETHYLENEDIDXY

)BENZOYLl-

191 3716

N1 RN

3717

N1

3718

N1

3719

PYRROLIDINE. 1 - 1 2 - l p - I 2-PHENYL-3-BENZOFURANYLlPHENOXY ) E T H Y L l - r HYOROCHLORIDE

25433-79-8 PYRROLIDINEt 1-(2-1 p - l2-PHENYL-3.4-OINYORO-I-NAPHTNY L IPHENOXY )ETHYL I-, HYOROCHLORIDE

- PYRROLIDINEI 1-1 2-( 2-PHENYLNAPHTNOI 2 t l - b IFURAN-1-YL IPHENOXY IETNYL 1p-I

RN

-

N1

- PYRROLIDINE, 1 - 1 2 - l p - I 2-PHENY LNAPHTHOI 1.2-b

RN

3720 N l RN 3721

-

N1

-

24365-61-5

25439-42-3 PYRROLIDINE, 1 - 1 2-lp-12-PHENYLNAPHTHOl2sl-b HYDROCHLORIDE 29166-48-1

N1

3723

N1

-

3724

RN N1

- 29325-83-5 - PYRROLIDINEB

3725 3726

PYRROLIDINE, 1 - 1 2- I p - I 4-TETRAHYDRO-2 p4-DIPNENY L-3-FURY L IPHENOXY IETHY L ) OXALATE, 12-olphe.3-bet~,4-kct~I54282-47-2 PYRROLIDINE, 1-l2-lp-l6~7~8~9-TETRAHYDRO-2-PHENYL-5H-CYCLOPENTAlflBENLOFURUI-3-YLlPHENOXY I ETHYL)-, HYDROCHLORIDE

RN

-

N1 RN

-

PYRROLIDINIW, 4630-95-9

N1

N1 RN

-

3729

N1

-

RN

-

3730

N1

-

3731

N1 RN

-

3732

N1 RN

3733

N1 RN N1

RN 3735

N1 RN

3736

N1 RN

3-PYRROLIDINOL,

BROMIDE

BRMIIDED

1-NITROSO-

56222-35-6

- 2-PYRROLIDINONE, 309-29-5

N1 RN

)FURAN-I-Y L IPHEN-

l.l-DIETHYL-3-DIPHENYLHETHYLENE-2-HETHYL-~

- P Y R R O L I D I N I W , l,l-DIHETHYL-3-HYOROXY-, LATE - alpha-CYCLOPENTYLUANOE 596-51-0

3728

3734

lBENZO(b1THIEN-3-YLI-

1 - 1 2 - l p - I 5.6 ,7,8-TETRAHYDRO-2-PHENYLNAPHlHDl2.3-b OXY I E T H Y L I - , HYDROCHLORIDE 25439-49-0

RN

3727

IFURAN-1-YLIPHENOXY )ETHYL)-,

PYRROLIDINE, 1-l2-lp-l2-PHENYL-6-l2-ll-PYRROLIDINYLlETHOXY PHENOXY I ETHYL)-, DIHYDRMHLORIDE

3722

RN

IFURAN-1-YL IPHENOXY )ETHYL I - ,

HYOROCHLORIDE

l-ETHYL-4-(2-MORPHOLINOETHYL)-3.3-DIPHENTL-

2-PYRROLIOINDNE n 1-ETHYL-4-1 2-HORPHOLINOETHY Ll-3,I-DIPHENYLMONOHYDROCHLDRIDEI MONOHYDRATE 7081-53-0 2-PYRROLIOIHONE, 1-I2-lp-l6-HETHOXY-2-PHENYLBENLO(blTHI~N-3-YLIPHENOXY 2-PYRROLIOINONE, 872-50-4

)ETHYL)-

1-METHYL-

-- lH-PYRROLILINE-7-HETAWL~ 2.3-DIHYDRO-l-HYDROXY-~ IS)26400-24-6 - Pl rY2 R, 3R, 3OaL, 8O,(8~~.-~H- E~ )XI ANHDYDDL RE IO - 5 - H Y D R O X Y - l ~ 3 ~ ~ 8 - T R I H E T H Y L - ~ lestcrl, 13aS-clsl-, SULFATE ( 2 : 1 1 - HETHYLCARBAMATE 64-47-1 - 9H-PYRROLO( 1' ~ 2 ' : 2 ~ 3 1 1 S O I H ) O L O ( 4 ~ 5 r 6 - ~IINDOL-9-ONE d 10-ACETYL-2,6,6~,7.lla~llb-HEXAHYDRD- ll-HYDRDXY-7~7-DIMEl'HVL-, l6a-~lph~~ll~~llb-~l~h~l- 18172-33-3 -- 54 H9 3- P3 -Y1R9R- 1O L 0 1 3 ~ 4 - b ~ P Y R A Z I N E5,716H)-DIOXO~ -- 5H-PYRROLOI 3rQ-dIPYRIMIOINE, 5 ~ 7 1 6 H I - D I O X O 56606-38-3

192 3737 N1 RN

3738 N1 RN

3739 N1 RN 3740 Nl

-- PYRROL012~1-b~WINAZOLIN~3~OL~ L,~~~B~-TETRAHYDRO6159-55-3 - PUINAZOLINEt 4-ANINO-6,7-DIHEnlO-2-(Q-l L-FUROYL)PIPLRUIN-l-YL)-, - HYDROCHLORIDE 19237-84-4

-- 2~4IlHr3H~-WINUOLINEDIM(E 86-96-4 - 6~WINAZOLINESULFO"IDE s

1~2~3~4-TETR~~DRO-7-CHLWO-2-NETHYL-4-OXO-3-O-TOLYL-

RN 3741 Nl RN

3742 N1 RN

3743 N1 3744 N1 RN 3745 N1 RN 3746 Nl RN 3747 N1 RN 3748 N1

RN 3749 N1 RN

3750 N1 RN 3751 N1 RN 3752 N1 RN 3753 Nl 3754 N1 RN 3755 N1 RN

3756 Nl

RN

3758 N1 RN 3759 N1 RN 3760 N1 RN 37b1 N1 3762 Nl RN

- 17560-51-9

-- 4IlH)-QUINAZOLINONE, 2,3-DIHYDRO-l-INDRPHOLI~CETYL)-3-PHENYL19395-58-5 -- 4llH)-QUINAZDLINONE~ 2r3-DIHYDRO-2-ll-NIPHTHYL)31785-60-1 - 21 1H )-WINAZOLINONE, 4-(p-FLUW)OPHENYL1-l-ISOPROPYL-7-HETHYL-

-- 36556-91-9 SH)-WINAZOLI"Er 2-HYDROXY-p-TOLYL )-Z-NETHYL-- 45060-52-6 1 )-WINAZOLINONEI 5-l4-HYDROXY-o-TOLYL)-Z-NETHYL-- 432700-76-8 1 3H)-WINAZOLINONEr -- 4t3H~-QUINAZOLINONE~ 2-METHYL-3-o-TOLYL72-44-6 -- 4(SO-56-7 )-WINAZDLIHOHEI ~-METHYL-~-o-TOLYL-.HYDROCHLDRIDE -- QUININE 130-95-0 3-1

41

3H

3-ISOPROPYl-2-~~~HETHO~PHENYL~~

3H

-- QUININE. FORWTE (SALT) 130-90-5

-- WININE. SULFATE 804-63-7 - WINOLINE, l4-AHINO-l-NElHYLBUTYL~AflINO)-6-HEnlOXY-sPHOSPHATE 11:2) - 63-45-6 - 3-QUINOLINECARBOXYLIC ACID. 1~4-DIHYDRO-l~ETHYL-~-FL~O~7~l4-~E~YL-l-PIPERUI~L~- 3-WINOLINECARBOXYLIC ACID, - 1~4-DI~YDRO-l~ETHYL-6-FLWRO-4-OXO~4~~-7~ll~PIPERUINYL~70458-96-7 7-CHLWO~4~lI4~IDIETHYLAHINO~~l~~TnYLBVnL~*nINO~-- WINOLINEr 54-05-7 - QUINOLINE, 7-CHLORO-4-f4-DIEMYLAHI~-l-~E~YL-B~LANI~~-, - DIPHOSPHATE 8-1

50-63-5

-- WINOLINE, 4-lp-lDIMETHYL*nINO)STYRYL)897-55-2 -- WINDLINE, 4-l~-IDI~THYMNO)STIRYL)~6~B-DI~THYL19716-91-3 ~-Ip-(DIHETHYL*nINO)SMRYL)-r M Y D R O E H L O R I D E -- WINDLIMEI 21970-53-6

- WINOLINE, i?-I4-f3-1 3-I)(DOLYL)pRDPYL)-l-PIPERUINYL)-s -- QUIt?OLINEr 8-NITRO607-35-2

DIMALEATE

193

3763 N1 RN 3764 N1

-- WINOLINE. 4-NITRO-, 1-OXIDE 56-57-5 - QUINOLINIW, BIS( 2-CHLDROETHYL)AMINO)PHENY L lFDRMIMIDOYL)-l-METHYL~~ 2-1 N-l p-I

CHLORIDE 25843-64-5

3765 N1

-

RN 3766 N1 RN

-

3767 N1 RN

-- a-wiNoLImL, ~-CHLORO-~-IWO130-26-7

3768 N1

-

RN

-

RN

3769 N1

-

QUINOLINIUnt 6-IDI~ETHYLA~INO~-2-12-l2~5-DIMETHYL-l-PnENYLPYRROL-3-YL~VINYL~-l-METHYL-. salt w i t h 4,4'-~ETHYLENEBISl3-NYOROXY-2-WIPnTHOIC A C I D 1 12:11 3546-41-6 8-WINOLINOL 140-24-3

2llH)-QUINOLINDNE, 5-13-111~l-DMETHYLETHYLlAlnINO~~2-HYDROXY'PROPOXY1-3~4-OIHIDRO-r MONDHYDROCHLORIDE 51781-21-6

- 8-HYDRDXY-5-~1-HYDROXY-2-Ill-~ETHYLETHYL)*EIINO)BUTYL)-~ 2llH)-QUINOLINONE, tlONOHYDROCHLDRIDEP HEIIIHYDRATEp IR*.S* )-I*- 1-

3770 N1 RN 3771 N1 RN

3772 Nl 3773 N1 3774 N1 3775 N1 3776 N1 RN 3777 N1 RN 5778 NI RN

3779 N1 RN 3780 NI RN

3781 ~i RN 3702

~i RN

3703 NI 3704 N1 RN

3735 N1 RN 37%

N1 RN

3707

~i RN

3788 N1 RN

- QUINOLIZINIW~ DECAHYDRO-3~lOI12~THIENYL~~ETHYLENEl-5-MElHYL-~ BROMIDE I E I- 71731-58-3 - 2~3-PUINOXALINE~METHANO1,lr4-DIOXIDE - 17311-31-0 - RAMIA DWETORLM Lam., fruit and seed extras1 - RAPESEED PROTEIN - RAPHANUS SATIVUS Linn., crude extract

- REHHANIA G W I " 3 A Libosch. crude extract - RELAXIN - 9002-69-1 -- RESORCINOLv 4-CHLORO95-88-5 - RESORCINOL, 4,4'-ll,e-DIETHYLETHYLENE)DI- a720-47-4 - RESORCINOLt 4-HEXYL- 136-77-6 - RESORCINOL, 2-p-~EMnA-lrO-DIEN-3-YL-5-PEHTYL-r - 13956-29-1

-- b89-86-1 .t.-RESMlCYLIC ACID -- RETINAllIDEr N-ETHYL33631-41-3 - RETINAMIDE, N-ETHYL-, all-trans- RETINAllIDEr N-12-HYOROXYETHYL)- 33631-47-9 - RETINOIC ACID, 13-cia- 4759-48-2 - RETINOIC ACID, all-trans- SO2-79-4 - RETINOIC ACID, all-trans-, S m I W SALT - 13497-05-7 - RETINOL. - 60-26-8

trMS-

l-)-(E)-

194 3789 N 1 RN 3790

Nl RN

3791

N1 RN

3792

N1 RN

3793 N1 RN

------

RETINOLI ACETATE 127-47-9 RETINOLs Sr6-EPOXY-5.6-DIHYDRO512-39-0 RETINOL. aU-trans-, 79-81-2

PALnI7ATE

RHOOILNllIII) CHLORIDE t 1 : I ) 10049-07-7 RICIN 9009-86-3

3794 N l RN 3795

N1

-

ROBAVERON

3796 N l 3797 N 1

- ROC-101 - ROTTLERIN,

3798

N1 RN

ROWACHOL 65546-74-9

3799

N1

3800

N1

3801

N1

3802

N1 RN

3803

Nl RN

3804

N1 RN

3805 N 1 RN 3806

N1 RN

3807

N1 RN

--

PENTAACETATE

ROWATIN

- RUDBECKIA BICOLOR Flutt., e x t r a c t - RUTA GRAVEOLENS, e x t r a c t -- SALICYLALDEHYDE 90-02-8

---

SALICYLAMIDE 65-45-2 SALICYLIC ACID 69-72-7

-- SALICYLIC ACID, 50-78-2

ACID, -- SALICYLIC 133-10-8

3809

N1 RN

---

3810

Nl RN

-- SALICYLIC ACID, 54-21-7

3808 N 1 RN

3811 N 1 RN 3812

N1 RN

5813

N1

3814

N1

3815

N1 RN

3816

N1

3817

N1

3818

N1

3819

N1 RN

*

---

ACETATE 4-WINO-,

SODIUM SALT

SALICYLIC ACID, DIHYOROGEN PHOSPHATE 6064-83-1 SALICYLIC ACIDI 87-20-7

ISOPENTYL ESTER

SALICYLIC ACID) HETHYL ESTER 119-36-8 )SONOSODIUM SALT

SALICYLIC ACID, PHENYL ESTER 118-55-8 SALICYLIC ACID, 5-llp-l2-PYRIDYLSULFA)SOYL)PHENrL)AZO)599-79-1

- SANGUISORBA OFFICINALIS L.

-

SAPINOUS TRIFOLIATUS L i n n . ,

seed e x t r a c t

-- SAPONIN 8047-15-2

-

SAPONIN-COLLARGOL, solution SAPONINS, from rhlzonies o f COSTUS SPECIOSUS IKoen) Sm

- SAPONIN, from XANTHOCEPHALUH HICROCEPHALA - SARKOnYCIN - 11031-48-4

195

3828 N1 RN

-- SCOPOLAMINE 51-34-3 -- SEBACIC ACID. DIBUTYL ESTER 109-43-3 9,10-SECOCHOLESTA-5.7,lO~l9~-TRIENE-3,24~2S-TRIOL~ 13-betar5L,7E)-- 40013-87-4 9,lO-SECOCHOLESTA-5.7,lOll9~-TRIEN-3-beta-Ol -- 67-97-0 - lbrl7-SECOES~A-l~3~5ll0~~6~8-PEWTAEN-17-OIC ACID. 3-HETHDX‘I-- 16~17-SECOESTRA-lr5~5s7~9-PENTAEN-17-OIC ACID. 3-METNDXY64024-07-3 -- 482-49-5 16~17-SECOESTRA-lr3~5~1O)-TRIEN-l7-OIC ACIDI 3-HYDROXYSECURININE, 1-1-- 5610-40-2 -- SELENIC ACID. DIPOTASSIUH SALT 7790-59-2

3829 N1 RN

-

3820 N1 RN 3821 N1 RN 3822 ~1 RN 3823 N1 RN 3824 N I 3825 Nl RN 3826 N1 RN 3827 N1 AN

N1 RN 3831 N1 RN

3830

3832 N1 RW

3833 N1 RN 3834 N1 3835 N1 RN 3836 N1 RN

3837 N1 RN 3838 Nl RN 3839 N1 RN 3840

N1 RN

3841 N1 3842 Nl RN 3843 N1 RN

3844 N1 3845 N1 5846 N1 3847 Nl RN 3848

SELENIC ACID, DISODIW SALT 13410-01-0

-- SELENIOUS ACIDP DISODIUM SALT 10102-18-8 -- SELENIOUS ACID. DISODIUn SALT, PENTAHYDRATE 26970-82-1 -- SELENIUM 7782-49-2 -- SELENIUMIIV) DIOXIDE (1:Z) 7446-08-4 - SEMECARPUS ANACARDIW Linn. cotyledon. -- SEMICARBAZIDE, ~-(o-CHLOROPHENETHYL)-~-THIO2598-75-6 f.,

- l-l~l~ha~alpha.alpha~alpha’~alpha’~~lpha’-HEXAFLUORO-3,5-XILYL~-4SEHICARBAZIDEP

3-THIO- -NETHYL24095-80-5 -- SEMICARBAZIDE. ~-IP-~ETHYLRIENETHYL)-~-THIO2598-74-5 -- SEHICARBAZIDEI MONOHYDROCHLORIDE 563-41-7

-

1-PHENETHYL- SEMICARBAZIDE, 3898-45-1 -- SEMlCARBIZIOEe 2-PH€METHYL-3-THIO3473-12-9 - SEPIA ESCULENTA H o y l e , crude extract DIAZOACETATE (ESTER) -- SERINEI 115-02-6 -- SERINE, 2-(2,T,4-TRINYDROXYBENZYL)HYRAZIDE, DL322-35-0 - SERIM. ANTIWALLAN RABBIT H E T E R O I W E - SESBANIA AESYPTICA Poir, flower extr act - SESBANIA SESBAN IL.) Herr. var. BICOLMI Y. b A., excluding r o o t s OILS. CRUDE -- SHALE 68308-34-9

mxtract

196 3849

N1

3850 N1 3851

Nl RN

3852

N1 RN

3853

N1

3854

N1 RN

3855 N1 3856

N1 RN

3857

N1 RN

3858

N1 RN

3859

Nl RN

3860

N1 RN

3861

N1 RN

3862

N1 RN

- SILANOL,

--

DIPHENYLMETHYL-

SILER DIVANICATUI

Bent Hook, crude extract

SI LI CI C ACID ( H2Si 03l r DISDDIVn SALT 6834-92-0

-- SILVERII) NITRATE 11:11 7761-88-8 - SMOKE CONOENSATEp CIGARETTE -- SOOILHI BICARBONATE (1:11 144-55-8 - S W I V n BORATE -- SWICM BORATE 1303-96-4 -

BROMIDE - SODIUM 7647-15-6 -- SOOIUM CARBONATE 1 2 : l I 497-19-8 -- SODIUM CHLORIOE 7647-14-5

-

CHLORITE - SODIUM 7758-19-2

- SODIUM CYANIDE - 143-33-9 .

3863

N1

3864

N1 RN

3845

N1 RN

3866

N1 RN

3867

N1 RN

-- SODIUM FLUORIDE 7681-49-4 - SWIUtl HEXACHLOROPLATINAJE HEXAHYORATE -- SODIUM IOOIOE 7681-82-5 -- SOOIUMII) NITRATE (1:l) 7631-99-4 -- SODIUM PENTAFLUOROSTAMJITE 22578-17-2 -- SOOIUPI SULFATE 1 2 : l ) 7757-82-6

3868

N1

-

3869

N1

3870

N1 RN

3871

N1 RN

3872

N1 RN

3873

N1

RN 3874

NI RN

5-SOLANIDANE,

122St25RI-

- 5-alpha-SOLANIOAN-3-beta-OL -- 5-alphm-SOLANI0AN-3-beta-OL1 474-08-8

122R,25SI-

I 22Sp25R 1-- 5-alpha-SOLINIDAN-3-beta-OL~ 11004-30-1 - SOLANID-S-ENE, 3-beta-IlO-6-DEOXY-alpha-L-~~OPYRA~YL-O-Ibeta-D-GL~OPYR~OSY-

-

L-beta- 0-GALACTOPYRANOSYL1OXY)20562-02-1

- SOLANID-5-ENE-3-betarl2-.lpha-DIOL 79-58-3 -- SOLANID-5-EN-3-bota-OL. lltS~25R)566-09-6

3675 N1

-

3876

N1

RN

-- SOLASW-5-EN-3-beta-OL 126-17-0

3877

N1

-

3878

N1

- SOLVENT REFINED COAL-11,

SOLANUM NIGRUM L.,

extract

SOLVENT REFINED COAL-I,

procerr rol\dent

heavy dirtlllat.

197

- SOnATOSTATIN

3879

N1

3880

N1

- 51110-01-1 - SOHATOSTATIN ISHEEPIr

RN

PHAN-' - 68463-41-2

RN

l-DE-L-ALANINE-2-DEGLYCINE-Q-L-HISTIDINE-S-L-HISTIDINE-8-D-TRYPTO-

3881

N1 RN

3882 N1

RN 3883 N 1 RN

3884 N 1

-

RN 3886

N1 RN

-

3887

N1

3885

N1

SORBITANI ?U3UllAURATE 1338-39-2 SORBITAN, MONOLAWATE WLYOXYETHYLENE d e r i v . 9005-64-5

- SDRBITAN, NONOOLEATE 1338-43-8

-

RN

SORBIC ACID 110-44-1

SORBITAN. MONOOLEATE WLYOXYETHYLENE d e r i v . 9005-65-6

3a.m

N1 RN

- SORBITAN, 1338-41-6 -- SORBITAN, 9005-67-8 -- SORBITAN, 9005-71-4

3889

N1

-

3890

N1

3891

N1 RN

3892

Nl

RN

MONOSTEARATE MONOSTEARATE POLYDXYETHYLENE d e r i v . TRISTEARATE, POLYOXYETHYLENE d e r l v s .

SOYA BEAN T R Y B I N IEHIBITOR

3893

N1

-- SPARTEINE, SULFATE 299-39-8 - SPECTINOMYCIN, DIHYDROCHLORIDEI PENTAHYDRATE - 22189-32-8 -- SPIRAHYCIN 8025-81-8 - SPIROIANDROST-4-ENE-3,2'-THIAZOLIDIN)-l7-bet.-OL,

3894

N1

-

RN

RN

SPIRO( 9H-BENZOle)FLVORENE-9,2'l3'H NEB

3'-METHYL-

~-FURDl3~2-b~-PYRIDIN~-1111H 14-

2,3,3'~,4,4',5',6,6',6e,6b.7,7',7'o,B,lla.llb-HEXADECAHYDR0-3-HYORN

3',6' ,lO,llb-TETRAHETHYL- ROXY469-59-0

3895

N1

-

3896

N1

- SPIRO(BENZOFURAN-P(SH I . 1 ' - ( 2 ICYCLOHEXENE1-3r4'-DIONE,

SPIROI 9H-BENZO( a )FLUORENE-9,2' l 3 ' H )-FUR01 L 2 - b )PYRIDIN)-3I 1H )-ONE, 2,3'a14',5r5'16,6',6a, 6b.7.7',7'a,8~llrllo~llb-HEXADECAHYDRO-3',6' rlO,llb-TETRAHETHYL-

7-CHLORO-2'4,6-TRIMETHOXY-b'-beta-

METHYL-

RN

- 126-07-8 - SPIRO(BENZ0FURAN-21 S H l , l ' - l ~ ) C Y C L O H E X E N E ) - ~ ' , ~ - D I O N E S 7-CHLORO-4,4'.6-TRIHETHOXY- 6'-beta-METHYL- 469-52-3 - SPIROI ESTR-Q-ENE-17r2' I3'H)-FURAN)-3-ONE, 4' ,5'-DIHYDRO-, - 1235-13-8 - STANNANE. ACETOXYTRIPHENYL- 900-95-8 - STANNANE. BISlISOOCTYLOXYCARBONYLMETHrLTHIOlDIOCTYL- 26401-97-8

3901

Nl RN

-- STANNINE. 1066-45-1

3902

N1 RN

RN 3897

N1 RN

3898

Nl

RN 5899

N1 RN

3900

N1

3903

Nl

RN

-

CHLOROTRIHETHYL-

STANNANE, CHLOROTRIPHENYL639-58-7 STANNANE, HYDROXYTRIPHENYL76-87-9

I 1 7 R 1-

198 3904 N1 RN 3905 Nl RN 3906 N1 3907 N1 3908 N1 RN 3909 N1 RN 3910 N1 3911 N1 3912 N1 3913 N1 RN 3914 Nl RN

3915 N1 3916 N1 RN 3917 N1 RN 3918 N1 RN

3919 N1

RN 3920 N1 RN 3921 N1 RN 3922 N1

-- STANNINE HETHYLTRICHLORO993-16-8 -- STANNINE, TRICYCLOHEXYLHYDROXY13121-70-5 - STAIE(*TEll-)r PENTACHLOROOI-I SODILM - STAPHYLOCOCCAL PHAGE LYSATE -- 9005-27-02-HYDROXYETHYL ETHER BUTYL ESTER -- STEARIC 123-95-5 v

STARCHI

At101

- STEMONA JAIWNICA M l q . ,

- STERCULIA FOETIOA OIL

crude extract

- STEVIA REBAUOIANA Bertai, extract -- 5-rrlpha-STIGHASTANE-3-beta~5~6-beia-~IOL~ 3-BENZOATE 59297-18-6 -- STI~AST-5-ENE-3-beta,7-a~pha-OIOL, DIBENZOATE 56698-81-8

-- STIGHAST-5-EN-3-beta-OL 83-46-5

STIGnAST-5-ENE-3-b~ta.7-beTa-DIOI.

OIBENZOATE

-- 59157-67-4 STIGHAST-S-EN-7-ONE, 3-b8ta-HYDRDXY-, BENZOATE -- 4-STILBENAHINEo IE 14309-66-+ - 4,4'-STILBENEDIOLt - 56-53-1

mlphrdphm'-OIETHYL-

-- 4.4'-STILBENEOIOL. alpha.alpha'-DIETHYL56-53-1 -- ~.~'-STILBENEOIOLI alpha,alpha'-DIEMYL-, 22610-99-7

12)-

- ~I~'-STILBENEOIOLIalphm,alph.'-OIETHYL-, BISIDIHYDROGEN - 522-40-7 - 4.4'-STILBENEDIOL, alpha~mlpha'-OIEMYL-~BJSfOIHYDROGEN PHOSPHATE TETRASODILM SALT, (El-- 4p4'-STILBENEDIOL~ alphr,rlphr'-DIETHYL-~DIPALMITATE 63019-08-9 PHOSPHATE ) P ( 1)-

RN 3923 N1

bs

3924 N1 RN 3925 N1 RN 5926 N1 3927 Nl 3928 Nl RN 3929 N1 3930 Nl 3931 N1 3932 N1 3933 N1 3934 N1

3935 N1

-- 4r4'-STILBENEOIOL, alpha,mlpha'-OIETHYL-~DIPROPIWATLI (E)130-80-3

- 4,4'-STILBENEDIOL, alpharalpha'-OIETHYL-~OISOOILM SALT - ~~~'-STILBENEOIOLI 4,4'-STILBENEDIOL, alpha,alpha'-DIMETHYL-r -- 552-80-7 - 4,4'-STILBENEOIOL, alpharalpho'-OIHE~YL-~DIACETATE fester), I E b - 4,4'-STILBENEOIOLr .lph.r.lph.'-OIHETHYL-r DIACETATE,

~lph~r~lph~'-DIEMYL-3,3'~5~5'-TETR~ETNYL~

I€)-

12)-

- 4,4°-STILBENEOIOLIalpharalpha'-OIMETHYL-~DIPROPIONATE, lE)-

- 4,4'-SlILBENEOIOL~ alpha-ETHYL- ~,~'-STILBENEDIOLI

alph.-HETHYL-mlpha'-PROPIL-

- 4,4'-STILBENEOIOL1

alph.-PHENYL-3,3'r5,5'-TETRAMETWYL-

- ~~~)'-STILBENEOJOLIdph.-PROPYL-

199 3936

N1

RN 3937

3938

3939

N1

N1 RN N1

RN 3940

3941

N1

RN N1

RN 3942

Nl

RN 3943

N1 RN

3944

N1

3945

N1

RN

RN 3946

N1

RN 3947

N1

-

2,2’-STIL6ENEDISULFONIC ACID, 4.4’ -61Sll4-ANILINO-6-1 12-HYOROXYETHYL)HETHYLAHINO)-t -TRIAZINZ-YLIAHINO)-, O I S O D I M SALT 13863-31-5 2,2’-STILBENEDISULFONIC

ACID,

4,4’-BIS14-PHENYL-1~2~3-TRIAZOL-2-Y~~~ DIPOTASSILM SALT 4-STIL6ENOLs 4’-16ENZYLOXY)-alphatslphe’-DIETHYL-

6202-26-2 D-STREPTAHINE.

O-3-lHINO-3-DEOXY-alpha-D-GLUCOPYRANOSYL-ll-6l-0-l6-AHINO-6-OEOXY-alpha-D- G L U C O P Y R A H O S Y L - I ~ ~ ~ ~ ) - N I S U ~ 11-1 4-AHIN0-2-HYDROXY-l-DXOBUTY 1I-2-DEOXY-r 37517-28-5

-

D-STREPTMINEr

-

- a l p h a - 0 - GLUCOPYRANOSYL-11-41-Nlsup 1 )-(4-AHINO-2-HYOROXY-l-OXO6UTYl )-2-OEOXY-s ISALTI 39831-55-5

I SI-

0-3-AHINO-3-DEDXY-alpha-D-GLUCOPYRANUSYL-l1-6~-0-16-AHINO-6-DEOXYI S ) - $ SULFATE I1:2)

- D-STREPTAHINE, -

O-~-AHINO-~-DEOXY-~~~~~-D-GLUCOPYRANUSYL-I~-~~-O-~~-AHINO-~-OEOXY- a l p h a - D-GLUCOPYRANOSYL-11-4) I-P-DEOXY59-01-8 D-STREPTAHINEI D-3-AHINO-3-DEOXY-a1pha-D-GL~OPYRANUSYL-l1-6~-0-l2,6-DIAHI~-2,3,4,6- TETRADEOXY-~lphi-O-er~~thro-HEXOPYRANOSYL~-I1-4~-2-OEDXY34493-98-6 STREPTAHINES D-3-AHINU-3-DEOXY-a1pha-O-GL~OPYR*NOfYL-ll-4~-O-l2,6-DIAHINO-2,3,6- TRIDEOXY-~lpha-D-RIBOHEXOPYRANOSYL-ll-6~-2-DEOXY-, D32986-56-4 D-STREPTAHINE, 0-2-AIIINO-~-lHETHYLAnINU~-2~3~4~6-TETRADEOXY-alph~-D-er~thro-HEXOPYRANOSY L~~-~~-~-~~-DEOXY-~-C-HETHYL-~-~HETHYLAHINU~-~~~P-L-ARABINOPYR~OSYL-I 1 - 6 1 )-t-OEOXY52093-21-7 0-STREPTAHINE,

0-3-DEOXY-4-C-HETHYL-3-lHETHYLlHINO~-beta-L-ARABINOPYR*NOSrLr1-6~-0-1 2 $6DIAHINO-2,3,4,6-TETRAOEOXY-~lpha-O-GLYCERO-HEX-4-ENOPYRA~YLl1-4))-Z-DEOXY-NlSup 11-ETHYL56391-56-1

- D-STREPTAHINEI -

0-3-DEOXY-4-C-HETHYL-3-1HETHYLAHINO)-beta-L-ARABINOPYRISYL-l1-6)-0l2rb-DIAHINU-2,3,4,6-TETRADEOXY-alpha-D-gl~cer~-HEX-4-E~PYRANOSYL-Il-4)l-Z-DEOXYN l s u p l)-ETHYL-, SULFATE l 2 : 5 ) 1 ~ ~ 1 7 ) 56391-57-2 STREPTAHINEs 0-beta-0-HAMPYRANOSY COPYRANUSYL-

L-I 1 - 4 1-2-DEOXY -2-1 HETHYUnINCi 1-alpha-L-GLU-

11-21-5-DEOXY-0-3-C-lHYDROXYHETHYL~-alpha-L-LYXOFURANOSYL-~1-4l-N-

3948 3949

RN

,N‘-DIAHIDINO-, - 128-46-1

N1 RN N1

- STREPTOMYCIN - 57-92-1 - STREPTMIYCIN,

RN 3950

N1 RN

3951

N1 RN

3952

N1

3953

N1 RN

- 298-39-5 -- STREPTOMYCIN, 3810-74-0 -

D-

SULFATE 11:3)

SALT

SULFATE 12:31 (SALT)

CHLORIDE HEXAHYDRATE - STRONTIlM 10025-70-4 - STROPHIMHM 6RATUS Franch., leaf and stem bark axtract - STRYCHNINE - 57-24-9

3954

N1 RN

3955

N1 RN

3956

N1 RN

3957

N1 RN

3958

N1 RN

3959

N1 RN

3960

N1 RN

3961

N1

-

- STYRENE 100-42-5 -- STYRENE, HETHYL25013-15-4 - SUCCINAHIC ACID, 3-IIIIM)-N-(.lph.-WRBOXYPHENETHYL)-, N-HETHYL rtereoiaomer - ESTER. 22839-47-0 - SUCCINIC ACID. tIERCAPT0-, DIETHYL ESTER, 5-ester w i t h 0.0-DIHETHYL PHOSPHORMITHIOATE -

121-75-5

--

SUCCIWIC ACIDv 1596-84-5

-

3544-94-3

~(2.2-DItIETHYUlYDRUIDEl

- SUCCINIC ACID, I"OESTER with 5-BUTVL-44 HYDROXYMETHVL1-1 2-DIWENY L-3,5-PYRUDLIDINEDIONE - 27470-51-5 - D-Threo-( SUCCINIC ACID, .lphr-HONOESTER With - )-2 t2-DICHLORD-N-t beta-HYDROXIalpha-~HVDROXYtiETHYL)-p-NITROPHENETHYL)ACETAHIDE - SVCCINIC ACID, .lphr-m))30ESTER th D-threo-(-)-2,~-DICHL(IRO-N-bet.-H~DROXY-.lph.Ul

lHYDROXYHETHYL)-p-NITROPHEHYL)ACETAHIDE, compd. with ARGININC

3964

N1 RN

----

3965

N1 RN

-- SUCCINIHIDE, 77-67-6

3966

N1 RN

3967

N1 RN

5962

Nl RN 5963 N 1 RN

3968 N 1 RN

3969

N1 RN

3970

N1

3971

Nl

3972

N1

3973

N1

3974 N l 397s

N1 RN

3976

N1 RN

3977

Nl RN

3978

N1 IN

3979

N1 RN

3980

-----

--

-----

SUCCINIC ACIDI HOWESTER ui th N-I 2-ETHVUlEXYL )-3-HYDROXYBUTYRIIIIDE 32838-28-1 H m I N I C WlYDRIDE 108-30-5 SUCCINIHIDE, N,2-DIHETHYL-2-PHEWL77-41-8 2-ETHYL-2-HETHYL-

SUCCINIHIDEi N-tIETHYL-2-PHENYL86-34-0 SUCCINONITRILE 110-61-2 SVCCINONITRILEB TETRAMETHYL3333-52-6 SUCROSE 57-50-1 WLFAtIIC ACID, DECAHETHYLENE ESTER SULFAMIC ACID, ETHYLENE ESTER SULFMIC ACID, 2-tIETHYL-2-PROPYLTRIHETHILENE ESTER SULFAIIIC ACID, TETRAIIETHYLENE ESTER SULFAHIC ACID, TRIHETHYLENE ESTER WLFANILIIIIDE 63-74-1 SULFANILAMIDE, N l r u p l)-AHIDINO57-67-0 SULFANIL*nIDE s N( rup 1 )-lS-tw-t-BUlYL-l 535-65-9

r3+THI*DIAZDL-2-YL)-

SULFANILAMIDE, 2-CHLORD-S-lIH-TETRAZOL-5-YL)-N(i~ 27589-33-9 SULFAHILAHIDE, N~I3~6-DIHETHOXY-4~P~IDAZIWL)1230-33-7

4bZ-lMENTL-

201 3981 N1 RN

39.92 Nl RN 3983 Nl

RN

--

SULFANILAMIDE, NISUP l ~ ~ I 3 ~ ~ - D I ~ E T H Y L - 5 - I S O W Z O L Y L ) 127-69-5

-- SULFANILAHIOE~ l)-l2~6-DIHETHYL-4-P~I~IDINYL)515-64-0 -- 57-68-1 SULFANILIXIVE, Nflup 1 )-I4,6-DIUETHYL-2-PYRIUIDINrL tNISup

3984

3985 N1 RN 3986 Nl RN

3987 N1 RN

59.91) N1 RN 39.99 N1 RN 3990 N1 RN 3991 N1 RN

3992 Nl RN

3993 Nl RN 3994 N1 RN

3995 N1 5996 N1

l)~l6-HEMOXI-2-HETHYL~4-P~IHIDINTL~-- SULFANILAHIDEr 3772-76-7 -- SULFANILAMIDE, Nlrup l)-II-HETHOXYPYRUINYL)152-47-6 -- SULFANILAHIDEI N I S W l)-I6-HETHOXY-3-PYRIDUINYL)80-35-3 -- SULFANILAUIDE Nlsup 1 )-I6-HETMOXY-4-PYRIHIDINTL)1220-83-3 NISW

v

---

SULFANILAMIDEi Nlsup l)-IQ-METHYL-2-PYRIMIDINYL)127-79-7 SULFANIUHIDE, NISup 1)-2-PYRIHIDINYL60-35-9

SULFANILAHIM, NlSup 1 )-2-PYRIHIDINYL-, M S I L V E R I 1,) SALT -- 22199-08-2 -- SULFANILAHIOEr N I S W 1)-2-PYRIHIDINYL-r M S M ) I U n SALT 547-32-0 -- SULFIDEr BISIDIHETnYLTHIbCARBA~YL) 97-74-5 SULFIDE, p-CHLOROPNENYL 2,4,5-TRICHLOROPHENYL --- SULFIDEr 2227-13-6 DICARBADODECABORANYLHETHYLETNYL- SULFIDEr DICARBADU)ECABOR*NYLET~YL~OPYL-

RN

--

SULFONE, p-CHLDROPHENYL 2r4v5-TRICNLOROPHENYL 116-29-0

3998 NI

-

SULFONIC ACID, rlpha-ALKENE-

3997 N1

3999 Nl RN

4000 N1 RN

4001 N1 RN 4002 Nl RN

4003 N1 RN

4004 Hl RN 4005

Nl RN

4006

N1 RN

4007

N1 RN

4001) N1 RN

-- SULFOXIMINEr S-I 3-AHINO-3-C*RBOXYPROPYL)-S-~TnYL-r DL1902-67-8 -- SULFUR DIOXIDE 7446-09-5 ACID, ALUnIMUII POTASSIW SALT l2:1:1), DODECAHYDRATE -- SULFURIC 7784-24-9 -- SULFURIC ACIDS CERIUn SALT I2:l) 13590-82-4

---

SULFURIC ACID, DIETHYL ESTER 64-67-5 SULFURIC ACID, DIUETHYL ESTER 77-7.9-1

-- SULFURIC ACID. GALLIIM s w 13494-91-2

---

i1:2)

SULFURIC ACID, W G N E S I W SALT ll:l)r sompd. ulth 2,2'-DITHI~ISlPYRIDINE) Iel -OXIDE 43143-11-9 SULFURIC ACID, TITANIWlQ*) U L T 27960-69-6 SULFURIC ACID, V W D I U I SALT 16765-81-2

202 N1 RN 4010 N1 4011 N1 RN 4012 N1 4013 Nl RN 4014 Nl PN 4015 NI 4016 Nl 4017 N1 RN 4018

N1

4019 Nl RN 4020 N1 RN 4021 N1 RN 4022 N1 4023 N1 RN 4024 N1

RN 4025 N1 4026 N1 RN 4027 N1 RN 4028 N1 RN 4029 N1

-- SUHISTAT PP 101 51635-68-2 - SWEET PEA SEEDS -- SYNTOX 12 66106-01-2 - 11 -- TACCHYSTEROLI 67-94-9 TAA

DIHYDRQ-

ACID -- TANNIC 1401-55-4

- TAR, TOBACCO - N-I TARIRONIC ACID, DIETHYL ESTER, conipd. with IBENZYLOXY ICARBONYLIGLYCINE -- TAURINE 107-35-7 - BACCATA Linn., leaf extract -- TELLURIUM 13494-80-9 -- TELLURIUM CHLORIDE 10026-07-0 -- TELLURIUM DIOXIDE 7446-07-3 - TERNINALIA ARJWA, BARK EXTRACT froin

TAXUS

-- TESTOSTERONE 58-22-0

-- TESTWTERONEI ACETATE 104s-69-8

- TESTOSTERONE-3-BOVINE SERUM ALBWIN

-- TESTOSTERONEv CYCLOHEXANECARBOXYLATE 14191-92-5 -- TESTOSTERONE. CYCLOPENTANEPROPIONATE 58-20-8 -- TESTOSTERONE, HEPTANOATE 315-37-7 - TESTOSTERONEB HEPTANOATE, and

(-~-l~-ETHYL-17-HYDROXY-l8~19-D1~-17-~lph~-~E~-~-~~~

20-YN-3-ONE 4030 N1 4031 N1 RN

- TESTDSTERONEm 7-alpha-METHYL- TESTOSTERDNE, HYDROCINNMATE - 1255-49-8

4032 N1 RN

-- TESTOSTERONES HYDROGEN SUCCINATE 521-15-3

4033 N1 RN

-

4034 N1

- 57-85-2 TESTOSTERONEr PROPIONATE - TESTOSTERONE. UNDECANOATE Ie r h r 1

4035 N1 RN

-

4036 N1 4037 N1 RN 4038 Nl RN

1-TETRADECWOL, HYDROGEN SULFATE, SODIW SALT 1191-50-0

- TETRAOLEANt PHOSPHATE - lr4~7~1D-TE7RAOXACYCLODODECANE - 294-93-9 -- 215r8,ll-TETRAOXADODE~NE 112-49-2

203 4039 N1 RN 4040 N1 RN 4041 N1 RN 4042 N1 RN 4043 N1 RN 4044 N1 RN

-- TETRALANE 6054-69-9 -

I ~ ~ . ~ B ~ - T E T R O X O C A2,4,6~8-TETRAMETHYLNEI 108-62-3

I I CHLORIDE 7791-12-0 - THALLIUnl SULFATE -- THALLIUM 10031-59-1 -- THEOBROMINE 83-67-0 TNEOBROMINE. l-l5-OXOHEXYLl-- 6493-05-6

4045 N1 RN

--

4046 N1

- THEOPHYLLINEm 7-1 3- I I 2-1 3,5-DIHYDROXYPHENYL I-2-HYDROXYETHYL )AMINO IPROPYL 1-1

RN 4047 N1 RN 4048 Nl RN 4049 Nl RN 4050 N1 RN 4051 N1 RN 4052 N1

-

THEOPHYLLINE 58-55-9

HYDROCHLORIDE 13055-82-8

-- THEOPHYLLINEr 7-12-HYDROXYETHYL)519-37-9 - THEOPHYLLINEr 7-l2-lbeta-HYDROXY-alpho-FIETHYL~ENETHYLAMINOlETHYL~- 58166-83-9 - 4-THIA-1-UABICYCLOl3.2.O)HEPTANE-2-CAR8OXYLIC ACID, DIMETHYL-~-OXO-PD-1-1- 6-12-ANINO-2-PHENYLACETAMIOOl-3s369-53-4

- 4-THIA-l-AZA8ICYCLOI3.2.O)HEPTANE-2-CARBOXYLIC 6-l2-AMINO-2-PHENYLACETAMIDO)-

ACID. ~B~-DIHETHYL-~-OXO-, TRIHIDRATE,

D- I - 1 7177-48-2

- 4-TnI~-l-AZABICYCLOI3.2.OlHEPTANE-2-CARBOXYLIC ACID, 6-13-CARBOXY-2-PUINOXALINECARBOXAMIDO)- 3,3-DIMETHYL-7-OXD-r

-

DIMDIlM SALl 985-32-0

- 4-THIA-1-AZA8ICYCLOl3.2.O~HEPTANE-2-CARBOXYLIC ACID, 6-(I 13-I2-CHLORO-6-FLUOROPHENYL~5-METHYL-4-ISOXAZOLYLlCARB~YL~ANINOl-3~3-DI~ETHYL-7-OXO-r NONOSOOIVn SALT, 12s-It-elphat 5-alphatb-bctd))-

RN 4053 N1

- 1847-24-1 - 4-THIA-1-AZA8ICYCLOI3.2.0lHEPTANE-~-CARBOXYLIC ACID, 3.3-DIHETHYL-6-( 1111 3-lNETHYLSULF0NYL)-

2-OXO-l-IMIDAZOLIDINYLlCARBONYL~A~INOlPHENYLACETYL~AMINOl-7-OXO-r RN 4054 N1

RN 4055 N1 RN 4056 Nl RN 4057 N1 RN

SODIUM SALT, l 2 S - l 2 - a l p h d . 5 - a l p h a , 6 - b . t P ) o ~ - 51481-65-3 - 4-THIA-1-AZA8ICYCLO~3.2.0)HEPTANE-2-CARBOXYLIC ACID. 3.3-DIHETNYL-7-OXD-6- I2-PNENOXYACETAMIDOl-~coapd.

--

M I th 4-IDINETHYLANINO~-1,4~4a,5,5a,6,11~12d-OCTAHYDRO3,6,10,12,12a-PENTAHYDROXY-N-lI4-l2-HYDROXYE7HYLl-1-PIPERUINYL~METHYLI-6-NETHYL-1~11-DIOXO- 2-WPHTHACENECARBOXAMIDE t1:lI 4599-60-4 4-THIA-1-AZABICYCLOI3.2.O~HEPTANE-2-CARBOXYLIC ACIDl 3.3-DIMETHYL-7-0x0-6- 12-PHENYLACETAMIDO)-r coinpd. w l th N.N'-DIBENLYLETHYLENEDI~INE 12:l) 1538-09-6

-

28002-18-8

- 4-THIA-1-AZA~ICYCLOl3.~.O)HEPTANE-2-CARBOXYLIC ACID. 3~3-OIMETHYL-7-OXO-6-l2-PHENYL= ACETAHIOO)-. NONOSODIUM SALl - 69-57-8 - 4-THIA-l-AZA8ICYCLOf3.2~O~HEPYANE-2-CARBOXYLIC ACID, 3 ~ 3 - O I N E T H Y L - 7 ~ O X O ~ 6 - I 2 ~ P H E N Y LSULFOACETAMIDOI-, -2~ DIMDILW SALT

204 4058

N1

- 64-~IA-l~AZABICYCLOl3.2.O~HEPT~-2-CARsoxYLIC ACID, -llll14-ETHYL-2~3-OIaXO-L~PIPERAZINY~~

RN

SALT, - MONOSODIUM 59703-84-3

CARBDNTL~AHINO~PHENYLACETYL~AHINO~~3~3~OI~ETHYL~7~OXO-~

4059

l2S-l2-alpha,5-alpha.6-betalS*)J)-

N1 4 - T H I A Z O L Y L ~ l H E T H O X Y I ~ I N )ACETVL O IAHINO)-O-OXO- s

RN 4060

N1

16R-16-alphr17-bctalZ 1)). SODIW SALT - 64465-93-4 - 53-I11AHJNOEARBONYL)OXY - T H I A ~ l ~ A L A B I C Y C L O I 4 ~ 2 . 0 ~ O C T ~ 2 ~ E N E ~ e - t I R B OACID, XYLIC )HETHYL)-7-112FURANYL l HETHYOXYIHINO IACETYL )AtlINO)-O-OXO-,

RN 4061

N1

RN

16R-16-alphar7-betalZ) 1)- 55268-75-2 - 53-(llAHINOCARBONYL)OXY - T H I A ~ l ~ * U B I C Y C L 0 1 4 ~ 2 ~ O ~ ~ T ~ Z ~ E H E ~ 2 - CACID, ~BOXYlIC )HETHYL)-7-112-

-

F U R U J Y L l H E ~ O X Y I H I N O ~ A C E T Y L ~ M I N O I ~ 8 ~tiOWSODIUN OXO~~ SALTS l 6 R - ( 6-alpha, 7-beta1 2 ) ) )36238-63-2

2-OXOETHYL~~I~3-DITHIETIN~2~YL~CAR~L~MIND~~7~~ETH~Y-3-lll1-~ElHYL-lH-TETRAZOL-5-YL) THIO)HETHYL)-8-OXO-s DISWIUI SALT, RN 4063

N1

RN

16R-Cls 1- 74356-00-6 - 5-THIA~1~AZABICYCLOl4~2~0~DC7~2~ENE~2-CARBOXYLIC ACIDS 7-1 114-1 2-AHINO-1-CARBOXI-

-

2-OXOETHILIDENE~-lr3-OITHIETAN-2-YL~CARBONYL~AHINO~~7-~ETHOXI-3-~Ill-METHYL-1H-TETRAZOL- 5-YL)fHIO)HETHYL)-~-OXO-~ l6R-l6-alpha,7-olpha) )69712-56-7

Nl

- 5-THIA-l-MIBICYCLOl4.2.O~OCT~2-E~-2-CARLICACID,

RN

- 51762-05-1

4065

N1

- 5-~IA-l-MABICYCLOI4.2.O~OCT~2~ENE~2-CARBOXYLIC ACID, 7-llAHINO-lr4-CYCLOHEXADIEN- l-YLACETYL)AHINO)-S-HETN~-8-OXO-r

4066

N1

- 5-THIA-l-A2ABICYtLOI4.2.O~O@T~2~ENE~~-CARBOXYLIC ACID,

4064

7-llAHINO-1,4-CYCLOHEXADIEN-l- Y L A C E T Y L ~ A H I N O ~ ~ I - M E T H O X Y ~ O ~ O X O - ~ 16R-~6-alphar7-brtalRr)) )-

DIHYORATE. l6R-l6-alpha,7-betalR*)))-

7-( lAMINO-l,4-CYCLONEXADIEN-

RN 4067

N1

l 6 R - I 6-alpha. 7-beta1 R * ) 38821-53-3

l-YLACETYL)AHINOl-3-HETHYL-8-OXO-,

) )-

- 5-THIA-1-AZABICYCLOl4.2.O~OCT~Z-ENE-P-CARBOXYLIC ACID) 7-1 IAnINOl4-HYDROXY~ENYL)ACETYL 1 AnINOl-3-HETHYL-O-OXO-, 16R-f6-alpha,7-betaIR*)) - 50370-12-2 )-

RN 4066

N1

-

RN

,7-betalR) I - 51627-14-6

5-THIA~l-A2ABICYCL0l4.2.O~OCT~2-E~-2-CARBOXYLIC ACID, 7-1 lA~INO(4-HYDROXYRIENYL)ACETYL)

AHINO~-d-OXO-3llIH-l~2r3~TRIAZOL-4-YL~IO~HE~YL~-r(6R~-l6-elph~

4069

N1

RN 4070

N1 RN

4071

N1

- 5-THIA-l-ALABXCYCLOl4.2.O~OCT-2-ENE-2-CARBOXYLIC -

-

7-lP-AIlINO-2-PHENYLACETA~IDO)l e r t e r ) , 03577-01-3

~ - T H I A L - ~ - U * B I C Y C L O I ~ . ~ . O I O C T - ~ - E N E ~ ~ - C A R B O X YACID, LIC 7-l2-AHINO-2-PnENYLACETAr(IDO)-3HETHYL-8-0x0-s D-

4072

Nl

)-

RN

ACETATE

- 15686-71-2 - 5-THIA~l-UABICYCLOI4.2.0~OCT-2~ENE~2-CARW)XTLIC ACIDS 7-lIAHINOPHENYLACETYL~AHINO~~3~CHLORO~ 8-OXO-, I 6 R - I 6-alphaB7-be t a l R* - 53994-73-3 - 5-THIA-1-AZABICYCLOl4.2.O)OCT-2-ENE-2-CARBOXYlIC ACID, 7-1 I I2-ANINO-4-THIAZOLYL IHETHOXYIHINO~ACEITLlAHINOl-8-ooQ)-. SALT. (6R-16-alphal 7-DctalZ) 1)- tlONOSOOIW 68401-62-1 ) )-

RN

ACIDI 3-lnlDROXYHETHYL)-O-OXO-.

205

4073

4074

N1

N1

RN

4075

N1

-

-

5-THIA-1-AZ4BICYCLOl4.2.0)OCT-2-ENE-2-CARBOXTLIC ACID, 7-1 2-1 ICYWOnETHYL)THIO)ACETAMIOO)~80x0-3-1 IlH-TETRUOL-5-YLTHIOlMETHYL~-~ SODIIN SALT

5-THIA-1-AZABICYCLOI4.2.O~OC7-2-ENE-2-CARBOXYLIC ACID. 7-1 I I ( CYANCMETHYLITHIOIACETYL I I I I I N O I 7-METHOXY~3-llll~METHYL-lH-TETRAZOL-5-YL~THIO~METHYLld-bm)-r 16R-c is I 56796-20-4

- 5-YHIA-l-AZABICYCLOl~.2.O)OCT-2-ENE-2-CARBOXYLIC 7-12-1 I2i3-010x0-4-ETHYL-1-

ACID,

PIPERAZINYLlFOR)UnIDOl-3-HYDRM(YBUT~R*nIDOl-7-METH~Y-3-~ 1 II-HETHYL-IH-TETRAZOL-5-YLlTHlOl

RN 4076

Nl RN

4077

N1

RN 4078

N1

HETHYL)-8-OXO-B

)IoNo9oOIW

SALTB

16R-16-~lpha,7-~lpha1,712R*,3S*ll)- 76648-01-6 - 5-THIA-l-AZABICYCLOl4~2~OlOCT-2-ENE-t-CARBOXYLIC ACID, 3-1HYDROXYMETHYL I-8-0x0-7-1 2-1 4- PYRIOY LTHIO IACETIIIIDO

-

ACETATE1 ESTER 24356-60-3

)- 8

)IoNoSoDIuI SALT

- 53-lHYOROXYflETHYLl-8-OXO-7-(2-(2~ - T H I A - l - A Z A B I C Y C L O l ~ . 2 . O l ~ T - 2 - E N E - 2 ~ C A ~ ~ Y L I CACID. T H I E N Y L I A C E T A M I O O ) ~ ~ACETATE - f1e5 3s-t6e1r-17 - C-THIA-l-AZABICYCLOl4~2.OlOCT-2-ENE-2-CARBOXYLIC ACID. 7-1 I I I14-HYOROXY-6-METHYL-3PYRIOINYLlCARBONYL)AMINOll4-HYOROXYF'iiENYL)ACETYL )ARINO)-3-1 III-METHYL-1H-TETRAZOL-5-YLI THIO)METHYLl-8-OXO-, HONOSOOIUM SALT, 1 6 R - ~ 6 - a l p h a . 7 - b c t a I R * l I 1-

4079

4080

N1

-

5-THIA-1-AZABICYCLOl4.2.OlOCT-2-ENE-2-CARBOXYLIC 7-W*NDELIIIIOO-3-I I I1-METHYLlH-TETRA~OL-5-YL)THIOlMETHYL)-8-OXO-~ 30034-03-8

ACIO,

m o D I W SALT. D-

RN

-

N1

- 5-THIA-I-AZABICYCLO14.2.O)OCT-2-ENE-2-CARBOXYLIC

ACID.

3-lll5-METHYL-1~3~4-THIADIAZOL~2~YL~

4081

RN

-

N1

- 5-THIA-1-AZIBICYCL0~4.2.OlOtT-2-ENE-2-CARBOXYLIC ACID. 8-OXO-7-l(lH-YETRAZOL-l-YLACETYLl

RN

4082

THIO~HETHYL~-8-OXO-7-ll~lH-TETRUOL-I~YLlACETYLlAMINOl~~ 16R-trans 1-. SODIU1 SALT 27164-46-1

N1 RN

4083

Nl RN

4084

N1 RN

-

A H I N O ~ - 3 - l l l ~ 3 ~ 4 - T H I A O I A Z O L - 2 - Y L m I O ) n E T H Y Ll~" O ~S ~ oOIu( 16R-trans )41136-22-5

1-YHIA-4~8-OIAZASPIROoDECAN-3-ONE~

3-(2-CHLOROPHEN0THIAZIN-lO-YL)PROPYL)-~HYDROCNLORIDE - 8-1 27007-85-8

- 1 ~ 3 ~ 4 - T H I A O I A ~ O L2-AMINOE~ - 4005-51-0 - I r 3 ~ 4 - T H I A O I A L O L E ~2 - M I N O - r -

-

HYDROCHLORIOE

26861-87-0 l r 3 ~ 4 - T H I A D I A Z O L E ~Z-AMINO-5-15-NITR0-2-F~YL)712-68-5

4085

N1 RN

4086

NI RN

4087

Nl RN

4088

N1

- I ~ ~ , ~ - T H I A D I A Z O L E2rZ'-IiETHYLENEBIS(IMINOI - 26907-37-9 - 1~3~4-THIAOIAZOLE-2-SULFONAMIOE~ 5-AMINO-. MONOSODIW

4089

NI

- 1~3~4-THIAOIAZOLE-5~SULFONAMIOE~ 2-1PHENYLSULFONYLAIiINO)-

RN 4090

N1 RN

4091

N1 RN

4092

N1 RN

-

1r3r4-THIAOIAZOLEs 2-ETHYUMlNO-

13275-68-8

- 3368-13-6 - THIAHINEI CHLORIDE - 59-43-8 - 4-THIAZOLEACETIC ACID* - 17969-20-9 - 5-THIAZOLEACETIC ACIOI -

18046-21-4

2-lp-CHLOROPHENYL)4-1p-CHLOROPHENYLI-2-PHENYL-

SALT

SALTS

206 4093

N1 RN

4094

N1 RN

4095

Nl

4096

N1 RN

4097

N1 RN

4098

N1

---

THIAZOLEI 2-AMINO-5-NITRO121-66-4 4-THIALOLECARBOXAHIDE~ Z - b ~ t a - D - R I 8 O F U R A N L 60084-104

- 4-THIAZOLIDINONE~ 2-(3~4-DI~ETHOXYPHENYLl-5-HETHYL- 5-l2-HYDROXYETHYLJ-3-~14-HYDROXY-2-METHYL-5-PYRIHIDINYLlME~YL)-4THIAZOLIVI). - -METHYL136-16-3 - tH-THIEN0(2,3-.1f ~~~~DIALEPIN-~-ONEI 1~3-DIHYDRO-5-(o-CHLOROPnENYL)-7-ETHYL-l-HETHYL-

-

33671-46-4

- lN-THIENOl3~4-d)IHIDAZOLE-4-PENTANOIC ACID, NEXAHYDRO-2-0x0-r 3aS-I b - a l p h a r 4 - b e t a r Ca-alpha 11- 58-85-5 - ~3-THIENOI 2.3-c )PYRIOINECIRBOXYLIC ACIDS ~ ~ I ~ I ~ - T E T R A H Y D R O - ~ - A ~ ~ N O - ~ - BETHYL E N L YESTER L ~ ~ HYDROCHLORIDE (

RN 4099

N1

4100

N1 RN

4101

Nl

4102

N1 RN

4103

N1 RN

4104

N1 RN

4105

N1

RN

-

T H 1 E W l 3 ~ 2 - c)PYRIOINE, 5-ll2-CHLOROPNENYL1tlETHYL)-4r516rT-TETRAHYORD~~ 53885-35-1

HYDROCHLORIDE -- T1084-65-7 H I D C H R O " ~ 7 ~ S U L F D N M I D E6-METHYL-r ~ lrl-DIOXIDE -- THIDCYANIC ACID, POTASSIIM SALT 333-20-0 -- TNIOtrORPHOLINE. 3-~ETHYL-4-IlS-NITROFURFURYLIDENE)-, lel-DIOXIDE 23256-30-6 THIOPEROXYDICARBDNIC DIAHIDEs N.N'-DIETHYL-NIN'-DIPHENYL-- 41365-24-6 - THIOPEROXYDICARBONIC DIAMIDE. TETRAHETHYL-r m 4 w t . w i t h (l-alpha~2-alpha,3-b.tor4-olphar 5-alpha,6-betm 1 - 1 ~ 2 ~ 3 , 4 ~ 5 ~ 6 - H E X A C H L O R O C Y C L O E X Aand NE

RN

COPPER( 2+ 1 SALT - TRICHLOROPHENDL 8066-27-1 -- 2-THIOPHENEACETIC ACID, 5-BENZOYL-alphm-HETHYL33005-95-7 N-f5-NITRO-2-THIAZOLYLl-- 2-THIOPHENECARBOXAHIOE~ 3810-35-5 ACID, alpha-AMINO-- 2-THIOPHENEPROPIONIC 139-86-6 - THIOXANTHENE-del tnl sup 9 ) galraa-PROPYLAtlINEr 2-CHLORO-N,N-DIMETHYL- 113-59-7 - NTHIOXUSTHENE-2-SULFOMIDE, ~N-DI~ETHYL~9~l3-I4-METHYL~l~PIPERALINYLl~OPYLIOENEl- 5591-45-7

N1

-

RN 4106

N1 RN

4107

N1 RN

4108

Hl RN

4109

Nl

4110

RN N1

4111

I

9H-THlOXANTHEN-9-DNEe

E-(DIETHYLAMINO IETHYL lAMINol-4-lHYDROXYMETHYL I- 1-1 3105-97-3 - 1-1 9H-THIOXANTHEN-9-ONE, 2-I DIETHYLAHINO IETHYL )AMINO 1-4-1 HYDRDXYHETHYL1- , HWDMETHANE(1.1 t - SJLFMJITE 23255-93-6 NITRATE -- THORIUn(IV1. 13823-29-5 (

RN 4112

N1

(

)

RN 4113

N1 RN

4114

N1 RN

4115

Nl RN

4116

N1

-- lh-R 79469-19-5

--

THYHDL 89-83-8

- THYROID

207 4117 N1 RN 4118 N1 RN 4119 N1

RN 4120 N1 RN

-- THYROTROPIN 9002-71-5 - THYROXINE - 7488-70-2 - THYROXINLr tKltWSODSu(

SALT, D-

-

SALT* L-

- 137-53-1

THYROXINEr -1Un

- 55-03-8

4121 N1 RN

-- TINIII) CHLORIDE (1:2) 7772-99-8

4122 N1 RN

-

4123 Nl RN 4124 N1 RN

4125 N1 4126 N1 4127 N1 4128 N1 RN

4129 N1 RN 4130 N1 RN 4131 N1 RN 4132 N1 RN 4133 Nl RN 4134 N1 RN 4135 N1 RN 4136 N1 4137 N1 RN 4136 N1 RN 4139 N1 RN 4140 N1

TITANIUW IWet powder) 7440-52-6

- 1ITANIUR CHLORIDE

- 7705-07-9 - TITANIUHr DICHLORO-DI-pt-CYCLOPENTADIENYL- 1271-19-8

-

TOBACCO LEAF, AQUEOUS EXTRACT

- TOBACCO LEAF, NICOTIANA GLAUCA - TOBACCO LEAF, NICOTIANA TLBACUI - ,r-TOLUAHIOE. N,N-OIETHYL- 134-62-3 - P-TOLUAMIOEn N-ISOPROPYL-~lpha-l2-METHYLNYDRAZINO)- 671-16-9 - P-TOLUAMIDEI N-ISOPRDPYL-~lpha-12-HETHYLHY~RAZINO)-r MONOHYDROCHLORIDE - 366-70-1 - TOLUENE - 108-88-3 - TOLUENE* - TOLUENE. alpha-CHLORD-

- 100-44-7 - TOLUENE-Z,S-DIAMINE, DIHYDR0CHLORJ.DE

- 615-45-2

-

TOLUENE-2r5-DIAMINE~SULFATE 6369-59-1 TDLUENE-tr3-DIAIlINE, mixed with TOLUENE-3.4-DIAnINE (2:3) rOLUENE8 DINITRO25321-14-6

- 0-TOLUENESULFONAMIDE - 88-19-7

- p-TOLUENESULF~~AMIDE,N-l5-AMINO-1-lCNLOROACETYL~PENTYL~-~ L-

- 2364-87-6 - p-TOCUENESUCFONAMIOE, N - ~ 5 - * M I N O - l - l C H L O R O A C E T Y L ~ P E N T Y L ~ - ~ HYDROCHLM1IDE~ L-

4141 N1 RN

4142 N1 4143 N1 RN 4144 N1 RN

-

u-TOLUENESULFONAMIDEIalpha-WINO-, MONOACETATE 13009-99-9

- P-TOLUENESULFONAMIDEIN-(alpha-lCHLOROACETYL)PHENE~YL)-, - TOLUENE, 2,4m6-TRINITRO- 118-96-7 - 0-TOLUIOINE - 95-53-4

I-)-

4145

N1 RN

4146

N1 RN

4147

N1 RN

4148

N1

4149

N1

4150

N1

4151

N1

4152

N1

-- 0-TOLUIDINE. 4-1o-TOLYLAZO)97-56-3 -- p-TOLUIDINES alph~~alpha~alpha-~RIFLUWIO-2~6-OINITRO-N,N-DIPROPYL1582-09-8 -- TOXAPNENE 8001-35-2

-

TOXAPHENE TOXICANT A

- TOXINt BACTERIUI CORYNE-BACTERIUH DIPHTNERIAEr DIPHTHERIA - TOXIN. PENICILLIM ROQUEFORT1 - TOXOFICTOR - 8-1 ~I33-~ 8I - T RLUOROBENZOY IAUSPIROl4.5)DEC~~4-ONE~ - 749-02-0 D-F

RN 4153

N1

4154

N1

RN

RN 4155

N1

RN 4156

N1 RN

4157

N1 RN

4158

N1

RN 4159

Nl RN

4160

N1 RN

4161

N1 RN

4162

N1 RN

4163

N1 RN

4164

N1 RN

4165

N1 RN

4166

N1

-

~~~~~~~,~,~-TRI~ATRIPHOSPHOR~NEI 2~2~4~4~6-PENTAK1Sl1-UIRIDINYL~~2~L~4~4r616~HEXAHYDRO-614-MORPHOLINYL )37132-72-2

-- 63980-20-1 TRlUENEe DIETNYL-

------

TRIlZENEv 3.3-DIETHYL-1-PHENYL13056-98-9 TRJlZENEi 3,3-DIETHYL-l-lrn-PTRIDYL~21600-43-1 TRIAZENE, 3 i 3 ~ O I M E T N Y L - 1 - l O - H E ~ Y l W E N Y L ~ ~ 20240-98-6 TRIAZENE, 3,3-DIHETHYL-l-PHENYL7227-91-0 TRIAZENE, 3r3-DIHETNYL-1-lm-PYRIDYL)19992-69-9

4167

N1 RN

4168

N1

4169

N1

3-ETnYL-3-METHYL-l-PYRIDYL--3-METNTL-l-PNENYL-3-(2-SULFOETHYL)-r ---- ¶-TRIUINE-Ir5(2Hr4H)-OI~E - ~2~4-TRIAZINE-3~512H~4N)-DIMSE~ -

4170

Nl

-

4171

N1 RN

-

RN

TRIAZENE, 64059-53-6

TRIALENEi l-ETNYL-3-PHENYL21124-09-4

TRIAZENE. 22670-79-7

sw)Iu( SALT

Y-TRIAZINE, 122-34-9

2-CHLORO~4~6-BISlETNYLAMINO)~

r-TRIAZINE, 1912-24-9

2-CHLORO-4-ETNYUMINO-6-ISOPROPILlnIND-

S-TRIAZINE, 1~2-DINYDRO-1-lp-CHLORDPHENYL~~4i6-DIAMI~-2~2-DIME~YL516-21-2 461-89-2

1 2-I 3-CHLORO-4-( 4-CNLOROBENZOY 1)WENY 1I-

~~-TRIAZINE-3~5l2H~4H~-OIONE~ 2-(4-1 1p-CHLOROPNENYL )SULFOmL)-Jr5-DInETHYLPHENTL)-

~s-TRIAZINE-~~~~~N~~H)-DIONEI P-( 4-I (0-CHLOROPHENY L )THIO )-3,5-DIHEltIYLPHEWL 1-

~~-TRIAZINE-3i5l2H~4Hl~DIONE~ 2-beta-0-RIBOFURANoSYL5W-25-1

209 4172

N1 RN

4173

N1 RN

4174

N1 RN

4175

N1 RN

4176

N1 RN

4177

Nl RN

4178

N1

-- a-TRIAZINE, HEXAHYORO-1~3~5-TRINITRO121-82-4 - s-TRIAZINE, 2,4.6-TRICHLORO- 108-77-0 - ~ - T R I A ~ I N E - 2 ~ 4 ~ 6 1 1 H ~ 3 H ~ 5 H ) - T DICHLORO-, RIONE~ - 2893-78-9

SODIUM SALT

4179

N1 RN

- S-TRIAZINE. 2~4~6-TRISIl-A~IRIDINYL~- 51-18-3 - as-TRIAZIN-312H)-ONE, 5-AtiINO-2-beta-O-RIBOFU?ANOSYL- 3131-60-0 - s-TRIAZIN-211H)-ONE, ~ - A M I N O - ~ - ~ ~ ~ P - D - R I B O F U R A N O S Y L - 320-67-2 - s-TRIAZOLE 5-1 m-( ALLYLOXY IPHENYL)-3-(o-€THYLPHENYL MONOHYOROCHLORIOE - 85681-50-1 - 5-TRIAZOLEt ~ - I ~ I - I A L L Y L O X Y J P H E N Y L ~ - ~ - ( O - T O L Y L ~ - 69095-81-4

4180

NI RN

-- S-TRIAZOLEI 61-82-5

4181

N1 RN

4182

N1 RN

- s-TRIAZOLEt - 85681-49-8 - s-TRIAZOLE* - 85303-89-5

4183

N1 RN

s-TRIAZOLE, -- 85303-88-4

4184

N1 RN

-

4185

Nl RN

- r-TRIAZOLE, - 69095-76-7

5-1 m-CHLOROPHENYL)-3-1 o-TOLYL)-

4186

N1 RN

-

5 - Io-CH LOROPHENYL 1- 3-I0-TOLY L )

RN

S -1RIAZOLE I

~-~~-BUTVLPHENYL)-~-II~-METHOXYPH€NYL~~-Io-BUTYLPHENYL)-~-PHENYL-

69095-74-5

-

-- 69095-79-0 I-TRIAZOLE* 5-1 p-CHLOROPHENYL)-3-1 o-TOLYL)3-(4-CHLORO-O-TOLYL)-5-l~-M€THOXY~€NYL)-- S-TRIAZOLE. 75318-76-2

4188

N1 RN

4189

N1 RN

4190

N1 RN

4191

N1 RN

4192

N1 RN

S-TRIAZOLE, - 85303-94-2 I-TRIAZOLE, -- 85303-95-3 -- 69095-87-0 s-TRIALOLE,

4193

N1 RN

-

4194

N1 RN

4195

N1 RN

41%

N1 RN

4197

N1 RN N1

3,5-BISIo-TOLYL)-

36791-04-5

N1 RN

PN

3-AMINO-

1.ZI4-TRIAZOLE-3-CARBOXAMI0€~ 1-beta-D-RIBOFURANOSYL-

4187

4198

)-

D

-

I -1RIAZOLE v 3-1 5-CHLORO-0-TOLY L )-5-lni-HETHOXYPHENY L 185303-96-4

3-1 o-CW€NYL)-5-lm-HEl'HOXYPH€NYL~-

1-TRIAZOLE, ~-Io-CLMENYL)-~-PHENYL69095-86-9

-- 85304-00-3 I-TRIAZOLEI -- r-TRIALOLEv 2039-06-7 -- I-TRIAZOLE, 85303-98-6 -

~-(~-CHLORO-O-TOLYL)-~-PH€NYL-

- s-TRIAZOLEI 69095-80-3 -- 6.5303-83-9 s-TRIAZOLE.

5-13~4-DIMETHOXIPHENYL~-3-~0-ETHYLF'H€NYL)3,5-DIPHLNVL5-lin-ETHOXYF'HENYL)-3-lo-ElHYLPtt€NYL~5-(in-€THOXYF'HLNYL 1 - 3 4 o-T0LYL)-

3-lo-E~YLPtiENYLI-5-(m-FL~O~€NYl~-

4199

N1 RN

4200

N1 RN 4201 N1 RN

---

--

~-~o-E~HYLPHENYL)-~-(~-~EIHOXYPHENYL)-

S-TRIALOLE I 85303-99-7

l H - 1 , 2 ~ 4 - T R I U O L E ~3-l2-ETHYLPHENILl-f-l3-HETNOXYPnENYL)69095-63-6 r-TRIALOLE, S-lo-ETHYLPHENYL~-S-PnE~L69095-88-1

- S-TRIAZOLEr

4202

N1 RN

4203

Nl RN

4204

Nl

4205

Nl RN

- 85303-87-3 3-lo-ETHYLPHENYL)-5-PJPERONYL-- a-TRIAZOLE, 3-fo-ElH'ILPnENYL)-5-f2~3-XYLYL)85303-84-0 -- ~-TRIAZOLEI I~lp-FLUOROPHENYL)-3-1~~TOLYL)69095-78-9 -- r-TRIAZOLE, 5-lm-HETHOXYPnENYL)-3-lm-TOLYL)85681-45-4

4206

N1 RN

I -TRIALOLE 9 5-1 in-HETHOXYPHENYL 1 - 3 4 o-TOLYL 1 69095-72-3

4207

Nl RN

4208

Nl RN

4209

N1 RN

4210

N1 RN

4211

N1 RN

4212

N1 RN

4213

N1 RN

4214

N1 RN

4215

N1

ma

RN 4216

N1

RN 4217

N1 RN

4218

N1

4219

N1

RN

RN 4220

Nl

RN 4221

N1

RN 4222

N1 RN

4223

Nl

4224 N1 RN 4225

N1 RN

--- r

-TRIALOLE 85681-46-5

-

, 5-In-HEWOXYPHENYL b3-1p-TOLYL

-- 69095-75-6 1-TRIAZOLE, -- I-TRIAZOLEt 85303-91-9

---------

S -TRIALOLE 85303-93-1

.-TRIALOLE. 75318-83-1

1-

~~~~~HETHOXYPHENYLI-~~IO-TOLYL~5-lm-HETHOXYPHENYLl-3-l2,4-XVLYL~-

, 5-lm-HEIHOXYPHENYL 1-3-12,5-XY LYL )~~I~~HEIHOXY-O-TOLYL~-~-IIII-HETHOXYPHENYL~-

1-TRIALOLE p 3-1 5-HETHOXY-o-TOLY L 1-5-1 m-tfETHOXYPMENYL b 85681-48-7 S-TRIMOLE. 60510-57-8

~-PHENYL-~-(o-TOLYLI-

r-TRIAZOLE~ 5-PHENYL-I-I2,4-mLYL~85303-90-8 s-TRIIZOLE, 656w-a7-2

~-IO-TOLYL)-~-~I~-TOLYL)-

I-TRIALOLE, 6569)-89-4

3-lO-TOLYL)-5-lp-TOLYL)-

s-TRIAZOLE~ I - t o - T O L Y L ) - 5 - l m l p h a ~ a ~ ~ h n ~ a ~ p h s - T R I F L L Y i ~ 69095-77-8

- 4H-1-lRIAZOL0l4~3-a~l 1~4)BENZDDIAZEPINE. 8-CHLORO-6-Io-CHLOROPHENYL)-l-HETHYL-

28911-01-5

- ~8-CHLORO-l-tlETHYL-6-PHENYLH-I-TRIAZOL~~~,~-~~I~,~~BENZOOIALEPINE. - 28981-97-7 -- ~75318-65-9 H - s - T R I A L O L O I ~ ~ ~ - ~ ~ I S O2-14-6IPNENYLYL)I~OLEI H - s - T R I A Z O L O I ~ ~ ~ - ~ ~ I S O I N2-Ip-CHLOROPHENYL)DOLE~ -- ~57312-03-5 H - s - T R I A Z O L ~ I ~ ~ ~ - ~ I I S O I 2-(in-ETHOXYPHENYLINOOLE~ -- ~57312-08-0

- ~H-s-TRIAZOL~I~,~-~IISOINDOLE~ -- 5H-11,2,4)TRlAZOL015rl-alISOINOOLE~ --

8-HETHOXY-2-lm-HEfOXYFtlENYL)-

2-(3-HETHOXYPHENYL1-

57170-08-8

5H-s-TRIAZOLOI5tl-a )ISOINDOLE. 2-PNENYL57312-00-2

211 4226 N1 4227 N1 RN

4228 N1 RN

4229 N1 RN 4230 N1 RN

- SH-S-TRIAZOL0(5~1-.)ISOIMOLEs L-PHENYL-- s-TRIAZOLO( 5.1-0 )IMPUINOLINE 2-(4-81PHENYLYL 175318-62-6 t

-

s-TRIAZOL0~5~1-~lISOQUINOLINE~ 2-(p-CHLOROPHENYLl66535-86-2

-- s75318-64-8 - T R I A Z O L 0 ~ 5 ~ 1 - ~ l I S O Q U I ~ L5,6-DIHYORO-2-(4-BIPHENYLYL)INE~ -- 55308-60-6 s - T R I A Z O L ~ ~ ~ ~ ~ - ~ ) I S O W I N 5~6-OIHYORO-2-lp-CHLOROPHENIL~OLINE~

4231 N1

-

4232 N1

- 5,6-DIHYDRO-2-( ~1~2~4)TRIAZOLO~5~1-~lISOQUINOLINE~ 3-METHOXYPHENYL

RN

4233 N1 RN 4234 M1 4235 N1 4236 N1 RN

4237 N1

-

-

s - T R I A Z O L ~ ~ ~ ~ ~ - ~ ~ I S ~ Q U5,6-OIHYDRO-2-(p-METHOXYPHENYL)INOLINE~ 1-

55308-37-7

s-TRIAZOL0~5,1-alIS0QUINOLINE, 5,6-OIHYDRO-2-PHENYL55308-57-1 s-TRIAZOLO15s1-alISCQUINOLINE. 5,6-DIHYORO-2-p-TOLYLS-TRIAZOLOI5,I-a )ISOQUINOLINEB Z-(III-ETHOXYPHENYL 1~1~2~41TRIAZOLO~511-~11S0QUIN0L1NE~ 2-~3-ETHOXYPHENYLl-5~6-OIHYORO55308-64-0

- s-TRIAZOLO(5.1-0 IISOQUINOLINEn 2-(p-FLUOROPHENYL 1-

4240 N1

-

RN

-

3H-l,2,Q-TRIAZOL-3-ONE~ 2 B4-OINYDRO-2-(3-(4-Or-CHLOROPHENYL1-1-PIPERAZINYLIPROPYL 1-4~5OIETHYL-. HYDROCHLORIDE 57775-22-1

4241 N1

-

I-TRIAZOL~(~,~-~)PYRIDIN-~(~H)-ONE.

4238 N1 4239 N1 RN

I-TRIAZOLOI5,l-a )ISOQUINOLINE, 2-1111-METHOXYPHENY L 1-

s-TRIAZOL0~5,1-a)ISOQUINOLINE, 2-PHENYL35257-18-2

2-( 3-(4-1 ,)I-CHLOROPHENY L I-1-PIPERAZINYL1pROPYL 1-

RN

4242 N1 RN 4243 N1 RN

4244 N1 RN

4245 N1 4246 N1

- 19794-93-5 - r - T R I A Z O L O ~ l r S - ~ I P Y R I H I D I N E , NnN-DIETHYL-5-HETHYL- 15421-84-8 - 7H-v-TRIAZOL0(4~5-dIPYRIHIOIN-7-ONE~5-AMINO-lv6-DIHYDRO- 134-58-7 - 4H-s-TRIAZOLO(3,4-c ITHIENO(2,3-e I ( 1 ,4)-DIAZEPINE, ~-(o-CHLOROPHENYL)-~-ETHYL-~-HETHYL- 40054-69-1 - TRIAZOQUINONE - TRICHOTHEC-9-ENE-3-aIphs.4-b~ta,8-alpha,l5-TETROL~12.13-EPOXY-, 4.15-OIACETATE 8- ISOVALERATE

RN

4247 N1

- 21259-20-1

-

TRICHOTHEC-9-EN-8-ONEI 4-~ACETYLOXYl-12~13-EPOXY-317rl5-TRIHYOROXY-~

RN

4248 N1 RN 4249 N1 RN 4250 N1 4251 N1 RN

(3-alpha.4-beta,7-betal- 23255-69-8 - TRICHOTHEC-9-EN-8-ONE~ 12,13-EPOXY-3,7~15-TRIHYOROXY-~ I 3-slpha97-alpha 1- 51481-10-8

-

TRICOSANTHIN 60318-52-7 2,6-TRIDECADIENOIC ACID, 3~11-DIMETHYL-10111-EPOXY-7-ETHYL-~ flETHYL ESTER

-- TRIETHYLAMINE 121-44-8

212 4252

Nl RN

4253

Nl RN

4254

Nl RN

4255

N1 RN

4256

N1

RN 4257

N1

4258

W N1 RN

4259

N1

--

TRIETHYLAPIINEo ~ - ( ~ - ( ~ - ( B E N C I L O X T J - ( I ~ ~ ~ ~ - ~ ~ Y L S ~ Y L ) P H E ~ ~ - I HYDROCHLORIDE 15624-29-0 TRIETHYLMINE~~ - ~ ~ - ~ ~ - ~ B E N Z Y L O X I ) - ~ ~ ~ ~ - M E ~ Y L S T Y R Y L J P H E ~ ~ - I HYDROCHLORIDE 15624-28-9 TRIETHYLAPIINEi 2-lp-ll.2-BIS(p-PIETHDXT~ENTL)-l-BUTENYL)PHE~YJ~ 33406-36-9

- TRIETHYLAMINEs 2-( p-( 1 2-BIS(p-PIETnOXYPHENY L1-1-BUTENYL lPHENOXl1-

-

s

9

CITRATE

42920-39-6

- TRIETHYLMINE, 2-tp-t 1,Z-BIS(p-PIETHOXYPHENY L)-l-BUTENYL )PHENOXTI-r

--

-

HYDROCHLORIDE, ( E l 35258-12-9 TRIETHYLMINEI 2-tp-t 1,t-BIS(p-PIEl'HOXYPHENY L )-l-BUTENYLIPHENOXY 1-1 HYOROCHLORIDEI ( 2 ) 42824-35-1 TRIETHYLAMINEr 2-tp-f 1rZ-BJS(p-HETHOXYPHENYL 1*3-PIETHYL-l-BUTENYL JPHENOXY 133406-37-0 TRIETHYUHINEi

2-~p-~1~Z~BISfp-HETHOXYPHENYLl~5~PIEMYL-1~BUTENYL~PHENOXYI-~ HYDROCHLORIDE

4260

N1 RN

RN

- TRXETHYLAI~INEI

Nl

4265

HI RN

4266

N1 RN

4267 N1 RN 4268

N1 RN

4269

N1

4270

AN N1

2-(p-( 1,Z-BIS(p-METHOXYPHENYL 1-1-PROPENYL JPHEWXY I-. CITRATE - 42824-33-9

( 1:11

- 2041-74-9 - TRIETHYLAHINEv 2-~p-fbcta-BRMlo-p-HETHOXY-slphr-PHENYLSTYRYLl-2~6-DIHETHYLPHENOX-

----

Y )TRIETHYLAPIINE~ P-~p-f2-CHLORO-l~2-DlRIEHTLVINTLlPHENOXYl911-45-5 TRIETHYLAMINE, 2-(p-( 2-CHLORO-li2-DIRIENYLVINYLJWE~XY 15690-57-0

1-9

(El-

TRIEMFLAMINEs 2-(p-(2-CHLORO-l~2-DIPHENYLVINYLJPHENOXY 15690-55-8

I-,

(21-

TRIETHYLAMINEe 2 4 p - t 2-CHLORO-l,Z-DIRIENYLVINYL)WENM(Yl-,

(1:1I - CITRATE 50-41-9

-

TRIETHYLAPIINEn t-~p-f2-CHL~O-l~2-DIPHENYLVINYLlPHENOXY~-r

E 1-- CITRATE 7599-79-3 TRIETHYLAMINE, I

RN 4271

I

N1 RN

4264

HYDROCHLORIDE 42824-26-0 ,

N1 RN

4263

-

- TRIETHYLAMINEt 2-lp-( l-(BISfp-HETHOXVPHENYL )PIETHYLENEJPROPYL JPHENOXY 1HYOROCHLORIDE - 42824-39-5

4261 N1

4262

- TRIETHYLAHINEI 2-fp-~l~2-BIS~p-HETHOXYPHEN~Ll-3-HETHYLBUTYLl~EWXYl-~

NI

(

2-(p-(2-CHLORO-l~2-DIPHENYLVINTL)PHENOXY I - r

- 2-(p-(3-1p-CHLOROPHENYL)-3i4-0IHYORO-2H-l-BENLOPYRAN~4~YLIPIIENOXYCITRATE ( 1 : l J ~ fZJ7619-53-6 TRIETHYLIPIINEi 1-

4272

N1

- TRIETHYLAMINEi 2-~p-~~-~p-CHLMIOPHENIL~-6-MEnlOXY-lr2~3r4-TETRA~YDRO-l-NAPHlHYL~PHENOXYI-I HYDRDCHLORIOE

213 4273

N1

-

TRIETHYLAHINE, 2-( p-( 2-( p-CHLOROPHENYL 1-2-HETHY L-19 2 I 314-TETR*HYDRO-l-NAPTHYL HENOXY I - , HYDROCHLORIDE

1P-

4274

N1

-

4275

Nl

- TRIETHYLAHINE, 2-~p-~2-~p-CHLORDPHENYLI-1~2~3r4-TETR*HYDRO-l-NAPH~YL)PHENOXY)-~

TRIETHYLAHINE. 2-(p-(6-(p-CHLOROPHENYL)-6r7,8~9-TETR*HYDRO-SH-BE~~YCL~EPTEN-S- Y L V PHENOXY 1 - e C I T R A T E i HEHIHYDRATE

IE)4276

N1

-

4277

N1

- TRIETHYLAHINE, 2-lp-(2-CYCLOHEXYL-l~2,3~4-TETR*HYDRD-l-NAPHTHYLlPHENOXYl-~

TRIETHYLAHINE, 2-~p-~2-~p-CHLOROPHENYLl-lrZ,5~4-TETRAHYDRO-l-NAPHTHYL~PHENYL~-~ (21-

CITRATE 4278

N1

-

4279

N1

- TRIETHYLAHINE, 23 4-DIHYDRO-6-HETHOXY-2-PHENY

TRIETHYLAHINEI 2-~p-~2-~3r4-DICHLOROPHENYL~-l~2~3~4-TETR*HYDRO-l-~PHTHYL~PHENOXY I - , HYDROCHLORIDE ( p- (

RN

4280 N1 4281

N1

4262

N1

-

B

L-1-NAPHTHY L )PHENOXY 1-

HYDROCHLORIDE 1178-99-0 TRIETNYLAHINEI HYDROCHLORIDE

- TRIETHYLAHINE, HYDROCHLORIDE - TRIETHYLAHINEi

Z-(p-(5~6-DIHETHOXY~2-~ENYL-Z-I"TL)PHENO~)-~ 2-~p-(5~6-DIMETHOXY-2-~ENYL-3-INDENYLl~ENOXYl-~

2,2"'-~(1~2-DIHETHYLETHYLENE)BIS~p-PHENYLENEOXY)lBIS-~

1- DIHYDROCHLORIDE, 15542-20-8 - TRIETHYLAHINE, 2,2"'-((1.2-DIMETHYLETHYLENE)BIS(p-PHENYLENEOXY1)BIS-, (+-

RN 4283

N1 RN

4284 N1

4285

-

DIHYDROCHLORIDE, 15515-40-9

meso-

- TRIETHYLAHINE, Z-(p-(alphs.beta-DIHETHYL-p-HETHOXYPHEHEY)-, HYDROCHLORIDE, 15623-99-1

threo-

RN

-

N1

- TRIETHYLAMINEv 2-(p-~2~2-DIHETHYL-7-HETHOXY-3-PHENYL-2H-l-BENZOPYRAN-4-YLl~ENOX-

RN

-

4286

N1

4287

N1

4288

N1

RN

I )-, 'HYDROCHLORIDE 57897-48-0

- T2-(2,6-DIHETHYL-4-(p-HETHOXY-slphs-~ENYLSTYRYLIPHEEEOXY)RIETHYLAHINE~ - TRIETHYLAMINE, 2-(p-(slphs,beta-DIHETHYL-p-HETHOXYSTYRYLlPHENOXYl-, HYDROCHLORIDE -

15542-03-7

- TRIETHYLAHINEI (DIMETHYLVINYLENE lBIS(p-PHENYLENEOXY) I B I S - r - 2e2" 15542-01-5 -- 54756-55-7 TRIETHYLAHINE, Z-(p-(Zr4-DIPHENYL-3-FURYL)PnEIJOXI)-- TRIETHYLAHINEv 2-(p-(3,4-DIPHENYL-2-FURYL)PHENOXY)54756-53-5 '-(

RN 4289

N1 RN

4290

N1 RN

4291 N 1

-

TRIETHYLAHINE. 2-tp-t

(El-

ISTYRYL IPHENOXY I-

RN

be ts-ETHYL-dpha-(p-HETHOXYPHENYL - 35258-20-9

4292

N1 RN

-

4293

N1

- TRIETHYLAHINE, ~-~~-~~-~O-FLWROPHENYL~-~~~~~~~-TETRU(YDRO-~-NAPHTHYLIPHE~XY~-~

TRIETHYLAHINE, 749-86-0

CITRATE

2-(p-(b.ta-ETHYL-nlph.-PHENYLSTYRYL)PHEN)-

214 4294 Nl

- TRIETHYLAHINE,

2-lp-lp-HETHOXY-mlpha~be~a-OIHETHYLPHENETHYL~PHENOXYl-, HYOROCHLORIOE, erythra-

RN

4295 N1

- 15515-39-6 - TRIEMYLAHINE~

2-lp-l6-HETHOXY-2-lp-HETHOXYPHENYLl~2-IWENYLlPHENOXYl~~ HYDRIOOIOE

4296 N1

- TRIETHYLANINEB 2-(p-(6-NETHOXY-Z-(p-HE~OXYPENYL)-3-INDENYL)PHE~XI)-t

4297 N1

- CITRATE TRIETHYLAHINEI

HYORIOOIDE

RN

4298 N 1 RN

4299 N1 RN

4300 N1 RN

4301 N1 RN

4302 N1 4303 N1

4304 Nl 4305 N1

4306

Nl RN

4307 N1 RN

4308 N1 4309 N1 4310 Nl RN

4311 N1 RN

4312 Nl RN

4313 N1 RN

4314 N1 RN

-

15624-34-7

- TRIETHYLAHINE, HYDROCHLORIDE

-

2-lp-~p-HETHOXY-beta-HETHYLPHENETHYLlPHLNOXIl-~

15624-33-6

- TRIETHYLANINEr HYOROCHLORIOE

-

2-lp-lp-HETHOXY-alpha-HETHYLPHENETHYLlPHE~XYl-~

2-Ip-lp-HETHOXY-alpha-WETHYLSTYRYLlPHENOXY)-~

15624-27-8 TRIETHYLMINE, 2-~p-lp-NETHOXY-betm-HETHYLSTYRYLlPHENOXY I - ,

OROCHLOR IDE - HY15624-26-7

-

TRIETHYLAHINEI Z - ( p - ( 6 - H E T H O X Y - 2 - P E ~ L - S - B E N Z O F U R A N T L E ~ X Y ) ~ ~

- HYDROCHLORIDE 1509-14-4

-

-

TRIETHYLAHINE. 2-l~-~6-NETHOXY-2-PHENYL-3~4-DIHYORO-I-NAPHTHYLlPHE~l~ TRIETHYLANINE~ 2-lp-t ~-HETHOXI-L-PHENYL-~I~-OIHYDRO-~-NAPHTHYL IPHENOXI )-s HYOROCHLORIOE TRIETHYLANINEn HYDROCHLORIDE

2-lp-l2-~p-HETHOXYPHENYLt-3-INDENTLlPHENO)(I~~~

TRIETHY LAHINE I 2-fp-f 5-HETHOXY-Z-PHENIL-3-IM)ENY HYDROCHLORIDE

LIPHENOXI 1 - s

TRIETHYLAHINE, 2 - ( P - 1 6 - ~ E T H O X Y - 2 - P H E N Y L I N D E N O m l - ~ HYDROCHLORIOE

- 64-96-0

--

TRIETHYLAHINE,

~-I~-~~-HETHOXY-~~~~~-~WENYLPHENETHYLIPHENOXYI-

6732-77-0 TRIETHYLAHINE, 2-(p-fp-HETHOXY-~lph~-PHENILfflENE~ILtPHEW)(rl-, CITRATE TRIETHYLMINE. 2-lp-(p-HETHOXY-alphm-~ENYLPHENETHYL)PHENOXY)-. HYDROCHLORIDE

- TRIETHYLANINE, - 2-(p-~~-~p-HEIHOXYPHEHTL)-l~PHENIL-I-BUTEMLlPHENOXY)35258-oe-3

-

TRI~THILMINEI 2-~p~l2~l~-HETHOXYPENILl~l~PHENYL-l-~UTENILlPH CITRATE E~XY~-~

11:l) - 42824-34-0 - TRIETHYLAHINE, 2-lp-~1-~lp-HETHOXYPHENYL~PHENI~ETHY~ENElPROPILlPHENOXYl-~ HYOROCHLORIDE - 42824-38-4 - TRICTHYLAHLNE~ 2 - ~ p ~ ~ 1 - ~ p ~ H E T H O X Y ~ E N I L l ~ 2 ~ ~ E N Y L P R O P t NCITRATE rL)PHEI~~~

-

13554-24-0

- CITRATE, TRIETHYLAHINE, 2-lp-lmlphm-lp-HETHOXYPHE~L~STYRILlPHENO)(rl-, - 13542-73-7NONOHYDRATE

215 4315

N1

-

4316

N1

-

4317

N1

4318

N1

TRIETHYLAMINE, 2-lp-~2-~p-HETHOXYPnENYLI-l~2~3~4-TETRAHYDRO-l-NAPHTHYL~PHENOXYl-, CITRATE, MONOHYDRATE TRIETHYLAHINE~ 2 - l p - l 6 - M E T H O X Y - 2 - P H E N Y L - l ~ 2 ~ 3 ~ 4 - T E T R I H Y X Y l - ~ HYORMHLORIDE, ( E 1-

4319

N1

4320

N1

-

4321

N1

- TRIETHYLAHINE.

4322

N1

RN

RH

4323

N1

4324

N1

4325

4326

4327

N1

-

RN

-

N1

N1 RN

4329

N1 RN

4330

N1 RN

4331

N1 RN

4332

N1 AN

4333

N1

TRIETHYLAMINE, 2 ~ 2 " ' - ~ ~ H E T H Y L V I N Y L E N E I B I S ~ p - ~ P H E N Y L E N E D X Y ~ l B I S - r DIHYOROCHLORIDE 15624-30-3 TRIETHYLAMINEi

2-(p-~2-NITRO-1~2-DIPHENYLVINYL)PHENOXYI-rCITRATE

TRIETHYLAMINE, HYDROCHLORIDE

2-lp-(2-PHENYL-3,4-DIHYDRO-l-NA?HTHYLlPHENOXY

2-(p-(2-PHENYLINDEN-3-YLIPE~XYI-,

2-lp-(2-PHENYLNAPHTHO(2,1-b)FURAN-1-YL)PHENOXYl-,

TRIETHYLAHINE,

2-(p-lalpha-PHENYLSTYRYL)PHENOXY)-,

-

-

-

TRIETHYLAHINE, 2-1 p-1 1 $ 2> 3,4-TETRAHYORO-Z-(p-CHLOROPHENYL 13073-86-4 TRIETHYLAHINE,

ZrZ',Z"-TRICHLORO-,

TRIETHYLENE GLYCOL 112-27-6 TRIETHYLENETETRAHINE 112-24-3 TRIOCTANOIN 538-23-8

- S-TRIOXANE, 7580-12-3

2,4,6-TRIISOPRDPYL-

RN 4337

N1

-

4338

N1

-

N1 RN

4336

RN

4339

N1 RN

TRISILOXANE,

1,1-DIR(ENIL-1,3r3~5.5-PENTAHETHYL-

l-alpha-H,5-alpha-H-TROPANE-2-beta-CARBOXYLIC ACID. 3-beta-HYDROXY-, 53-21-4

METHYL ESTER,

BENZOATE ( e s t e r ) ,

l-alpha-H15-alpha-H-TROPANIUPI, 8-~p-BUTOXYBENZYLl-3-.lph.-HYDRDXY-~ 29025-14-7

BROMIDE,

HYDROCHLORIDE

I-)-TRDPATE

l-alpha-H15-olpha-H-TROPANIW,

BROMIDE.

( -')-TROPATE

l-alpha-H,5-olpha-H-TROPANIUPI, 8-CARBOXY-3-HYDROXY-8-HEWYL-r PHENY L ESTER t CARBAZATE ( e s t e r I l-alphd-H.5-alpha-H-TROPANIWs 6-beta.7-beta-EPOXY-3-alpha-HYDRDXY-8-HETHYL-~ ( - )-TROPATE 18067-13-5

- BROMIDE, l-alpha-H,5-elpha-H-TRDPANIW, (+-)-TRDPATE -

INAPHTHYL IPHENDXY 1 -

HYDROCHLORIDE

- B-BUTYL-6-beta.7-bcta-EPDXY-3-Plpha-HYDRDXY-, 149-64-4

4335

(21-

817-09-4

N1

N1 RN

IPHENOXY I - ,

(El-

TRIETHYLAHINE, 2 ~ 2 " ' - l P R O P Y L E N E B I S ~ p - P H E N Y L E N E O X Y l l B I S - ~ DIHYDROCHLORIDE 15624-39-2

-

4334

CITRATE

TRIETHYLAMINEt 2-(p-(2-PHENYL-1~2,3~4-TETRAHYDRO-l-NAPHWYL)PHE~XYl-~

,3.4-TETRAHYDRO-l-NAPHTHYL

I-,

CHLDRATE

TRIETHYLAHINE, HYOROCH LOR I D E 25433-83-4

- TRIETHYLAHINE, 2 - l p - ( 2-PHENYL-1,2

N1

RN

4328

-

TRIETHYLAMINEs 2 - ( p - ( 6 - H E T H O X Y - E - ( p - T O L Y L ) - 3 - 1 ~ E N Y L I P H E N O X Y ) - ~ HYDROCHLORIDE

22254-24-6

METHYL SULFATE,

3-alpha-HYDROXY-8-ISDPRDPYL-,

216 4340 N1

- BRMlIOE l-elpha-Hr5-.lph~-H-TROPANIUnr 3-dpha-HYOROXV-8-ISPROPYL-r 1-TROPATE HYDRATE - l-alph~-Hr5-alph~-H-TROPM-3-elphr-OL, 6-betm~7-beta-EPOXY-. - bTROPATE estar I HYOROBROtlIOE e ( 4-

4341 N1

- 114-49-8

(

(

RN

4342 N1 RN

4343 N1 RN

4344 N1 RN

4345 N1 RN

s

-- TRYPSIN IHIIBITOR. PANCREATIC BASIC 9087-70-1 -- 54-12-6 TRYPTOPHAN, OL-- TRYPTOPHAN, L73-22-3 N-ACLTYL-r L-- TRYPTOPHANI 1218-34-4

4348 N1 RN

-- TRYPTOPHAN) 5-HYOROXV56-69-9 -- TRYPTOPHAN, 5-HYDROXI-, DL114-03-4 -- TRYPTOPHANi 5-HY0ROXY-t 4350-09-8

4349 N1 RN

-- TUNGSTEN 7440-33-7

4346 N1

RN 4347 N1 RN

4350 NX RN

4351 NI

RN 4352 N1

RN 4353 N1 RN

4354 Nl RN 4355 N1 RN 4356 N1

RN 4357 N1 RN 4368 Nl

IN 4359

N1

L-

-- TVNGSTIC ACID, SODIUM SALTS OIHVDRITE 53125-86-3 -- TUNICACIYCIN 11089-65-9 -- 60-18-4 TYROSINE, L-- 775-06-4 OL-- 51-46-9 L-TYROSINE. 0 - ~ 4 - H ~ D R O X Y ~ 3 ~ 5 - D I I O D O P n E N V ~ ~ ~ 3 ~ 5 ~ 0 1 1 ~ 0 ~ -- 66-22-8 URACIL -- URACIL. l-betA-D-ARABIWlRAWSVL3083-77-0 m-TYROSINE,

BENZVLTHIO-- URACIL, 33086-27-0 -- URACILv 314-40-9 - URACIL, I,~-OICIETHYL-~-~

~-BR~-~-~.c-BUTIL-~-~LM~L-

3-~4-~~~H€~~YPn€NYCl-2-PIPERAZIMYL~PROPPYUI(INO-

- 34661-75-1 -- URACILv 5-FLWRO51-21-8 - URACILI 5-FLUORO-l-(TEIRAHYDRO-1-FURVL)-- URACIL, 5-FLVORO-l-(TETRAHYORO-2-~URYL 117902-23-7 - URACIL, 5-FLUORO-l-~TEIRANYORO-~-FURVL)- m l w t . -- URACIL, 5-~NVOROXT~E~VLl~6~HETHYL~ 147-62-1 )-

RN 4360

N1 RN

4363

HI

4362 NI RN

4365 Nl 4364 Nl RN 4365

N1

4366 N1 RN

- URACIL, 5-IODO-2-THIO-- URACIL, 6-HETHYL626-48-1

uith W M I L (114)

217 4367

N1 RN

4368 N1

RN 4369

N1

4370 N1

RN 4371

N1 RN

4372

N1 RN

4373 N1 RN 4374

N1

4375 N1 RN 4376

N1 RN

4377

N1

RN 4378

N1 RN

4379

N1 RN

4380

N1 RN

4381

N1

4382

N1 RN

4383

N1 RN

4384

N1 RN

4385

N1 RN

4366 N1 RN 4387

N1 RN

4386 N1 RN

4390 N 1 RN 4391 4392 4393

N1 RN N I RN N1 RN

-- URACIL, 6-METHYL-2-THIO56-04-2 -- URACILI b-PROPYL-2-TnIO51-52-5 - URACILs 6-PROPYL-2-THIO-e m d IODINE -- URACILt Z-THIO141-90-2 -- URANIWr BIS(NITRAT0-0.0' )OIOXO-r (OC-6-11136478-76-9 -- UREA 57-13-6 -- UREA. 1-~~p-ACETYLRIENYL~SULFONYLl-3-CYCLOnEXYL~ 968-81-0 - UREA, ADIPIC ACID mixed with CARBOXYHETHYLCELLULOSE ACIDS 1-AHIDIHO-3- (p-NITROPHENYL HONOHYDROCHLWIDE -- UREA 51-58-1 - UREA, 3-~~4-AHINO-2-METHYL-5-PYRIMIDINYLlMETHYL~-l-~2-CHLOROETHYLl-1-NITROSO- MONOHYDROCHLOR IDE - 55661-38-6 9

-

)-

I

UREA, 1-(2-8EI(ZIHIOAZOLYLl-S-METHYL-

21035-25-4

-- UREA. lr~~BIS~2~CNLOROETHYLI-l-NITROSO154-93-8 1-8UTYL-3~3-DIHETHYL-l-NITROSO-- UREA, 56654-53-6 -- UREA, 1-BUTYL-I-NITROSO869-01-2

----

UREA. BUTYL- and SOOIW NITRITE ( 2 : l l UREA, 1-BUTYL-3-SULFANILYL-

339-43-5 WEA. l-BUtYL-3-~p-TOLYLtULFONYLl64-77-7

UREA, l-BUlYL-3-(p-~LYLSULFONYLl-, 473-41-6

SODIW SALT

- UREA, 1-( -

( p-( 2-( CHLORO-0-AHISAMID0 )ETHYL IPHENYLISULFONYL I-3-CYCLOHEXY L10238-21-8

-- UREA. 1-( 2-CHLOROETHYL 1-3-CYCLOHEXYL-1-NITRDM13010-47-4

---

UREA, 3 - ~ p - C H L W O ~ E N Y L ) - l ~ l - D I H E T H Y L 150-68-5 UREA. J-~p-CHLOROPHENYLl-l-METHOXY-1-HETHYL1746-81-2

-- UREA. l-((~-CHLOROPHENYLlSULFONYLI-S-ISOPROPYL2281-78-9 -- UREA, l-((p-CHLOROPHENYLl!NLFONYLI-S-PROPYL94-20-2 -- UREA. S-I~-C~LORO-P-~L'IL)-I.~-DI~ETHYL15545-48-9 - WEA. l-CYCLOHEXYL-3-( (p-( 2-( 5 - n E T H y L - 3 - I t O X * Z O L E C A R ~ m O IETHY L )WENYLISULFONYLI- 24477-37-0

4395 N1 RN

-- 565-33-3 -- 664-95-9

4396 Nl RN

3-(3r4-DICHLOROPHENYL 1-1 rl-DIMETHYL-- UREA, 330-54-1

4394 N1 RN

4397 N1 RN 4398 Nl RN 4399 N1 4400

N1 RN

4401 N1 RN 4402 N1 RN

4403 N1 RN

4404 N1 4405

N1

4406 N1 RN

4407 N1

UREA, l-CYCLOHEXYL-3-(4-WETHVLWETINILYL UREAi l-CrCU)HEXYL-3-(p-fOLYLSUL~~YLl-

- MALEATE UREA, ~ - ~ ~ I ~ ~ - ~ ~ D E H V D R O - ~ - V E ~ H V L E R G O L I N - ~ - ~ ~ ~ ~ ~ - Y L ~ - ~ I ~ - O I E T H V L - , (1:lI

- 19875-60-6 -- 96-31-1lr3-OIMETHVLUREA.

- HYDRATE UREA, l ~ l ~ O I ~ E T H Y L ~ 3 ~ ~ 5 ~ M E ~ V L - ~ ~ B E N Z I VHYDROCHLORIDE, IOAZOLVL~-~

-- 13256-32-1 1~3-DIHETHVL~l-NITROSO-- UREA. ln3-DIflETHYL-2-THIO534-15-4 UREA,

-- UREA. ETHYL625-5L-5

-- 759-73-91-ETHYL-1-NITROSO- UREAI ETHYL- and NITRITE (1:lI UREA,

SOOIUn

-

UREA, ETHYL- and SOOIUfl NITRITE 12:ll

-- UREA. 1-ETHYL-2-THIO625-53-6

- VREAv 1-(HEXAHVOROCYCLOPENTAI - 21187-98-4 - UREA, HVOROXY- 127-07-1

C

RN 4408

N1 RN

J-

IPYRROL-Z( 1H I-YL I-3-tp-TOLYLSULFMJVL )-

4409 N1 RN

-- UREAL, I-~~-HVOROXV-~-BORNYLI-~-(~-TOLYLSULFONVLI-I llR12R,S5,4Sl26944-48-9

4410 N1 RN

-

UREA, 1-(2-HYDROXYETHYLI-l-NITROSO13743-07-2

4412 N1

- UREA, ISOPROPYL- and SODIUM NITRITE (2:11 - UREA, ~METHYLETHANEDIYLIOENElBIS~HYDRALIHOFOR~IVIDOYL-2-THIO-

4413 N1

-

4411 N1

4414

N1 RN

4415

N1

RN 4416

N1 RN

$417 N1 4418 N1 AN

4419 N1 4420 N1 RN 4421

N1

RN 4422 N1 RN

UREA; METHYL and SOOIUn NITRITE ( 1 : 2 1

R E A , l-METHYL-2-THIO-- U598-52-7 -- UREA, N-NITROSO-N-PROPYL016-57-9 3-HITROSO-1~1~3-TRIETHYL~ -- UREA, 50205-70-6

- UREA, -(PHENYLACETYLI-

1-(3-OXO-1,4-ANDROSTADIEN-17-beta-VLI-

UREA,

63-98-9

- UREA, (1:31

(2-PHENYLBUTYRVLI-Im d 5-ETHYL-3-METHYL-5-PHENYLNYDANTOIN

-- UREA, l-PnENYL-3-(1~2rS-THIADIAZOL-5-YLI~ 51707-55-2 -- UREA, 1-PHENVL-2-THIO103-85-5 SULFANILVL-- UREA, 547-44-4

219 4423

Nl RN

4424

N1 RN

4425

N1 RN

4426

N1 RN

4427

N1 RN

4428

N1 RN

4429

N1 RN

1,1,3,3-TETRAMETHYL-- 6UREA, 32-22-4 -- UREA, II~~~,~-TETRIHETHYL-~-THIO2782-91-4 -- UREA, 2-THIO62-56-6 -- UREA. Irlr3-tRI~THYL-3-WITROM3475-63-6 -- U1198-77-2 R I C ACID, SALT -- U5 9R-I1D4I-N3E i 5-BROMI-2'4EOXY-- URIOINEI 2'-DEOXY-5-FLUMIO50-91-9 -- URIOINE, 2'-DEOXY-5-100054-42-2 W(.(OSOOIIM

4430

N1 RN

4431

N1

-

4432

N1 RN

-- VALERAMIOE. 4171-13-5

4433

N1

-

4434

N1 RN

VACCARIA PYRAMIOATA M e r l k , c r u d e e x t r a c t 2-EllIYL-3-METHYL-

VALERIC ACID, 4-AMINO-5-l1~3-DIOXO-2-ISOINDOLINYLI-5-OXO-

4436

N1 RN

ACID, 2 ~ 2 - O I M E T H Y L - 5 - 1 2 ~ 5 - X Y L Y L O X Y l -- VALERIC 25812-30-0 - HYOROCHLORIOE VALERIC ACID, 2.2-DIPHENYL-. 2-lDIElHYLAIfIHOlETHYL - 62-68-0 -- VALERIC ACID, 2-PROPYL99-66-1

4437

N1

-

4435 N1 RN

4438 N1 RN 4439

N1

4440

Nl

4441

N1

RN

RN

-

Nl

-

4443

N1

-

4444

N1 RN

4445

N1 RN

4446

N1

-1SOPROPYL-, 152-11-4

4447

N1 RN

C A L C I W SALT 1 2 : l )

tlOIlOHYDROCHLORIOE

VALERONITRILEI

4.5-EPITHIO-

VALEROPHENONEp 3-(p-CHLOROPHENYL)-4'-HYDROXY-4-nE~YL-2-PHE~L-. e r y t hro31365-02-3

3-lp-CHLOROPHENYL)-2-lp-HYOROXYPiiENYLl-, erythro-- VALEROPHENONE, 31365-03-4 -- VALEROPHENONE. arythro31365-01-2 - VALEROPHENONE, 3-(p-CHLOROPHENYL I-4-METHYL-2-PHENIL-4 ' - 1 2-( 1-PYRROLIOINYL IETHOXY- 3 1 3 0 1er-ythro-21-0 - VALEROPHENONE, 3-lp-CHLOROPHENYLI-2-PHENrL-4'-~2-ll-PYRWLIDINYL~ETHOXY~-~ )-,

RN

2-PROPYL-.

-- VALERIC At101 2-PROWL-r SODIUM SALT 1069-66-5 -- 65-14-5 VALERONITRILE, 2,3-BISlp-HYOROXYPHENYL)- VALERONITRILE. 2-13~4-DIHYDROXYPHENYL~~3~l~-HYDROXYWENYLl-2-METHYL- VALERONITRILEv 5-113~4-DIMETHOXYPHENETHYLIMETHYLAMINO~-2~l3~4-OIMETHOXYPHENYL~-2-

4442

RN

VALERIC ACID.

ESTER,

-

erythro31301-19-6

4448 N1

'RN 4949

Nl RN

4450

N1

RN 4451 N1 RN 4452

N1 RN

4453

N1 RN

--

VALEROPHEMNEs 3-1 p-CHLOROWENYL~~2-Ip-12-Il-PYRROLIDINYL)ElliOXV )WENVL I-, c r y thro-

31301-22-1 VALEROWENONE, 31301-23-2

OI~-DIPHENYL-~'-HVOROX~-,arythro-

VALEROWENONE, ~ I ~ - O I P H E N ~ L - ~ ' ~ ( ~ - ( ~ - P I R R O L I O I N Y L ) E I H O X V ~ - ~ ary thro31301-18-5 VALEROPHENONEi 3-l~-METHOXYPHENYL~~2~PHENYL~4'~I~~(l~PYRROLIDINYL~ETHOXY)-~ eryfhro33249-16-0 L-VALINAHIDE, N I W p 2 )-II (l-CARBOXY-2-PHENYLETNYL )AHINOlCARBOmLI-L-ARGINYL-N-(4( 1 AHINOIMINOHETNVL)AMINO )-l-FORHYlBUTVL )37691-11-5 VALINE. N - ~ N - A C E T Y L ~ S - ~ ~ ~ ~ B I S ~ ~ - C H L O R O E T H Y L ~ A H I N O ~ P H E N Y LE~MAY~LH T L ~ - I ESTER 13425-94-0

-- VALINE, 52-61-5

3-HERCAPTO-I

4454

Nl RN

4455

N1 RN

4456

N1 RN

4457

N1 RN

4458

N1 RN

- 1314-62-1 -- VANILLIN 121-33-5 -- VASOPRESSIN, 50-57-7

4459

N1

-

D-

- VANADIC ACID, A#DNIWi SALT - 7803-55-6 - VANAOIUM PENTOXIOE (dust

B-L-LYSINE-

VESETABLE ISOYBEAN) OIL, brorninated

4466

N1

- VENDHr SCORPIONI AMROCTONUS AMOREUXI - VENOM, SNAKE, NAJA NIGRICOLLIS - VENOM. SNAKE, VIPERA ASPIS - VERATRAMANIUH, 17~23-EPOXY~3~HYDROXY~28~~8-DIMETNYL-ll-OXO-~ IODIDE, (3-beta,tS-betel- 66409-99-2 - VERATRAHINE - 60-70-8 -- VERATRINE 8051-02-3 - VLRATRW CALIFORNICW

4467

Nl RN

-

4468

N1

4460

N1

4461

Nl

4462

N1

4463

N1 RN

4464

4465

N1 RN N1 RN

4469

N1

4470

N1

4471 N1 RN 4472

N1 RN

4473

N1 RN

4474

N1 RN

VERATRYLAMINE 5763-61-1

- VERBENA BONARIENSIS Llnn.. - VICOA IhUICA WiIld. D.C. - VIDR-ZGO -- 865-21-4 VINCALEUKOBLASTINE

----

extract

VINCALEUKOBLASTINE, SULFATE 1181) (SALT1 143-67-9 VINYLAIIINEI N-ETHYL-N-NITROSO13256-13-8 VINYLIOENE CHLORIDE 75-35-4

(inhibited)

221 4475

N1 RN

4476

N1

RN 4477

N1

4478

N1

4479

N1

IN

4480 N1 RN

4481 N1 4482 N1 4483

N1

4484 N1 4485 N l 4486

N1

RN 4487 4488

N1 RH

N1 RN

4489

N1 RN

4490

N1 RN

4491

N1

4492

N1

4493

Nl

44%

Nl

4495

N1

RN

RN RN

-- V52988-10-4 IamCIN

--

VITAMIN K 12001-79-5

-

XANTMINEr lr8-OIMETHYL-3-PHENYL-

- VITEX N E G W U L i m a , reed W t r p C t -- 8018-01-7 WNOOLEB - WATAPANA SHIM#!M( -- WATERI HEAVY (02-01 7789-20-0 - WELDING FlME PARTICLES - WEAT. e x t r a c t - WITHANIA SOWIFERA, r o o t s - UOWFOROIA FRUTICOSA Kurz. flwer e x t r a c t -- XANTHINE. 3-HYDROXY13479-29-3 -- XYLENE 1330-20-7 -- ni-XYLENE 108-38-5 -- o-XYLENE 95-47-6

- p-XYLENE - 106-42-3 - m-XYLENEt

5-CHLORO-

- ni-XY LENE-alpha alpha ' -DIOL, ~Ipha'-~~tert-BUTYLAMINO~HETHYL~-4-HYOROXYI

- 16559-94-9 - m-XYLENE. aIpha.al~ha,~lpha.alpha'~alpha'~alpha'-HEXleHLaRO- 881-99-2 - p-XYLENE. alpha.~lpharalph~~alpha'~alph~'~alpha'-HEXACHLORO- 68-36-0 - I-bcta,2O-alpha-YOHIH6AN-16-beta-CAR6OXYLIC ACID, 10-CHLORO-18-bet~-HYOROXY-l7-alpha- WTHOXY-t METHYL ESTER,

4496

RN

. 4 ~ 5 - T R I ~ E T ~ X Y B E N Z O A T E( e s t e r ) - 37008-24-4

N1

-

RN 4497

N1

RN 4498

N1 RN

4499

Nl

RN

~ - ~ E ~ ~ ~ Z O - ~ ~ ~ ~ ~ - Y O H I ~ A N - ~ ~ - CACID, ~T~-CARBOXYLIC 1-1 2-IOIETHYLAMINO )ETHYL)-18-beta-HYOROXY11~17-alphA-01METHOXY-~ METHYL ESTER. 3~4r5-TRInElt4OXYBEHLO*TE fester I 53-18-9

- 3-bcta.20-alpha-YOHINBAN-16-beta-CARI)OXYLIC ACID, I- f 2- IDIETHY LAMINO I ETHYL I - 18-be t a-HYDROXY-

l l ~ l 7 - a l p h ~ - O I M € T H O X Y - , METHYL ESTER, 3 , 4 , 5 - T R I M E l H O X r B E H T ~ ( e s t e r ) , TARTRATE 1111-44-0

- 3-beta,20-al~ha-YOHI~~-l6-be~~-CAR~OXYllC ACID, 18-bata-HYOROXY-ll~17-alpha-~IMETHOXY-~ = M E M Y L ESTER.

- wlth 4-HYOROXY-3~5-DIMETHOXYBENZOIC

ESTER ACID ETHYL CARBONATE

84-36-6

- 18-bets-HYDROXY-ll~I7-alpha-DIMETHOXY-~ ~ - ~ R ~ ~ , Z O - ~ ~ D ~ ~ - Y O H I ~ ( B I N - I ~ - ~ ~ ~M~X- OC. U I B O K Y L I C METHYL ESTERS 3,415-

-

50-55-5

222 4500

Nl

- I8-bcTo-HYOROXY-ll.17-clpha-OIHETHOXV- 3-betarZO-alpha-YUiI~AN-16-beta-CARBOXYLIC

RN

-

Nl RN

4501

4502

N1

RN 4503

N1 RN

4504

NX RN

4505

N1 RN

4506

N1 RN

4507

N1 RN

4500

N1 RN

3-betar20-alpha-YOHIflF3AN-16-beta-CARBOXYLIC ACID, nETHVL ESTER l e s t e r l , PHOSPHATE

3,4,5-TRInETnOXVBENATE 1263-94-1

---

ACIO. 18-beta-HYOROXY-17-al~h~-lIETHOXV-~ HETHYL ESTER, 3,4,5-TRIMETHOXYBENZOATE ( e s t e r 1 131-01-1 YOHIMBAN-16-CARBOXYLIC ACID, 18-113-~4-HYOROXY-3-METHOXYPHENYLI-I-OXO-2-PROP~NYLIOXYI11s17-OIMETHOXY-, METHYL ESTER. I3-beta ,16-betar17-alpha.l6-beta, 20-alpha I35440-49-4 YTTEREIW CHLORIDE 10161-91-6 YTTERBIUM NITRATE 13768-67-7

-- Y10361-93-0 T T R I W ( I I I 1 NITRATE (1x31 - ZINCATEIJ-In INt N-BIS( 2-( EIS(CARB0XYtlETHYLIAHINO IETHYL IGLYCINATOI5- I I-, RISOOIW - T11082-36-5 -- ZINC, BIS(OIME~YLDITH1OCAREAHATOI137-30-4 -- ZINC, BIS(P-PYRIDYLTHIOI-I N,N'-OIOXIOE 13463-41-7

223

Appendix I1

ACETIC ACID, SODIUM SALT. compd. with THEOPHYLLINE ( 1 : l ) ACETIC ACID, (3.5,6-TRICHLORO-2-PYRIDYLOXY)ADENINE, 9-bete-D-ARABINOFLRANOSYL-. MONOHYDRATE ADENOSINE, 3'-DEOXYADENOSINE, 2'-DEOXYADENOSINE, 4'-C-FLUORO-,5'-SULFAMATE ADIPIC ACID, compd. with 3-(2-AMINOElXYL)INDOL-5-OL. HYDROCHLORIDE (1:2:21 ALUMINUM. PENTAKIS(N(sup 2)-ACETYL-L-GLlJTAMINATO)T~AHYDROXYTRIANDROST-b-EN-3-ONE. 17-beta-HYDROXY- 1 7 - M m L T-ARSABICYCLO(2.2.1)HEPTA-2.4,~-TRIENE,1-HYDROXY-, 1-OXIDE ARSENIC ACID ( s o l u t i o n ) ARSENIC ACID, SODIUM SALT 2-AZABICYCL0(2.2.1)HEPTANE. 2-MElXYL1-AZABICYCLO(3.2.O)HEpr-2-PTE-2-CARBOXYLIC ACID, 3-((2AMINOEl'HYL)THIO)-6-(l-HYDROXYETHYL)-7-OXO-, (5R-(5-alpha.6-alpha(R*)))

-

3-AZABICYCLO(3.2.O)HEPTANE-2,b-DIONE. 3-(2-NAPHTHALENYL) 6-AZABICYCLO(3.2.1 )OCTANE. 1- (m-HYDROXWHENYL)-6-METHYL-

I

(+)

-

8-AZABICYCL0(3.2.1)OCTANE-2-CARBOXYLIC ACID, 3-(BENZOYLOXY)-8-MGIHYL-. PROPYL eSTER.HYDROCHLORIDE (1R- (2-endo,3-exo)) -

2-AZABICYCLO)2.2.1)HEPTANE. Z-GIHYL-

AZIRINO( 2' ,3':3.'4)PYRROLO(l.2-a)INDOLE-'4,T-DIONE. 6-AMINO1 la,2.8.8a.8b-HEXAHvDRO-8-(HYDROXYMETHYL)-8a-METHOXY-5METHYL-.CAWAMATE (ester) I

3-AZONIABICYCLO(3.2.1)OCTANE, 1.3

TETRAMETHY METHYL-^- (3-(TR1MEl"fL

AMMONIO)PROPYL)-.BIS(METHYL SULFATE)

BENZ(a)ANTHRACENE. 7.12-DIMETHYLBPTZAMIDAZOLE, 2-(2-PIPERIDINO~L)BPTZAMIDE, N ,N-DIMETHYL-3,k-M€THYLENEDIOXYTHIOBENZAMIDE. N- (4.7-DIHETHOXY-6-(2-PIPERIDINOETHOXY)- 5 - B E N Z O W L ) - , HYDROCHLORIDE BENZENAMINE. HYDROCHLORIDE BBCZENEAcmIc ACID. ~ ~ P ~ ~ - M ~ L - ~ - P H ECALCIUM N o x Y -SALT. , DIHYDRA~,

(+-I-

BENZENEDIAZOSJLWNIC ACID. P-(DIMET?WLAMINO)-. SODIUMSALT 1.2.'4-BENZENETRICARBOXYLIC ACID lI2-AMiyDRIDE 2H-BENZIMIDAZOL-2-IMINE. 1I 3-DIHYDRO-l-((HsPrrLOXY)METHYL-J-METHYL-,

MONOHYDROCHLORIDE

224 2H-BENZIMIDAZOL-2-IMINE. 1,3-DIHYDRo-l-METWYL-3-((OCTYLOXY)METHYL)-, MONOHYDROCHLORIDE

BENZIMIDAZOLE. 1 - ( 2 - ( D I M E n r r L A M I N O ) - l - M ~ L ~ L ) - 2 - ( 2 MORPHOLIN0)ETHYL-, HYDROCHLORIDE BENZIMIDAZOLE. 2-(2-(1-PYRROLIDINYL)GTHYL)BENZIMIDAZOLE. 5,6-DIM-LBENZIMIDAZOLE, 1-(2-(DI~LAMINO)-1-M!ZT?lYLETHYL)-2-(2PIPERIDINO)F17IYL-, HYDROCHLORIDE BENZIMIDAZOLE. 2-tert-BWLBENZIMIDAZOLE, 2-BENZYL-1-(2-(DIMETHULAMINO)-l-M!ZT?lYLLTHYL)-, HYDROCHLORIDE BENZIMIDAZOLE. 1-(2-(DIsMYLAMINO)ETHYL)-2-(p-WETHOXYBENZYL)BENZIMIDAZOLE, 2-(2-(EI'HYLTHIO)LTHYLTHIO)-

-

BENZIMIDAZOLE, 2-(6-MGTHYL-2-PYRIDYL) BENZIMIDAZOLE, 1- (2-AMINOETHyL)BENZIMIDAZOLE. 2-CYCLOHEXYLBENZIHIDAZOLE. 2-PBNTApLUOROFI1M-4.5.6.~-TLTRACHUlROBENZIMIDAZOLE, 2-ISOPROPYLBENZIMIDAZOLE. 2-AMINO-5-CHLOROBENZIMIDAZOLE, 1- (2-DILTHYLAMINOSnm)-2-(2-MORPHOLINOsMYL)-5-NITRO-, HYDROCHLORIDE BENZIMIDAZOLE, l-CHLOROMEIWL-,HYDROCHLORIDE BENZIMIDAZOLE, 1-(3-(DIMETWY~INO)PROPYL)-2-(2~(PYRROLIDIN-1~ YL)W L ) , HYDROCHLORIDE

-

BENZIMIDAZOLE. 5-NITRO-2-(2-(1-PYRROLIDINYL)~)BENZIMIDAZOLE, 1-(2-(DI6THYLAMINO)ETHYL)-2-(2-MORPHOLINO~)-, HYDROCHLORIDE BENZIMIDAZOLE, 2-BENZYL-1-(3-DIMElWLAMINOPROPYL)-, HYDROCHLORIDE BENZIMIDAZOLE. 2-MGTHYL-5-NITROBENZIMIDAZOLE, 1-( 3-(DIMETWYLAMINO)PROPYL)-5-NIl'RO-2-(2PIPERIDIN0hTHYL)-, HYDROCHLORIDE

BENZIMIDAZOLE.~ - B E N ~ - ~ - N I T R O -

-

BENZIHIDAUILE. 2-((2,4-DICHLOROHENoxY)METtiYL)

-

BENZIMIDAZOLE,5-NITRO-2-(2-PIPWIDINOElWL) BENZIWIDAZOLE. HYDROCHLORIDE BENZIMIDAZOLE. 2-(2-MORPHOLINOLTHYL)-5-NITRO-

BENZIMIDAZOLE. 1- (3-(DIWgI1IYLAnINO)PROPYL)-2-(2-MORPHOLINOETHyL)-5NITRO-. HYDROCHUlRIDE BENZIWIDAZOLE. 2-(2-MOSjPHOLINOsMYL)BENZIMIDAZOLE, 1~(2~(DIBMYLAMINO)ETHYL)~5~NITRO~2~(2~PYRROLIDIN-1YL)ElWL-, HYDROCHLORIDE

225 BENZIMIDAZOLE. 1-(2-(DIGMYLAHINO)ElWL)-2-(p-METHOXYPHENYL)1-BENZIMIDAZOL~ARBOXYLICACID, 5.6-DICHLORO-2-(TRIFLUOROMEI"L)-. P H F N L FSTER

2 - B E N Z I M I D A Z O L L , alpha-PHEWL-

-

2-BENZIMIDAZOLML , alpha- (0-CHUIROPHENYL)

-

2-BENZIMIDAZOLPIGMANOL. alpha- (p-CHUIROPHENYL)

B E N Z I M I D A Z O L E M E L , alpha-(p-CHLOR0PHPM)-. HYDROCHLORIDE 2-BENZIMIDAZOLETHIOL. ZINC SALT 2-BENZIMIDAZOLETHIOL BENZIMIDAZOLINE-1-PROPIONITRILE. 3- ( 1- (p-CHLORO-alpha-MEMYLBENZYL)4PIPERIDYL)-2-OXO-.HYDROCHLORIDE

2-BENZIMIDAZOLINONE, 1-ACEIYL-3- (1-(3-(p-FLUOROBENZ0YL)PROPYL)-4PIPERIDYL)2-BENZIMIDAZOLINONE, 1- (1-(3-(p-FLUOROBENZOYL)PROPYL)-4-PIPERIDYL)- , HYDROCHLORIDEMONOHYDRATE 2-BENZIMIDAZOLINONE. 1-( 1- (3-(p-FLUOROBENZOYL)PROPYL)-4-PIPERIDYL)-3PROPIONYL2-BENZIMIDAZOLINONE. 1.3-BIS(HYDROXYMETHYL)2-BENZIMIDAZOLINONE, 1- (1- (3-(p-FLUOROBENZ0YL)PROPYL)-&-PIPERIDYL)-3HYDROXYWETHYL2-BENZIMIDAZOLINONB. 1- (1-(3- (p-FLUOR0BENZOYL)PROPYL)-4-PIPERIDYL)-3MGMYL- , HYDROCHLORIDE

1,2-BENZISOTHIAZOLIN-3-ONE. 2-(2-OXO-3-PIPERIDYL)-. 1.1-DIOXIDE 1,2-BENZISOXAZOLE-7-ACWICACID, alpha-Menm-3-PHENYL-

2H-lI4-BENZOD1AZEPIN-2-ONE,1,J-DIHYDRO-l-METHYL-7-NITR0-5-PHENYL2H,1,4-BENZODIAZEPIN-2-ONE. HYDROXY3H-I ,4-BEHZODIAZEF'INE, 7-CHLORO-2-(MFTHYLAMINO)-5-PHENYL-, 4-OXIDE 1,3-BENZODI0XOLEI 5,6-DI ( H Y D R O X Y M W L )

-

1.3-BENZODIOXOLE. 5-MFMOXY-6-NITRO1 ,j-BENZODIOXOLE. ~-CHLORO-2-(2-(2-(DIETHYLAMINO)ETHOXY)ETHYL)-2~ METHYLBENZOFURAN

BB4ZOPURAN. 5-CHLORO-3-M~-2-NITROB E N Z O M , 'j-MRl?lOXY-2-NITRO-

2-BENZOFURANCARBOXYLIC ACID, 4-BROMO-6-( (DIMElNYLAMIN0)METHYL)-5HYDROXY-. bTHyL STRR HYDROCHLORIDE 3-BWZOPURANCARWXYLIC ACID, 6-CHLORO-4- (DIMETHYLAMINOHETHYL)-5HYDROXY-2-MEmL-, El'HYLESTER j-B~ZOFURANCARBOXYLICACID. 4-CHUIRO-5-HYDROXY-2-tUXHYL-6-( ( 4 - U C m L 1-PIPauZINYlJIEIwL)-. ETHYL ESTER 3-BENZOFURANCARBOXYLIC ACID. 6-(DXMeTHYwslINOMFnm) -5-HYDROXY-2m esTw

r n L - .

226 3-BENZOFURANCAPBOXYLIC ACID, 4-CHLORO-6-(DIMEmLAMINOMeTHn)-5HYDROXY-2-PHRWL-, ElWLEsTFA 3-BENZONRlwCARBOXYLIC ACID, 6-BROMO-5-HYDROXY-2-MML-4l-PIPERAZINYL)MEIliYL)-,ML ESTER

((4-MFmL-

3-BENZOFURANCARBOXYLIC ACID. 2-((DIMFmLAMINO)MFPHYL)-5-M~OXY-, ETHn ESTW. HYDROCHLORIDE 3-BENZOFURANCAPBOXYLIC ACID. 4-CHLORO-6- (DIE"LAM1NOMETHn) -5HYDROXY-2-HETHYL-, FmLFSTER 2-BENZONRlwCARBoxyLIC ACID, 4-( (DIMFmLAMINO)METHuL)-5-HYDROXY-. GTHYL ESTER. HYDROCHLORIDE

-

3-BENZOFURANMFnruLAMINE. 2-erWYL-N- (3-MEX'HOXYPROPYL) 3-BENZO~El'HYLAMINE. 2-erWYL-N-(2-MFIHOXYFTHYL)3-BENZONRANMETHYLAMINE. 2-ElWYL3-BENZOF"MEIXYLAMINE.

N.2-DIETHYL-

7-BENZOFIRANOL. 2.3-DIHYDRO-2.2-DIMEYL-,

DIMETHYLCARBAMATE

5-BENZOFURANOL. 4-BROMO-2-PHENYL-6- ( (~-PHENYL-~-PIPERAZINYL) METHYL)- , 5-BENZOFlJRANOL. 3-CHLORO-4- (DI!3lXYLAMINOMmrYL)-2-PHENYL-, HYDROCHLORIDE 3-CHLORO-4-( (DIMETHYLAMINO)M€l?lYL-2-PHENYL-,

5-BENZOF"0L. HYDROCHUlRIDE

6-BENZOFURANOL. 2-BROMO-7-((DIMFmLAMINO)MFL)-3-PHENn-. HYDROCHLORIDE 5-BENZOFURANOL. 4-(DIMETHYLAHINOMEL)-3-PHENYL-2-( PIPERAZINYL-METHYL)

-

(4-PHENYL-l-

5-BENZOFURANOL. J-BROMO-&-( (DIMETHYLAMIN0)MFPHYL)-2-PHENYL-, HYDROCHLORIDE 5-BENUlF"OL. 2,4-DIBROMO-3-PHENYL-6- ( ( 4-PHENYL-1PIPERAZ1NYL)METHYL)

-

5-BENZOFLMNOL. 2,4-DIBROMO-6- (DIETHYLAMINOMETHYL)-3-PHENYL- , HYDROCHLORIDE 5-BENZOFURANOL. 4-( (DIMElWLAMIN0)MML)-2-PHENYL-, HYDROCHLORIDE 5-BENZOFURANOL. 4- ( (DIMETHYLAMIN0)METHYL)-3-PHENYL-, HYDROCHLORIDE 5-BENZOFlJRANOL 4-BROMO-6- (DIMFPIFYLAMINOMETHYL)-2-PHF3YLI

5-BENZ0FURANOL1 2-CHLORO-4- ( DIMFPHYLAMINOMRWYL) -3-PHENYL5-BENZOF"0L.

3-CHLORO-2-PHENYL-4- ( (4-PHENYL-l-PIPEFlAZINYL)M~L) -

6-BENZOmrrvWOL. 7-( (D1METHYLAMINO)METHYL)-3-PHENyL-, HYDROCHLORIDE 5-BENZOFURANOL. 4- ( (DIMETHYLAMIN0)MEYL)-6-NITRO-2-PHENYL-, HYDROCHLORIDE 5-BENZOFURANOL. 2-BROMO-4- ( (DIMemYLAHINO)METHYL)-3-PHENYL-. HYDROCHLORIDE 2(3H)-BENZOFLIRANONE, 3-(2-(DIELAMINO)ETHYL)-3-PHENYL-, HYDROCHLORIDE

BENZOFURAZAN, 4-(4-(3-METHOXYPHENYL)-l-PIPERAZINYL)-7-NITROBENZOFURAZAN, 4-NITR0-7-(4-PHENYL-l-PIPER4ZINYL)-,1-OXIDE

227 BENZOFVRAZAN. 4-NITRO-5-(4-PHENYL-l-PIPEFIAZINYL)-,

1-OXIDE

4-BENZOFURAZANAMINE. N.N-DIMR'HYL-7-NITRO-. 1-OXIDE BENZOIC ACID, 4,4'-1MINODI-. cmpd. with 3-(2-AMINOEI'HYL)INDOL-5-OL, HYDROCHLORIDE, HYDRATE(1:2:2:2) 2-BENZIMIDAZOLINONE. 1-( 1-( 3-(P-FLUOROBENZOYL)PROPYL) -4-PIPERIDYL)2H-l-BENZOPYRAN-3-CARBOXYLIC ACID, 8-(3-(HYDROXYMERCURI)-2MEl'HOXYPROPYL)-2-OXO-. SODIUM SALT, compd. with THEOPHYLLINE (1:l) ( 1)BENZOPYRANO( 3.4-b)FUR0(2,3-h) ( 1)BGNZOPYRAN-6(6aii) -ONE. 1.2.12.12aT~DRO-2-alpha-ISOPROPENYL-8,9-DIMFIHOXY

-

2.1,3-BENZOSELFNADIAZOLE, 5-METHYL2.1,3-BENZOSELENADIAZOLE, 5.6.-DIMML-

BENZOSELENAZOLE. 2.5-DIMGI71YLBENZOSELENAZOLE. 2-METWLBENZOSELENAZOLIUM, 3-~YL-2-(3-(3-ETHYL-2-BENZOSELEZOLINYLIDENE)-2METHYLPR0PENYL)-. IODIDE 2.1,3-BENZOTHIADIAZOLE. 5-CHLORO-4-(2-IMIDAZOLIN-2-YL)BENZOTHIAZOLE. 6-((p-(DIFI1PILAMINO)PHFNYL)AZOBENZOTHIAZOLE. 2-AMINO-5.6-DICHLOROBENZOTHIAZOLE. 2-AMINO-6-METHOXYBENZOTHIAZOLE. 2.2'-DITHIOBIS7-BWZOTHIAZOLESULRlNIC ACID. ~-(P-AMINOPHENYL)-~-METHYL6-BENZOTHIAZOLINESULFONIC ACID, 2,2'-AZINOBIS(3-ETHYL-,AMMONIUM SALT (1:2) 3H-2,l-BENZOXAMERCUROLE.7-NITR0-3-OXO-

2-BENZOXAZOLINONE. 6-(2-THENOYL)2-BENZOXAZOLINONE, 6-BENZOYLBENZYL ALCOHOL, 4-AMINO-alpha-( (tert-BUTYLAMIN0)METHYL)-3-CHLORO-5(TRIFLUOR0METHYL)-.HYDROCHLORIDE 4.4 ' -BIPHENYLDICARBOXYLIC ACID, compd. with 3-(2-AMINOETHYL)INDOL-5OL. ACETATE (1:2:2)

BUTYROPHENONE. 4'-FLUORO-b(4-HYDROXY-4-(alpha.alpha.alpha-TRIFLUOROm-T0LYL)PIPERIDINO)CADMIUM SULFATE (1 :1 ) HYDRATE (3:8) CADMIUM SULFATE, HYDRATE CAFFEINE. a-moxyCAFFEINE, 8-MERCAPTO-,HYDROCHLORIDE CARBAMIC ACID. METHYL-, m-CYW-5-YL ESTER C A N M I C ACID. METHYL-. 3.4-MERiYLENEDIOXTPHENYL ESTER CARBAMIC ACID, (~-((~-CYANOPENTYL)CARBAMOYL)BENZIMIDAZOL-~-YL)-,METH~L ESTER

228 CARBAMIC ACID, METHYL(MFI7IYLTHIO) -, 2.3-DIHYDRO-2,2-DIMETWn-7BFNzoFuRAmL ESTER

- , 2.3-DIHYDRO-2.2-DIMETHYL-7-

CARBAMIC ACID, ldBIlM(PHENYLTHIO) BENZOFURANYL ESTER

CARBAMIC ACID, METHYL( (4-MEl'HYLPHENYL)THIO)-. 2,3-DIHYDRO-2.2DIMEI'HYL-7-BENZOFlMNYL ESI'W CAFDAMIC ACID, MEl'liYL((3-MEIlWLPHENYL)THIO)-. 2.3-DIHYDRO-2.2D I M E " H Y L - 7 - B E N Z O F L FSI"I' CARBAMIC ACID, DIETHYLDITHIO-, 2-BENZOTHIAZOLYL ESTER CARBAMIC ACID, MCPHYLNITROSO-. 2.2-DIMEPHYL-3-OXO-2,3-DIHYDRO-7BWZOWRANYL BSTW CARBAMIC ACID, ((DIBvrYLAMINO-~IO)METHn-,2,2-DIMETHYL-2.3-DIHYDRO7-BENZOFURANYL ESTER CARBON MONOXIDE CARBON TETRACHLORIDE CARBONIC ACID, CYCLIC l-(HYDRoXYMETHn)-2-MEI'HYLETHYLENE ESTER, ESTER with 6-(2-AMIN0-2-PHB4YLACETAMIDO)-3,3-DIWsnm-7-0XO-~-THIA-1AZABICYCLO(3.2.O)HEFTANE-2-C~XYLIC ACID.HYDROCHU)RIDE CINNAMIC ACID, alpha-(p-AE(INOPHENYL)-, 3-TRoPANyL ESTER. HYDROCHLORIDE, HYDRATE (4:5) CLINDAMYCIN-2-PHOSPHATE CYCLACILLIN CYCLOHEXANOL. l-EI"YL-. CARBAMATE

4-CYCLOHEXENE-112-DICARBOXYLIC ANHYDRIDE, 4-CHLORO4-CYCLOHEXENE-1,2-DICARBOXIMIDE, N-METHYLCYCLOPENTA(c ) ~ O 3'( -2' :4,5) FURO( 2,3-h) (l)BENZOPYRAN-l,11DIONE.2.3.6a.9a-TETRAHYDRO-~-M~OXY1H-CYCLOPENTAFYRIMIDINE-2.4 (3H,5H)-DIONE. 6.7-DIHYDRO-3-CYCLOHEXYL-

3-CYCLOPE"E-1.2-DIOL, ( 1R,2S,3RS5R)

-

3- (6-AMINO-gH-PURIN-9-YL)-5-(HYDROXYNETHYL)-,

CYCLOPROPANECARBOXYLIC ACID. 3-(2,2-DIBROMOETHENYL)-2,2-DIMElWLCYANO( 3-PHENOXYPHENYL)MElWL ESTER, ( 1R- ( I-alpha (S*),3-alpha) )

-

CYCLOPROPANECARBOXYLIC ACID, 2,2-DIMETHYL-3-(2-MBPROPPIYL)-, ESTER with N-(HYDROXYMFPHYL)-1-CYCLOHEXENE-1,2-DICARBOXIMIDE. (+)-(E)DEXTRAN 5 DEXPRAN 10 DEXTRAN 11 DFXTRAN 40 1.3-DIAZABICYCLO(3.1 .O)HEX-3-ENE. 2.2-DIMETHYL-6-(p-NITROPHENYL) -4PHENYLDIBENZ( b .a)OXEPIN-dalta(sup 11 (6H),gamma)- P R O P W I N E , N.N-DIMETHYL- , HYDROCHLORIDE

6H-DIBENZO(b.d)PYRAN-l-OL. 6a.7.8.10a-TETR4HYDR0-6,6.9-TFlIMETHYL-3PENTYL-

229 1,4:5. ~ - D I M E ~ W N O N A P ~ L F ~1.4,4a. E. 5.8.8a-HEXAHYDRO-l.2.3,4,10.10HEXACHLORO-. endo. excnixture (more than 60% ALDFUN) EBURNAMENIN-14-0L. 14,15-DIHYDRO-, (3-alpha,lu-beta)-( + - ) W O N 1007 W O N 820 EF'ON 1001 EWXY R E I N ERL-2795

FSCIN M O L . 2-CHLOROEI'HANOL. 2-( ((2-EnruL-3-BENZOFURANYL)MGI71YL)AMINO)ETHANOL. 2-PROPOXYFI1IyLAMINE. 1-MCTHYL-2- (2.6-XYLYLOXY)

-. HYDROCHLORIDE

ETHYLENEDIAMINE, N,N-DIETHYL-N'-((2-EI'HYL-3-BENZONL)MGI71YL)FORMAMIDE. N- (~-McnrYL-~-OXO-~.~-DIHYDRO-1.2~DI~IOt0(~ .3-b)PYRROL-6YL)

-

be ta-D-FRUCTOFLJRANOSE, 4-0-beta-D-GALACTOPYOSYLFUMARIC ACID, compd. with 3-(2-AMINOGI71YL)INDOL-5-OL. ACETATE (1:2:2) GLUCARIC ACID, 1,4:6.3-DILACTONE, DIACETATE, DGLUCOFURANOSE, 3-0-(2-(DIEI1IYLAMINO)ETIWL)-1:2.5:6-DI-OISOPROPYLIDENE-, alpha-DGLUCOF"OSE,

1:2,5:6-DI-O-ISOPROPYLIDENE-, alpha-D-

GLUTAMIC ACID, N-(p-( ((2-~IN0-3.4.5.6.7.8-HExAHyDR0-4-0X0-6PTERID1NYL)METHYL)AMINO)BPIZOYL) , L-

-

GLUTAMINE. N-(2-(5-HYDROXY-3-INDOLYL)EXHYL)GLUTARIC ACID, compd. with 3-(2-AMINO~)INDOL-5-OL. HYDROCHLORIDE (1:2:2) GLYCOLS, POLYETHYLENE. O C n L PHENOL condensed O C W L PHENOL condensed OCTYL PHENOL condensed OCTYL PHENOL condensed

MONO((1.1.3.3-T~AMCLITYL)PHENYL)

with with with with

ETHER

MOLES GI71YLwE OXIDE 6-10 MOLES GI71YLENE OXIDE 16 MOLES F m L E N E OXIDE 3 MOLES ETHYLENE OXIDE 20

GUANIDINE. l-WGTHYL-3-NITRO-l-NITROSOGUANOSINE. O-METHYLGUANOSINE. 2'-DEOXYHOMATROPINIUM, &METHYL-, BROMIDE HYDRATROPIC ACID, p-(1-OXO-2-ISOINDOLINYL)HYDRAZINE. (2-(3.4-METHYLENEDIOXYPHENOXY)ETWL)-. HYDROCHLORIDE HYDROGEN CHLORIDE (aerosol) HYDROGEN CHLORIDE 1H-IMIDAZO(1,2-b)PYRAZOLE, 2.3-DIHYDRO-

230 IMIDAZO(4,~-c)PYRIDIN-~-ONE, 2-( (2-3-~~1N0-6(3-AMINO-6-(3-AMINO-6-(3MINO-6-(3-AMINO-6( 3.6-DIAMINOHEXANAMIDO) HEXANAMIDO)HEXANAMIDO) HEXANAMIDO)HEXANAMIDO)HEXANAMIDO)-2-DEOXY-alpha-DOLUC0PYRANOSYL)MINO)-3.3a.5.6.7.7a-HEXAHYDRO-7-HYDROXY - ,6'-CAREAMATE 4H-IMIDAZ0(4 .~-C)PYFIIDIN-~-ONE, 2 - ( (2-(3-~1No-6-( 3-AMINO-6-(3-AMINO-

6-(3-AMINO-6-(3.6 D I A M I N O H ~ A M I D O ) H E X A N A M I D O ) H E X A N A M I ~ ) H ~ N A M I D O l HUV\NAMIDO)-2-DEOXY-alpha-D-GULOPYRANOSYL)AMINO)

-3,3a.5.6,7.7a-HUDRO-7-HYDROXY-,

6'-CARBAMATE

1H-IMIDAZOLE, 4,5-DIHYDRO-2-((2-METHYLEENZO(b)THIEN-J-YL) M E m L ) HYDROCHLORIDE 1H-INDAZOLE, 3-CHLORO-6-NITRO1H-INDAZOLE, l-(~-(DIMETHYLAMINO)PROPYL)-~-M~HYL-3-PHENYL-. HYDROCHLORIDE 1H-INDAZOLE, 5-( (P-(DIMcnrru\MINO)PHPrrL)AZO)1H-INDAZOLE. 7- ( ( p- ( DIMEnrYLAMIN0)PHENYL)AW)) INDOL-)-OL.

3-(2-AMINOETHYL)-. ADIPATE

INDOLE, 2.3-DIMElWL-7-NITROINWLE, 3-(2-MINOPROPYL)-6-CHLORO-, HYDROCHLORIDE INDOLE, 5-AMINO-3-(1-PYRROLIDINYLM~L)INDOLE. 5-M~OXY-3-)1-PHEN~-4-PIPERIDYL)MGTHnINDOLE, 3-(3-PIPERIDYLMEnrrL)INDOLE, ~ - ( D I ~ L A H I N O ) -

-

INDOLE, I-M~L-3-(4-PIPERIDYLMBMYL) , HYDROCHLORIDE INDOLE, 3- (2-AMINOPROPYL)-4-CHLORO-. HYDROCHLORIDE INDOLE, 2-(2-AMINOBUTYL)-bCHLORO-, HYDROCHLORIDE INDOLE. 3-(2-AMINOBuTuL)-6-CHLORO-, HYDROCHLORIDE INDOLE, 3-( (DIMETHYLAHINO)MeTHYL)-7-NITROINDOLE, 3-(2-(HYDROXYAMINO)PROPYL)-, HYDROCHLORIDE. (+-)INDOLE, 3-(~-~1NOernYL)-5-MGTHOXY-,HYDROCHLORIDE INDOLE, g~HETHOXY-3(4-PIPERIDYLMEZWL)INDOLE, 3-(l-PHENETHYL-4-PIPERIDYLMKTHYL)INDOLE, 3-( l - B E N m - 4 - P I P W I D Y L M e ) - 5 - ~ O X Y - ,HYDROCHLORIDE INDOLE. 3-(2-AMINOPROPYL)-5-nUOUORO-,HYDROCHLORIDE

-

INWLE, 5-HETHOXY-3-(2-(~INO)PROPYL)

INWLE, 3-(2-(0IMEIIMAMINO)EMYL)-5-HEIWLTHIOINWLE. 3-(2-MFIHYLAMINOPROWL)-)-MBMYLTHIO-

INWLE. 3-(2- ( D I W E T H Y L A M I N O ) P R O P ~ ) - ~ - ~ T H I O -

-

INDOLE. 3-(2-PIPERIDYLMETHYL) INDOLE, 3-( PIPERIDINOMETHYL)-

INDOLE, 5-BWmLTnIO-3-(2-DIMFLAHINO)PROPYL)-

231 INDOLE, 5-BENZYLTHIO-3-(2-METHYLAMINOPROPYL)INDOLE, 3-(2-PYKIDYLMETHYL)INDOLE, 3-(1-MLTHYL-3-PIPERIDYLMmL)INDOLE. 5-DIMEl'HYLAMINO-3-(2-(DIMETHYLAMINO)ETHYL)INDOLE, 5-(DIM~LAMINO)-3-((DIMGI71YLAMINO)METHYL)INDOLE. 3-BENZYL-5-(DIMETKYLAMIN0)INDOLE, 5-(DIMETHYLAMINO)-3-(PIPERIDINOMETHYL)INDOLE, 3-((DIMETHYLAMINO)METHYL)-6-NITROINDOLE. 5-(DIMETHYLAMINO)-3-MORPHOLINOMETHyLINDOLE. 5-METHOXY-3-(2-AMINOPROPYL)-. HYDROCHLORIDE INDOLE, 5-METHOXY-3-(2-(l-PYRROLIDINYL)ETHYL)INDOLE. 3-(2-AMNO-2-METHYLPROPYL)INDOLE. 3-(2-(DIMETHYLAMINO)E"HYL)-, HYDROCHLORIDE INDOLE, 3-( (DIMCTHYLAMINO)METHYL)-7-METHYLINDOLE. 3-(2-AMINO-1.1-DIMEl'HYLiTHYL-5-FLUOROINDOLE. 3-(2-AMINOETHYL)-7-METHYLINDOLE. 3-METHYL-2-(p-(2-(1-PYRROLIDINYL)ETHOXY)PHF.NYL)INDOLE. l-MCTHYL-3-(l-PHENETHYL-4-PIPERIDYLMGI"HYL)INDOLE, 3-(3-AMINOBUTYL)INDOLE. 3-METHYLINDOLE. 3-(2-AMINOPROPYL)-4-FLUORO-.

HYDROCHLORIDE

INDOLE, 3-(2-AMINOPROPYL)-5-CHLOROINDOLE. 3-(2-AMINOBUTYL)-4-CHLOROINDOLE, 3-(2-AMINO-2-METHYLPROPYL)-5-BROMOINDOLE, 3-(2-AMINO-2-METHYLPROPYL)-5-CHLOROINDOLE. 3-(2-AMINOPROPYL)-7-CHLORO-, HYDROCHLORIDE INDOLE. 3-(2-(MEXWLAMINO)ETHYL)-5-METHYLTHIOINDOLE. 3-(2-AMINO-l,l-DIEXWLETHYL)INDOLE-3-AClTIC ACID, 2-ISOPROPYLHYDRAZIDE INDOLE-3-AClTIC ACID. 1- (4-AZIDOBENZOYL)-5-METHOXY-2-METHYLlH-INDOLE-3-ACFPIC ACID. 1- (4-CHLOROBENZOYL)-5-METHOXY-2-METHYL-2-(4(3-( (4-(BPIZOYLAMINO)-5-(DIPROPYLAMINO)-1.5-DIOXOPENTYL)OXY)PROPYL)- 1PIPERAZ1NYL)ETHYL ESTEB ( + - ) - , (Z)-2-BUTENEDIOATE (1:2) 1H-INDOLE-3-BUTANOIC ACID INWLE-3-CARBOXALDEHYDE. 5-DIMCTHYLAMINOINDOLE-3-CARBOXYLIC ACID, HYDRAZIDE INDOLE-5-CARBONITRILE. 3-FORMYL-

232 INWLE-5-CARBONITRILE,3-ACElYLINDOLE-5-CARBONITRILE,3-BENZOYLINDOLE-5-CARBONITRILE, 3-(PHENYLACETYL)-

-

INDoLE-5-CAFWNITRILE,3-( alpha-HYDROXYPHENFmL) INDOLE-5-CARBONITRILE, 3-BENZYL-

-

INDOLB-5-CAREONITRILE, 3-(2-DIMRI'HYLAMINOEI'HYL) INDOLE-5-CARBONITRILE, 3-(DIMFnryLAMINOMETHYL)3-INDOLEMGPHANOL. alpha-MEI'HYLAMINOMFmLINWLINE. l-MeMYL-5-(PHENYLAZO)2-INDOLINONE, 3-HYDROXY-3-(2-PYRIDYL~L)ISOINDOLE. 4.5,6.7-TFIW\HuDR0-5-MEnrYL-2-PHPMISOINDOLINIUM. 4,5,6,7-TpTRlrCHLOR0-2-ML-2-(2(TRIMmMAMMONIO)EIWL)-, DICHLORIDE ISONIPEOTIC ACID, 1 - ( 5 - N I T R O ~ 3 - I N D O L Y L M ~ ) ~ 4 - P H E N y L - ,ETHYL ESTER, HYDROCHLORIDE ISOPHTHALIC ACID, cmpd, With 3-(2-AMINORI'HYL)INDOL-5-OL. HYDROCHLORIDE (1:2:2) JACOBINE KETONE. 2-INWLYL MFMOXYMETHYLKFPONE. 2-ETHYL-3-BENZOFU"IL p-HYDROXYPHENYL

KEMNE. HYDROXWeMYL 2-INDOLYLKEMNE, 3.5-DIBROMO-4-HYDROX~HXuPHENYL2-ETHYL-3-BENZOPL KETONE, 3-INDOLYL 4-PIPERIDYL KETONE, 5-DIMcIlruLAMINO-3-INDOLYL PHENYL KEMNE. H Y D R O X Y M m M 2-METHYL-3-INWLYL

KETONE. ~-INDOLYLPIPERIDINOMETHYL KETONE,~-INDOLYLMORPHOLINOMSMYL KETONE, HYDROXYMEIWL l-MFPHYL-3-INWLYL

LASIOCARPINB LLlTEINIZING HORMONE-RELMSINO HORMONE, (D-TRP(sup 6 )-PRO( sup EMYLAMIDE MALONAMIC ACID, N-(2-CAReOXY-3.3-DI~L-7-OXO-4-THIA-lAWBICYCLO( 3.2.0)HEPT-6-YL)-2-PiMYL-, 1-PHENYL ESTER

-

MALONIC ACID, (lI3-DITHI0L-2-YLID~E) , DIISOPROPYL ESTER

MALONONITRILE. (PIPERONYLIDENE)MERCURY, (~-(0-~CARBoX~XY)BENwwIW)-2-MEMOXYPROPYL)HYDROXY-, MONOSODIUM SALT, compd. with THEOPWLLINE I(wCURY(I1) IODIDE (solution)

233 METHANESULFONIC ACID, ETHYL ESTER METHANESULFONIC ACID, METHYL ESTER METHANONE, (2-CHLOROPHENYL)(2-((DIETHYLAMINO)METHYL)-1H-IMIDAZOL-1YL)-5-NITROPHENYL)-.trans-2-BUTENEDIOATE MOMORDICA CHARANTIA L.. fruit extract MONOCROTALINE MORPHINAN. 3,17-DIMETHYL-,(!+alpha, 13-alpha.ll)-alpha)-, PHOSPHATE (1:l)

MORPHOLINE. 4- (3.4-MEl'HYLENED10X~1OC1NNAM0YL)

-

MORPHOLINIUM. (3-INDOLYLMETHYLENE)-,HWCHLOROSTA"ATE(2-)

(2:l)

2,7-NAPHTHALENEDISULMNIC ACID, 3-HYDROXY-4-((4-SULM)-l-NAPHTHYL)AZO)-,

TRISODIUM SALT NITRIC ACID (red fuming) 4-OXA-l-AZABICYCL0(3.2.O)H~ANE-2-CARBOXYLIC ACID, 3-(2HYDROXYETHYLIDINE)-7-OXO-. SODIUM SALT, (2R-(2-alpha,32.5-alpha))

7-0XA-3-AZABICYCLO(4.1.O)HEFTANE. 3-NITROSO5-OXA-AZABICYCLO(4.2.O)OCT-2-ENE-2-CARBOXYLIC ACID, 7-(2-CARBOXY-2-( p HYDROXUPHENYL)ACETAMIDO)-~-METHOXY-~-(((1-METHYL-lH-T~ZOL-~YL)THIO)MEfHYL)-8-OXO-. DISODIUM SALT, (6R.7R)-

7-OXABICYCLO(2.2.1)HEPT-5-ENE-2,3-DICARBOXYLIC ACID, AMINE SALT, (endo)-

7-OXABICYCLO(2.2.1)HEPTANE-2,3-DICARBOXYLIC ACID, DISODIUM SALT 6-OXABICYCL0(3.1.O)HEXANE-2-CARBOXYLIC ACID, 1.5-DIMETHYL-3-METHYLENE-

4-OXO-. METHYL ESTER 6-OXABICYCLO(3.1.O)HFXANE-2-CARBOXYLIC ACID, 3-BROMO-3-(BROMOMETHYL)1.5-DIMETHYL-4-OXO-

~-OXABICYCLO(4.1.O)HEFT-3-ENE-3-CARBOXAMIDE.6-AMINO-2,5-DIOXO7-OXABICYCLO(4.1.O)HEPTANE-3-CARBOXYLIC ACID, 4-MEl'HYL-. ALLYL ESTER

7-OXABICYCL0(4.1.O)HEPT-3-ENE-2,5-DIONE, 3-HYDROXY-4-METHYL-. stereoisomer

7-OXABICYCLO(4.1 .O)HEPT-3-EN-2-ONE, 5-HYDROXY-3-(1-HYDROXY-3-METHYL-2BUTENYL)- , (1s-(1-alpha,3(S") .5-alpha.6-alpha)) 7-0XABICYCLO(4.1 .O)HEPl'-2-ENE 7-OXABICYCLO(4.l.O)HEPTANE-2-PROPIONIC ACID, alpha-(2AMINOPROPIONAMIDO)-5-OXO-,stereoisomer 7-OXABICYCLO(4.1.O)HFFT-3-ENE-2.5-DIONE. 3-HYDROXY-4-METHYL7-0XABICYCLO(b.1.O)HEPTANE. 3-(EPOXYETHYL)7-OXABICYCLO(II.l.O)HEPT-3-ENE

-

1,~-OXATHIOLANE.5-(CHLOROMETHYL)

2H-l.3.2-OXAZAPHOSPHORINEE.2-(BIS(2-CHLOROElWL)AMINO)TETRAHYDRO-2OXIDE 2H-1.3.2-0XAZAF'HClS'HORINE. OXIDE, MONOHYDRATE

TerrvUrYDRO-2-(BIS(2-CHLOROEI'HYL)AMINO)-. 2-

234 II3,2-OXAZAPHOSPHORINE,3-(2-CIiLOROKTHYL)-2- ( (2CHLORO~L)AMINO)TBIRUIYDRO-, 2-OXIDE ~OXY)-, PHENTHYLAMINE. E ~ ~ ~ E - M B ~ L - ~ , ~ - ( M ~ ~ E N B D (+-)-

PENICILIN 0 . ALUMINUM complex with SULFAMETHOXYPYRIDAZINE PENICILLIN, compd. with CHOLINE CHLORIDE -2PHENOL, p-(5-(5- (~-MElWYL-1-PIPERAZINYL)-2-BENZIMIDAZOLYL) BENZIMIDAZOLYL) ,TRIHYDROCHLORIDE

-

PHENOL, 4,4'-ISOPROPYLIDENEDI-, TETAAMER WITH l-CHLORO-2.3EPOXYPROPANE PHENOL, 4,4'-1SOPROPYLIDENEDI-, DIMER with 1-CHLORO-2.3-EPOXYPROPANE PHENOL, 4,4' -1SOPROPYLIDENEDI-, MONOMER with l-CHLORO-2.3-EPOXWROPANE PHENOLPHTHALEIN PHOSPHORODITHIOIC ACID, S-( (6-CHLORO-2-OXO-3(2H)BENZOXAZOLYL)METHYL)O,O-DIETHYL ESTER PHOSPHORUS (red) PHTHALIC ACID, COD@. HYDRATE (1:2:2:1)

with 3-(2-AMINOETHYL)INDOL-5-OL. HYDROCHLORIDE,

PHTHALIMIDE, 4,5,6,7-TETRACHLOROPHTHALIMIDE, N-( (HeWuluDRO-1H-AZePIN-l-YL)METHYL) PHTHALIMIDE, N-(2,3-EPOXYPROPYL)PHTHALIMIDE, N-ISOBUTYLPHTHALIMIDE. N- (4-( HEXAHYDRO-lH-AZEPIN-l-YL)BUT-2-YNYL)PIPERAZINE. 1.4-(BIS(2-2-MEnrYL-1,3-BENZODIOXOL-2-YL)~L)) PIPERAZINE.

1-( (6-METHYL-3-PHENUL-2-BE"YL)MFPHYL)

-4-PHENYL-

PIPERAZINE. 1- ( (5-NITRO-3-PHENYL-2-BENZOFL)METHYL)-II-PHENYLPIPERAZINE. l-(p-CHLOilO-alpha-PHENYLBENZYL)-4-METHYLPIPERAZINE, 1-PIPERONYL-4-(3,7,11-TRIMETHYL-2,6,10-DODECATRIENYL) 1-PIPERAZINECARBOXAMIDE,N ,N-DIETHYL-4-METHYL-

1-PIPEfUZINEEX"OL. 4-(2- (2-METHYL-1,3-BENZODIOXOL-2-YL) ETHYL)-.DIHYDROCHLORIDE

-

l-PIPERAZINEETnANOL,4-(7-NITROBENZOFURAWIN-4-YL)

2-PIPERIDINEACETIC ACID, alpha-PHENYL-. HETHYL ESTER 1-PIPERIDINEFIWNOL, 4-(3-1NWLYLMBmL)PIPERIDINIUM, l-ElWL-1-(2-HYDROXuBmL)-, BROMIDE, BENZILATE (ester) PIPERONAL. DIBENZYLMERCAPTAL PLATINUM(II), DIAMMINEDICHLORO-, cisPOLYDIMWL SILOXANE PREGNA-1.I)-DIENE-3,2O-DIONE.6-alpha,9-DIFLUORO-11-beta.17.21TRIHYDROXY-. 21-ACETATE.17-BUTYRATE 1.3-PROPANEDIAMINE. N,N-DIETHYL-N'-((Z-mL-3-B~ZOrrnRANYL)METHYL)-

235 1-PROPANOL, 3-( ( 2 - E T i Y L - 3 - B E N Z O F L ) M m M I N O ) 2-PROPANOL, l-(lH-INDOL-4-YLOXY)-3-((1-MFI1FIL617FIL)AMINO) 2-PROPANOL, l - ( I S O P R O P Y L A M I N 0 ) - 3 - ( 1 - N A P ~ L O X Y ) 2-PROPANOL, 1-(1,2-BENZISOTHIAZOL-4-YLOXY)-3-((1,l-DIMETHYL-2PR0PYNYL)AMINO) 2-PROPANOL, 1-( (2-( 6.11-DIHYDRODIBENZ(b,e)OXEPIN-llYL)ETHYL)METiYLAMINO)-3- PHENOXY2-PROPANOL. 1-(1,2-BENZISOTHIAZOL-4-YLOXY)-3-((1-METHYLBU"L)AMINO)2-PROPANOL, 1-METHOXY1-PROPANONE, 2-HYDROXY-1-(3-INDOLYL)1-PROPEN-1-OL. 3-(1.3-BENZODIOXOL-5-YL)-. ACETATE 2-PROPENOIC ACID. BUnL ESTER PROPIONAMIDE. N-(2-(3-AZABICYCL0(3.2.0)HEFT-3-YL)-l-METHYLETHYL)-N-2PYRIDYL-, ( + - ) PROPIONIC ACID, 2- (4-CHLOROPHENOXY)-2-METiYL-. 2-(1.2,3.6-TETRAHYDRO1,3-DIMETiYL-2,6-DIOXO-7H-PURIN-7-YL) ETHYL ESTER PROPIONIC ACID, 2-(2-BENZIMIDAZOLYL)PSEUDOCAINE. TARTATE 6H-PURIN-6-ONE. 1.9-DIHYDRO-2-AMINO-9-((Z-HYDROXYETHOXY)METHYL)PURINE, 2.6-DICHLORO-7-METHYLPURINE-3-OXIDE PYRE3WIIM 1.2-PYRIDAZINEDICARBOXIMIDE. TETRAHYDRO-4-(CHLOROMERCURI)-5-METHOXY-NMETHYL1,2-PYRIDAZINEDICARBOXIMIDE. TETRAHYDRO-4-(BROMOMERCURI)-5-METHOXY~H-PYRROLO(2.3-d)PYRIMIDINE-5-CAOXAMIDE. b-AMINO-7-beta-DRIBOFURANOSYL7H-PYRROLO(2.3-d)PYRIMIDINE. 4-AMINO-7-beta-D-RIBOFURANOSYL-

RKTRONECINE. 3.8-DIDEHYDRORIBOFURANURONAMIDE. 1-(6-AMIN0-9H-PURIN-9-YL)-l-DEOXY-N-METHYL-. HEMIHYDRATE SEBACIC ACID, compd. w i t h 3-(2-AMINOETHYL)INDOL-5-OL. ACETATE (1:2:2) SELENIUM (COLLOIDAL) SENECIONAN-11,16-DIONE. 12-HYDROXYSENECIONANIUM, 8,12-DIHYDROXY-4-METHYL-l1,16-DIOXOSOLCOSERYL SPIRO(l-alpha-H,~-alpha-H-NORTROPANE-8.1'-PYRROLIDINIUM).3-alphaHYDROXY-. CHLORIDEBENZILATE

D-STREPTAMINE. 0-2,6-DIAMINO-2.6-DIDEOXY-alpha-D-GLUCOPY~DOSYL-(14)-0-(beta-D-RIBOFlJFiANDOSYL-(1-5))-2-DEOXY-

236 D-STREFl'AMINE. 0-3-DEOXY-4-C-METHYL-3-(METHYLAMINO)-beta-LARABINOPYRANOSYL-(1-6)-0-(2.6-DIAMINO-2,3.4,6-TEl'RADEOXY-alpha-Dglycero-HBX-4-ENOPYRANOSYL- ( 1-4)-2-DEOXYSTREFTOLIN A. SULFATE SUCCINAMIC ACID, N-( (2-MsIlraxY-3-( (1.2.3.6-~0~0-1.3-DIMETWL2,6-DIOXOPURIN-7-YL)MEFlCURI)PROPYL)CARBAL)SUCCINAMIC ACID, N- ( ( 2-MsntOXY-3- ( ( 1 ~ 2 1 3 , 6 - ~ D R 0 -3-DIMETWL1, ~,~-DIOXOPURIN-~-YL)MEFICIJRI) PROPYL)CARBAMOYL)-. SODIUM SALT SUCCINIC ACID, MERCAPTO-. DIETHYL ES'EB, S-ester with 0,O-DIHETWL PHOSPHORODITHIOATB TWOMINE TELLURIUn OXIDE "EREF'HTHALIC (1:2:2)

ACID,

CWpd.

with 3 - ( 2 - A I ( I N O ~ L ) I N D O L - 5 - O L

and ACGTATE

TERMINALIA ARJUNA, BARK WIRACT 5H-TETRAZOLOAZEPINE, 6,7,8.9-=DRO~ P H Y L L I N ,E a-pENTyL-

THEOPHYLLINE. 7 - ( 1 , 3 - D I O X O L M - 2 - Y L L ) THEOPHYLLINE, 8 - B V m - , HYDROCHLORIDE TfiEOPWLLINE, 8 - B E w Z n - 7 - ( 2 - ( E T H Y L ( 2 - H Y D R O ~ L ) A M I N O ) ~ ) ,HYDROCHLORIDE "HEOPHYLLINE, 7-(2-(cUCLOHnrrLAMINO)EI1M)-. HYDROCHLORIDE

-

THWPHYLLINE, 7- (2-( (3-PYRIDYLMEIWL)AMINO)Fnm)

7-THEOPHYLLINEACEI'AMIDE,OXIME, HYDROCHLORIDE 7-THEOPHYLLINEPROPIONAMIDE, OXIME, HYDROCHLORIDE THEORPHYLLINE, 7-(2-((3-PYRIDnM~L)AMINO)ETHYL)-, NICOTINATE 5-THIA-l-AZABICYCL0(4.2.O)OCT-2-ENE-2-CARBOXYLIC ACID, 3-(HYDROXYMETHYL) -8-0x0-7-(2-(2-THIENYL)ACGTAMIDO)-,ACEI'ATE, MONOSODIUM SAGT 5-TliIA-l-AZABICYCLO('4 .2.O)OCT-2-ENE-2-CARBOXYLIC ACID, 3(((AMINOCARBONYL)OXY)METHYL)-7-MEl'HOXY-8-OXO-7((2THIWLACETYL)AMINO)-. (6R-cis)5-THIA-l-AZABICYCLO(4.2 .O)OCT-2-ENE-2-CARBOXYLIC ACID, 7-(2(CYANOACGT~IW)-3-(WYDROXYMFPHYL)-8-0XO-l, ACETATE (ester), MONOSODIUM SALT 4-THIA-l-AZ,WICYCLO( 3.2 .O)iiF,PTANE-2-CARBOXYLICACID, 3.3-DIMETHYL-6( ( ( 5 - W ~ L - 3 - P H ~ L - 4 - I ~ ~ L ~ -7-0x0~ O ~ I D E ) 4-THIA-l-AZABICYCLO(3.2 .O)HEPTANE-2-CARBOXYLIC ACID, 6-((AHINO(4HYDROXYPHENYL)ACETYL)AMINO)-3,3-DIMETHYL-7-OXO-, TRIHYDRATE. (2S-(2alpha,5-alpha,6-beta(S*)) )

-

4-THIA-l-AZABICYCW( 3.2.O)HEPTANE-2-CARBOXYLIC ACID, 6-(3-(0CHLOROPHENYL)-5-WEl'HYL-~-IsO~LscARBOXAMIDO) -3,3-DIMETHYL-7-OXO-, SODIUM SALT, MONOHYDRATE 4-THIA-l-AZABICYCLO( 3.2.O)HEPTANE-2~CARBOXYLIC ACID, 3,3-DIMEIWL-7OXO-6( 2-PHENOXY-ACETAMIDO)-, MONOPOTASSIUM SALT

237 4-TMA-l-AZABICYCL0(3.2.0)~ANE-2-CARBOXYLIC ACID. 6((AMINOPHWYLACETYL)AMINO)-3,3-DIM~-7-OXO-. (2.2-DIMEI'HYL-10XOPROPOXY)METHYL ESTER. HYDROCHLORIDE

~-THIA-~-AZABICYCM (3.2 - 0 )HEPTANE-2-CARBOXYLIC ACID, 6-( ( (HEXAHYDROHYDROXYMm ESTER. PIVALATE (ester).MONOHYDROCHLORIDE. ( + I 4-THIA-l-AZABICYClA(~.~.O)H~PTANE-~-CAREOXYLIC ACID, 6( (AMINOPHprm\CETYL)AMINO)-3,3-DIMEI?lYL-7-OXO-. 1((~0XYCARBONYL)OXY)EI'HYLESTER. HYDROCHLORIDE 4-THIA-l-AWBICYCLO(3.2.0) HEI'TANE-2-CARBOXILIC ACID, 3.3-DIMETHYL-7OXO-6-(Z-PHENuw\CET=AMIDO)-, c~mpd.With 2-(DIETHnAMINO)FIHn pAMINOBENNZOATE ( 1 : l ) . MONOHYDRATE 4-THIA-A-AWeXCYCLo(3.2.O)H~~E.2-CARBOXYLIC ACID. 3.3-DIMEIWL-70x0-6-(PHENOXYPHENYLACETYL)AMINO)-. MONOPOTASSIUW SALT

ACID, 35-THIA-AZABICYCL0(4. 2 . O ) O C T - 2 - P I E - 2 - C A O X n I C (HYDROXYMEIWL)-8-0x0-7(2-(THIENYL)ACETAMIDO)-. SODIUM SALT THIENO(~.~-C)PYRIDINE-~-CARBOXYLIC ACID, 2-AMINO-6-BENZYL-4.5.6.7TRRAHYDRO-. ETHYL ESTER.HYDROCHLORIDE 3-THIOPHENEMALONAMIC ACID, N- ( 2 - C A R B O X Y - 3 , ~ - D I M ~ ~ 7 ~ O X O ~ ~ ~ ~ I A - l ~ AUIBICYLO(~.~.O)HEPT-~-YL)-.DISODIUM SALT THYMOL. 6.6'-( 3H-2.l-BENZOXATHIOL-3-YLIDENE)DI-, S,S-DIOXIDE s-TRIAzOLo(4.3-a)PYRIDINE. 5.6.7.8-TcI7wruDRO-3-(2-(4-(0-TOLYL)-1PIPERAZ1NYL)ETliYL) ,HYDROCHLORIDE

-

4,5-d)PYT4IMIDIN-7-AMINE ~H-v-TRIAZOLO( I-alpha-H,5-alpha-H-TROPAN-3-alpha-OL. 3- (p-HYDROXYPHENYL)-2PHENYLPROPIONATE (ester)ACETAATE (ester). HYDROCHLORIDE l-alpha-H.5-alpha-H-TROPAN-3-alpha-OL. 2-(p-CHLOROPHENYL)-2PHENYLACETATE. HYDROCHLORIDE l-alpha-H.5-alpha-H-TROPAN-3-beta-OL. BENZILATE (ester) l-alpha-H,5-alpha-H-TROPAN-3-beta-OL. HYDROCHLORIDE

TROPANE, 3-(alpha-(o-TQLYL)BENZYLOXY)-, HYDROBROMIDE TROPANE, HYDROCHLORIDE l-alpha-H.5-alpha-H-TROPANE-2-beta-CARBOXYLIC ACID, 3-beta-HYDROXY-, METHYL ESTER. BENZOATE l-alpha-H.5-alpha-H-TROPANE-2-beta-CARBOXYLIC ACID. 3-beta-HYDROXY-. BENZOATE (ester).HYDROCHLORIDE I-alpha-H.5-alpha-H-TROPANE-2-CARBOXYLIC ACID, 3-OXO-, MEl'HYL ESTER, HYDROCHLORIDE 1-alpha-H.5-alpha-H-TROPANIUM. 8-(p-JXiYLBENZYL)-3-alpha-HYDROXY, BROMIDE, (+-)-TROPATE,transl-alpha-H.5-alpha-H-TROPAPIIUM.

3-HYDROXY-8-(p-OCTYLBENZYL) -, BROMIDE.

BENZOATE (ester) TRYPTOPHAN. N-ACEWL-l-NITROSO-. METHYL ESTER, DLD-TRYPTOPHANAMIDE. N(sup alpha)-(N-ACETYL-D-PHENYLALANYL)IIREA. 1-(2-CHLOROEmL)-l-NITRoso-3-RIBOFURANOSYL-, 5'-(pNITROBENZOATE), 2',3'-CYCLICACETAL with ACCM)NE

UREA. 1-(2-BENZoniIAZOLYL)-3-MFPHYL-

238 UREA, N,N'-BIS(1,3-BWZOMTHIOL-2-YLTHIO)METHYL)-

UREA. (alpha-(2-WF3'HYLIiYDRAZINO)-p-TOLUOYL)-. MONOHYDROBROMIDE UREA, N-MEl'HYL-N-NITROSOVANADIUM PENTOXIDE (Fume) XANTHINE, 7-(5-HUDROXYHEXYL)-3-MmL-1-PROPYL-l-PROPYLXANTHINE. 3-1SOBUTYL-l-METHYLZINC OXIDE ZINC, Complex with 1.10-PHENANTHROLINYLENE ZINC CHLORIDE ZINC SULFATE (1 :1) ZINC, (N,N'-PROPYLENE-1,2-BIS(DITHIOCARBAMATG))

239

REPRODUCTIVE HAZARDS IN INDUSTRY: IDENTIFICATION AND PREVENTION

Kari Hemminki and Marja-Liisa Lindbohm

.

INTRODUCTION Changes in industrial structure over recent decades brought about the need for additional labor force and resulted in the increasing employment of women. The increased participation of pregnant women in the labor force raised concerns about the effects of occupational exposure of offspring: Therefore protective legislation concerning women workers was passed in many countries. Recently, both social and scientific events have caused the issue to be seen in a new light. Examples of these events include women's movement for equal employment opportunities and data on the sterilizing effects of exposure to dibromochloropropane in male workers. The latter discovery proved that reproductive hazards are not only the problem of pregnant women; rather the vulnerability of paternal reproductive health must also be kept in mind. In the present article we survey the application of experimental and epidemiologic approaches in the prevention of reproductive hazards in the work place. We also discuss the types of chemicals that women are exposed to and the changing role of women in the labor force. 1

MECHANISMS OF REPRODUCTIVE TOXICITY Harmful agents in the occupational environment can affect reproduction preconceptionally, during pregnancy, and after birth (1-4). Preconceptional hazardous events can affect the testes. the ovaries, or the maternal or paternal gametes which contain the hereditary information of the offspring. Experimental studies have identified large numbers of mutagens that can potentially damage male and female gametes. No differences in the sensitivity 2.

240

of female or male cells to the toxic actions of exogenous agents are known to exist. Thus the prevention of preconceptional damages caused by mutational effects implies the protection of both sexes from harmful exposure. Postconceptionally. during pregnancy, the offspring's exposure to harmful agents depends mainly on the mother's exposure. The placenta acts as a barrier against some agents but many toxic agents traverse the placenta. spontaneous abortion. fetal death, congenital malformations. growth disturbances, or functional disorders can result from fetotoxic effects. Genotoxic effects during pregnancy can cause childhood cancer or genetic disorders in the gametes of the child. Teratogenicity testing has been concerned with postconceptional events. In humans, most reproductive studies have focused on postconceptional events and relate to maternal exposures at the time of pregnancy. some studies on paternal exposures have also been carried out but they are technically even more complicated than the ones on female exposure. 3. EVIDENCE ON OCCUPATIONAL HAZARDS

Reproductive epidemiology has only recently attracted concentrated research effort. The field is now at the stage where relevant outcomes have been investigated and study designs validated. It has become apparent that these studies pose a number of special problems in epidemiology, such as the rarity, recurrence, and sensitivity of events. voluntary decisions involved, and the exact timing of reproductive processes (5-6). The acquisition of data on exposure is particularly demanding in occupational and environmental studies, and the common inaccuracies and misclassifications are likely to weaken any associations. As the associations are likely to be relatively weak anyway (because the levels of environmental exposures are relatively low), misclassifications may lead to unwarranted conclusions about the absence of risk. The literature on epidemiologic findings is surveyed in other chapters of this book and elsewhere ( 5-7). As a aummafy, studies on food poisoning episodes have shown that the ingestion of alkylrnercury and food oil contaminated by technical polychlorinated biphenyls leads to congenital defects in the offspring. It also appears to be relatively well proven that

241

laboratory work poses reproductive problems, possibly because of exposure to many types of solvents. Although exposure to anesthetic gases at the levels now used probably does not entail detectable hazard. other exposures that occur in hospitals, such as exposure to antineoplastic agents (8-9) or ethylene oxide, may pose risk, unless well controlled. By this time there should be sufficient understanding and agreement on methods and data bases large enough for case retrieval in order to assess further the role of occupational and other environmental factors in reproduction (see e.g. 5.6). We thus feel that epidemiologic studies on reproduction have a n important role in occupational health. The role is emphasized due to the lack of validation of animal models, as discussed later. Thus this field of epidemiology appears as a key research instrument in the prevention of occupational hazards. In the same token as we acknowledge that epidemiology is the only measure of disease outcomes in man, w e have to admit that it suffers from several limitations. such as sample-size problems and costs. It has even been maintained that a systematic epidemiologic research has failed to identify a single human teratogen so far. Experimental studies that are relatively inexpensive could potentially provide useful information about embryotoxicity of chemicals. Unfortunately, no comprehensive assessment of the validity of animal tests in predicting human risks has been done. Anyway,such assessment is hampered due to the lack of epidemiologic and experimental data. Correlations between humans and animals exist on a qualitative basis, but from a practical point of view only quantitative relationships would be useful. Judged from the very limited amounts of data available, some quantitative correlations between tests o n humans and animals may exist (10). Because the predictive value of animal tests remains to be established, animal tests cannot prove teratogenicity of a chemical in humans. However, most prudent preventive strategies use both epidemiologic and experimental approaches to identify hazards and to reduce exposures in the workplaces. PREVALENT EXPOSURES Extensive industrial hygiene surveys have been carried out in many countries, and they have provided information o n t h e types 4.

24 2

of chemicals used in the workplace. However, exposure of male and female workers have not been distinguished in such surveys. This is a shortcoming, as women are an,essential part of the labor force today. Additionally, the workforce is generally segregated into typical male and female jobs; women tend to be exposed t o different kinds of occupational hazards than men. There has been a general trend towards an increase in w o m e n l s participation in the paid labor force after the Second World War. In many industrialized countries the proportion of economically active women in the total female population is nowadays over 40 0 . In the future, the growth of the female labor force has been predicted to continue. women tend t o work in a narrow range of traditional female jobs (11). In Finland, 45 % of the women were employed in occupations totally predominated by women: at least 91 0 of the workers were women (12). Women are most often employed as service workers, clerical workers, or professional and technical workers. For instance, in Finland the most common occupations of women in 1980 were farm worker, cleaning woman, sales worker, office clerk and nurse (13). Typical occupations of women in industry are textile, clothing, food industry, or packing work. The recent growth of the female labor force in Finland has occurred mainly in the traditional female occupations. In the future, the occupational structure of the labor force will change due t o the new technology. However, the growth of large traditional female occupations, like health care professions, cleaning work. and hygiene and beauty treatment, will continue. In general, the need of workers will increase considerably in the service trade. Also the proportion of clerical personnel in the labor force will grow. whereas the decrease in the number of industrial jobs - a general trend in many western countries - has been predicted to continue. In Finland. the only growing sectors of industry are probably metal, chemical and electronics industry The prevalence of various exposures among women have been considered in a Scandinavian Working Group on Reproductive Hazards. The order of prevalence, but not necessarily the order of reproductive importance, is shown in Table 1. Organic solvents, inorganic gases and textile dust were thought to be the most prevalent chemical factors to which working women are exposed to. Organic solvents are undoubtedly important also from

243

the toxicological point of view, and they probably constitute the main reproductive problem for exposed women in the workplace. TABLE 1. Most prevalent chemical exposures of working women in the Scandinavian countries. Organic solvents Inorganic gases Textile dust-colors Plastics chemicals, pyrolysis products Pesticides Formaldehyde Rubber chemicals Anesthetic gases Solder fumes Metals Oil mist In the future the nature of chemical exposure has been predicted to change. The level of exposures will decrease, but at the same time simultaneous exposure to many chemicals with low concentration will become more general as the usage of chemicals in the society is growing continuously. In western countries. approximately 200-1000 new chemicals (in quantities of 5 0 0 kg or more) are developed and introduced into the marketplace every year. A potential reproductive hazard, in addition to chemicals, is ionizing and nonionizing radiation, the use of which will also grow in future work environment. It has been estimated that internationally the number of workers exposed to radiation will increase over 100 % by the year 2000. 5. CLUES FROM EXPERIMENTAL DATA

Several hundred chemicals have been tested for teratogenicity and embryotoxicity in experimental animals. Such tests are required by national agencies supervising the safety of food, drugs, pesticides etc. Yet uncertainties exist about the predictive value of animal tests; extensive attempts to assess the validity of the animal expeEiments (10) have not shown a convincing concordance, nor have they shown a complete discordance. It is likely that the animal tests for teratogenicity and embryotoxicity will remain in the arsenal of toxicology. For most chemicals, the absence of human data leaves animal data the only basis of reproductive risk assessment. It must not be ignored by occupational health staff nor by those setting occupational safety standards.

244

The hygienic standards and norms have been established to protect most of the workers from acute toxicity of industrial exposures. Teratogenic properties of industrial COmpOUndS have not been an important factor influencing the eetting of the hygienic standarde. This is understandable as very few epidemiological studies are available to show a n aSSOCidtiOn between a parental occupational exposure and malformations in the offspring. Moreover, the predictive power of the animal tests has not been firmly established. Reviews of the teratogenicity tests have indicated that the effective concentration of metals in animal tests generally exceeded the calculated human exposures by about 100 times or more (14). By contrast, many organic compounds had generally such high TLV values that they probably do not guarantee the safety of the developing human embryo exposed in utero. In Table 2 the compounds are listed for which the safety margin between TLV and the effective animal doses does not appear to be large enough. The safety margins allow less than a factor of 10 for acrylonitrile, carbon disulfide, chloroform, chloroprene, methylene chloride, styrene, tetrachloroethylene, and toluene. Exposure to these compounds at the TLV would appear hazardous. For another group of compounds - including 1.1-dichloroethane, ethylene oxide, methacrylate esters. trichloroethylene. and xylene - the apparent safety margin is still probably not large enough and the TLVs could be lowered to ensure larger safety margins. TABLE 2 . Compounds with low safety margins 1- to 10-fold

10- to 50-fold

Acrylonitrile Carbon disulfide chloroform Chloroprene Hethylene chloride styrene Tetrachloroethylene Toluene

1.1-dichloroethane Ethylene oxide Metacrylate esters Trichloroethylene Xylene

Daily exposure of workers (mg/kg body weight) at TLV levels of chemicals (OSHA, 1976) was compared to effective doses of the chemical in experimental animals (see ref. 14).

245

It should be emphasized that this kind of comparison is quite theoretical, and it does not provide absolute unsafe exposures, nor does it specify safe levels. However, with the present understanding of the animal experiments it would appear prudent to lower the TLV values for the compounds for which the human exposure may be up to 1/100 of the effective human dose. Even though the extrapolation from animal tests is compounded by uncertainties, the revision of the hygienic standards concerning the pregnant worker appears justifiable in such cases. With ever-increasing female participation in the work force, more emphasis should be placed on reproductive hazards and their prediction, in the absence of adequate epidemiologic data. from experimental results. CONCLUSIONS Reproductive hazards in the workplaces can be identified through epidemiologic research. outcomes such as spontaneous abortions and malformations require large sample sizes that cannot usually be collected from single workplaces. Several workplaces need to be pooled and a coordinated effort is required in the execution of the studies. However, a systematic follow-up of the rates of spontaneous abortions and malformations by industrial physicians may offer clues to reproductive hazards. On other outcomes, such as birthweight of children and sperm abnormalities in exposed men, smaller sample sizes are required but many types of confounding factors may exist that impede the interpretation of the results. Relatively few occupational chemicals or exposures have been shown or suspected to cause reproductive hazards in ran. They include laboratory work and solvents, anesthetic gases, dichlorobromopropane, ethylene oxide and anticancer drugs as occupational exposures. and alkylmeqcury and technical polychlorinated biphenyls as food contaminants. Yet allert occupational health practice also considers results from experimental animals, and, in general, helps to organize the work of pregnant women so that undue chemical exposures are prevented at any time of pregnancy.

246

REFERENCES B.R. Strobino, J. Kline, and 2. Stein, Chemical and physical exposures of parents: Effects on human reproduction and offspring. Early Hum. Dev. 1, 1978, 371. 2. P . M . Sullivan and S.M. Barlow, Congenital malformations and other reproductive hazards from environmental chemicals. Proc. R. SOC. Lond. (Biol.) 205, 1979, 91. 3. K. Hemminki, M. Sorsa and H. Vainio, Genetic risks caused by occupational chemicals. Scand. J. Work Environ. Health 5, 1979, 307. 4. J.F. Haas and D. Schottenfeld, Risks to the offspring from parental occupational exposures. J. Occup. Med. 21, 1979, 607. 5. K. Hemminki, 0. Axelsson, M-L. Niemi, and et al. Assessment of methods and results of reproductive occupational epidemiology: spontaneous abortions and malformations in the offspring of working women. Am. J. Ind. Med. 4, 1983, 293. 6. K. Hemminki and H. vainio, occupational epidemiology and reproduction. In: Recent Advances in Occupation Health, ed. by J.M. Harrington. Churchill Livingstone, Edinburgh, 1984, p. 117. 7. M-L. Lindbohm, H. Taskinen and K. Hemminki, Reproductive health of working women. Public Health Rev., in press. 8. K. Hemminki, P. K y y r h e n and M-L. Lindbohm, Spontaneous abortions and malformations in the offspring of nurees exposed to anesthetic gases, cytostatic drugs and other potential health hazards in hospitals based o n registered information of outcome. J. Epid. Comm. Health 39, 1985, 141. 9. S.G. Selevan, M-L. Lindbohm, R.W. Hornung and K. Hemminki, A study of occupational exposure to antineoplastic drugs and fetal loss in nurses. N e w Engl. J. Med. 313, 1985, 1173. 10, K. Hemminki and P. vineis, Extrapolation of the evidence on teratogenicity of chemicals between humans and experimental animals: chemicals other than drugs. Teratog. carcinog. Mutag. 5 , 1985, 251. 11 International Labour Organisation. Advisory committee on salaried employees and professional workers. Problems of women non-manual workers: work organization, vocational training, equality of treatment at the workplace, job opportunities. Report 1 1 1 . International Labour Office, Geneva, 1981. 12 K. Kauppinen-Toropainen, E. Haavio-Mannila, I. Kandolin and M. Simonsuuri-Sorsa, Women and work. Ty6terveyslaitoksen katsauksia 57. Lanai-savo Oy, Mikkeli,. 1983. (in Finnish) 13. Official statistics of Finland VI C: 106. Population and housing census 1980. Central Statistical Office of Finland. Government printing centre, Helsinki, 1983. 14. K. Koskinen and K. Hemminki, Experimental teratogenicity and embryotoxicity of occupational chemicals. In: Occupational Hazards and Reproduction, ed. by K. Hemminki. M. Sorsa and H. Vainio. Hemisphere. Washington D.C., 1985. p. 127-144. 1.

I

I

247

TERATOGENIC CHEMICALS I N UNDERGRADUATE GENERAL CHEMISTRY LABORATORIES

DORIS K. KOLB

Several y e a r s ago a s t u d e n t came up t o me i n t h e l a b o r a t o r y , q u i e t l y e x p l a i n e d t h a t she was p r e g n a n t , and asked i f t h e r e would be a n y t h i n g t h e c l a s s m i g h t be w o r k i n g w i t h t h a t day t h a t she s h o u l d a v o i d .

She was a s k i n g a

v e r y good and i m p o r t a n t q u e s t i o n , b u t I was s u r p r i s e d t o h e a r h e r ask i t . one had e v e r asked me t h a t q u e s t i o n b e f o r e .

No

Fortunately, the laboratory

e x e r c i s e t h a t day i n v o l v e d m e t r i c measurements and d e n s i t y d e t e r m i n a t i o n s , and

I c o u l d t e l l h e r w i t h c o n f i d e n c e t h a t i t posed no r i s k . t h a t e v e r y week?

But could I t e l l h e r

Probably n o t .

I had t o a d m i t t h a t I had n e v e r r e a l l y contemplated what hazards o u r l a b o r a t o r y experiments m i g h t p r e s e n t t o s t u d e n t s who happened t o be e x p e c t a n t

I had no i d e a as t o whether o r n o t some o f o u r l a b o r a t o r y c h e m i c a l s

mothers.

m i g h t be t e r a t o g e n i c .

Yet t h e e n r o l l m e n t i n o u r c h e m i s t r y c l a s s e s f o r s t u d e n t s

i n h e a l t h - r e l a t e d f i e l d s i s about 90% female, and many o f t h e s e s t u d e n t s a r e We s h o u l d e x p e c t now and t h e n t o have s t u d e n t s who a r e pregnant.

married.

I began t o g i v e more a t t e n t i o n t o t h e p o s s i b l e dangers t h a t m i g h t be a s s o c i a t e d w i t h t h e m a t e r i a l s o u r s t u d e n t s were u s i n g i n t h e l a b o r a t o r y .

As

f o r t h a t p a r t i c u l a r s t u d e n t , she was sometimes excused f r o m l a b o r a t o r y work, e s p e c i a l l y when t h e r e would be exposure t o v o l a t i l e o r g a n i c l i q u i d s o r n o x i o u s gases.

On those days she would g e t a l l t h e i n f o r m a t i o n f r o m h e r p a r t n e r f o r

w r i t i n g up l a b r e p o r t s .

H a p p i l y h e r baby was b o r n normal and h e a l t h y .

O f course, one way t o c i r c u m v e n t t h e problem o f p o s s i b l e t e r a t o g e n s i n t h e l a b o r a t o r y would be t o e x c l u d e a l l pregnant s t u d e n t s f r o m l a b o r a t o r y c h e m i s t r y courses.

Even i f t h a t c o u l d be accomplished, i t s t i l l would n o t s o l v e t h e

problem.

Students who s i g n up f o r c h e m i s t r y courses c o u l d be p r e g n a n t w i t h o u t

knowing i t .

Since t h e f i r s t t r i m e s t e r i s an e s p e c i a l l y v u l n e r a b l e p e r i o d f o r

t h e r a p i d l y d e v e l o p i n g embryo, damage c o u l d be done b e f o r e a woman even began t o r e a l i z e t h a t she m i g h t be a t r i s k . C l e a r l y we need t o l o o k a t t h e m a t e r i a l s we a r e u s i n g i n o u r General Chemistry l a b o r a t o r i e s and d e t e r m i n e whether o r n o t t h e y a r e s a f e f o r students

.

248

1.

POTENTIAL TERATOGENS IN GENERAL CHEMISTRY LABORATORY MANUALS Most academic chemistry departments some years ago addressed the problem of carcinogenic chemicals i n the laboratory. Many have tried t o eliminate the use of materials such as benzene and carbon tetrachloride, which have been linked t o human cancer. B u t w h a t about the chemicals t h a t might cause birth defects? Examination of twenty widely used laboratory manuals (refs. 1-20) indicates t h a t a number of chemical substances classified as potential teratogens (refs. 21-23) are currently being used i n General Chemistry laboratories. The manuals

include some t h a t are used in freshman level General-Organic-Biochemistry courses, as well as those used in more traditional General Chemistry courses. The fact that many of the experiments in these manuals use materials that are possible teratogens does not in itself necessarily constitute a significant health risk. In order for a teratogen t o cause damage, i t must get into the body o f a pregnant woman, and then i n t o the fetus. In other words, i t must be ingested through the mouth or taken in through the respiratory tract or the skin. Solid materials may be inhaled if a i r turbulence happens t o carry the solid powder into the a i r , o r they may accidentally reach the mouth i f fingers t h a t have been handling the powder happen to touch the face. However, i t is those gases and liquids t h a t might be inhaled or absorbed t h r o u g h the skin t h a t are the biggest cause for concern. The current l i s t of potential teratogens already exceeds 4000 and i t continues t o grow, so i t i s likely t h a t the substances considered here are only me of the potentially teratogenic materials encountered in General Chemistry laboratories. I t should also be noted t h a t other undergraduate laboratories use quite a few additional materials t h a t are possible teratogens. Organic chemistry laboratories, especially those in which "unknowns" are given o u t frequently, may use hundreds o f different organic compounds, and there might well be dozens of potential teratogens among them. In the interest of safety for a l l students, instructors o f chemistry laboratories should look up all the materials t o be used in their classes t o see whether or n o t they might be potential carcinogens or teratogens. Common materials such as sodium chloride, carbon dioxide, and cottonseed oil are not included in Table I , nor are such food ingredients as cholesterol, caffeine, lactose, and leucine, even though they are used i n some of the laboratory experiments and they do appear in the l i s t o f potential teratogens (ref. 22). Students would get much more exposure to these compounds i n their daily lives than i n the chemistry laboratory. Of the various potential teratogens included in Table I , some can be handled quite safely and do not really represent a health risk. However, some of the materials should probably be avoided by students who are pregnant or

Table 1 .

Some P o t e n t i a l l y Teratogenic Substances Used i n General Chemistry Laboratories

+

C

P

C

r

0

r

r

r

U

r

r

U

P

T r

r

0

r

I-

r

ttt

x

lx

X I

X I

-&

I X I X I X

C

I

I-

a

0

I-

1x1

1x1

U

d

u

n

-s

r

ul

m

v1

c1

.-

I I I I 1x1

*

CO i s n o t a r e a c t a n t n o r an intended product, b u t i t i s produced whenever burners a r e used.

249

**

The numbers r e f e r t o Laboratory Manuals l i s t e d i n t h e numbered references ( r e f s . 1-20),

260

by any females who possibly might be. an i n d i v i d u a l basis.

1.1

Each substance ought to be looked a t on

Potentially Teratogenic Metals Table 1 l i s t s two common metals, lead and mercury. The highly teratogenic organic compounds of these metals are not ordinarily handled i n the undergraduate laboratory. Inorganic, s a l t s of lead and mercury are discussed in the next section. I t i s only the f r e e elements that are addressed here. Lead is a solid t h a t melts a t 327OC. Simply handling pieces of lead shot or lead f o i l should pose no appreciable health risk f o r students. Mercury, on the other hand, i s a liquid of significant vapor pressure, and working with metallic mercury i s known t o be hazardous. The long term risk of breathing mercury vapor applies to a l l students, b u t there i s a special, more immediate risk f o r the student who happens to be pregnant. Typical exposure to mercury in the General Chemistry laboratory occurs d u r i n g ( A ) Boyle's Law experiments, ( 6 ) thermal decomposition of mercuric oxide, ( C ) displacement of mercury from i t s dissolved s a l t s , and (0) cleaning up s p i l l s from broken thermometers. The Boyle's Law experiments ( A ) often require f a i r l y large amounts o f metallic mercury. One popular type of apparatus requires about 300 grams of mercury per team of students, and i t employs a wooden plunger, which tends t o leave mercury droplets behind on the counter tops. Often there are ten o r more of these units in use during a single laboratory session. Perhaps t h i s experiment might be j u s t as successful i f students watched i t on videotape, reading the data directly from close-up shots o f the apparatus on the television screen. Taping this experiment several dozen times could produce a random collection of s l i g h t l y different experiments providing many individual s e t s o f d a t a . Thermal decomposition o f mercuric oxide ( B ) i s a c l a s s i c experiment that i s very much worthwhile in the freshman laboratory. I t i s an excellent example of how different a compound can be from i t s component elements. I t is also the historical reaction that Joseph Priestley carried o u t when he discovered oxygen. However, i t need not be done individually by every student. If the instructor demonstrates t h i s experiment, the students' exposure t o mercury i s greatly reduced. (Note t h a t this experiment generates hot mercury vapor, which i s more hazardous t h a n the same amount of cool liquid mercury.) This reaction could also be shown t o students by means of a film strip o r video tape. The displacement of mercury from a dissolved mercury s a l t ( C ) using a metal such as copper, f o r example, might easily be substituted by the similar displacement of s i l v e r from s i l v e r n i t r a t e solution. Occasional accidents involving broken thermometers ( D ) are almost inevi-

251

table, so long as glass thermometers are used i n chemistry l a b o r a t o r i e s . However, the use o f thermometers f i l l e d w i t h colored alcohol can h e l p t o reduce the mercury contamination from s p i l l s t h a t end up between t h e cracks. 1.2

P o t e n t i a l l y Teratogenic Inorganic Compounds The inorganic compounds i n Table 1 include arsenic compounds, cadmium salts,

lead c h l o r i d e , l e a d n i t r a t e , and mercury s a l t s . These are h i g h l y poisonous compounds as w e l l as being suspected teratogens, and they need t o be handled w i t h e x t r a care.

Fortunately, most o f these substances are used o n l y i n d i l u t e

s o l u t i o n and u s u a l l y i n semi-micro q u a n t i t i e s .

Solutions o f arsenic, cadmium,

lead, and mercury s a l t s a r e t y p i c a l l y used i n connection w i t h Q u a l i t a t i v e Analysis procedures, and the amounts used are o f t e n no more than a few drops. Hand washing a t the end o f t h e l a b o r a t o r y p e r i o d i s e s p e c i a l l y important a f t e r working w i t h s o l u t i o n s such as these. 1.3

P o t e n t i a l l y Teratogenic Organic Compounds There a r e two s o l i d organic compounds l i s t e d i n Table 1, phenol and

s a l i c y l i c acid. pressure.

Phenol i s a low m e l t i n g (41-43OC) s o l i d w i t h a h i g h vapor

I t i s a severe s k i n i r r i t a n t i n a d d i t i o n t o being h i g h l y t o x i c and

p o t e n t i a l l y teratogenic.

Since i t i s normally dispensed as a l i q u i d ( w i t h a l i t t l e water), phenol i s l i s t e d w i t h the organic l i q u i d s i n Table 2. S a l i c y l i c a c i d (m.p. 157-159OC) i s a c r y s t a l l i n e s o l i d widely used i n the

General Chemistry l a b o r a t o r y .

A l l b u t t h r e e o f t h e l a b manuals examined use

s a l i c y l i c acid, u s u a l l y f o r making a s p i r i n o r o i l o f wintergreen.

When handled

properly, s a l i c y l i c a c i d should pose no s i g n i f i c a n t hazard f o r students i n t h e laboratory. The o n l y appreciable uptake o f t h i s compound t h a t might occur would be through i n h a l a t i o n o f the t i n y p a r t i c l e s picked up and c a r r i e d by the a i r stream.

This can be minimized by avoiding work areas where t h e r e i s a i r

turbulence o r v e n t i l a t i o n currents. The organic l i q u i d s i n Table 1 include ethanol ( e t h y l alcohol), which i s a common solvent and chemical reagent. During normal exposure i n t h e l a b o r a t o r y such a s m l l amount o f ethanol i s i n h a l e d o r absorbed through t h e s k i n t h a t i t would correspond t o only a miniscule t a s t e o f the l i q u i d . However, denaturants i n " l a b a l c o h o l " can modify i t s t o x i c i t y . Denatured alcohol o f t e n contains about 5% o f an a d d i t i v e such as benzene o r methanol. O f the twenty l a b manuals examined, eighteen use ethanol. general

, methanol

The o t h e r two s p e c i f i e d methanol instead.

In

i s considerably more t o x i c than ethanol.

The o t h e r organic l i q u i d s i n Table 1 are a l s o l i s t e d i n Table 2, along w i t h concentrated s o l u t i o n s o f phenol and formaldehyde. These l i q u i d s , as a group, are probably the most hazardous o f a l l the p o t e n t i a l teratogens found i n the

252

General Chemistry laboratory. All are volatile t o some degree, as indicated by their boiling points, and some are carcinogens as well. Table 2.

Potentially Teratogenic Liquids in the General Chemistry Laboratory

B.P.

Organic Liquids

(OC)

Toxic When Absorbed Inhaled Through Skin

Aniline

184

Yes

Yes

Benzene

80

Yes

Yes

2-Butanone

79.6

Yes

Carbon Disu 1f i de Carbon Tetrachl ori de

45.6

Yes

Yes

76.7

Yes

Yes

Ch 1or0 f orm

61

Yes

*

96

Yes

182

Yes

Yes

110

Yes

Yes

Formalin Phenol To1 uene

* **

**

Some Possible Toxic Effects

intoxication; headaches ; skin lesions; anemia bone marrow damage ; 1eukemi a ; apl asti c anemia ; depression headache; eye irritation (suspected carcinogen) nausea; hallucinations; tremors ; blood changes nausea; headache; cancer; kidney damage; liver damage; septic dermatitis 1 iver and kidney damage ; cancer (less toxic than CC14) skin irritation; cancer; vapors irritating t o mucous membranes nausea ; paralysis ; severe skin i rri tat1 on ; poi son i ng ; liver and kidney damage nausea ; headache; mi I d anemia central nervous system damage (less toxic than benzene)

Formalin i s a 40% aqueous solution of formaldehyde gas. Pure phenol i s a solid, b u t i t liquefies with about 8%water.

Aniline i s a severe skin i r r i t a n t , and i t can produce headaches in a d d i t i o n t o being a potential teratogen. I t is, used i n only two of the lab manuals t h a t were examined, and i t could readily be removed from those. Benzene i s suspected t o cause leukemia as well as b i r t h defects. Although many laboratories have tried t o phase o u t the use of benzene i n recent years, six of the laboratory manuals i n Table 1 s t i l l use i t . Toluene, which i s a common substitute for benzene, i s also on the l i s t of potential teratogens. However, i t appears t o be much less toxic than benzene. When benzene or toluene i s needed only as a solvent, some other hydrocarbon (such as hexane)

253 might p o s s i b l y be used instead, b u t when t h e hydrocarbon must be aromatic, t h e use o f a s u b s t i t u t e may n o t be f e a s i b l e .

I t does appear t h a t the qylenes are

l e s s t o x i c than toluene, and much s a f e r than benzene, so they might be used t o replace benzene o r to1 uene. 2-Butanone i s an eye i r r i t a n t and suspected carcinogen as w e l l as a potent i a l teratogen. I t i s used i n t h e undergraduate l a b o r a t o r y as a sample f o r making t e s t s on the ketone group. Acetone can be used j u s t as w e l l . Carbon d i s u l f i d e (CS2) i s a h i g h l y flammable, v o l a t i l e , and extremely f o u l smelling l i q u i d t h a t causes a burning sensation on t h e skin.

I t can produce

psychic and v i s u a l disturbances as w e l l as nausea, vomiting, and convulsions. T y p i c a l l y carbon d i s u l f i d e i s used as a solvent f o r substances such as s u l f u r o r phosphorus. There a r e o t h e r solvents ( t h e methylene h a l i d e s o r t h e w l e n e s , f o r example) t h a t would be more pleasant t o work w i t h and much l e s s hazardous. Both carbon t e t r a c h l o r i d e (CC14) and chloroform (CHC13) may cause l i v e r and kidney damage, as w e l l as cancer and b i r t h defects.

Even though many labora-

t o r i e s have discontinued the use o f CC14 and CHC13, three-fourths o f the l a b manuals examined here s t i l l use one o r t h e o t h e r o f these chemicals, and f i v e o f them use both. I n those experiments t h a t avoid the use o f CC14 o r CHC13 methylene c h l o r i d e (CH2C12) i s commonly used instead. 1.4

P o t e n t i a l l y Teratogenic Gases Since gases get i n t o t h e body so e a s i l y through t h e lungs, those t h a t are

p o t e n t i a l teratogens would appear t o be s i g n i f i c a n t hazards f o r pregnant women. Two o f the compounds l i s t e d i n Table 1 a r e gases. Carbon monoxide (CO) i s a deadly poison as w e l l as a p o t e n t i a l teratogen. I t i s r a r e l y made d e l i b e r a t e l y i n a chemistry laboratory, b u t i t i s produced

t o some degree whenever organic f u e l i s burned. Bunsen burner, carbon monoxide i s generated.

Every time a student uses a

The l e v e l can be minimized by

t u r n i n g o f f burners when they are n o t i n use and by making sure t h a t the room i s well ventilated. Another common gas t h a t appears on t h e l i s t o f p o t e n t i a l teratogens i s formaldehyde.

Since i t i s normally used as a 40% aqueous s o l u t i o n ("formalin"),

i t i s l i s t e d i n Table 2 w i t h the organic l i q u i d s . Only f o u r o f t h e twenty l a b manuals use formaldehyde: one i n a clock r e a c t i o n , two t o t e s t f o r t h e presence o f t h e aldehyde group, and t h e o t h e r t o make a polymer o f t h e phenol-formalde-

hyde type. I n none o f these i s t h e use o f formaldehyde e s s e n t i a l . There are o t h e r simple c l o c k reactions, t h e r e are o t h e r l e s s hazardous aldehydes, and t h e r e a r e o t h e r polymerization r e a c t i o n s t h a t would be more s u i t a b l e f o r an i n t r o d u c t o r y chemistry course.

264

Conclusion Of the twenty potentially teratogenic chemicals l i s t e d i n Table 1 , the ones t h a t appear t o present most risk f o r the pregnant chemistry student are the organic liquids given in Table 2. Some of these (aniline, butanone, carbon disulfide, formaldehyde, and phenol) could easily be omitted from introductory laboratory courses. Benzene and toluene m i g h t be substituted by xylene ( o r perhaps by other hydrocarbons), and both chloroform and carbon tetrachloride could be replaced by methylene chloride. El im i flat i ng poten t i a1 teratogens from Organic Chemistry 1aboratori es woul d be much more d i f f i c u l t . Many different v o l a t i l e liquids and low melting solids are handled i n the Organic laboratory, and the common practice of issuing "unknowns" to students , especially in Organic Analysis courses , greatly increases the number and variety of compounds t o which students m i g h t be exposed. Fortunately, there i s a strong movement a t present toward the miniaturization of glassware and experiments in undergraduate laboratories. Among the many benefits of t h i s trend i s the reduced volume of organic waste materials and the diminished student exposure t o potentially hazardous chemicals. The inorganic material t h a t probably poses the greatest risk to General Chemistry students i s the liquid metal, mercury. One way t o reduce the level of mercury vapor i n the laboratory would be t o have the instructor do some of the experiments as demonstrations. Any metallic mercury that must be kept in the laboratory should be stored in covered containers, so t h a t there are no open pools, and mercury s p i l l s should be cleaned up immediately. The use of film strips and video tapes can also be used t o minimize the exposure of students to chemicals that might be harmful. Hands-on experience in the laboratory i s valuable, b u t an occasional well-done experiment on video tape can allow students to become familiar w i t h important reactions involving hazardous chemicals without actual exposure t o the materials. Of course, v o l a t i l e substances t h a t might be toxic should always be used in the hood, and students should be urged to make i t a habit to wash t h e i r hands before leaving the chemistry laboratory. Safe practice i n the undergraduate laboratory should always be one o f the prime concerns o f any chemistry faculty. REFERENCES

M.R. Abraham and M.J. Pavelich, "Inquiry Into Chemistry", Waveland Press, Prospect Heights, IL, 1980. 2. J.M. Bauer and M.M. Bloomfield, "Laboratory Manual f o r Chemistry and the Living Organism", 3rd ed., Wiley, New York, NY, 1984. 3. J.A. Beran and J.E. Brady, "Laboratory Manual f o r General Chemistry", 2nd ed., Wiley, New York, NY, 1982. 1.

255 4. 5. 6.

7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20 * 21.

22. 23.

E. Boschmann and N. Wells, "Chemistry i n Action", Revised ed., McGraw-Hill , New York, NY, 1985. W.E. B u l l , W.T. Smith, and J.H. Wood, "Laboratory Manual f o r College Chemistry", 6 t h ed., Harper & Row, New York, NY, 1980. M. Hein, L.R. Best, R.L. Miner, and J.M. Ritchey, "College Chemistry i n t h e Laboratory", Brooks/Cole, Monterey, CA, 1984. G.R. Hered, W.H. Nebergall, and W. Hered, "Basic Laboratory Studies i n College Chemistry", 6 t h ed. , Heath, Lexington, MA, 1980. J.R. Holum and R.C. Denison, Laboratory Manual f o r "Fundamentals o f General Organic and B i o l o g i c a l Chemistry", 2nd ed., and "Elements o f Organic and B i o l o g i c a l Chemistry", 6 t h ed., Wiley, New York, NY, 1982. W.T. L i p p i n c o t t , D.W. Meek, K.D. Gailey, and K.W. Whitten, "Experimental General Chemistry", Macmillan, New York, NY, 1984. K. Liska and L.T. Pryde, " I n t r o d u c t o r y Laboratory Chemistry f o r Health Professionals", Macmillan, New York, NY, 1984. J.H. Nelson and K.C. Kemp, Experiments f o r "Chemistry: The Central Science" by Brown and LeMay, 3rd ed., Prentice-Hall , Englewood C l i f f s , NJ, 1985. T.I. Pynadath, Basic Experiments f o r " I n t r o d u c t i o n t o General , Organic, and B i o l o g i c a l Chemistry" by G i l l i l a n d , West, S t . Paul, MN, '1982. J.J. Roberts, J.L. Hollenberg, and J.M. Postma, "General Chemistry i n the Laboratory", Freeman, New York, NY, 1984. G . I . Sackheim and D.D. Lehman, "Laboratory Chemistry f o r the Health Sciences", 5 t h ed., Macmillan, New York, NY, 1985. G.H. Schenk and D.D. Ebbing, " Q u a l i t a t i v e Analysis and I o n i c E q u i l i b r i u m " , Houghton M i f f l i n , Boston, MA, 1985. A. Sherman, S. Sherman, and L. Russikoff, "Laboratory Experiments f o r Basic Chemistry", 3 r d ed., Houghton M i f f l i n , Boston, MA, 1984. E.J. Slowinski, W.C. Wolsey, and W.L. Masterton, "Chemical P r i n c i p l e s i n t h e Laboratory", 4 t h ed., Saunders, Philadelphia, PA, 1985. S.R. Smith and W.L. Masterton, "Laboratory Manual f o r I n t r o d u c t i o n t o Chemistry", Saunders, Philadelphia, PA, 1984. K. Timberlake, "Laboratory Manual f o r Chemistry", 3rd ed., Harper & Row, New York, NY, 1983. G.S. Weiss, R.K. Wismer, and T. Greco, "Experiments i n General Chemistry", 2nd ed., Macmillan, New York, NY, 1985. R.E. Beyler and V.K. Meyers, "What Every Chemist Should Know About Teratogens--Chemicals That Cause B i r t h Defects", J. Chem. Educ. 59 (1982) 759-62. V.K. Meyers and R.E. Beyler, "How t o Make an"Educated Guess" About t h e Teratogenicity o f Chemical Compounds", ed. by S.M. Somani and F.L. Cavendet, Charles C. Thomas, S p r i n g f i e l d , I L , 1981, pp. 124-161. V.K. Meyers and C.Y. Meyers, "Chemicals Which Cause B i r t h Defects-Teratogens", A B r i e f Guide, 1980, Carbondale, I L , paperback, 37 pages. A v a i l a b l e from t h e authors a t cost ($3.00).

266

SAFE HANDLING OF TERATOGENIC CHEMICALS BLAINE C. MCKUSICK The s a f e handling of teratogenic chemicals is a special case of the s a f e handling of chemicals i n general. There are general principles t h a t apply t o the handling of a l l chemicals. These are modified for p a r t i c u l a r chemicals depending on t h e i r physical, chemical, and toxicological properties on the scale and place of operation. It is convenient t o discuss the subject as i t applies t o three main places where chemicals are handled: laboratories,

e w i l l begin with i n d u s t r i a l operations, and out i n the community. W the place where the problem of handling teratogens is most s t r a i g h t forward, a place well known t o many readers of t h i s book: the laboratory. 1.1. HANDLING TERAToawS IN

THE LABORATORY.

Laboratories typically handle a large number and v a r i e t y of chemicals. L i t t l e or nothing is known about the toxicological properties of many laboratory chemicals. Some,especially i n research laboratories, are new substances about which very l i t t l e is known, perhaps not even the structure. Hence the key t o s a f e t y i n the laboratory is t o have a general procedure for handling chemicals such t h a t no matter what the properties of the chemical, whether i t is explosive, corrosive. highly flammable, highly l e t h a l , allergenic, carcinogenic, teratogenic, or some combination of these and other dangerous properties. one is unlikely t o get i n t o serious trouble. Such a general procedure is described i n the National Research Council report, "Prudent Practices f o r Handling Hazardous Chemicals i n Laboratories" (1). and other books on laboratory s a f e t y provide similar advice ( Z , 3 ) . Briefly, the procedure calls f o r carrying out most laboratory operations i n a well-ventilated area (e.g., a fume hood or a glove box) and avoiding skin contact with chemicals. A more detailed description follows. Before starting work with a chemical, one should find out whatever of its pertinent physical, chemical, and toxicological properties are known so t h a t these can be teken i n t o account i n handling it safely. Safety gleesee should be worn at a l l times i n a laboratory, and these may be supplemented by goggles. a face mask. or other eye protection f o r operations especially hazardous t o eyes. such aa pouring large amounts of corrosive substance. Avoid eating,

257

d r i n k i n g . or smoking i n l a b o r a t o r i e s .

C l e a r l y l a b e l a l l chemicals and

i n c l u d e warning l a b e l s i f they p r e s e n t a s p e c i a l hazard. impervious gloves and o t h e r s p e c i a l c l o t h i n g as needed.

Wear Good

v e n t i l a t i o n is e s s e n t i a l : t h e rate o f flow o f f r e s h a i r i n t o a l a b o r a t o r y should be such t h a t t h e a i r changes

4 t o 12 times an hour,

and t h e a i r should be w e l l d i s p e r s e d as i t e n t e r s t o avoid turbulence. A hood is a l a b o r a t o r y ' s most important s a f e t y apparatus.

P r o p e r l y used, hoods n o t only p r o t e c t l a b o r a t o r y personnel from p o t e n t i a l l y poisonous vapors and d u s t s , b u t they a l s o act as a b a r r i e r from s p l a s h e s , f i r e s , and minor e x p l o s i o n s , and they c o n t a i n accidental s p i l l s .

The v e l o c i t y of a i r flowing i n t o a hood a t i t s

f a c e should be 8-30 meters (60-100 f e e t ) / m i n u t e ; a gauge or some s o r t

of continuous monitoring d e v i c e should be p r e s e n t t o i n d i c a t e whether

a hood is o p e r a t i n g p r o p e r l y . P e r i o d i c i n s p e c t i o n s should check both a i r v e l o c i t y a t s e v e r a l p o i n t s along t h e f a c e of t h e hood and t h e a i r t i g h t n e s s of t h e exhaust system. Hoods are working a r e a s , n o t s t o r a g e a r e a s : material and equipment not i n use should be k e p t t o a minimum, as they may p a r t i a l l y block v e n t s and lower hood e f f i c i e n c y . Operations should be c a r r i e d o u t as f a r back i n t h e hood as convenient, but a t least 5 c e n t i m e t e r s ( s i x i n c h e s ) behind t h e hood f a c e , as a hood's e f f i c i e n c y rises markedly going from t h e f a c e t o t h i s distance. Chemicals known t o be e x c e p t i o n a l l y hazardous because of high t o x i c i t y r e q u i r e s p e c i a l p r e c a u t i o n s beyond t h e g e n e r a l g u i d e l i n e s j u s t described,

Highly p o t e n t t e r a t o g e n s , such as thalidomide and

dimethylmercury, f a l l i n t o t h i s c l a s s . a r e a of l i m i t e d access.

They should be s t o r e d i n an

Each l a b o r a t o r y worker's w r i t t e n p l a n s f o r

working with such a t e r a t o g e n and d i s p o s i n g o f t h e wastes a f t e r w a r d s should be approved by t h e l a b o r a t o r y s*!pervisor i n advance o f use.

A

log should be kept o f t h e amount i n s t o r a g e ; each time some is removed, t h e amount taken, t h e d a t e , and t h e name o f t h e u s e r s should be recorded. The p r e c a u t i o n s t o be taken w i l l vary with t h e p r o p e r t i e s of t h e chemical.

For example, dimethylmercury is v o l a t i l e (bp 92'C). o i l

s o l u b l e , and flammable.

Hence i t should be handled w e l l back i n a

hood, i t s c o n t a i n e r should be open a s l i t t l e as p o s s i b l e . gloves of o i l - r e s i s t a n t material (neoprene or n i t r i l e rubber) should be worn, t h e u s e r ' s f r o n t should be p r o t e c t e d by a rubber apron i f more than a

gram or so is used, and no open flame should be nearby.

With

thalidomide. a s o l i d of n e g l i g i b l e v o l a t i l i t y and low o i l - s o l u b i l i t y , prompt s t o p p e r i n g o f an opened c o n t a i n e r would be less important, t h i n

rubber gloves f a v o r i n g manual d e x t e r i t y would s u f f i c e , b u t d r a f t s t h a t might blow thalidomide d u s t around would have t o be scrupulously avoided. The question o f whether t h e r e should be r e s t r i c t i o n s on t h e handling of t e r a t o g e n s by women s~metimesarises.

No r e s t r i c t i o n s should be necessary i n l a b o r a t o r i e s following t h e good s a f e t y

p r a c t i c e s o u t l i n e d here.

However, i f r e s t r i c t i o n s are deemed

necessary, then simply excluding pregnant women from an o p e r a t i o n o r a l a b o r a t o r y is not enough; a l l women of child-bearing p o t e n t i a l should be excluded because t h e most s e n s i t i v e period f o r many t e r a t o g e n s is b e f o r e pregnancy is u s u a l l y recognized.

1.2 HANDLING TERATOOENS IN INDUSTRIAL OPERATIONS. The q u a n t i t i e s of chemicals used i n i n d u s t r i a l o p e r a t i o n s are g e n e r a l l y f a r g r e a t e r than i n l a b o r a t o r i e s , so t h e i r h e a l t h hazard is potentially greater. several other factors:

Counterbalancing t h i s f a c t o r of s c a l e are more i s known about t h e p r o p e r t i e s o f most

i n d u s t r i a l chemicals than about many of those used i n l a b o r a t o r i e s , engineering c o n t r o l s ( v e n t i l a t i o n , enclosed o p e r a t i o n s , remote c o n t r a l s ) can be i n s t a l l e d t o g r e a t l y l i m i t o p p o r t u n i t i e s f o r exposure, and good o p e r a t i n g procedures can be designed f o r t h e v a r i o u s processes. As i n t h e l a b o r a t o r y , s p e c i a l precautions are r e q u i r e d f o r

o p e r a t i o n s with h i g h l y t o x i c substances, such as highly p o t e n t teratogens.

Usually i t is p o s s i b l e t o design and o p e r a t e processes

involving t e r a t o g e n s i n ways t h a t make o p p o r t u n i t i e s f o r s i g n i f i c a n t exposure so s l i g h t t h a t women need not be excluded from such processes.

However, t h e r e are s i t u a t i o n s where exclusion o f women has

t o be considered.

An example would be a process employing l a r g e

q u a n t i t i e s of a t e r a t o g e n i c s o l v e n t t h a t r e a d i l y p e n e t r a t e s s k i n , and with some small p o s s i b i l i t y of s i g n i f i c a n t s k i n exposure t o t h e l i q u i d e x i s t i n g d e s p i t e good engineering c o n t r o l s , p r o t e c t i v e c l o t h i n g , and work p r a c t i c e s .

The d e c i s i o n is a weighty one, f o r , as mentioned i n

t h e s e c t i o n on l a b o r a t o r i e s , i f e x c l u s i o n is deemed necessary. i t should apply t o a l l women of child-bearing p o t e n t i a l , not j u s t t o pregnant women.

I f exclusion is deemed necessary, i t may be p o s s i b l e

t o mitigate its e f f e c t s : t h u s , i n t h e p r e s e n t example, s t a g e s of t h e process involving s u b s t a n t i a l amounts o f t h e t e r a t o g e n i c l i q u i d might be i s o l a t e d s u f f i c i e n t l y t h a t women could work i n t h e preceding and following s t a g e s .

259

1.3 HANDLINQ "ERATOOENS I N THE COMMUNITY. This is a much d i f f e r e n t s i t u a t i o n than the last two because most of the public is notoriously unknowledgable about how t o handle chemicals, and l i t t l e control of t h e i r actions is possible.

Hence

potent teratogens should not be put i n the hands of the public.

The

use of weak ones i n consumer products should be avoided as much as possible, and i f used, they should be i n forms and concentrations where the p o s s i b i l i t y of adverse e f f e c t s is remote.

Labels with

warnings and directions f o r proper use a r e of course e s s e n t i a l . and indeed a r e often required by law. REFERENCES

1

2

3

Committee on Hazardous Substances i n the Laboratory, National Research Council, "Prudent Practices f o r Handling Hazardous Substances i n Laboratories", National Academy P r e s s , Washington, D.C., 1981, pp. 30-56, 193-212. L. Baretherick. "Hazards i n the Chemical Laboratory". 3rd ed, Royal Society of Chemistry. London, 1981. M.E. Green and A. Turk, "Safety i n Working with Chemicals", McMillan, New York, N . P . , 1978.

260

USE OF REGISTERED DATA IN STUDIES OF OCCUPATIONAL EXPOSURE AND PREGNANCY OUTcoWg

Marja-Liisa Lindbohm and Kari HemIninki

1. INTRODUCTION

Epidemiological studies on the effects of occupational exposure to reproduction pose several special problems related to the collection of valid and reliable information on pregnancy outcome and potential occupational exposures during or before pregnancy. Generally the data have been obtained either by interviewing the workers or by collecting the pregnancy data from medical records and occupational exposure data from company or union records. Biological monitoring data or industrial hygienic data could also provide a good measure of exposure, but they are seldom available (1). Both interview and register data have their pitfalls. Inaccuracy of spontaneous abortion recall has been observed in retrospective questionnaire studies (2, 3). Response bias and some evidence of recall bias has also been reported ( 2 , 4). The use of registered data may help to avoid these problems. However, register data can also be erroneous, and especially exact and complete information of exposure may be unavailable. Here the Finnish registers will be described and some examples of their use in the investigations of the effects of occupationdl exposure to spontaneous abortion and congenital malformations will be presented. 2. STUDY STRATEGY

The registered data have been used for the identification and restriction of the study population. The general strategy of the studies has been as follows (Figure 1.). First, the workers have been identified from the existing national registers or the

261

STUDY S T R A T E G Y

(sg. f a c t o r y files, Union rsgfstar)

MflLFORMflTIONS

WORKERS

EXPOSURE I N F O R M f l T I O N

STUDY SUBJECTS

M E A S U R E O F OCCURENCE RELflTIONSHIP

Fig. I. Study strategy in studies of occupational exposures and pregnancy outcome.

262

personnel files of the employers. Secondly, the data on a working population has been linked with the aid of a personal identification code (a unique number assigned to an individual at birth) to the Hospital Discharge Hegister and to the Finnish Register of Congenital Malformations in order to identify the pregnancies of the study population. Finally, information on occupational exposures during the critical period of pregnancy has been obtained from the occupational health care personnel of the workplaces or the individuals themselves. Also the data on occupation and industry obtained from the population census has been used to classify the workers into job exposure categories to characterize the exposure. 3. REGISTERS ON PREGNANCY OUTCOME

The Finnish National Board of Health maintains a computerized nation-wide HoeDital Discharue Reaister of all the patients discharged from hospital. The register includes all the women who have been treated in hospital for spontaneous abortion, induced abortion and who have given birth to a child. For every discharged patient data on personal identification code, diagnosis, dates of admission and discharge and hospital code are recorded in the register. The register has been supplemented with spontaneous abortions treated on an outpatient basis. The reliability of the hospital register has been studied by analysis of the coverage and the accuracy of the data. In 1982 the register covered 968 of all officially recorded births and 90% of all recorded induced abortions. The coverage of spontaneous abortion data is difficult to estimate. The problem is related to the patterns with which the hospital services are used in the community. A comparison of interview and register data among hospital personnel found that the mean length of gestation was longer f o r spontaneous abortions included in the hospital register than for abortions only reported by the women by questionnaire ( 5 ) . If exposure causes early abortions in particular, the use of hospitalized cases leads to underestimation of its effects. The detection of spontaneous abortions from the register was also associated with the education level among hospital personnel. This could be explained by differences in seeking medical care or by differences in recognition and reporting of spontaneous abortions.

263 A study on the accuracy of spontaneous abortion diagnosis was

performed in one Helsinki hospital (5). The study indicated that the diagnosis in the discharge register agreed with the hospital records in 91% of the cases. In the policlinic of the same hospital, the diagnosis of spontaneous abortion, given at the time of treatment, remained unchanged in 87 % of the cases: after the pathologic-anatomic examination and in other 1 0 0 of the cases pregnancy had been verified earlier by a pregnancy test (H. Taskinen, personal communication). One important presumption for linking hospital discharge data to occupational data is the correctness of personal identification codes. The proportion of errors in the codes has been decreasing steadily from 8.9 % in 1973 to 1.6 % in 1983. The Finnish Register of Conqenital Malformations was established in 1963. Register is based on compulsory notifications of all malformations detected during the first year of life. The notification lists the names and dates of birth of the mother and child, a description of the delivery, and the malformation type of the child. Additionally a matched-pair register has been established for investigation of selected indicator malformations (6). It has been estimated that the failure rate in detection of malformations in the Finnish surveillance system is of the order of 30% (6). The failure rate varies by the type of defect, and is probably related to the severity and clinical significance of the malformation. Particularly minor malformations are underreported. When analysing them it has to be considered to what extent register deficiencies might introduce any bias or otherwise hamper the study on occupational reproductive hazards. The registered pregnancy data has its advantages. They are readily available and they include information on large populations. By linking them to the records of the workers the study can be restricted to those women only who have been pregnant thus reducinq the study size remarkably. When using the registered data, a number of problems of the interview studies, namely memory defects, low response rate, and selection between respondents and nonrespondents can also be avoided. The problems related to pregnancy registers are imperfect coverage of the records. possible selection among spontaneous abortions patients in seeking hospital care and in the case of the malformations possible selection in their notification.

264

4. REGISTERS ON OCCUPATIONAL GROUPS

There are three types of data sources which may be used for the identification of workers: 1) registers based on occupation (e.9. Union registers, Register of Health Care Personnel). 2 ) local registers of the employers, and 3) population census. Many Finnish trade unions have nowadays computerized nation-wide membership recristers. Generally they contain data on the actual members' identification code, name, employer. local trade union, and the date of joining the union. Data on the members who have resigned the union have to be collected separately from the manual records or from the computerized payment registers. The usability of the union registers depends in part upon the unionisation of labour of the industry. In Finland this is generally high; for instance in the metal industry estimated at 9 5 t by the union officials. Ununionized workers are probably short-term employees or those who work in smaller workplaces than unionized workers. Workforces in smaller enterprises may experience more hazardous conditions than the workers in large industries. If they fall outside the scope of the study the effect of high exposures rnay be missed. Another problem related to the use of union registers is that the dates of joining and resigning the union may differ from actual dates of hire and termination of the employment. There has also been Shortcomings in the registration and updating of the data on the employer and occupation. All the workers in health-related occupations in Finland are listed in the Central Reaister of Health Car e Personnel. The coverage of the register can be considered good as the personnel is registered at graduation and data are updated by employers at hire and termination. The individuals themselves are responsible for the updates of demographic data, which are not alvays current. The register contains information for instance on personal identification code, name, job title, date of employment, and workplace. Information on occupational groups rnay also be obtained from the pormlation cenaus. In the census information is requested on demographic factors. occupation and industry. These data can be used to classify the workers by jOb-eXpOSUre. The occupation stated on the census form only relates to the job held ac a

265

certain point in time. Therefore, these data are more reliable in industries with relatively stable populations. One possible source for the identification of the study population are the personnel records of the local ernDlovers. Nowadays they are computerized in many larger companies. Usually employers collect data on identification code, name, date(s) of hire and termination, and the job title of the worker. The employment dates recorded by the company are more accurate than those of the union. Employers are requested to maintain employee records for taxation purposes for 6 years. However, it may be difficult to obtain the worker records from the smaller enterprises and thus a portion of the exposed workers may fall outside the study. Additionally, the employee records may have disappeared, if the company has closed down or the owner has changed. The collection of the data from local records is also more laborious, expensive and time-consuming than the use of national registers. Given the limitations above, the national and local records may be considered as useful sources for the identification of the study population. They can be used for the restriction of the study to a population in which the particular exposure is fairly common thus increasing the effectiveness of the study. However, the data on occupational exposures in these registers are often unspecific or missing. The specific exposure data during the critical period of pregnancy must be clarified from other sources 5.

EXAMPLES

1. Studies on nurses

Nurses working in selected departments of general hospitals in Finland were collected from the Central Register on Health Personnel in Finland. Using the Hospital Discharse Resister and the Reaister of Consenitdl Malformations case nurses were selected who had a spontaneous abortion or a malformed child between years 1973-79. Controls consisted of 3 nurses with a normal birth; the control nurses were matched on age and hospital of employment. Information on exposure in the first trimester of pregnancy was sought through the head nurses of the hospitals (7). Exposure to antineoplastic drugs was associated with malformations in the offspring. The odds ratio was 2.0 when antineoplastic drugs were handled less than once a week, but it

266

rose to 4.7 (p = 0.02) when they were handled more often. The increase in the latter group was contributed by 8 malformations of various organ systems. The second study used a similar design but i t focused on nurses employed in hospitals that ranked high in the use of antineoplastic drugs (8). Information o n the exposure was obtained by self-administered, mailed questionnaires. The odds ratio for hospitalized spontaneous abortions in relation to exposure to antineoplastic drugs was 2.3 (p = 0.01).

The design of these studies is as follows: central Register on Health Personnel Nurses Deparments

Selected cases and controls

linkage

--

) .

Hospital Discharge Reqi st er Register o n Congenital Malformations

Exposure information Head nurse Nurse herself

2. Census study on occuDation/exposures

In a Finnish study, based on the data of a National Census from 1975, (9) the occupations were grouped according to presumed exposure into seven categories: exposure to solvents; metals; exhaust fumes; polycyclic aromatic hydrocarbons; other chemicals; textile dust: and animal micro-organisms. The relative risks of spontaneous abortions, obtained from HosDital Discharue Reuister, were not significantly increased in any exposure group. As the wornens' exposure was deduced from their occupations it is possible that the heterogeneity'of occupations with respect to intensity of exposure had diluted the possible effects. The analysis of detailed occupational categories showed some female occupations with a n increased risk. After controlling for age, number of children and place of residence spinners, fabric

267

inspectors and women in nonspecific occupations related to cutting and sewing had an increased risk (p
In addition,

butchers and sausagemakers, laboratory assistants and workers caring for fur-bearing animals had a significantly elevated risk.

The design of this study was: National Population and Housing Census of 1975 Occupational, social. 4 demographic data

+ linkage

Hospital Discharge Register, 1973-1976

Pregnant women

k

H

3. Occupational study in plastics industry based o n union files

The study population comprised all female workers in the plastics industry who were found in the files of the national Union of Chemical Workers in 1979 or who had resigned from the Union during 1978 and 1979 (10). The workers' reproductive data for 1973 to 1980 were collected from the Hospital Discharae Register. Information on occupational exposures was obtained fromthe occuDationa1 health services of the workplaces. No increased risk of spontaneous abortions was observed among workers processing polymerized plastics or heated plastics made of vinyl chloride, or styrene. The odds ratio for workers actually processing polyurethane was increased

(1.9, not

statistically significant). and that for all workers in polyurethane processing factories was significantly increased (3.0, p=O.O2).

268

The design of the study was: Membership file of t h of Chemical Workers ~

Pregnant women in the Union of Chemical workers

Selected cases and controls

r I,

Expoeure information Factory occupational health service

A

4. Occupational study in Pharmaceutical industry based on company

files Information about all female workers who had been employed in the Finnish pharmaceutical industry during the 1970's were obtained from the files of the companies (11). The workers' pregnancy data were collected from the HosDital Discharue Reaieter. A case-control study was carried out in which the cases were women who had had a spontaneous abortion during employment in the pharmaceutical factory. Three age-matched female pharmaceutical factory workers who had given birth to a child were chosen as controls for every case. The information about occupational exposures was collected from questionnaires which were completed by the occupational Physician or nurse at the factory. For methylene chloride, which is very commonly used as a solvent in the pharmaceutical industry. the increase in odds ratio was of borderline significance (odds ratio 2.3, p = 0.06). In a logistic regression model (which included estrogen exposure, solvent exposure by frequency of the usage and heavy lifting), the odds ratio was increased for estrogens (odds ratio 4.2, p = 0.05) and for continuous heavy lifting (odds ratio 5.7, p = 0.02).

269

, Personnel files of eight pharmaceutical companies in Finland

linkage

Hospital Discharge Register

~

Selected cases and controls

Exposure information Factory occupational health service

6. CONCLUSIONS

We have discussed here the advantages and disadvantages of registered data in reproductive studies. The availability of registered data on the outcomes secures information free from biases in recall, reporting and response. Furthermore, the data are readily accessible and may cover large populations. Various occupational data sources are useful in the initial definition of the study population. They are, however, rarely detailed enough to provide time-specific exposure information, and this has to be obtained on a n ad hoc basis. The use of register linkage allows resources to be focused on the laborious phases of ascertainment of exposure.

REFERENCES 1

2 3

4

G.K. Lemasters and S.G. Selevan, Use of exposure data in occupational reproductive studies. Scand. J. Work Environ. Health, 10 (1984) 1-6. L.Z. Heidam and J. Olsen, Self-reported data on spontaneous abortions compared with data obtained by computer linkage with the hospital registry. Scand. J. SOC. Med.. 13 (1985) 159-163. A. Wilcox and L.F. Horney, Accuracy of spontaneous abortion recall. Am. J. Epidemiol. 120 (1984) 727-733. G. Axelsson and R. Rylander, Exposure to anaesthetic gases and spontaneous abortion: response bias in a postal questionnaire study. Int. J. Epidemiol., 11 (1982) 250-256.

210

5

6

Niemi, K. Hemminki and M. sallm6n. Application of hospital discharge register for studies on spontaneous abortions. In: K. Hemminki, M. Sorsa and H. Vainio (eds): "Occupational hazards and reproduction". Washington DC, Hemisphere Publishing Co, 1985, pp. 237-247. L. saxdn, Twenty years of study of the etiology of congenital malfromations in Finland. In: H. Kalter (ed.): "Issues and reviews in teratology" Vol 1. Plenum Publishing Co, 1983, pp.

M-L.

73-110.

K. Hemminki, P. Kyyrtinen and M-L. Lindbohm, Spontaneous abortions and malformations in the offspring of nurses exposed to anesthetic gases, cytostatic drugs and other potential hazards in hospitals based on registered information of outcome. J. Epid. comm. Health 39 (1985) 141-147. 8 S . G . Selevan, M-L. Lindbohm, R.W. Hornung and K. Hemminki, A study of occupational exposure to antineoplastic drugs and fetal loss in nurses. N. Engl. J. Med. 313 (1985) 1173-1178. 9 M-L. Lindbohm. K. Hemminki and P. KyyrUnen, Parental occupational exposure and spontaneous abortions in Finland. Am. J. Epid. 120 (1984) 370-378. 10 M-L. Lindbohm, K. Hemminki and P. KyyrUnen, Spontaneous abortions among women employed in the plastics industry. Am. J. Ind. Med. 8 (1985) 579-586. 11 H. Taskinen, M-L. Lindbohm and K. Hemminki, Spontaneous abortions among women working in the pharmaceutical industry. Br. J. Ind. l e d . 43 (1986) 199-205.

7

271

LONG-TERM EFFECTS OF CHEMICALS ON DEVELOPING BRAIN AND BEHAVIOR

M. MIRMIRAN and S. DE BOER

1 CHEMICAL HAZARDS FOR DEVELOPING BRAIN AND BEHAVIOR The developing fetus and child are exposed to a wide - and still expanding - range of possibly hazardous substances, e.g. as a result of environmental pollution, through various types of noxious food constituents or a vast number of drugs. Many, if not most, of these substances easily pass the placenta and/or are excreted into the breast milk. They may even accumulate in the fetus, which does not yet have the metabolization and excretion capacity of the adult. High levels of various chemicals may therefore accumulate in the brain, which during the first part of its development is not yet or inadequately protected by a blood-brain barrier. After the period of main organogenesis (ref. l), the final stages of brain development are spread across a long period and continue even deep into childhood (refs. 2 - 4 ) . Thus, chemicals may influence its development not only before but also during and after birth. Effects on brain development in their turn may have far-reaching consequences for behavioral development. Even when no morphological abnormalities can be found, behavioral development may still be affected. Effects on brain and behavioral development may result in later sleep difficulties such as were found for antihypertensive clonidine (ref. 5), changed sexual orientation seen with diethylstilbestrol (ref. 6 ) , lowered IQ and mental retardation as found in cases of excessive prenatal exposure to alcohol (see section 1.3) or various types of environmental and food pollution (see section 1.1). It will be clear that these and many other types of effects on brain and behavioral development may profoundly affect the quality of life and, in addition, have adverse economic consequences (ref. 7). The present proportions of the problem are not easy to gauge due to two major problems. Namely, until recently not much attention had been paid to this problem. Also i t is difficult to relate subtle behavioral consequences of prenatal exposure to adverse influences, which may not become apparent until many years after birth. However, the presently available knowledge on neurobehavioral teratological effects of many substances on laboratory animals and the human fetus and infant suggests that the significance of the problem is considerable (refs. 8 , 9).

272

In this chapter, emphasis will be

put

on,

respectively,

the degree

of

exposure of developing humans to potentially neurobehavioral teratogenic substances, their vulnerability to noxious effects, the ways in which brain development may be influenced, the animal neurobehavioral literature and methodological problems. Since neurobehavioral development does not stop at birth, in this chapter we proceed from a working definition that teratogenesis is the science of all developmental disturbances, morphological and functional, including those induced after birth.

1.1 Environment and nutrition as sources of neurobehavioral teratogens Environmental pollution may reach the fetus and infant through a variety of .outes. Inhalation of polluted air in industrial areas and areas with a high traffic density, and of substances in the working environment of the pregnant or lactating woman may result in high concentrations of potentially teratogenic substances in the developing fetus or infant. The food ingested by mother or infant is another important source of adversely acting substances. It may contain pollution from the environment, residues from pesticides or animal drugs, food additives or natural poisons. Amongst others, various metals, volatile solvents and pesticides have been shown to affect adult human brain and behavior, and in addition affect neuronal and/or behavioral development in animals (refs. 10-12). Therefore such compounds may be suspected to have also behavioral teratogenic effects in humans. A common example of neurobehavioral teratogenic effects caused by polluted food is the Minamata disease. In a number of areas in Japan methylmercury from industrial waste accumulated in fish which was one of the main sources of the food of the local population. Another case of poisoning with methylmercury occurred in Iraq, where people consumed grain seed treated with a methylmercury fungicide. Women with only minimal poisoning symptoms gave birth to children that showed many neurological and behavioral abnormalities, such as mental retardation, coordination deficits and seizures (refs. 12, 13). Lead is another well-known behavioral teratogen. It may reach the fetus by the placenta, or the infant may ingest i t through the mother’s milk. Young children may ingest i t with lead-polluted dust. Lead can also be taken up from polluted air or drinking-water. A positive relation was found between the presence of lead in drinking water and prenatally caused mental retardation (ref. 14). Adverse effects of lead poisoning on the neurological and behavioral development of young children have been found in children ingesting lead containing paint particles. Furthermore, a negative correlation was observed between tooth lead concentration and school performance in young

273

school children. (refs. 12, 15). Some other cases of neurobehavioral teratogenesis were caused by ingestion of food polluted by polychlorinated biphenyls. High concentrations of polychlorinated biphenyls in rice oil consumed by pregnant women caused impaired neurobehavioral development of

the child: low IQ, sluggishness,

clumsy and jerky movements, apathy and hypotonia. Maternal intake of lower doses through consumption of contaminated fish caused, amongst other things, smaller head circumference and poor neuromuscular maturity in neonates

(ref.

16).

The use of food additives and excess nutritional supplements adds to the the exposure of the developing human organism to potentially neurobehavioral teratogenic influences. Noxious effects of food additives on behavior of young children which have been found (refs. 12, 17) may implicate potential hazards for normal development. A well-known teratogenic factor is excess of vitamin

It reduces adult brain size and produces effects on behavior that do not correlate with the effect on brain size, when given to rats on gestational days 14 and 15 in doses that do not induce high rates of mortality (ref. 18). When treatment took place on gestational days 17 and 18, no effect on brain size was found, but in adulthood the animals seemed to have a slight motor deficit (ref. 1 9 ) . A.

Monosodium glutamate (MSG), a food additive which is commonly used as a flavor enhancer and salt substitute, has been shown to cause physical, neuronal and behavioral teratogenic effects when administered to rats in relatively high doses (refs. 20, 21). Although neither intestinal tract nor placenta are highly permeable for this substance, Frieder and Grimm (ref. 20) showed that 10 g/kg MSG given in drinking water to pregnant rats on gestational days 7 to 20 did affect feeding behavior, activity levels and discrimination learning in their offspring. Therefore, in spite of the intestinal and placental uptake barriers, MSG seems capable of reaching the fetus in doses high enough to cause adverse effects. Lecithin is another food constituent which has been shown to cause neurobehavioral teratogenic effects in rats. It is added to foods as an emulsifier, but i t is also present in soy lecithin preparations vhich are consumed as 'healthy' food supplements. Soy lecithin preparations contain various phospholipids which can be incorporated into the brain as membrane constituents or acetylcholine, and conceivably may affect brain development if available in high levels. Pregnant dams were fed a lecithin-enriched diet (prepared by adding a commercial soy lecithin preparation) from gestational day 7 until weaning. Subsequently, the pups were also fed this diet. Treated pups showed faster rightening responses on postnatal days 1 and 2 and slower

214

responses on day 4 . Negative geotaxis latencies were shorter in the treated pups. At the age of 7 7 days morphine-induced analgesia measured by means of the tail-flick response was absent in the pups from the lecithin-enriched group. In other words, the diet induced long-lasting behavioral effects. Furthermore, biochemical measures of cerebellar and cerebral cortical development such as ornithine decarboxylase activity, DNA and RNA content and protein content, were all affected, suggesting a compression in time of cerebellar development and a delayed maturation of cerebral maturation. Similar measurements in the midbrain failed to elicit effects (ref. 2 2 ) . In a subsequent study Bell et al. (ref. 2 3 ) found that a lecithin-enriched diet resulted in age- and brain region-dependent changes in utilization rates of noradrenaline and dopamine, transmitter uptake capacities and tyrosine hydroxylase activity. The character of the changes found on day 60 suggests a promotion of impulse activity in both midbrain and brain stem, and reduced activity in the cerebral cortex. 1 . 2 Therapeutically used drugs

In the prescription of drugs to pregnant women often little attention is paid to possible adverse effects on brain and behavioral development of the fetus. Drug intake during pregnancy is relatively high (refs. 2 4 - 2 9 ) . Effects elicited during the first trimester, in which gross anatomical aberrations may be caused, have now been confirmed. Since the thalidomide tragedy, 20 years ago, drugs have been tested routinely for this type of adverse effects (ref. 1). However, the risk of functional teratological effects, which may also be caused in later stages of development, even after birth, is not yet generally taken into account. An example of a drug which causes various delayed effects in the offspring of women treated during pregnancy is diethylstilboestrol ( D E S ) . This drug had been prescribed for many years in high doses to pregnant women, with the aim to prevent miscarriages. After the discovery of its carcinogenous effects on female offspring, It was withdrawn from the market. Later i t appeared to have induced not only carcinoma but also morphological alterations in the reproductive tract and psychological aberrations in daughters of treated women, viz., changed sexual orientation (refs. 1 , 6, 2 8 ) . Many other drugs given t o pregnant women have been found to induce changes in the development of nervous system and behavior (refs. 2 9 , 3 0 ) . Examples of drugs prescribed to pregnant women, which are probable neurobehavioral teratogens are: barbiturates (ref. 3 1 ) , benzodiazepines (refs. 3 2 , 3 3 ) , tricyclic antidepressants (refs. 3 0 , 3 4 - 3 6 ) , various antihypertensive agents (refs. 5 , 3 5 , 3 7 - 3 9 ) , anticonvulsants (refs. 4 , 4 0 ) , neuroleptics

276

(refs. 30, 4 1 ) , and anesthetics (ref. 4 2 ) . Among the drugs used to treat the fetus or neonate there are also potential neurobehavioral teratogens which might affect further development of the ch.ild. For instance, prenatal corticosteroid treatment of preterms in order to improve lung function may induce adverse effects on psychomotor development (refs. 4 3 , 4 4 ) . Prenatal betamethasone treatment of rhesus monkeys resulted in decreased brain weight at birth among other abnormalities (ref. 4 5 ) . Theophylline, which is used to treat apnoea in premature infants (ref. 4 6 ) is metabolized to caffeine. The latter compound was found to be teratogenic in the rat (ref. 4 7 ) . Neuropeptides are a new class of potential teratogenic drugs about t o be marketed and suggested to have teratogenic effects (ref. 4 8 ) .

1.3 Addictive drugs Children of women addicted t o opiates, cannabinoids or alcohol or chronically treated with benzodiazepines during pregnancy are often born with withdrawal symptoms, and/or show retarded behavior and various other abnormalities when growing up. Therefore, relatively extensive research has been performed in this field. Animal studies have shown that behavioral abnormalities found in laboratory animals treated prenatally with these substances extended well into adulthood (ref. 8 ) . For instance, children exposed to opioids before birth show hyperactivity, disturbed sleep and increased lability of state from 12 weeks to 6 months. In addition, as they grow up, they show impaired organizational and perceptual abilities and poor self-adjustment. In situations requiring motor inhibition, they exhibit heightened activity (ref. 4 9 ) . Since the discovery of the fetal alcohol syndrome (FAS), extensive research has been carried out on the teratogenic effects of alcohol. The consequences of early exposure to this substance can serve to illustrate the multiplicity of effects that a chemical can cause. Chronic exposure of the fetus to high levels of alcohol has been found to result in many cases in a large spectrum of characteristic developmental abnormalities, consisting of: a) neurological and behavioral abnormalities, such as delayed motor development, microcephaly, low 10, hyperactivity and sleep disturbances; b) growth deficiencies; c ) a number of characteristic craniofacial malformations; and d ) various other malformations, such as limb, joint and cardiac abnormalities (ref. 50). A high percentage of newborns of alcohol addicted mothers shows at least some of these characteristics. Among these deviations, brain and behavioral abnormalities have received a great deal of attention, because a high percentage of the children is mentally retarded. It has been shown that the

degree of microcephaly caused by alcohol,

as well

as other

abnormalities,

decreases significantly when heavily drinking women decrease their alcohol intake in the last two-thirds of their pregnancy, suggesting that the PAS characteristics are especially induced after the period of organogenesis (refs. 51, 52). Microcephaly in the rat can still be induced during the brain growth spurt after birth, by treatment with ethanol or propanol on postnatal days 5-8, a developmental stage corresponding to part of the last trimester in humans (ref. 53). Not only the brain abnormalities but also the facial malformations characteristic of the human FAS appeared to be reproducible in experimental animals. In the mouse, ethanol exposure on gestational day 7 (gastrulation stage of embryogenesis) has been shown to induce craniofacial abnormalities similar to those found in humans. These skull malformations, especially those in the median part

of

the

face, are

probably

caused

by

underdevelopment of the medial part of the forebrain (ref. 54). In addition to these gross aberrations, which were found in animals as well as in man, various microscopic changes in brain development have been found in animal studies (see section 3.3).

1.4 Intake of psycho-active substances integrated in common life patterns Noxious substances inhaled when smoking, caffeine absorbed from coffee or other drinks, ethanol-uptake from alcoholic drinks are examples of potentially neurobehavioral teratogens absorbed by pregnant women as part of everyday social life patterns. Caffeine, which is present in coffee, tea, cocoa and cola, but also in various over-the-counter medications, has been shown to be clearly teratogenic in rats in doses comparable to those ingested daily by many people (refs. 30, 47, 55). West et al. (ref. 47) found that a dose as small as 5 mg/kg caffeine (comparable to the content of 4 cups of coffee) administered on gestational days 3-19 in the rat, affected not only physical development (e.g. delayed incisor eruption in males and females, vaginal opening in females, slower growing body weight) but also development of the auditory startle reflex, food and water intake, passive and active avoidance at adult age. Tobacco smoking during pregnancy was reported to induce decreased size and hyperactivity of infants, and decreas,ed reading or mathematical ability at the age of 11 years (ref. 30). Naeye and Peters (ref. 56) found higher activity, shorter attention span and decreased scores for spelling, reading and arithmetic performance at the age of 7 in children prenatally exposed to smoke constituents as compared to siblings that were not exposed during pregnancy. Slotkin et al. (ref. 57) showed that prenatal nicotine exposure in rats resulted in various preand postnatal changes in brain ornithine

211

decarboxylase activity, DNA synthesis, and DNA, RNA and protein content. Furthermore, CO from smoke reduces fetal blood oxygen transport capacity (ref. 58), while hypoxia can cause neurobehavioral teratogenic effects (ref. 59). Effects of low doses of alcohol are considered to be not as dramatic as those of heavy drinking. The occurrence of teratogenic effects decreases when addicted women cut down on alcohol intake or stop drinking altogether after the first trimester (refs. 51, 52). However, McLeod et al. (ref. 60)) found a disappearance followed by a decreased level of fetal breathing movements for 3 hours after the intake of a low dose of alcohol (0.25 g/kg). Therefore, if these movements have a function in the development of the fetus, regular social drinking may have some noxious effects as well. In addition, rat studies have shown that postnatal ethanol treatment can still cause abnormalities in the development of the brain (see section 1.3). 1.5 Effects of exposure to 5 combination of various chemicals Above we gave a number of examples of chemicals that may affect development of brain and behavior. It should be realized that the fetus will often be exposed to combinations of various potentially teratogenic substances. For

instance, many pregnant women use more than one drug (ref. 28). Addicted women often do not restrict themselves t o only one drug of abuse. In addition, they may also use clinically prescribed drugs (refs. 4 9 , 51, 52, 61). Caffeine and/or nicotine and/or alcohol are ingested by many women during pregnancy in addition to possible drugs. Mother and fetus may also be exposed to environmental and food pollution and food additives. There are also non-chemical teratogenic factors that may contribute their effects, e.g., radiation, stress and, especially in addicted women, undernutrition and poor health. Even if enough knowledge were available on the potential functional teratogenic effects of each of the individual chemical and non-chemical class of influences mentioned above, the effect of combinations of these factors would still be unpredictable. 2 PASSAGE OF POTENTIALLY NOXIOUS SUBSTANCES INTO THE FETUS AND INFANT The placenta is permeable to many types of drugs and chemical pollution. Especially lipophilic and nonionized substances with low molecular weight ( < 500-1000) can pass rapidly. Not all fetal b l o o d passes the liver. Furthermore, the liver develops its metabolizing capacity only gradually, which is far from complete at birth. Renal excretion of adverse chemicals is likewise very limited during most of the gestation period. Therefore a vide range of potentially harmful chemicals which easily reaches the fetus may hardly or not

278

be metabolized or excreted. As a consequence of the resulting accumulation, the fetus throughout gestation may be exposed to higher levels of toxic substances than the mother (refs. 1, 62, 63). After birth the infant can be affected by toxic substances taken up by the lactating mother and excreted into the milk. Different drugs and environmental polluting chemicals have been shown to be excreted in milk. Clinically prescribed drugs normally do not reach high levels in breast milk, but there are exceptions. Especially chemicals which cannot be metabolized by the infant may occur in high levels, and thus become potentially harmful (refs. 64, 65). The blood-brain barrier in the fetus and newborn infant is highly permeable for chemicals, since i t develops gradually a permeability comparable to that of the adult only by the first year of life (ref. 3). Metals may reach high concentrations in the fetus. Infants exposed to methylmercury before birth have higher blood levels than the mother, whereas infants which only received the poison after birth through the milk had lower or equal blood levels compared to their mothers (ref. 10). In animal studies i t was found that mercury is concentrated in the fetal brain and may reach levels that are 2 to 4 times those found in the mother’s brain (ref. 13). Methylmercury appeared to induce neurological and behavioral abnormalities in prenatally exposed mice even at doses that induced neither overt signs of abnormal development nor significant changes in brain weight, protein, choline acetyltransferase or cholinesterase (ref. 66). Lead is also known to reach higher levels in the immature as compared to the mature brain. Lead is absorbed to a higher extent and excreted in smaller amounts by the young organism (ref. 14). In general, children have a higher gastrointestinal absorption of metals as compared to the adults. Metals are absorbed from milk to a higher extent than from other types of nutrition which makes young infants especially vulnerable to contaminated milk (ref. 15). For therapeutic drugs similar results as those above have been found. Diazepam given to pregnant rats can easily pass the placenta and accumulate in fetuses because of its small size and lipophilic character and because of the inability of the fetus to metabolize or excrete the drug and its metabolites. The concentration in the fetus may reach a level that exceeds that in the dam. These levels have been shown to be toxic when applied on human tissue culture cells. Accumulation of diazepam and its metabolites in the infant from the mother’s milk is also possible (refs. 32, 67). Theophylline and caffeine are not metabolized completely by preterm neonates, resulting in relatively long half-life time of these drugs (refs. 46, 68). Caffeine accumulates in fetal brains (ref. 55). Alpha-methyldopa, used to treat hypertension in pregnant women, reaches concentrations in the fetus which are similar or higher

279 compared to those in the mother (ref. 3 8 ) . Alcohol ingested by the pregnant woman reaches comparable levels in mother and fetus, but may disappear from the fetus at a much lower rate than from the mother because of accumulation in the amniotic fluid (refs. 60, 69, 70). Hutchings (ref. 4 9 ) found indications that prenatally administered methadone accumulated and persisted in neonatal rat brain and liver for long periods, while the half life of hours.

this substance in adult rat plasma was only a few

3 DERANGEMENTS OF BRAIN DEVELOPMENT

There has been a substantial awareness among clinicians of the gross teratological effects with respect to developing organs, in particular since the thalidomide tragedy. In order to prevent teratological effects elicited by use of drugs during the period of organogenesis, warnings for prescription of suspected drugs are often limited to the first trimester of pregnancy. Less attention has been paid, however, to the possibility of inducing finer developmental disturbances after development of the main structures. Slight disturbances in neural development can easily be overlooked after birth. For example, fnctional disturbances may not show up until a more advanced age, e.g. after the child starts going to school or during puberty or adolescence. When effects do not come to expression until years after birth, the possible relation with toxic influences that might have been present during fetal development is not easy to establish and often this possibility will be disregarded altogether. Psychotropic drugs especially can be expected to affect brain and behavioral development. After the development of the main structures of the brain, effects may occur on processes such as cell migration, cell differentiation, development of receptors for different neurotransmitter substances, brain hormones and peptides, development of electrical activity of neurons, etc.. Each deviation from normal development may have a chain of consequences leading disturbances in later life.

to complex neurobehavioral

3.1 Effects on brain size Many chemicals cause a decrease in brain size during fetal development. Changes in brain size can be caused in various vays. A decreased brain weight may be a consequence of general undernutrition caused by effects on placental functioning. Examples of other possible mechanisms are inhibition of cell multiplication or cell growth, increased cell death, disrupted trophic effects induced by changes in cell maturation and neurochemistry. In the assessment of human development, head circumference appears to be a

280

good measure for brain size (ref. 2). Human neonatal head circumference was found to be reduced after treatment with the antihypertense alpha-methyldopa (refs. 37, 38). Propanolol, hydantoin, alcohol and estrogens were reported to have similar effects (ref. 28). In the rat Mirmiran et al. (refs.34, 35) found decreased brain weights after early postnatal treatment with clonidine and clomipramine. In the rhesus monkey prenatal treatment with betamethason caused decreased brain weight (ref. 45). Caffeine also was shown to reduce the weight of some brain parts when administered in the rat during gestation and up to weaning (ref. 55). 3.2 Effects on biochemical measures of brain cell growth and maturation Ornithine decarboxylase activity in the brain reflects its pattern of maturation, whereas inhibition of this enzyme is accompanied by disrupted behavioral development (ref. 71). The pattern of activity of this enzyme may change after treatment with chemicals. Slotkin et al. (ref.57) showed that prenatal treatment with nicotine (dams were injected with 3 mg/kg nicotine twice daily from gestational day 4 to 20) resulted in changes in brain ornithine decarboxylase activity before and after birth, as well as in DNA synthesis, and DNA, RNA and protein content after birth. The pattern of biochemical changes suggested that the timing of cellular maturation was disrupted in a region specific way. Bell and Slotkin (ref. 22) found effects on similar biochemical measures after nutritional supplementation of rat dam and pup diets with a lecithin enriched preparation (see section 1.1). Caffeine changed DNA, RNA and protein content of some brain parts in rats after administration during gestation and until weaning (refs. 5 5 , 72). Reserpine an increase of cholesterol treatment on gestational day 16 caused concentration (especially on day 30) and of DNA concentration (mainly on day 60). The development of incorporation of precursors in cholesterol was also changed in a region specific way (ref. 73). 3.3 Effects on brain structure Changes in brain structure can occur in many different ways. For instance, neuronal death or disruptions in neuronal maturation (see also section 3.2), differentiation (see also section 3.7), migration, synaptic formation, glial and neurochemical development (see also section 3.41, can all have effects on brain structure. Various microscopic aberrations have been detected in the brains of ethanol treated animals. Exposure to alcohol of rat pups on postnatal days 1-10 resulted in development of aberrant mossy fibers in the hippocampal CA3 field. The increase in body weight was not affected. Such mossy fibers were not found

in pups treated prenatally with alcohol during gestational days 1-10 or 11-21, but were found in rats treated with alcohol during the whole gestation period (refs. 74, 7 5 ) . Alcohol treatment of rats during gestational days 10-21 was found to reduce the number of hippocampal CA1 pyramidal cells, but not the number of dentate gyrus granule cells. Again’the physical growth of animals was not affected (ref. 76). Furthermore, fetal exposure to low levels of ethanol delays cortical neuronal development. A temporary retardation of postnatal cerebellar development was found after prenatal alcohol treatment. Prolonged treatment into the lactation period induced more severe effects on cerebral cortex and cerebellar development (refs. 50, 70). As already suggested by the examples mentioned above, a range of brain developmental mechanisms appear t o be influenced by ethanol. Indications have been found that the process of cell proliferation is affected (ref. 5 4 ) . Protein synthesis has been reported to be decreased by chronic prenatal alcohol treatment. The developmental pattern of ornithine decarboxylase activity is changed after alcohol treatment. An important factor in the disruption of development of brain structure by ethanol is a disorganization of cell migration. In humans large numbers of brains cells were found to migrate in an erratic fashion, to areas such as the leptomeninges (ref. 5 0 ) . In the mouse also heterotopic neuroepithelial cells were found (ref. 5 4 ) . Furthermore, dendritic arborization, myelination and axonal distribution were shown to be affected (ref. 50). Neurochemical changes caused by exposure to some drugs (see section 3 . 4 ) may result in changes in maturation and morphological development since neurotransmitters probably play a trophic role in morphologic development (ref. 77). For instance, prenatal dopamine (DA) depletion in rabbits was shown to result in a decreased number of mature boutons and an increased number of growth cones in the putamen and less mature striatal perikarya. Thus presynaptic DA may play a neurotropic role in the development of target neurons in the neostriatum (refs. 78, 79). Noradrenaline probably has a neurotropic effect on development of pyramidal cells in the cerebral cortex in the rat (ref. 80). Serotonin may also influence development of its target neurons in the rat. Namely, serotonin depletion results in delayed and prolonged neurogenesis in serotonin-innervated cell populations (ref. 81). Endogenous peptides probably also play a role in brain development. For example, indications have been found that neonatal beta-endorphin injection from day 1 to 7 decreases the number of brain opiate receptors on day 9. In addition, various endogenous substances have been shown to affect brain and behavioral development if administered exogenously (ref. 82). Early administration of lead has been shown to affect hippocampal structure

282

(refs. 83, 84). The hippocampal sensitivity for developmental effects of lead may be related to the accumulation of lead and zinc in this brain region. Although the lead content of hippocampi of early lead-treated rats is not increased compared to that found in controls (ref. 85), the whole brain lead content is increased while that of zinc is decreased (ref. 86). Prenatal and early postnatal diazepam exposure was shown to induce gliosis and perivascular cuffing in the brains of 45- to 64-day-old rats suggesting inflammatory processes and direct cell damage. These changes were possibly a consequence of effects of diazepam on the immune system or blood-brain barrier (ref. 67).

3.4 Effects of drugs development of brain receptors neurochemistry Pre- or early postnatal exposure to chemicals which influence brain neurochemistry may disturb brain development in various ways (refs. 7 7 , 87; see also section 3 . 3 ) . Neonatal blockade of dopamine (DA) receptors by penfluridol treatment changed the activity of the mesolimbic DA system at the age of 4 weeks (ref. 8 8 ) . Prenatal haloperidol or alpha-methyl-p-tyrosine-methyl ester in the rat resulted in a decreased DA receptor function in postnatal caudate tissue which was still present at the age of 60 days in the haloperidol group, despite a' gradual decline of the difference with saline treated controls. Postnatal exposure to haloperidol through the dam's milk resulted in a supersensitivity of caudate DA receptors (ref. 8 9 ) . DA receptor blockade by treatment with haloperidol during the entire gestation and lactation resulted in reduced functional sensitivity of DA autoreceptors at the age of 50 days and behavioral supersensitivity of cholinergic receptors (ref. 90). Postnatal DA receptor blockade by haloperidol treatment during days 15 to 24 was found on day 28 to have caused a functional hypersensitivity of DA receptors and an increased Bmax accompanied by a functional hyposensitivity of muscarinic cholinergic receptors (ref. 91). In general, chronic prenatal DA receptor blockade turned out to have consequences for adult receptor sensitivity that are opposite to those of comparable postnatal treatment (ref. 90). Prenatal treatment with a low dose of amphetamine (0.5 mg/kg) resulted in an increased conversion of precursor in DA and NA (noradrenaline) and an increased tyrosine hydroxylase activity in adulthood, while DA and NA levels themselves were normal (ref. 9 2 ) . Prenatal diazepam treatment in the rat decreases the hypothalamic NA level and turnover after the age of 28 days and in adulthood (refs. 93-95). Treatment of rat pups at the age of 2 and 3 weeks with clonidine affects NA turnover in the hypothalamus on day 29 (ref. 96).

283 Neonatal treatment with chlorpromazine or lysergic acid diethylamide (LSD) 5HT (5 Hydroxy Tryptamine) levels in

in rats resulted in lowered brain

adulthqod (ref. 9 7 ) . Perinatal methadone treatment in rats was shown to decrease not only total brain weight, but also to retard synaptic development of central 5-HT, DA and NA neurons (ref. 98). Early diazepam treatment was found to affect uptake of choline in 60 day old male rats (but not in females) and uptake of GABA (Gamma Amino Butyric Acid) and 5HT in 60 day old females (ref. 99). Prenatal exposure of rats to diazepam reduced the number of benzodiazepine receptors in the thalamus at the age of one year (ref. 100). Pre- and postnatal administration of chlordiazepoxide also were shown to reduce benzodiazepine binding sites in hippocampus and cortex on day 60 (ref. 33). There are indications that early exposure to lead decreases acetylcholine release and turnover (ref. 101). In addition, neonatal administration of lead has been shown to increase the number of GABAergic receptors at the age of 60-70 days (ref. 14). Effects of early lead exposure on dopamine and noradrenaline levels may also exist (ref. 102).

3.5 Effects of drugs 0" development of brain electrophysiological activity Pre- and postnatal lead exposure was shown to depress selectively electrical activity at a frequency of 6-7 Hz in the hippocampus of 70 day-old rats (ref. 84). Neonatal lead treatment was also found to affect the electrically elicited hippocampal afterdischarge at (ref. 103).

the age of 15 weeks

3.6 Effects on later brain plasticity Treatment with lead during lactation was shown to decrease the rearrangement of cholinergic afferents to the outer molecular layer of the hippocampal dentate gyrus following unilateral perforant path transection at the age of 100 days. This suggests a decrease in neuronal plasticity in adulthood after early lead treatment. Comparable effects have been found after glucocorticoid treatment (ref. 8 3 ) . Prenatal ethanol exposure of rats has been shown to alter the post-lesion sprouting response in the central nervous system after the age of 90 days (ref. 1 0 4 ) . Neonatal clonidine treatment of rats on days 8-21 was shown to prevent the increase in brain size that occurred in saline treated controls as a consequence of rearing under enriched environmental conditions (refs. 105, 106). Prenatal imipramine and excess vitamin A treatment of rats prevented the effect of enriched environmental conditions during rearing on maze behavior and on brain weight, cortical thickness and neuronal diameter (refs. 107, 108).

Changes in brain plasticity as a consequence of exposure to chemicals during development may also have consequences during neurobehavioral aging. A diminished plasticity might promote the expression of functional deficits that. develop at high ages as a consequence of aging processes in the brain (ref. 109).

3.7 Endocrine effects influencing neuronal development Early lead exposure may disturb the hepatic catabolism of estrogen and progesteron, leading to changed hormone levels. Furthermore, sex hormone levels and receptor sensitivity in the pregnant mother may also be affected by lead. These hormonal effects can lead to indirect changes in neurobehavioral development (ref. 14). Increased luteinizing hormone levels have been found in adult males treated perinatally with delta-9-THC (ref. 110). Treatment of rats with naltrexone on postnatal days 1-10 has been shown to result in blockade of estradial benzoate induced LH release on day 24, suggesting an effect on sexual differentiation of the brain (ref. 111).

3.8 Consequences of effects on prenatal motility It has been suggested that prenatal motility has a function in the development of the central nervous system. Therefore, prenatal effects of chemicals on fetal movement patterns might have consequences for brain development. Spontaneous fetal activity of rats has been shown to be depressed after treatment of the mother with alcohol (ref. 69). Fetal breathing movements were depressed until 3 hours after acute alcohol administration in humans (ref. 60). Some of the aberrations in brain structure found after prenatal ethanol treatment (see section 3.3) might be related to changes in prenatal behavioral functioning. Changes in prenatal movement patterns may also be related to the development of behavioral states. The latter can be altered as a consequence of pre- or early postnatal exposure to various drugs (see section 4). 4 EFFECTS ON BEHAVIORAL STATE DEVELOPMENT The three main behavioral states, wake, quiet sleep and Rapid Eye Movement (REM) sleep gradually develop in fetal and postnatal life. Wake is characterized by a low amplitude EEG (Electro EncephaloGram) with high frequencies, presence of muscle tonus, and behavioral waking (regular slow movements). Quiet sleep is accompanied by a high voltage, low

frequency EEG,

presence of muscle tonus, absence of behavioral waking (or behavioral sleeping), regular breathing and heart rate, absence of rapid eye movements and of phasic jerky random movements. REM sleep is defined by a low voltage,

high frequency EEG, absence of muscular tonus, presence of relaxed sleeping posture, occurrence of rapid eye movements and random rapid phasic movements of various parts of the body. Breathing and heart rhythm show irregularities. Some of the state characteristics develop earlier than others. For instance, the REM sleep-like movements develop before any EEG can be measured. The association of the various characteristics of the three states develops gradually from a total absence of association in early development to a strong association in adulthood. In the rat, which is born relatively immature, the different states in their adult appearance cannot be distinguished until the age of about 12 days (ref. 112). This was established by using phasic activity, REM, and disappearance of muscle tonus. The percentage of total sleep time spent in REM sleep in the neonatal rat is high during the first 10 days after birth and then gradually decreases. In species born more mature, such as the guinea pig, this early stage of state development occurs before birth (ref. 113). In man, REM state characteristics show association from the gestational age of 35-37 weeks on. Before that age, they occur more independently of each other (ref. 114). Time spent in the REM state is considerable in the last trimester, and also in the first period after birth (refs. 115, 116). The REM state may have a special function in the maturation of the central nervous system in the developing organism (ref. 116). In addition i t may play a role in information processing and/or the maintenance of nervous system function in the adult (ref. 117). Therefore, REM sleep, or some of the brain mechanisms underlying its characterizing phenomena, may play an essential role in brain plasticity during development as well as in adulthood. A normal development of the association of state characteristics may be essential for normal brain function. Deviations in this association or in other aspects of state organization may be related to neurobehavioral disturbances (refs. 114, 118, 119). Mirmiran et al. (refs. 34, 35) suppressed REM sleep in postnatal rats with two pharmacologically different drugs, the antihypertensive clonidine (a selective noradrenergic agonist) and the antidepressant clomipramine (a monoamine reuptake blocker, which is relatively selective for serotonin). They showed that this treatment resulted in various neurobehavioral changes in adulthood. After treatment with clomipramine (25 or 30 mg/kg daily on neonatal days 8-21), the animals showed changes in ambulation in an open field (interpreted as a higher level of emotionality), disrupted male sexual behavior, and higher response rates in a left-right alternation task in a Skinnerbox. Furthermore, their brain weight was lower than that of controls. They also showed an increased level of REH sleep and myoclonic jerks during

286

REM sleep at the age of about 11 months. Rats treated neonatally with clonidine (daily 135 g/kg on neonatal days 8 and 9 and 200 ug/kg on days 10-21) showed an increased ambulation in an open field, disrupted masculine sexual behavior, and increased myoclonic jerks during REM sleep. A slight increase in REM sleep did not reach significance. Brain weights of these animals were decreased (ref. 35). In an experiment in which animals were treated with 150 g/kg clonidine per day on postnatal days 8-18, the NA turnover in hypothalamus and amygdala on day 29 was decreased in treated animals (ref. 96). Rats treated with clonidine neonatally were also slower in a latent T-maze learning task after the age of 33 days (ref. 96). In a later study, rats treated neonatally with clomipramine (15 or 30 g/kg/day on postnatal days 2-14) showed disturbed male sexual behavior and a decrease in time spent in wakefulness in adult age. In contrast, rats treated at the same age with 200 mg/kg/day alpha-methyldopa (a false NA transmitter) showed only slightly disturbed sexual behavior (ref. 120). Alpha-methyldopa, an antihypertensive commonly used in pregnancy, also suppresses REM sleep in neonatal rats and cats (refs. 96, 121, 122). Cats treated with alpha-methyldopa neonatally showed a delayed development of motor coordination (ref. 122). Similarly treated rats showed higher activity levels and increased rate of shuttlebox acquisition at the age of 35 to 50 days (ref. 121). Hilakivi and colleagues (ref. 123, 124) demonstrated strain-dependent changes in alcohol intake in rats after neonatal REM sleep deprivation by means of clomipramine. Prenatal clomipramine treatment was further reported to affect emotionality (ref. 125) or anxiety (ref. 126) at the ages of respectively 2 months and 35-42 days, as measured in tests investigating exploration and social interactions. Clonidine and alpha-methyldopa have also been reported to induce neurobehavioral changes in humans after prenatal treatment. Clonidine treatment during fetal development resulted in slight hyperactivity and increased occurrence of sleep disturbances at the age of about 6 years in children (ref. 5). A child treated with alpha-methyldopa prenatally showed an abnormal development of its sleep-awake rhythm and number of body movements during REM sleep (ref. 39). Prenatal alpha-methyldopa treatment also decreased headcircumference

in boys

(ref. 38).

These data suggest that in laboratory

animals as well as in man disturbance of REM sleep during development may be a cause of later deviations in neurobehavioral development. Denenberg et al. (ref. 127) showed that the development of behavioral states in newborn rabbits was markedly changed for at least 40 days after one single theophylline injection on the first day of life. REM sleep was suppressed, the development of quiet sleep was delayed, and the level of wakefulness was increased. The development of

behavioral

states

in rabbits

207

closely resembles that

in humans, and the theophylline dose applied gave a

peak plasma level of the same magnitude as did doses used for treatment of apnea in human neonates. Hutchings (ref. 4 9 ) reviews a number of studies in which effects of prenatal exposure to heroin and methadonewere shown to change sleep patterns in newborns. Infants exposed prenatally to heroin or methadon showed a decrease in quiet sleep and an increase in REM sleep in a number of studies, and a decrease in both sleep states in one other study. At the age of a few years such children still showed behavioral deviations from non-exposed control groups, such as irritability, high activity and a decreased performance in a number of cognitive tests (ref. 4 9 ) . In a rat study, Hutchings (ref. 4 9 ) found also sleep disturbances in animals prenatally exposed to methadon. Livezey et al. (ref. 100) found that prenatal exposure to diazepam induced changed quiet sleep patterns in adulthood. Treated rats showed more light slow wave sleep and less deep slow wave sleep than controls. Furthermore, uninterrupted waking episodes in diazepam treated rats were lengthened, and the EEG during both slow wave states showed a diminished degree of sychronization compared to the control group. Neurobehavioral teratogenic properties were demonstrated for benzodiazepines (refs. 32, 9 3 ) . Hilakivi (ref. 128) found that in rats prenatal alcohol exposure during the entire period of pregnancy resulted in less active sleep, more wake and a more frequent interruption of the quiet sleep state by waking episodes on neonatal age. Human newborns with FAS may show abnormal EEG profiles and sleep disturbances such as reduced REM sleep (ref. 25). This information suggests that early pharmacological REM sleep suppression or other types of state disorganization may disrupt brain and behavioral development. Behavior in adulthood may still be changed as a consequence of the abnormal development, but

also as a result of the aberrant adult sleep

pattern. Therefore, chronic early REM sleep-like state suppression or other types of state disorganization may be important neurobehavioral teratogenic mechanisms (see also refs. 7 7 , 118, 1 2 9 ) .

5 EXPERIMENTAL EFFECTS OF CHEMICALS ON BEHAVIORAL DEVELOPMENT There is a vast amount of literature on the effects of chemicals on behavioral development. In many cases, other effects are also found, such as changes in physical development (body weight, eye opening, incisor eruption, testes descent or vaginal patency). Effects on behavior are often found with doses that do not seem to cause other easily observable physical effects. This has been shown, for example, for the effect of methylmercury on swimming

288 behavior in the mouse (ref. 66). If test batteries containing a larger

number

of behavioral tests are used, the following is often found. In a number of tests effects are found, whereas in a number of different tests there is no effect. It is not yet possible to determine whether consistent patterns of related behavioral effects exist. Changes in early behavioral functioning can be expected to have consequences for development of adult behavior. Thus, i t can be expected that in the future i t might be possible to find clusters of functions which are affected together by similar treatments. For instance, a change in early exploration of the environment (ref. 130) or sensory functioning, or other aspects of the animals' interactions with the environment, may well have consequences for development of adult behavior. On the other hand, behavioral changes may not become apparent until adulthood. Thus, i t is necessary to examine adult as well as young animals for behavioral teratogenic effects. Even behavioral aging can theoretically be affected by effects of chemicals on early development. In fact, effects may show up for the first time in any stage of life. In order to investigate the effects of chemical substances on behavioral development, many different tests have been applied. In this section some examples of effects reported on a number of behavioral categories are given, illustrating the variety in effects found, as well as in the test methods applied. 5.1 Development of reflexes, neuromotor coordination and sensory capacity Development of reflexes, neuromotor coordination and sensory capacity

are

aspects of neurobehavioral functioning that are tested relatively often. In particular, different reflex and neuromotor tests have been developed. These behavioral tests have the advantage that they can also be measured in young rat pups. Furthermore, normal neuromotor and sensory functioning can be assumed to be prerequisites for normal performance in most other behavioral tests. Diazepam administration from gestational day 13 to 20 was.shown to cause a changed relation between the amplitude of the acoustic startle response and the level of background noise at the ages of 12-20 days (ref. 131). Rats exposed via the placenta to ethanol from gestational day 1-20 showed more rapid and vigorous righting responses (measured on days 4-12) and shorter dowel grasping times (measured from the day of eye opening on) (ref. 132). Pre- and/or early postnatal methadone treatment in the rat affects startle behavior, the righting reflex, paw withdrawal in reaction on a pain stimulus, bar grasping, tail hanging, edge aversion, visual orientation and auditory reflex (ref. 133). Treatment with 2 or 6 mg/kg methylmercury on gestational days 6-9 was found to delay development of surface righting and swimming,

289

while a lower dose accelerated negative geotaxis turning and swimming angle development (ref. 134). In another study identical treatment with methylmercury also affected olfactory discrimination and auditory startle habituation in preweaning rats (ref. 135). Modification of the auditory startle reflex by a stimulus presented before the acoustic stimulus can be used to test sensory function in rat Treatment with

pups as well as

in adult animals.

the aminoglycoside antibiotic kanamycin caused a deficit in

reflex modification, which was still present on postnatal day 38 (ref. 136). 5.2 Activity

and

exploration

Activity and exploration are also frequently measured in behavioral teratological research. Many different test situations can be chosen, e.g. small or large open fields, 8-maze, holeboard, activity cages, activity wheels, etc.. Although the behavior measured in different tests is indicated by the same terms, i t should not be expected that activity in one situation is affected in other test situations in exactly the same way. Each test is likely to elicit slightly different aspects of activity and/or explorative behavior. On postnatal day 21 rats treated on gestational days 12-15 with amphetamine showed lower activity than did controls in a small open field. No significant differences on postnatal days 13, 15, 18 in the same field or on days 46 and 60 in a larger open field were found. In the same study, rats treated and tested in the same way but with chlorpromazine, showed a decreased locomotor activity on postnatal days 13 and 15 (ref. 137). Mice treated with phenobarbital on the last 6 to 7 gestational days showed increased locomotor activity in an open field at the age of 75 days (ref. 138). Rats treated prenatally (gestational days 5-8, 11-14 or 17-20) with chlorpromazine or reserpine showed higher activity in a rotary activity wheel on the age of 97-98 days. Meprobamate-treated rats were not different from controls. Rats treated in the same way as above, but tested from days 35 to 77 in a cubicle showed only an effect of meprobamate, namely a decrease of activity. In both tests the stage of pregnancy in which the injections were given also affected activity levels in the control groups (ref. 139). Postnatal treatment on days 8-21 with clomipramine or clonidine was found to increase open field activity Postnatal alpha-methyldopa in 70-75 day-old rats (refs. 34, 35, 1 2 3 ) . treatment on days 4-24 resulted in increased locomotor activity in an open field at the age of 35 days (ref. 121). Neonatal treatment with monosodiumglutamate (MSG) resulted in lowered spontaneous motor activity in automex chambers at the age of 109-131 days (ref. 21). Prenatal administration of MSG through the drinking water also resulted in decreased activity at the age of 35 days in an open lield (ref. 2 0 ) . Prenatal lead exposure of rats

290

resulted in increased open field activity at the age of 40-42 days, whereas postnatal treatment with lead did not affect later open field activity Postnatal treatment at the age of 5-45 days with (refs. 84, 101). phenobarbital, haloperidol, diazepam, amphetamine, and chlorpromazine affected open field behavior of rats at the age of 90 days (ref. 140). After gestational imipramine treatment rats showed normal locomotor activity, but a diminished number of exploratory responses in an open field (ref. 141). Prenatal methadone treatment. resulted in depressed ambulation scores in an open field at the age of 28-31 days (ref. 142). Exploratory behavior in a holeboard test on postnatal day 37 was changed (lower number of head-dips, decrease in time spent head-dipping, and lower locomotor activity) after neonatal treatment with clonazepam on days 1-21 (ref. 143). Buelke-Sam et al. (ref. 135) found a significant raise in 8-maze activity in male rats on ages varying from postnatal day 21 to 120, after prenatal treatment with methylmercury. In their study, prenatal amphetamine treatment did not induce consistent effects on postnatal behavior. 5.3 Effects on learning behavior Learning capacity of experimental animals can be studied in a wide range of different tests. These tests can be divided into different categories, such as simple and complex tasks, appetitively and aversively motivated tasks. These tasks measure different aspects of cognitive behavior in rats. It is essential that different tests are used in order to prevent that effects can be missed. Many of these tests have methodological disadvantages. For example, long and labor-intensive training periods, food or water deprivation, or stress induced by punishment may interact with effects of neurobehavioral teratogens. Performance of the experimental subjects in many of these tests can be affected by a wide variety of functional deficits, e.g. deficits in sensory functioning, a decreased ability to inhibit reactions on stimuli, an increased level of activity, changes in motivational factors or attention, etc.. Therefore, additional research is always necessary in order to be able to interpret test outcomes. In particular, the more complex tests can be expected to be good apical tests. Namely, the test result can be affected by influences on many different aspects of the behavioral functioning of the animal, and may therefore be sensitive to a variety of effects on behavior. However, the animal might compensate for deficits in functioning by adopting slightly

different strategies and show normal levels of performance in spite of changes in functioning (ref. 109). 5.3.1 Effects on appetitive learning behavior

5.3.1.1

Maze behavior

A number of investigators have reported results of teratological studies in which effects on maze behavior were tested. A variety of different types of mazes and maze-tasks was used. Effects of early treatment with cannabis or THC on maze behavior have been studied by Gianutsos and Abbatiello (ref. 144) and Uyeno (ref. 145). Food deprived and pre-trained (food rewarded) rats whose mothers have been treated with 250 mg/kg Cannabis sativa extract on gestation days 8-11 were tested in a 4-unit 8-cul Lashley I11 maze, starting at the age of 65 days. These rats made more errors, needed more trials to reach a certain criterion (ref. 144), and spent more time in the maze than did controls. Uyeno (ref. 145) who treated pregnant rats with 30, 60 or 120 mg/kg THC on gestational days 10-12, found no effect of this treatment in the 20 day-old offspring in a two channel maze. Coyle (ref. 141) and Coyle and Singer (ref. 107) studied effects of prenatal treatment of rats with imipramine (5 mg/kg during the entire period of pregnancy) on T-maze alternation, performance in a swimming maze, and food-rewarded performance in a Henderson-type maze. Testing started when the animals were 60 days old. No effects were seen in offspring reared from weaning under deprived cdnditions (one rat per cage). However, when reared under enriched conditions (more rats per cage with toys) performance of imipramine-treated offspring was impaired compared to that of controls. De Boer et al. (ref. 120) found no effect of the related tricyclic antidepressant clomipramine (7.5 and 15 mg/kg, administered subcutaneously to rat pups on postnatal days 2-14) on acquisition and performance in an eight arm radial maze and on food rewarded learning of a series of Hebb-Williams mazes. Alfano and Petit (ref. 101) observed a decreased T-maze alternation in rats exposed to lead (administered via the maternal food) for the first 25 postnatal days. An increased number of errors was made by rats nursed from postnatal days 1-21 by lead-injecte? dams in a series of Hebb-Williams mazes (ref. 146). These rats also needed a larger number of trials to reach a criterion than did placebo-treated controls (testing began at the age of 43 days). Experiments were also reported with rats treated with lead during 21 days after weaning (day 22 to 42) and during testing, and also starting at an adult age (about 100 days), 21 days before testing and continued during testing. In spite of clear signs of intoxication in animals treated with the highest dose level, lead-treated rats d i d not make more errors nor did they require more trials for a criterion to be met in the Hebb-Williams test compared to placebo-treated controls. Rosen et al. (ref. 147) did not find effects of treatment during postnatal days 1-20 with lead on performance on an 8-arm radial maze at the age of 25 or 90 days.

292

Coyle and

Singer

(ref. 107) found

that vitamin A

treatment

(100 000

i.u./kg) applied to pregnant rats on gestational days 6-10 decreased performance of their offspring in a water maze and in a food rewarded Henderson type maze. This was observed only when the animals were reared in an enriched environment. These results parallel those obtained with imipramine. Hoffeld and Webster (ref. 148) treated pregnant rats with three tranquillizing drugs, reserpine (0.1 mglkg), chlorpromazine (6.0 mg/kg), and meprobamate (60.0 mg/kg) during gestational days 5-8, 11-14 or 17-20. From the age of 86 days on, the offspring was trained (with food reward) in a Lashley type-I11 maze to a criterion. Rats treated during early pregnancy (days 5-8 of gestation) with chlorpromazine needed more trials to reach the criterion than did the controls. Treatment during mid-pregnancy (days 11-14 of gestation) with the same drug resulted in faster learning of the maze as compared to controls. No effect was seen from the other treatments. Prenatal treatment via the drinking water with monosodiumglutamate resulted in decreased water rewarded learning performance in a 6-unit black-white simultaneous discrimination maze (ref. 20). Morphine pellets implanted subcutaneously on postnatal day 5 or 11 increased the number of errors made in a Lashley I11 maze at the age of 72-77 days (ref. 149). Barbiturates have been shown to affect spontaneous alternation and radial maze performance in mice (ref. 150). Rats treated prenatally with aluminum showed a deficit in radial maze acquisition (ref. 151). Neonatal clonidine treatment delayed choice of a water rewarded arm in a T-maze by water deprived rats which had been pretrained in this maze with food reward (ref. 33). 5.3.1.2 Skinnerbox performance Differential reinforcement of low rate (DRL) responding in a Skinnerbox has been used in different studies as a test for teratogenic effects on behavior. Prenatal treatment of rats with haloperidol resulted in normal baseline level of lever pressing in a Skinnerbox for a water reward. However, like after postnatal haloperidol treatment, an increase in the number of sessions to criterion for DRL responding was observed in these animals (ref. 41). Simple acquisition of the bar-press response for water reward was shown to be affected by prenatal treatment with chlorpromazine, but not by prenatal amphetamine treatment (ref. 137). The response rate, but not response accuracy, in a left-right alternation learning test in a Skinnerbox was increased after neonatal clomipramine treatment ref. 34). 5.3.2

Aversive learning behavior

293

5.3.2.1 Active avoidance Neonatal treatment of

rats on days 1-14 with the monoamine oxidase inhibitor pargyline decreased acquisition performance in a shuttlebox and increased rate of extinction of the response. On the other hand, an analogous treatment with acetylcholesterase inhibitor pyridostigmine decreased the rate of extinction of this behavior (ref. 152). Acquisition of shuttlebox performance at the age of 84 days was significantly affected by prenatal treatment with meprobamate and chlorpromazine. Subsequent extinction of the behavior was significantly affected by the latter two drugs and by reserpine. These effects were dependent on the stage of pregnancy in which the animals had been exposed (ref. 153). Exposure to methadone throughout gestation and lactation decreased shuttlebox performance in rats at the age of 6 weeks (ref. 154). Exposure to ethanol through the mother's milk on days 0-17 decreased shuttlebox acquisition of rats at the age of 75 days (ref. 155). 5.3.2.2 Passive avoidance Teratological effects on passive avoidance behavior have been tested

in a number of studies. It is often assumed that passive avoidance performance during the test session reflects memory capacity of the animal tested. However, such performance can also be considered a test of fear or arousal (ref. 138). Mice treated with phenobarbital (40 mg/kg) on the last 6-7 days before birth showed decreased passive avoidance latencies in the test session at the age of 90 days (ref. 138). Delta-9-THC treatment during pregnancy caused a decreased rate of learning a passive avoidance response on postnatal day 21. However, on day 90 no difference in passive avoidance learning was found (ref. 156). Rats exposed to lead through the maternal milk o,n the first 25 postnatal days showed impaired passive avoidance acquisition at the age of 66-100 days (ref. 101). 5.3.2.3 Conditioned taste aversion Riley et al. (ref. 157) have shown that 10 and 15 day-old offspring of rats treated on gestational days 6-20 with ethanol ingest less of a saccharin solution paired previously with LiCl than controls, although they show a clear taste aversion. They interpret this result as additional evidence for a

deficient passive avoidance learning. A decreased passive avoidance performance using the more traditional shock punishment has also been shown in rats prenatally treated with ethanol. However, pre-exposure to unpleasant

294

treatments can weaken subsequent taste avoidance conditioning. Therefore, the observed phenomenon might occur not only after pre-exposure to the US (Unconditioned Stimulus) used in the conditioning procedure, but also after pre-exposure to different US’S (ref. 158). In addition, i t has been shown that rats can acquire conditioned taste avoidance in utero (refs. 159, 160). Therefore, weakened postnatal taste aversion conditioning could be a result of the aversiveness of prenatal poisoning, instead of decreased postnatal learning capacity. Thus, the conditioned taste aversion procedure may be a less suitable test for investigating behavioral teratogenic effects. 5.3.2.4 Water maze learning Rats treated prenatally with naloxone showed a deficit in backward Biel maze learning at the age of 57 days (ref. 161). Coyle and Singer (ref. 107) found effects of prenatal imipramine or excess vitamin A exposure on performance in a swimming maze, but only i f the animals were reared in an enriched environment. 5.4 Social behavior There are a number of categories of social behavior that can be investigated. For example, interactions of the pup with other pups and with the dam can be studied early in ontogeny. Play behavior and social exploration in encounters with other rats can be studied at a more advance age. From puberty on, sexual, agressive and maternal behavior are important categories of social behavior. All of these categories should be studied in order to assess potential adverse effects of early exposition to chemical substances. These various categories of social behavior do not seem to be studied as frequently in neurobehavioral teratological research as, for example, learning or activity. 5.4.1 Sexual behavior Development of sexual behavior can be affected by neonatal pharmacological treatment with the monoamine oxidase inhibitor pargyline, the monoamine depletor reserpine as well as with the acetylcholine esterase inhibitor pyridostigmine. These results suggest that biogenic amines are involved in sexual differentiation of the brain (refs. 162, 163). Pargyline treatment from day 1 to 14 or day 15 to 28 resulted in earlier development of puberty in female rats and delayed appearance of puberty in male rats. Male sexual behavior was decreased in both sexes. Treatment with reserpine on days 1, 4 , 7 and 10 delayed the manifestation of puberty in both sexes, and caused disturbed female ovarian cycles and decreased male mounting behavior.

295

Administration of pyridostigmine during the first two neonatal weeks resulted in advanced puberty and increased male sexual behavior in males and females. Pyridostigmine-treated females which had been ovariectomized postpubertally and treated with an androgen, showed increased male sexual behavior to females, decreased female sexual behavior, and increased aggression towards males. Therefore, drugs affecting brain monoamines may change development of brain and sexual behavior. Jarzab et al. (ref. 1 6 4 ) studied the effect of neonatal (first 7 days after birth) alpha-adrenergic receptor stimulation or blockade on sexual development of female rats. Their results suggest that alphal-receptor blockade and/or beta-receptor stimulation increases feminization and decreases the defeminizing effect of testosterone. Furthermore, they observed that neonatal clonidine treatment resulted in + decreased lordosis behavior of ovariectomized, oestrogenprogesteron-treated female rats. Mirmiran et al. (ref. 3 5 ) found that neonatal clonidine treatment of male rats (days 8-21) resulted in disrupted adult male sexual behavior. In addition, neonatal treatment with clomipramine also disrupted adult male sexual behavior (refs. 3 4 , 3 5 , 120). Alpha-methyldopa possibly exhibits similar effects. Male rats treated perinatally with delta-9-THC have been found to be sexually less responsive at adult age (ref. 110). 5.4.2 Other categories of social behavior

An example of pup-dam interaction changed by chemicals is reported by Barrett and Livesey (ref. 1 3 0 ) . They found that methylmercury-treated pups were nursed for a longer period than controls. A study in which effects of neonatal treatment of rats with diazepam and lorazepam on adolescent (days 3 5 - 4 0 ) behavior was tested failed to produce significant effects in a social interaction test. However, aggressive behavior in a resident-intruder aggression test was found to be changed after treatment with both drugs. Treatment with 0.1 mg/kg clonazepam enhanced offensive behaviors when the animals were confronted with an intruder in their home-cage. However, submissive behaviors were increased when the animals intruded into territories of other rats. Rats treated with 0.5 and 1 mg/kg behaved more dominantly when they were intruders (ref. 1 4 3 ) . Social dominance in a task in which adult rats had to compete for water was reduced in animals prenatally exposed to methadone (ref. 1 6 5 ) . 5 . 5 Food and water intake

Food and water intake in adult rats does not

seem to have been studied frequently. Yet, changes in these behaviors might in some cases be a possible

296

explanation for differences in body weight.

However,

ingestive

behavior

of

pups has been used as a test for neurobehavioral functioning. Suckling behavior of pups is affected by prenatal ethanol exposure and the animals show longer attachment latencies and decreased suckling pressure (ref. 166). 6 METHODOLOGICAL ASPECTS OF NEUROBEHAVIORAL TERATOLOGY As shown in section 5, there is a wide variety of methods applied in neurobehavioral teratology, even within each behavioral category. When comparable tests are used, differences in methodology in most cases can result in different teratogenic effects. Even carefully controlled experiments using identical procedures do not always yield the same results (ref. 135). Although there are many uncertainties about the optimal test strategy and interpretation of the results, most investigators agree that i t is necessary to include neurobehavioral testing in routine neuro-toxicological studies for purposes of regulating use of chemicals. 6.1

Some methodological

issues There are a number of theoretical and practical factors

that

have

to

be

taken into account in behavioral teratology. A complete overview can be found in literature (refs. 62, 109, 167-169). In this section only some of the most important problems are discussed. One issue is the statistical unit that has to be taken into account. Some investigators are of the opinion that i t is not correct to consider rats from the same litter as independent units. They suggest that litter means should be used as the unit for statistical analysis, instead of the individuals (refs. 169-172). Litter can significantly affect behavior, even at ages long after weaning (Buelke-Sam et al., 1985). However, using litter means may result in a conservative statistical test, which is undesirable in toxicology. It may be more appropriate to test only one animal from each litter in any given test. For instance, if one would have litters of 8 pups, 4 male and 4 female, one male and one female from each litter could be used in a separate part of the testing program. In case of prenatal treatment, care should be taken that pups are fostered appropriately (ref. 169). Otherwise, postnatal effects of changes of maternal behavior resulting from the treatment might be confounded with prenatal effects of fetal exposure to chemicals. Changes in pup-dam interactions, caused by effects of postnatal treatments on either the dam or the pup, may lead

to indirect

teratogenic effects.

It is difficult to distinguish such

effects from direct teratogenic effects. Furthermore, exposure of dam and fetus or pup to chemicals may cause indirect effects because of induction of

291

undernutrition or decreased supply of oxygen, which in turn are also teratogenic factors (refs. 59, 173, 174). Maternal stress caused by exposure to chemicals may also play a role (ref. 175). In addition, cagemate behavior after weaning may also affect behavioral development (ref. 176). Choice of proper control treatment

is also an

important issue. Since

placebo treatment can also affect offspring behavior (ref. 139), it is essential to have at least one placebo treated group. However, some investigators include an untreated group as additional control.(ref. 135). Furthermore, in case of altered caloric intake by the drug treated dam (e.g. in the case of treatment with an anorectic drug), pair-fed controls have to be included. If the tested substance has a caloric value of itself, as in the case of ethanol, control animals should get a diet which corrects for this factor. If the predictive value of the tests used is not yet known, a positive control group, treated with a substance with known neurobehavioral teratogenic properties, can be of help in evaluating the results (refs. 109, 177). The nature of control group(s) which have to be included is determined by the research question. Dose-effect relations in neurobehavioral teratology may be complex. For instance, high doses of naloxone may stimulate certain aspects of development, while lower doses have the opposite effect (see below). A prenatal dose of 10 mg/kg methadoneresulted in a larger increase in activity of rats on postnatal days 17 and 22 than a dose of 15 mg/kg (ref. 49). This type of dose-effect relations is very common in psychopharmacology, and probably also in neurobehavioral toxicology. Careful choice of dose range is necessary since ineffectiveness of a certain dose level does not always mean that all lower doses can be assumed to have no effect. Interpretation of effects of chemicals on brain and behavioral development is another difficult issue. For instance, should every developmental change be considered detrimental to the organism? It is clear that in most cases effects on behavioral development consist of delays and decreased performance. However, effects of chemicals on brain development are not necessarily adverse. For example, neonatal naloxone treatment in preweaning rats was shown to stimulate body and brain growth. This effect was dose-dependent. Lower dose was found to inhibit growth (refs. 178-180). Prenatal naloxone has also been reported t o stimulate physical and behavioral development of rats, although the same treatment decreased Biel water maze learning performance (ref. 161). Neonatal administration of Met-enkephalin has been reported to facilitate maze performance of adult rats (ref. 181). Neonatal undernutrition during development also can "improve" learning behavior in rats, although physical as well as neurobehavioral development is clearly retarded in other respects

'

298

(refs. 173, 174). However, the safest assumption is that true improvements are unlikely to occur. Within the framework of developmental continuity i t is essential that any given developmental process shall develop at the right moment. Therefore, even in the case of improvement of some functions, any change of behavioral development can be expected to cause imbalances in the development of the behavioral repertoire as a whole. One must be careful not to interpret the results of "accelerating" developmental processes as a "positive" effect of chemicals. 6.2 Different approaches & neurobehavioral teratological research When making a choice of test situations, some investigators are biased by the effects of the tested substance in adulthood. Based on this knowledge, i t is possible to formulate and test a specific hypothesis about aspects of brain and behavioral development that are expected to be affected. For instance, haloperidol can be expected to alter development of the dopamine system and motor activity, whereas clonidine can be expected to affect development of the catecholamine system and REM sleep. A quite different approach is adopted by investigators interested in all possible toxic effects, independent of the effects expected on the basis of current knowledge. Often no specific hypothesis is possible in case of screening for possible adverse effects of chemicals on development. Moreover, i t is essential to take into account that unexpected effects might occur. Therefore, i t is necessary to investigate effects on a wide range of behaviors in order to decrease the chance of missing an important effect. There are important differences between the fundamental and applied research, such as different objectives, and research methods and approach. However, both areas can benefit from each other's results. Fundamental research can yield new test methods,,and may help in interpreting certain effects. Applied research, which often involves screening programs, is inclined to test a wider range of behavioral categories and may therefore yield unexpected results and new problems or viewpoints for fundamental research. 6 . 3 Behavioral screening batteries

In order to test whether some substance affects neurobehavioral development, i t is necessary 'to choose tests which in principle cover the whole behavioral repertoire of the animal at different stages of development. Tests should be performed of reflex- or neuromotor development, sensory functioning, activity, emotionality, exploration, motivation and attention, as well as learning (appetitive and aversive learning in simple and complex

299

tasks), various categories of social behavior, and food and water

ingestion.

Within each behavioral category different methods are available (see section 5 and refs. 62, 109, 177, 182). It is advisible to choose a number of methods within each category, since different tests often address different aspects of the same behavioral category and therefore do not necessarily yield the same results. In the USA test batteries have been developed for the purpose of screening for behavioral teratological effects. Two important batteries of tests for rats are the Cincinnati Behavioral Teratology Test Batteries and the battery used in the Collaborative Behavioral Teratology Study (CBTS). Both batteries test: a) the development of a number of landmarks, like incisor eruption, eye opening, testis descent, vaginal opening, and b) development of a number of reflexes, and neuromotor coordination and sensory functioning, such as negative geotaxis, surface righting, olfactory discrimination, acoustic startle, pivoting locomotion, auditory startle onset, olfactory orientation and swimming ontogeny. The Cincinnati battery also measures: c) figure-8 or open field activity on pre-weaning age, d) acoustic startle behavior, figure4 or open field activity, operant conditioning, water maze performance, spontaneous alternation, M-maze and Y-maze performance, active and passive avoidance behavior all measured after weaning (not all of these tests are used in each battery). An extensive methodological study using the CBTS battery indicated that i t is possible to find consistent results with this battery in spite of differences in behavioral testing results between replications within laboratories and between laboratories. The test battery has been used in order to investigate the effects of prenatal administration of amphetamine and methylmercury. After amphetamine treatment no consistent effects were found. However, methylmercury revealed clear behavioral teratogenic effects. The Cincinnati test battery has been used to test a variety of chemicals and also proved to be sensitive to teratogenic effects. Overall, the sensitivity of both test batteries seems to be comparable. However, they test slightly different aspects of behavioral development. The CBTS battery puts much emphasis on activity measurements, while the Cincinnati battery includes a larger range of learning tests (refs. 135, 177, 183-187). The studies using the batteries mentioned above have yielded important contributions to the field of behavioral teratology. Their results strongly suggest that neurobehavioral teratological testing yields reproducible and reliable measures. However, they do not yet cover the whole area of rat behavioral development. Notably, they do not screen for effects on social behavior. This is a serious disadvantage in view of endocrinological and behavioral teratological effects found in animal and man. It seems essential

300

to test social functioning of treated animals during development as well as in adulthood. For instance, social exploration, play behavior, maternal behavior, sexual and aggressive behavior, could be included to complete a test battery. Furthermore, the batteries only use relatively simple tests of cognitive functioning in rats. It is important to include tests of learning, memory, and problem solving in more complex tasks. For example, latent learning might be added. Measurements of wake/sleep states during development as well as in adulthood might be very valuable. The importance of such measurements is discussed in section 4.

A complete behavioral teratology battery should include the following types of tests: a) Tests of sensory functions. Olfactory, visual, auditory, vestibular and tactile functioning and pain and temperature sensitivity should all be tested. Not only the presence or absence of sensory functioning, but also the range of sensitivity should be investigated. For instance, not only the capacity to hear is important, but also the range of frequencies that can be detected. There are tests for most aspects of sensory capacity, several of which can be used in their present form in young rat pups (see e.g. refs. 109, 136, 177, 182, 186, 188). b) Tests of the development of reflexes and neuromotor coordination. Various tests for reflex development and neuromotor coordination are included in the existing batteries (see above and refs. 177, 182, 188, 189). c) Tests of social behavior. Investigation of pup-pup and pup-dam (ref. 130) interactions can be performed in early age. Development of play behavior and social exploration can be investigated (ref. 126). In adolescent and adult rats, male and female sexual behavior should be tested (refs. 34, 35, 120, 162, 163). Furthermore, aggressive behavior should be tested (refs. 109, 182, 190). d) Tests of spontaneous activity, exploration and emotionality. Various tests of activity and exploration are already included in the existing batteries (refs. 109, 177, 182, 188). Open field size may interact with effects on activity. Therefore, motor activity and exploration should be tested in 2 or 3 differently sized open fields, as well as in a simple (empty open field) as compared to a complex (maze-like, or open field with objects) situation. Home cage activity and response to stimuli (e.g. a tone) can be tested automatically. Activity and exploration

of pups might also be studied in the homecage (ref. 130). In

301

e)

f)

g)

h)

addition, a number of tests of emotionality could be included, such as latency to enter an open field or a social exploration test (ref. 126). Since the activity shows a circadian rhythmicity, i t is important to test whether changes in this rhythm occur. Tests of behavioral states. Recording sleep-wakefulness is a valuable test to be added to neurobehavioral screening batteries. Behavioral state disorganization or suppression may be predictive of deviations in later neurobehavioral functioning. The recordings can be carried out both during development and in adulthood. Sleep disturbances may well be a mediatory factor underlying behavioral changes. The profound circadian rhythmicity of sleep-wake pattern is another important biological factor that can be measured (see section 4). Food and water consumption. Suckling behavior in young rat pups can easily be tested (refs. 166, 191). There are indications that aberrations in this behavior in humans have a predictive value for later neurobehavioral functioning (ref. 166). Effects on suckling behavior in animals may have a high predictive value for adverse effects in humans. Namely, the organization of suckling in animals and man may very well be comparable to a large extent. Food and water ingestion and their circadian patterns could be measured in adulthood. Tests of simple cognitive functioning. Simple learning tests are, for instance, habituation to a tone, passive avoidance, simple tests of operant learning, simple maze tests (e.g. T or Y mazes), or learning in a runway. Tests using a variety of aversive and appetitive reinforcements should be selected (e.g. shock, food or water, sexual reinforcement, water-escape tasks). Examples of this type of tests can be found in the existing screening batteries (ref. 177). Tests of complex cognitive functioning. Possibilities for tests of complex cognitive functioning are as follows: Hebb-Williams maze problem solving behavior, behavior in a radial maze or a Morris water tank maze, learning set formation, multiple T-mazes and DRL learning in a Skinnerbox (refs. 3 4 , 3 5 , 62, 120). Although the value of apical tests is not yet clear (ref. 167), the Hebb-Williams test could serve as an example of such a test. In this test measures of activity, motivation, learning, memory and problem solving capacity can be determined in one single test situation. It is importaflt that learning and memory tests selected for inclusion in screening batteries are sensitive to toxic effects. Tasks requiring long training even in normal animals may be unsuitable. The necessity of giving

a long pretraining may indicate a low degree of "preparedness" of the animal species for the task. Such tasks may not be the most suited ones for measuring normal functioning. It is possible that the learning performance of relatively untrained animals reflects different neurobehavioral processes than that of the extensivily trained animals. The latter animals may behave almost robot-like. Performance of such an animal may have become extremely stable and therefore highly resistant to influences of drugs or toxicants. Selection of learning tests which are relatively well adapted to the natural behavioral repertoire of the species of animal used, may lead to less time consuming and also more sensitive tests. For instance, a rat can quickly learn a spatial information. Tests of spatial behavior with minimal pretraining could be developed. For example, in a Hebb-Williams maze the number of errors usually decreases predominantly during the first few trials and therefore these first trials may yield sufficient information. Radial maze performance is acquired quickly. Two weeks of testing is probably enough to make a reliable estimation spatial learning capacity.

of

the animals'

i) Tests of brain plasticity. Early environmental stimulation affects neurobehavioral development and therefore may interact with behavioral teratological effects (refs. 47, 106-108, 192). It is possible that some subtle effects on neurobehavioral development come to expression only in case of optimal development of the control group. Then the rearing in an enriched environment might increase the probability of detection of neurobehavioral defects. On the other hand, environmental enriched rearing conditions might stimulate recovery from slight damage, and thereby obscure effects. Therefore, more attention should be directed to possible interactions of rearing conditions with neurobehavioral damage. In general, research on interactions of various kinds of environmental factors with neurobehavioral teratogenic effects deserves greater attention, because such research can potentially reveal methods to stimulate recovery of the young organism from some types of brain damage. 6.4 Screening strategy It is almost impossible and certainly impractical to use a complete battery as indicated in section 6.3 for testing multiple doses of large numbers of chemicals. It is clear from the literature (ref. 183) that i t is expensive, laborious, as well as time-consuming to perform, for example, even a limited size CBTS study. Ideally, one would wish to study various doses of each chemical, different stages of neurobehavioral development and also the effects

303

in adulthood and during aging. This should be done using more than one

route

of administration and using more than one animal species. A complete test battery as indicated above could be developed, in which a large range of tests of sensory, motor and other behavioral functions to be carried out on specific ages is included. Each test procedure could be specified exactly for each age group, as well as the sequences of tests which are allowed to be performed using the same animals. In order to reduce the number of tests that should be performed per chemical, the battery might be subdivided in a number of sub-batteries, not all of which would have to be carried out in every study. A general strategy for choice of tests and ages on which the tests are performed could be developed. The sub-batteries might be applied in order of increasing complexity, costs, and age. Only if a previous battery indicates no adverse effects, a next battery would be used. For instance, a

first battery might

test

for effects on reflex development,

neuromotor coordination, sensory development, suckling behavior, and development of sleep-wake states. A next battery could contain tests on activity, exploration, emotionality, food- and water consumption and circadian rhythms. A subsequent battery could test for effects on simple learning behavior. Next batteries then might contain tests of complex cognitive behavior and social behavior. If in some battery effects are found, and if further study of these effects is of interest, tests for further analysis could again be selected from the large overall battery. Such an approach would limit the number of tests necessary in case a substance is found to be teratogenic and would offer the possibility to analyse effects into more detail. Collaboration of laboratories is indispensible for standard procedures to be developed, to collect data on normal baseline levels of performance of non-treated animals, and to determine the effect profile of a number of standard-teratogens in the complete battery. During the process of collecting data i t may become more clear which tests are most useful and which tests could be excluded. For instance, it may become clear whether application of apical test strategies has advantages over using separate tests for various functions (ref. 167).

It must also be realized that much information might already be present in the human population. Epidemiological studies of behavioral teratogenic effects of various substances to which developing humans have already been exposed, can yield much valuable information about the eventual dangers of many 'old' chemicals. In addition, such studies can help to find a reliable way to extrapolate findings in animal studies to risks for human development.

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Based on the results found in animals one may be able to predict what kind

of

effects in humans may be expected after exposure to 'new' chemicals. Exposure to some chemicals (pollution, food additives and drugs) occurs not only in man, but also in domestic animals. Thus, screening for effects on functioning in these animals might supplement results of epidemiological studies in man and those of laboratory animal studies. For instance, effects on reflex development, motor coordination and sensory functioning, as well as effects on state development, food and water ingestion and activity could all be studied in domestic animals. Tests of social behavior and cognitive functioning could possibly also be performed in some cases. This additional information would supplement screening studies which are typically done on a single laboratory animal species. Generally, a one-animal species screening is not sufficient for reliable risk evaluation. Furthermore, i t may be attempted to develop simple evertebrate and/or in vitro models for screening for some types of effects. Possibly the use of such tests could help limit the necessity for performing a too wide range of vertebrate tests.

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313 172 M.H. Teicher, D.E. Pearson, B.A. Shaywitz and D.J. Cohen, Identifying experimental unit and calculating experimental error, Science, 213 (1981) 931. Lynch and J. Sands, 173 J.L. Smart, J. Dobbing, B.P.F. Adlard, A. Vulnerability of developing brain: Relative effects of growth restriction during the fetal and suckling periods on behavior and brain composition of adult rats, J. Nutrition, 103 (1973) 1327-1338. 174 J.L. Smart and J. Dobbing, Vulnerability of developing brain. 11. Effects of early nutritional deprivation on reflex ontogeny and development of behaviour in the rat, Brain Res., 28 (1971) 85-95. 175 R.F. Smith and L. Goldman, Behavioral effects of prenatal exposure to ethylene dibromide, Neurobehav. Toxicol. Teratol. 5 ( 5 ) (1983) 579-585. 176 D.E. Pearson, M.H. Teicher, B.A. Shaywitz, D.J. Cohen, J.G. Young and G.M. Anderson, Environmental influences on body weight and behavior in developing rats after neonatal 6-hydroxydopamine, Science, 209 (1980) 715-717. 177 C.V. Vorhees, Comparison of the Collaborative Behavioral Teratology Study and Cincinnati Behavioral Teratology test batteries, Neurobehav. Toxicol. Teratol., 7(6) (1985) 625-633. 178 I.S. Zagon and P.J. McLaughlin, Naltrexone modulates growth in infant rats, Life Sci., 33 (1983) 2449-2454. 179 I . S . Zagon and P.J. McLaughlin, Increased brain size and cellular content in infant rats treated with an opiate antagonist, Science, 221 (1983) 1179-1180. 180 I.S. Zagon and P.J. McLaughlin, Opioid antagonist-induced modulation of cerebral and hippocampal development: Histological and morphometric studies, Develop. Brain Res., 28 (1986) 233-246. Coy, Neonatal 181 A.J. Kastin, R.M. Kostrzewa, A.V. Schally and D.H. administration of Met-enkephalin facilitates maze performance of adult rats, Pharmacol. Biochem. Behav., 13(6) (1980) 883-886. 182 A. Chester, D. Hallesy and F. Andrew, Behavioral methods in reproductive and developmental toxicology, Neurobehav. Toxicol. Teratol., 7(6) (1985) 745-752. 183 C.A. Kimmel and J. Buelke-Sam, Collaborative Behavioral Teratology Study: Background and overview, Neurobehav. Toxicol. Teratol., 7(6) (1985) 541-545. 184 J. Adams, J. Buelke-Sam, C.A. Kimmel, C.J. Nelson and D.R. Miller, Collaborative Behavioral Teratology Study: Preliminary Research, Neurobehav. Toxicol. Teratol., 7(6) (1985) 555-578. 185 J. Adams, J. Buelke-Sam, C.A. Kimmel, C.J. Nelson, L.W. Reiter, T.J. Sobotka, H.A. Tilson and B.K. Nelson, Collaborative Behavioral Teratology Study: Protocol design and testing procedures, Neurobehav. Toxicol. Teratol., 7(6) (1985) 579-586. 186 J. Adams, D.M. Oglesby, H.S. Ozemek, J. Rath, C.A. Kimmel and J. Buelke-Sam, Collaborative Behavioral Teratology Study: Programmed data entry and automated test systems, Neurobehav. Toxicol. Teratol., 7(6) (1985) 547-554. 187 C.J. Nelson, R.P. Felton, C . A . Kimmel, J. Buelke-Sam and J. Adams, Collaborative Behavioral Teratology Study: Statistical approach, Neurobehav. Toxicol. Teratol., 7(6) (1985) 587-590. 188 S.M. Barlow, United Kingdom: Regulatory at t i tudes toward behavioural teratology testing, Neurobehav. Toxicol. Teratol., 7(6) (1985) 643-646. 189 M.J. Kallman and L.W. Condie, A test battery f o r screening behavioral teratogens in mice, Neurobehav. Toxicol. Teratol., 7(6) (1985) 727-731. 190 S.E. File, Effects of neonatal administration of diazepam and lorazepam on performance of adolescent rats in tests of anxiety, aggression, learning and convulsions, Neurobehav. Toxicol. Teratol., 8 ( 3 ) (1986) 301-306. 191 L.P. Spear, E.K. Enters and D.G. Linville, Age-specific behaviors as tools for examining teratogen-induced neural alterations, Neurobehav. Toxicol.

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315

TERATOGENICITY OF PESTICIDES AND OTHER ENVIRONMENTAL POLLUTANTS

KLAND

M.J. 1.

INTRODUCTION

1.1 E a r l y H i s t o r y :

The N a t u r a l P e s t i c i d e s

The u s e o f a g r i c u l t u r a l p e s t i c i d e s h a s p a r a l l e l e d t h e development o f

agrarian s o c i e t i e s , and was p r e v a l e n t l o n g b e f o r e t h e Roman Empire e x i s t e d ( r e f . 1 ) . From a n t i q u i t y t o t h e p r e s e n t day n a t i v e p l a n t s and t h e i r e x t r a c t s have been used as i n s e c t i c i d e s .

The a p p l i c a t i o n o f

n a t u r a l p l a n t e x t r a c t s as a means o f p e s t c o n t r o l p r o b a b l y o r i g i n a t e d i n

Asia and was i n t r o d u c e d t o Europe by t h e Venetian t r a v e l l e r Marco P o l o i n the late 13th o r e a r l y 14th century.

By

1848 t h e e x t r a c t s o f d e r r i s

r o o t and tobacco ( s o u r c e s o f r o t e n o n e and n i c o t i n e , r e s p e c t i v e l y ) were a l s o i n use.

The l a t t e r 1 9 t h c e n t u r y saw t h e l i s t of i n s e c t i c i d e s

expanded t o i n c l u d e d i n i t r o p h e n o l and hydrogen c y a n i d e .

By t h e e a r l y

1900s, bromomethane. p-dichlorobenzene and n a p h t h a l e n e had been added t o

the list ( r e f . 2b). C u r r e n t l y p e s t c o n t r o l by n a t u r a l p l a n t e x t r a c t s is p r a c t i c e d p r i m a r i l y by s u b s i s t e n c e f a r m e r s i n t h o s e less developed p a r t o f t h e world where i t is s t i l l an economic n e c e s s i t y . ( r e f .

3 ) . O f the

a p p r o x i m a t e l y 2000 p l a n t s p e c i e s w i t h known i n s e c t i c i d a l p r o p e r t i e s (ref.

4 ) . few have been developed commercially.

p y r e t h r i n s . r o t e n o n e s and some of t h e a l k a l o i d s .

These i n c l u d e t h e P y r e t h r i n s were t h e

most i m p o r t a n t n a t u r a l p l a n t e x t r a c t s i n t h e e a r l y commercial i n s e c t i c i d e f o r m u l a t i o n s and were a l r e a d y i n u s e i n P e r s i a and Yugoslavia d u r i n g t h e e a r l y 1800s. United S t a t e s were

By

1939 pyrethrum i m p o r t s t o t h e

13.5 m i l l i o n l b s , d e c l i n i n g from t h i s peak as t h e

s y n t h e t i c a n a l o g s ( e . g . , t h e a l l e t h r i n s ) appeared on t h e market.

The

a d d i t i o n of s t a b i l i z e r s ( a n t i o x i d a n t s ) and s y n e r g i s t s t o t h e o r i g i n a l pyrethrum f o r m u l a t i o n s saved t h e n a t u r a l p r o d u c t from commercial extinction.

C u r r e n t l y t h e demand f o r pyrethrum flowers i s s t i l l o v e r

25,000 t o n s p e r annum--met

by hand-harvested c r o p s from Ecuador, Kenya

and Tanzania ( r e f . 5 ) . I n o r g a n i c s have a l s o c o n t r i b u t e d t o t h e e a r l y h i s t o r y o f p e s t i c i d e development, a l b e i t somewhat less s p e c t a c u l a r l y t h a n i n s e c t i c i d e s o f plant origin.

The n a t u r a l i s t P l i n y t h e E l d e r (70 A . D . )

u s e of a r s e n i c as an i n s e c t i c i d e .

recommended t h e

The s u l f i d e ( s ) of a r s e n i c are a l s o

316 believed to have been used for this purpose in China in the 1500s. By the nineteenth century a number of other metal salts had joined the ranks of the arsenic compounds (ref. 6). For reviews of the literature on insecticides from plants see USDA Agricultural Handbooks 154 (1958) and 461 (1975). and The American Chemical Society publication: "Natural Pest Control Agents" (1966), all cited in reference 4. Further citations are given by Balandrin et al. (ref. 3). The chemistry and mechanism(s) of action of naturally occurring herbicides is treated by Putnam in a recent report in Chemical and Engineering

N w s (C&EN) (ref. 7).

1.2 Synthetic Pesticides The 19th and early 20th centuries experienced phenomenal scientific growth, particularly in chemistry and physics. However, it was the impetus of a second world war with its massive demands for substitutes for scarce fuels, pesticides, medicines, weapons and transportation that catalyzed the exponential growth in these areas. Among the beneficiaries of this incentive were the petrochemical-based polymer industry, pharmaceuticals and large scale agribusiness with its escalating need for fertilizer and pesticides to compensate for monoculture-induced soil depletion and disease problems (refs. 8 and 9). The post-war revolution in agriculture was not without its critics, first among biologists and early environmental scientists: later, among lay citizens concerned with their air, water and food. Perhaps the most prophetic of early writings on the pollution of aquatic ecosystems was Rachel Carson's "Silent Spring". which reached well beyond the biological science community in its influence (ref. 10). An aquatic biologist on the University of Maryland Zoology staff, Carson was herself a victim of cancer, adding to the poignancy of her message. Eugene Odum, another concerned ecologist, argued persuasively for the application of ecosystem development theory to human ecology, and the need to devise a strategy leading to ecosystem stability, rather than short term gains at great environmental cost. Monoculture leads to soil depletion and disease susceptibility; excessive pesticide use, to the destruction of beneficial species, etc. (ref. 11). By the time Hardin's "Tragedy of the Commons" (ref. 12a) and Commoner's "The Closing Circle: Confronting the Environmental Crisis" (ref. 12b) were published, the environmental movement had taken on a

317 life of its own and the EF'A* was a jaft accompti, having been established by Congress in 1970.

1.3 Definition and Sources of Pesticide Information The term pesticide is defined by Risebrough as "material useful f o r the mitigation, control or elimination of plants or animals detrimental to human health or economy" (ref. 13). The Pestfcide Indez (ref. 14) lists the following categories of pesticides:

acaricides, attractants, chemosterilants, defoliants,

fungicides, herbicides, insecticides, molluscicides. nematicides, plant regulators, repellents, and rodenticides. Listings are in alphabetical order with structural and molecular formulae for single chemical entities. Other data include: CAS nomenclature and number: Wiswesser Line Notation; LD-50 and test animal data when available: physical appearance and safety information. Also provided are: a CAS nomenclature index; separate molecular (line) formulae of chemicals identified by their common names: a separate section of Wiswesser line notations, also with common names; an appendix of manufacturers. and an appendix of recent publications dealing with pesticide names. The recent looseleaf Agrochemicats Handbook (ref. 15) will have the advantage of currency, since the prospectus promises periodic updates. Designed primarily for manufacturers and users of agrichemicals, it has features that should make it useful as a reference for the teratologist and toxicologist as well (a bioactivity index, health and safety information and ingredients listings for commercial formulations). 1.4 Classes of Pesticides and Their Modes of Action Pesticides may be broadly classified by use as insecticides, herbicides, fungicides, fumigants, end antimicrobials. etc. Of the 7100 separately indexed entries appearing the 5th edition of the Pesticide Index, 1600 are main entries. Hence this discussion will of necessity be limited to a small number of compounds in each class, selected for their broad class characteristics as well as their importance. Insecticides fall largely into three main chemical groups: 1) the organochlorines whose action is primarily on the peripheral nervous system: 2 ) organophosphates, and 3 ) carbamates. The latter two classes are cholinesterase inhibitors. Historical accident dictates that the chlorinated pesticides be considered first. It is well over a century since Othmar Zeidler first *Environmental Protection Agency

318 synthesized DDT (2,2-bis(p-chlorophenyl)-1,1,l-trichloroethane) i n the laboratory of Professor Adolph von Bayer (1873) ( r e f . 16).

Nearly a

half century earlier (1825) the photochemical addition of 3 moles of chlorine t o benzene t o give the hexachloride had been achieved.

However

recognition of the insecticidal properties of these compounds came much

later--1935 f o r the hexachloride and 1939 f o r DDT--when Dr. Paul MUller repeated Zeidler's synthesis.

H e w a s investigating compounds of the

general formula I* i n search of a liposoluble contact poison:

I Mllller found DDT t o be remarkably effective against a variety of arthropods, including f l i e s , mosquitoes and other insects, as w e l l as the Colorado potato beetle.

The discovery earned MUller the 1948 Nobel

award i n chemistry. The timing of Milller's discovery insured i t s early application i n the Mediterranean and South Pacific theaters of World War I1 t o

malaria, f i l a r i a s i s , dengue fever; also typhoid fever, carried by lice and fleas.

eliminate mosquito-vectored diseases:

The efficacy of DDT i n controlling morbidity and reducing mortality r a t e s from pest-vectored diseases was probably a major f a c t o r i n the world population explosion of the '70s (Metcalf, r e f . 16).

A s with human disease vectors, so DDT succeeded i n i t i a l l y with some ** By the e a r l y 1970s over 4 b i l l i o n

of the major agricultural pests.

pounds of the insecticide had been used--approximately 80% of it on agricultural crops.

I t was also i n wide use f o r pest control i n home

flower and vegetable gardens, and domestically as protection against moths and carpet beetles. The phenomenal success of DDT stimulated f u r t h e r research, and by

1946 the two DDT analogs, DDD and methoxychlor (Table 1 , A ) had been produced (Tables a r e a t the end of the chapter).

The observation of

greater i n s e c t i c i d a l a c t i v i t y i n those organochlorine compounds t h a t lose their HC1 more e a s i l y led t o yet another group of chlorinated derivatives. the condensed r i n g chlorocyclodienes (Table 1 , B ) .

Thus,

nearly a l l of the chlorinated pesticides currently i n use had been ~~

~

*Compounds of formula I were known t o act as stomach poisons against moths and beetles. wt

The coddling moth (deciduous f r u i t s ; pink bollworm (cotton): the gypsy moth and spruce budworm, two defolialors of our forests.

319

synthesized by 1950--less than ten years after DDT was marketed. 1.5

"The Other Side of The Coin": Environmental Persistance and Insect

Resistance At first blush the physicochemical characteristics of DDT seemed very nearly ideal. It had the desired high fat/low water solubility, low volatility and resistance to photo-oxidation, to insure that it would survive long enough to be effective. Its primary degradation product DDE had nearly identical characteristics. But precisely those traits that were built into the DDT molecule to guarantee its survival in s f t u and its insect toxicity have made it one of the most formidable of environmental pollutants. DDT and its degradation products are ubiquitous in the global environment--in soil and water; in the body fats of mammals, and in insect and plant lipids. In those organisms constituting trophic webs the concentration factors of DDT and DDE are estimated at 10 percent per trophic level (ref. 1 7 ) . Harrison et al. found an overall DDT concentration in Lake Michigan (water-amphipods-fish, e.g., Coho salmon, lake trout) of approximately lo7 (Metcalf, ref. 16. p. 512). The environmental persistance of DDT and its immediate metabolite DDE is characteristic of chlorinated organic pesticides as a class. Given the well-documented long term detrimental effects of many of these chemicals on species at all levels of the food chain--particularly on avian and estuarine species, insects and plants beneficial or even essential to agriculture, it is a fortunate accident of nature that resistant target pests evolved within a single generation. Unfortunately these resistant species also included the vectors of killer diseases along with the housefly--the first insect to develop resistance (ref. 18). In addition, 27 agricultural pests had become DDT resistant by 1970. many of these of economic importance. This feat of "accelerated microevolution" involved the genetically controlled production of a dehydrochlorinating enzyme ("DDT-ase") that converted DDT to DDE. Microsomal oxidation of the latter produced polar degradable compounds. 2. THE ORGANOHALOGEN AROMATIC AND CYCLIC PESTICIDES AND RELATED

COMPOUNDS 2.1 Modes of Action and Biochemistry of-TDD oraanics. DDT acts as a nerve poison on insects and mammals.

Symptoms of

320

intoxication include hyperexcitation, increasingly severe tremors resulting in convulsions, prostration, and finally, death. The tremors arise from the multiplication of single initial nerve impulses, producing a cascading effect. In general, the chlorinated pesticides have wide spectrum application. They penetrate the outer chitin layer of susceptible insect species, producing paralysis of the peripheral nervous system. A detailed discussion of their metabolic pathways is beyond the scope of this chapter and is available elsewhere (refs. 19a.b). While chemical theories of action at the molecular level abound, none provides a universally consistent rationale for the biotoxicities of all DDT analogs. Proposed mechanisms evolved from a classical pharmacologic conductophore-toxaphore picture in the 1940s. to a stereochemical approach in the early ‘50s. This was followed by theories of selective adsorption of the DDT analog at a suitable lipoprotein interface, and of toxicity based on appropriate molecular size and shape, so as to achieve interstitial fit of the DDT analog into the nerve membrane lattice. As with other areas of synthetic organic chemistry, the use of accurate Fisher-Hirschfelder type models here proved useful in predicting analog fit. Theories related to the mechanism of action of DDT analogs are summarized in Fig. 1 (Figures are at the end o f the chapter). A more detailed review is given in ref. 16, pp. 515ff. Like the arachnids, vertebrates have evolved mechanisms for coping with the toxic effects of chloroorganic-type pesticides. Upon ingestion the compounds are largely absorbed from the 01 tract, carried to the liver via the portal vein, and deposited in other organs throughout the body. Most solid chlorinated pesticides are also efficiently absorbed by the skin. Excretion is mainly by feces: however residual elimination is slow, and soye chloroorganics persist in body tissues and fluids long after ingestion. Table 2 lists proximate excretion times and relative toxicities in qualitative terms for some common commercial pestkide products. The main metabolite of DDT found in the liver and fats of mammals is its first dehydrochlorination product DDE, along with the unchanged DDT. A second step may occur leading to the oxidative dehydrochlorination of DDE to the substituted acid DDA, p,p’-dichlorodiphenylacetic acid (Fig. 2). This metabolite is excreted aa the conjugate glucuronide. Unsaturated analogs of DDT are generally transformed to expoxides by liver enzymes, stored in adipose tissue, or further metabolized to

321

hydrophilic substances and excreted as conjugates. Thus aldrin is epoxidized to dieldrin and heptachlor to its epoxide for storage in adipose tissue. In mammals these epoxides may then be enzymatically dechlorinated, hydroxylated, oxidized or conjugated and the resulting hydrophils excreted in the,feces. In toxaphene partial dehydrochlorination results in the excretion of chloride. Since its metabolites are water soluble toxaphene has less of a tendency to accumulate in fatty tissue and is more readily cleared. Commercial lindane (hexachlorocyclohexane;BHC) is an isomeric mixture whose composition will determine which metabolic path(s) predominate. The gamma isomer (la,2a,3b,4a,5a,6B) is dehalogenated and excreted largely as the glutathione conjugate. In the other isomers degradation paths vary and may occur extrahepatically as well as in the liver. The principal metabolic path for p-dichlorobenzene is via monohydroxylation.

2.2 The Teratologist's Dilemma. Past experience has taught us that much of the pesticide information of greatest relevance to human health and safety will be derived from inadvertent human exposure, either during the manufacture, o r the largescale application of pesticides. From Percival Pott's description of occupational cancer of the scrotum in British chimney sweeps* (1775; ref. 21). to the more recent occurrence of a rare liver angiosarcoma among workers exposed to vinyl chloride (VC) monomer (refs. 22a.b); to the carcinogenic and reproductive hazards of the soil fumigant and nematocide, dibromochloropropane (DBCP), whose use is no longer permitted (refs. 23a.b.c.d)

. . . man has remained the ultimate test

animal. The reason is not hard to find. With the advent of large scale agriculture, fertilizers and pesticides have become an economic fact of life. *I

, OSHA***, and FIFRA****, hence were "grandfathered" in. Legally mandated testing logistics are such that the EPA must depend largely on toxicology data provided by manufacturers' studies, done either in-house or by outside commercial laboratories retained by them. Neither arrangement insures adequately against bias, as will be seen in the Many formulations were in use long before the passage of TOSCA

*"Chirurgical Observations", 1775. PL94-469: Toxic Substances Control Act of 1976. ***PL91-596: Occupational Safety and Health Act of 1970. (I*

**** Amended

(?%$.

396: Federal Insecticide, Fungicide and Rodenticide Act as

322

l a t e r DBCP example; and i n a t least one case on record a major commercial l a b o r a t o r y submitted f r a u d u l e n t d a t a ( r e f . 120).

Recent

i n c r e a s e d emphasis on c o s t - b e n e f i t c o n s i d e r a t i o n s has f u r t h e r eroded t h e o r i g i n a l i n t e n t of t h e l e g i s l a t i o n , enacted d u r i n g t h e environmental r e v o l u t i o n of t h e '70s. More o f t e n than not t h e hidden c o s t s may involve t h e h e a l t h and s a f e t y o f t h e worker--or

an unexplained cluster

of i l l n e s s e s , miscarriages andfor b i r t h d e f e c t s i n a community a f t e r heavy spraying with a known t o x i c p e s t i c i d e . 2.3 T e r a t o n e n i c i t y and Remoductive E f f e c t s of Organochlorine Pesticides. A number of once f l o u r i s h i n g b i r d s o f prey ( r a p t o r s ) have now become

endangered s p e c i e s , no longer a b l e t o produce v i a b l e eggs. source o f food, i . e . ,

Their main

f i s h , c o n c e n t r a t e DDT i n t h e i r t i s s u e s .

Osprey

and o t h e r p r i n c i p a l avian p r e d a t o r s of t h e a q u a t i c food c h a i n , were exposed t o large q u a n t i t i e s of DDT and i t s metabolite DDE.

These

compounds impair avian calcium metabolism r e s u l t i n g i n t h e production of f r a g i l e , calcium- d e f i c i e n t egg s h e l l s t h a t break before t h e embryo can be brought t o term ( r e f . 83).

A similar f a t e has b e f a l l e n t h e brown

p e l i c a n , t h e peregrine f a l c o n , t h e bald e a g l e , etc. (Risebrough e t a l . ref. 82a).

Deleterious e f f e c t s of DDT and r e l a t e d organochlorine

p e s t i c i d e s i n f i s h are not confined t o t h e reproductive impairment of raptors.

The C a l i f o r n i a Department of f i s h and game documented

e x t e n s i v e f i s h k i l l s mainly by c h l o r i n a t e d p e s t i c i d e s i n 1963. ranged from hundreds t o 30,000

Numbers

(8 cases) t o over 100,000 ( 3 cases).

S i g n i f i c a n t numbers o f game f i s h were involved, and p o t e n t i a l l y dangerous r e s i d u a l l e v e l s of DDT were d e t e c t e d i n some i n s t a n c e s .

Since

then i n t e n s i v e monitoring and improved cooperation between t h e concerned

state agencies ( f i s h and game; a g r i c u l t u r e ) has reduced t h e number and magnitudes of f i s h k i l l s (10 cases reported i n 1969 involving 36,955 f i s h , r e f . 82b). Stored DDT and d i e l d r i n p r e s e n t i n l a k e t r o u t eggs a t spawning time can affect t h e u l t i m a t e s u r v i v a l o f t h e young ( r e f . 8 2 c ) .

is i n h i b i t e d even a t low concentrations of DDT.

Oyster growth

This c h a r a c t e r i s t i c

growth s e n s i t i v i t y o f a number of mollusks t o DDT, and t h e rates a t which DDT is flushed o u t when t h e mollusk is t r a n s f e r r e d t o f r e s h water, has been used as a p e s t i c i d e monitoring t o o l ( B u t l e r , r e f . 8 2 d ) . Among t h e known sequelae of exposure t o c h l o r i n a t e d organics i n

mammals is t h a t of e s t r o g e n - l i k e a c t i v i t y ( r e f . 84a). DDT i n h i b i t i o n of t e s t i c u l a r growth and secondary s e x c h a r a c t e r i s t i c s development i n white

323

leghorn cockerels was reported as early as 1950 (ref. 854. Later studies showed that mice fed DDT (200-300ppm) developed smaller ovaries and testes: that DDT administration interfered with ova implantation in mice and resulted in a higher incidence of cystic ovaries and persistent vaginal estrus in rat neonates (ref. 84b). Low doses of DDT administered over extended periods (50 d. to 21 mo.) increased the mean estrus cycle. At higher doses (100 to 250 ppm DDT) fertility, gestation, lactation, survival times of parents and offspring and viabilities of offspring were all significantly affected. Deichmann et al. reported low reproductive activity in beagles on 12 mg/kg/d DDT for 14 months. Findings included delayed estrus, reduced libido, high offspring mortality rates and stillbirths (ref. 85b). Unfortunately early studies with DDT often used technical grades o r did not specify isomeric composition. Some of the best-documented reports of estrogenic behavior of DDT involve studies of the o,p'-isomer of DDT which appears to be more active than the p.p'-isomer in this respect. Among DDT congeners it is the 0.p'-isomer that most closely resembles estradiol in its estrogenic behavior. Thus, it is a strong inducer of uterine ornithine carboxylase. elevates the concentration of cytosol progesterone receptor, and, when administered to immature rats, it elevates the uterine induced protein, IP. (Kupfer et al., ref. 84a, p. 125-128). Generally endogenous o r synthetic estrogens will have an exposed o r masked phenolic substituent (e.g., OCH3). However the purified o,p'-DDT from which all detectable phenolic impurities had been extracted continued to show estrogenic activity. Since in ufuo metabolism of the compound produces a number of phenolic derivatives with estrogenic potential, it was assumed that prior hydroxylation,must occur. Evidence from in uitro binding experiments howe:er suggests that unchanged 0.p'DDT may also be involved (Kupfer. et al., p. 132). While the literature abounds with reports of the undesirable reproductive consequences of DDT exposure at all levels of animal systems, little human research in this area has made its way into the open literature. Shepard's Catalog OJ' Teratogenfc Agents (ref. 86) and Nisbet-Karch (ref. 47) each list only the work of O'Leary et al. (ref.

87), correlating spontaneous abortion in human females with human pesticide residues, and prematurity of human fetuses with DDE levels found in fetal whole blood. Perhaps the more serious risk with DDT and DDE is the significant presence of these two along with other

324

organochlorine pesticides in the breast milk, where they concentrate and continue to exert an influence on growth, development and hormonal, CNS and enzyme systems (Barlow and Sullivan, ref. 80. p. 26). Other chlorinated pesticides that fall into the category of selective concentraters in breast milk include aldrin, dieldrin, chlordane, chlordecone (kepone). heptachlor epoxide, the antifungal agent hexachlorobenzene (HCB) and mirex. Two related industrial chemicals-the polybrominated and polychlorinated biphenyls resist biodecomposition and maintain persistent residence in mammalian tissue. It is possible that for them selective concentration and excretion via breast milk may constitute the main (or sole) route of elimination. Some of the organohalides known to concentrate in breast milk have been assigned MACE* by the U.S. Food and Drug Administration (FDA) and ADIS** by the WHO.*** However it is not unusual for a nursing infant to ingest amounts exceeding these values (Table 3; ref. 88). DDT is currently (W 1985) under test for chronic toxicity at Northwestern University and is scheduled for future epidemiologic study at the Center for Environmental Health (ref, 89). 2.4 DDT Analoas: The Chlorinated Diarvlethanes DDT analogs are substituted diarylethanes: R

= Halogen,Me-,

CI

R'

-OMe, etc.)

II

The action spectrum for DDT and its structural analogs is known to be quite broad and cannot be attributed to simple enzyme inhibition. as in the case of the carbamates or the organophosphates. The presence of chloroaryl moieties. as well as steric effects at receptor sites, both appear to be factors affecting insecticidal activity. In addition to DDT itself, its metabolites DDE and DDA and DDD have some activity. Efforts to overcome insect resistance and to produce more biodegradable analogs led to the introduction of substituents other than chlorine for *MAC-maximum allowable concentration. **ADI-allowable daily intake.

***WHO-World

Health Organization

325

R and R' in the aryl moieties (e.g., methoxychlor. methylchlor) and to moving R and/or R' to the ortho position. Animal toxicity studies led to the early (1950) observation of the hormonal action of DDT and its analogs and the later attribution of greater estrogenic activity to the o,p'-isomer of DDT (ref. 84a). Methoxychlor is degraded in vivo by 0-dealkylation and excreted as mono-and bis-phenols. It is much less environmentally persistent; also much less toxic to rats (oral LD50> 6000 mg/Kg compared with LD50 118 mg/Kg for DDT; Metcalf, ref. 16). However, methoxychlor toxicity in fish approaches that of DDT. and in cold water fish, e.g.. Atlantic salmon, it can accumulate to excessive levels. Although much less toxic in mammals than DDT it is similar in its estrogenic action. Methylchlor is less toxic to fish than methoxychlor, but also rather ineffectual as an insecticide. Comparison of the persistence characteristics of the methyl and methoxy analogs of DDT shows the microsomal side chain oxidation of the alkyl group to be more efficient than microsomal 0dealkylation.

2.5 Chlorinated Benzenes and Pentachlorophenol Of 12 chlorinated benzenes, three have found most frequent use as pesticides--the ortho and p-dichlorobenzenes and hexachlorobenzene (HCB)*.

The dichlorocompounds (DCBs) are used as insecticides and

fumigants; HCB, as a fungicide, and in seed treatment. Pentachlorophenol (PCP) has been used as an insecticide, a fungicide, defoliant, herbicide and wood preservative. As a street drug of abuse it is known as 'angel dust'. PCP is a metabolic stimulant and has caused deaths from hypothermia.

It can also produce peripheral

motor neuropathies when absorbed via the skin. The halogenated benzenes have relatively high vapor pressures due in part to the interaction of unbound (resonance) electrons on the halogens with conjugated aromatic double bonds:

111 Ring symmetry is also a determinant, greater symmetry favoring higher vapor pressure. The tendency of HCB to sublime, coupled with its stability, favor cross-contamination of the environment by HCB, from *Hexachlorobenzene (HCB; CgCl6)

326

soil to air and water, and vice versa. A recent inhalation study (Dow-Chemical,1985) of the teratogenic potential of 0- and p-dichlorobenzenes on pregnant rats (days 6 through 15) and rabbits (days 6 through 18) concluded that the pesticides were neither fetotoxic nor teratogenic under experimental conditions, despite maternal toxicities. However, rat doses (0,100,200,400 ppm) resulted in significant decreases in weight gain, while liver weight increased for the dams at 400 ppm. Rabbits showed a similar loss of weight after 3 days' exposure to 400 ppm of o-DCB or 800 ppm of the p-isomer. Dichlorobenzene exposures were for 6 hours/day throughout the experiment (ref. 96). The deaths of breast-fed infants in the mid-fifties in Turkey, and an epidemic of skin sores and discolorations (porphyria cutanea tarda) were associated with the accidental consumption of HCB-contaminated seed grain (refs. 93-94). Clinical symptoms included weight loss, enlargement of lymph nodes and thyroid, abnormal growth of body hair and skin photosensitization. In 1973 a small community in Louisiana exhibited enzyme disruptions attributed to the presence of up to 23 ppb HCB in the blood of affected inhabitants (ref. 93). HCB is known to cross the rat placenta, accumulating in the fetus. At high dose levels to the dam many suckling pups died before weaning, the viability index being zero f o r the F1 generation. Hence dietary HCB decreased the number of pups that survived to weaning. A minimum, e.g., no effect, dose level of 20 ppm of HCB was established (refs. 95a,b,c). As with other chloroorganics, HCB affects the CNS and with it a variety

of essential vital functions. HCB accumulates in catfish (x 15000) and is toxic to some birds. Its half-life in sheep and cattle ( - 90 days) speaks for its stability and in vivo persistence.

2.6 HexachloroDhene ( 2 , 2 ' -methylenebis(3,4,6trichlorophenol), HCP) This compound is a substituted diphenyl methane, hence structurally Cl@cH*@ CI CI CI

' CI

IV

a DDT analog, as well as a chlorinated phenol analogous to PCP. It is used as a bactericide and fungicide, and was at one time available in

327

over t h e counter formulations as a s k i n c l e a n s e r , i n t a l c s , e t c .

It i s

r e a d i l y absorbed v i a t h e s k i n and h i g h l y neurotoxic p a r t i c u l a r l y t o newborns (Mennuti, r e f . 9 0 a ) .

C l u s t e r s o f similar malformations were

observed i n i n f a n t s o f workers exposed t o HCP i n d e t e r g e n t washes ( l o c .

c i t . p. 45).

Brandt e t a l . reported t r a n s p l a c e n t a l passage and

accumulation of HCP i n a mouse study ( r e f . 9 1 ) .

I n f a n t s exposed t o a 6%

HCP powder showed brainstem v a c u o l i z a t i o n similar t o t h a t induced i n newborn experimental animals repeatedly t r e a t e d t o p i c a l l y with 3% HCP. Moreover examination o f h i s t o l o g i c b r a i n s e c t i o n s of dead premature i n f a n t s i n d i c a t e d a p o s i t i v e c o r r e l a t i o n between HCP b a t h s and l e s i o n s i n b r a i n white matter ( r e f . 9 2 ) . S i n g l e doses of HCP (75-125 mg/kg) administered t o male rats caused degenerative changes i n t h e seminiferous tubules ( r e f . 8 4 c ) .

The

t o p i c a l exposure of female neonates t o HCP d i d n o t a f f e c t f e r t i l i t y o r c y c l i c ovarian a c t i v i t y ; nor d i d i t alter v a g i n a l opening.

However,

t r e a t e d males e x h i b i t e d lower f e r t i l i t y , probably due t o t h e i r i n a b i l i t y t o e j a c u l a t e , s i n c e sexual behavior and spermatogenesis were both normal (Rao e t a l . , pp. 156-157. r e f . 8 4 c ) .

The s t r u c t u r a l l y r e l a t e d d i - and

trichlorophenoxy a c i d h e r b i c i d e s (2.4-D and 2.4,s-T) p r e s e n t a s p e c i a l problem i n t h a t they are contaminated with t h e h i g h l y t o x i c c h l o r i n a t e d dibenzo-l,4-dioxins.

and w i l l be discussed l a t e r i n connection with

Agent Orange. 2.7

Lindane (benzene hexachloride, C6H6C16; BHC. HCH)

A s commonly used i n commercial formulations t h i s i n s e c t i c i d e ( t e r m i t i c i d e ) c o n t a i n s a number of isomers o f which t h e a c t i v e i n g r e d i e n t gammexane i s t h e ( l a , 2a, 38.4a, 5a. 68) - 1 , 2 , 3 , 4 , 5 , 6 hexachlorocyclohexane:

V

Lindane i n 1% cream, l o t i o n and shampoo formulations is a l s o used as a p a r a s i t i c i d e and ovacide ( K w e l l ) i n t h e treatment o f lice ( r e f . 92, p.

1446). Lindane has a l o c a l irritant a c t i o n and can be absorbed dermally.

Acute t o x i c i t y i n humans may occur by a l l exposure r o u t e s :

i n g e s t i o n , i n h a l a t i o n or dermal ( r e f . 97).

A l l isomers of BHC act on

t h e c e n t r a l nervous system (CNS), but n o t i d e n t i c a l l y :

t h e gamma and

328 alpha isomers are CNS s t i m u l a n t s , t h e p r i n c i p a l symptoms of a c u t e t o x i c i t y being convulsions, whereas t h e 6-and &isomers are CNS depressants.

The predominant metabolic r o u t e f o r lindane is

dehalogenation followed by g l u t a t h i o n e conjugation.

Since t h e technical

grade formulations are mixtures, t h e i r metabolic pathways are a function of composition o f t h e mixture. BHC is less p e r s i s t e n t i n t h e environment, hence is viewed

a s less o f a problem. t o x i c i t y t o mammals.

This may be a misperception i n view o f i t s A dose of

45 mg administered as a vermifuge

r e s u l t e d i n s e r i o u s i l l n e s s f o r t h e p a t i e n t , i n c l u d i n g convulsions ( r e f .

99).

Seizures i n young c h i l d r e n a f t e r t h e a p p l i c a t i o n of l i n d a n e

p r e p a r a t i o n s have a l s o been reported ( r e f . 92. p. 1446).

Topical use of

l i n d a n e p r e p a r a t i o n s on pregnant women should be avoided i n view of t h e i r s k i n p e n e t r a t i n g power and p o t e n t i a l f o r CNS t o x i c i t y .

The use of

v a p o r i z e r s containing lindane h a s a l s o r e s u l t e d i n a c u t e poisoning, probably due t o overheating with some decomposition. The gamma isomer of BHC has by f a r t h e greatest a c u t e t o x i c i t y i n l a b o r a t o r y animals b u t i t s f a i r l y r a p i d e x c r e t i o n by t h e kidneys prevents massive body accumulation.

Consequently t h e 7-isomer e x h i b i t s

t h e lowest chronic t o x i c i t y on repeated exposures.

The B-isomer has t h e

h i g h e s t chronic, b u t lowest acute t o x i c i t y . Chronic d e r m a t i t i s f r e q u e n t l y occurs among workers i n BHC p l a n t s . Symptoms o f a c u t e BHC poisoning i n man and experimental animals are

similar.

Animal pathology mimics t h a t of DDT, and t h e treatment f o r

a c u t e BHC o r DDT t o x i c i t y is e s s e n t i a l l y t h e same ( r e f . 99). Administration of s e p a r a t e isomeric forms of BHC ( a , B ) produced l i v e r tumors and lung metastases i n mice, whether bred f o r a low or high incidence o f spontaneous tumors ( r e f . 100).

E f f e c t s of BHC reported on

exposed humans i n c l u d e l i v e r c i r r h o s i s and chronic h e p a t i t i s i n 8 workers: a l s o c a s e s of a p l a s t i c anemia and leukemia ( r e f . 100, p. 157). Animal s t u d i e s t o d a t e focused p r i m a r i l y on t h e reproductive e f f e c t s of l i n d a n e are both i n s u f f i c i e n t and inconclusive.

Earl e t al. reported

f e t o t o x i c e f f e c t s ( s t i l l b i r t h s , p e r i n a t a l d e a t h s ) i n beagles ( r e f . 101a).

On t h e o t h e r hand a l a t e r study (ref. 101b, R i v e t t e t a l . ) found

l i v e r enlargement b u t no t e r a t o g e n i c e f f e c t s .

F i n a l l y two s t u d i e s

(Palmer, e t a l . ) one on CD s t r a i n rats ( r e f . lOlc), t h e second on CFY

rats and New Zealand white r a b b i t s ( r e f . lOld) reported enlarged hepatocytes and vacuolated cytoplasm (rats), but no adverse reproductive e f f e c t s or s e l e c t i v e embryotoxicities.

329 A more recent Indian study of premature labor and abortions reported

significantly higher pesticide concentrations both in the circulating blood and placental tissues of the affected women when compared with their full-term counterparts (ref. 102). Finally, three of four lindane studies under the National Toxicology program were scheduled for completion in 1985 (ref. 89. p. 60). Meanwhile the use of lindane as a pesticide is to be severely restricted, and products containing the compound may no longer be used in vaporizers o r as indoor smoke fumigants (ref. 103).

2.8 Aldrin, Dieldrin, Endrin Aldrin belongs to a group of chlorinated condensed ring insecticides classified as cyclodienes from the degree of unsaturation of the parent structures. Dieldrin and endrin are isomeric epoxides of the parent aldrin, each having one remaining double bond. All three compounds were widely used at one time, chiefly as crop insecticides and termiticides, but also as fumigants in the moth proofing of carpets and woolens. At present their use is severely restricted, many applications having been cancelled o r denied registration (ref. 103, pp. 1, 4 and 8).

c1m0

clm CI bl CI H HI

CI

CI

CI

Aldrin (hexachlorohexahydro-1,4.5,8dimethanonaphthalene): a cyclodiene, VI

Dieldrin Endrin

}

isomeric epoxides of Aldrin, VIIa,b

The oxidation of aldrin to dieldrin occurs rapidly throughout the ecosystem in soil, plants, and animals. However, dieldrin degrades slowly, hence is a world-wide environmental contaminant, albeit at low levels. Endrin. the isomer of dieldrin, is the most toxic to the liver and kidneys of the three compounds (Morgan, ref. 20, p. 15). However both dieldrin and endrin exhibit the acute liver effects characteristic of chlorinated hydrocarbons. Thus, DDT and dieldrin both caused enlargements in hepatocytes in rats, particularly in the central zones of the liver (ref. 100. p. 153). Exposure to all three compounds may be by ingestion, inhalation, o r through dermal absorption, with consequent severe CNS effects. From 1- to 4-hour exposures to aldrin result in irritability, convulsions and depression, and unconsciousness. Eventual liver damage occurs with chronic exposure (ref. 99, p. 381). Dieldrin greatly reduces or eliminates appetite, apparently through CNS action.

330

Either the nervous symptoms o r the anorexia may appear first. Effects of both dieldrin and aldrin are similar in animals and man. Aldrin and endrin are listed as indefinite animal carcinogens; dieldrin, as a known animal carcinogen (ref. 104). Dieldrin has been shown to cross the placenta in rats (ref. 106a) and decrease litter size and fertility in mice significantly (10 ppm dieldrin fed 30 days prior to mating and during gestation: ref. 106b). Administration of aldrin to birds (chick, pheasant, quail) induced malformations primarily of the genital tract, decreased pregnancy rate and litter size in mice, and was teratogenic to the golden hamster (ref. 107). Dieldrin has been undergoing fn vftro mutagenesis/genetic toxicity testing (CHO cells) to have been completed in 1985. Testing on endrin for mammalian mutagenesis/genetic toxicity (mouse lymphoma cells) was to have started in 1985 (ref. 89, pp. 37 and 49). Endrin is known to cause birth defects in laboratory animals, hence the EPA advises against exposure of female workers during pregnancy (ref. 103. p. 9) and the routine use of special protective clothing for women. Early studies of cyclodienes revealed reproductive effects on mice, rats, and dogs associated with changes in the estrus cycle (ref. 100, p.

154). Ottolenghi et al. (ref. 105) observed teratogenic effects on mice and hamsters at 1/2 LD50 doses of aldrin, dieldrin and endrin. In addition to the anomalies observed (cleft palate, webbed feet and open eyes), growth retardation and fetal deaths occurred. Effects on the dams were not reported, but none of the expected overt toxic symptoms associated with chlorinated cycloalkenes was in evidence (ref. 105). For a more detailed review of the earlier reproductive studies the Ottolenghi reference should be consulted.

2.9 Chlordecone (Kepone) and Mirex. Kepone (decachloroctahydro-1 , 3 ,h-methano - 2H-cyclobuta [cd] pentalene-2-one) was patented in 1952 by Allied Chemical and registered for ant and cockroach control. Its chief use. however, was against the banana root borer in Central and South America, where the pesticide was CI obtained from Qermany (refs. 108a,b).

CI

Kepone, VIII

CI

Mirex, I X

331 The h i s t o r y o f t h e kepone f i n d i n g s is i n s t r u c t i v e .

The blood sample

o f a worker with symptoms o f n e u r o l o g i c a l i l l n e s s was submitted t o CDC* f o r e v a l u a t i o n and found to c o n t a i n kepone i n t h e ppm range.

Life

Sciences Products (UP). I n c . , t h e Hopewell, V i r g i n i a , manufacturer of kepone, was ordered t o d i s c o n t i n u e t h e kepone process by V i r g i n i a a u t h o r i t i e s and complied v o l u n t a r i l y .

This a c t i o n was followed by

r e t r o s p e c t i v e and c u r r e n t epidemiological e v a l u a t i o n s of o t h e r employees, and sampling of t h e James River f o r kepone contamination. Early r e s u l t s from t h e F P A l a b o r a t o r y a t Research T r i a n g l e Park (RTP) revealed t h a t kepone was ubiquitous throughout t h e t i d a l r i v e r e s t u a r y , with c o n c e n t r a t i o n s reaching 2 . 1 pg/g i n f i n f i s h and 0.48 pg/g i n o y s t e r s ( r e f . 108, p. 918).

The E P A preliminary survey a l s o showed

e x t e n s i v e environmental contamination i n t h e neighborhood o f LSP i n a i r p a r t i c u l a t e s and s o i l .

Added t o t h e EPA d a t a was t h e h o s p i t a l i z a t i o n of

a number o f employees with t h e c o l l o q u i a l l y dubbed 'kepone s h a k e s ' . Governor M i l l s Godwin faced t h e unenviable d u t y of c l o s i n g t h e e n t i r e t i d a l r i v e r , with i t s t r i b u t a r i e s t o f i n f i s h and s h e l l f i s h h a r v e s t i n g a s a p u b l i c h e a l t h measure, p u t t i n g a l a r g e number o f fishermen o u t of work.

Worse y e t , commercial o y s t e r beds must be seeded with j u v e n i l e s

(1 t o 6 cm) and r e q u i r e approximately

3 y e a r s t o mature.

An estimated

70% of t h e production from V i r g i n i a ' s p r i v a t e o y s t e r beds depends on

such o y s t e r s e e d l i n g s from t h e lower James River. t h e r e f o r e i n i t i a t e d t o determine t h e rates a t which

A "crash" study was

contaminated

o y s t e r s would purge themselves o f kepone when t r a n s p l a n t e d t o c l e a n

water.

F o r t u n a t e l y f o r t h e seafood i n d u s t r y , about two weeks of purging

a t summer temperatures and 7 weeks a t w i n t e r temperatures d i d reduce kepone l e v e l s i n t h e s e e d l i n g s s u f f i c i e n t l y t h a t h a r v e s t i n g of seed o y s t e r s was again permitted.

Action l e v e l s were adopted by t h e FDA i n

February and March of 1976:

0 . 1 pg/g i n t h e e d i b l e p o r t i o n o f f i n f i s h ,

0.3 pg/g i n mollusks and 0.4 p/g i n e d i b l e p o r t i o n s of b l u e c r a b were pronounced s a f e ( r e f . 108a, p. 919). The observation t h a t 85%of t h e f i s h t h a t exceeded t h e kepone a c t i o n l e v e l were males l e d t o a n a l y s i s of t h e r o e o f g r a v i d females.

I t was

found t h a t g r a v i d females do indeed t r a n s f e r a p a r t of t h e i r kepone burden t o t h e eggs.

This was e q u a l l y t r u e for shad ( r e f . 108a, p. 920)

and t h e blue c r a b ( r e f . 1 0 9 ) .

Species o t h e r than f i s h i n t h e James

River region a l s o accumulate kepone; t h e s e i n c l u d e waterfowl, t h e blue heron, Canadian geese, t h e osprey, bald e a g l e , white-footed mouse, e t c . *Center f o r Disease Control.

332 I n general, l e v e l s of kepone detected a r e a function of feeding patterns and length of residence i n contaminated areas, with the highest l e v e l s found i n f i s h feeders. Sediments on the James River bottom are a reservoir f o r kepone, r e c y c l i n g t h e compound through t h e trophic l e v e l s of plants and animal organisms, back t o benthic animals.

Approximately 500 km2 of the James

River area contain detectable kepone l e v e l s ( > .02 pg/gm)

.

I n addition t o i t s neurotoxicity i n man, kepone is a known animal hepatocarcinogen (mice. r a t s : r e f . 110) and a suspect carcinogen i n humans.

Reproductive and teratogenic e f f e c t s have been reported f o r

animal species ranging from sheepshead minnow and Japanese q u a i l t o mice, r a t s and man (Table 4A; r e f . l l l a ) , with open l i t e r a t u r e data on the l a t t e r very limited.

Sternberg ( r e f . 100, p. 155) alluded t o "a

group of workers a t a kepone manufacturing plant" (see above) who developed enlarged l i v e r s and suffered t e s t i c u l a r damage along with NisbetIKarch reports occupational exposure as leading

neurotoxicity.

reproductive f a i l u r e ( r e f . 47; Table on p. 173; r e f s . l l l a , c ) .

Taylor

e t al. found a s i g n i f i c a n t reduction i n the sperm motility of 13 out of

148 men working i n a kepone manufacturing plant ( r e f . l l l b , Table 48). A NIOSH report alluded t o the l o s s of l i b i d o and reduced sperm counts i n

men occupationally exposed t o kepone (ref. l l l d ) .

A l l registered

products containing kepone were e f f e c t i v e l y cancelled by May 1, 1978 ( r e f . 103, p.

13).

An e a r l y mirex report t o t h e EPA noted t h a t i f male r a t s were fed

mirex during the breeding period only, and bred t o females fed 25 ppm mirex

(45 t o 102 days), s i g n i f i c a n t l y fewer offspring were born a l i v e Also, from 33 t o

and fewer survived t o weaning than i n the controls.

46% of the offspring developed cataracts.

The pathologic e f f e c t s of

mirex on the eyes was traced t o i t s ingestion during the suckling period (refs. ll3a,b).

There is evidence t h a t mirex stimulates l i v e r

microsomal metabolism.

P r o l i f e r a t i o n of endoplasmic reticulum and an

increase i n oxidative metabolism were observed ( r e f . 113a, p. 51). Although e x i s t i n g stocks of mirex (dodecachloro analog of kepone) could not be sold a f t e r June 30, 1978,- formulations containing the compound a r e s t i l l registered f o r r e s t r i c t e d applications ( r e f . 103, pp. 16-17). Mirex decomposes t o kepone i n the environment ( r e f . 112), possibly by oxidative hydrolysis of the

CCl2 group t o

GO.

Thus the

persistance/toxicity/contamination problem is s t i l l with us. Currently both kepone and mirex a r e c l a s s i f i e d a s animal positive

333

carcinogens, kepone as a suspect human carcinogen, and mirex as an experimental teratogen (refs. 114a.b). Both compounds are being investigated under the National Toxicology Program -kepone for reproductive/developmental toxicity and mirex for carcinogenicity (ref.

llle). 2.10 Toxaphene Toxaphene (CloHloC18) is a mixture of polychlorinated camphenes (bicyclic terpenes). Currently in restricted use as an insecticide, it is toxic to fish, birds and wildlife and may be fatal to shrimp, and crab, etc. (ref. 103. p. 26). Its toxicity and routes of entry in mammals are typical of the cyclic chlorinated hydrocarbons as a class:

Toxaphene

X namely, it is highly neurotoxic and can cause degenerative changes in the liver parenchyma and renal tubules. Toxaphene is an animal carcinogen (refs. 114-115), a suspect human carcinogen and animal teratogen (ref. 114d). Because it is environmentally persistent as well, the EPA description of its current permitted uses is so circumscribed with restrictions as to raise the question of regulatory feasibility (see ref. 103, pp. 25-28). Allowed restricted uses include: control of scabies on beef cattle or sheep: minor use for army worm, cutworm and grasshopper control: minor use for mealybug and pineapple moth: sicklepod in soybeans and peanuts; insects in corn, and in dry and southern peas. Emergency use until December 31. 1986 is allowed when warranted. Mammalian teratogen studies are summarized in the following sources: ref. 2a, p. 178; Zielhuis (ref. 116); ref.

84, p. 152: ref. 100. p. 157. Zielhuis reviewed a Russian

reproductive study of Il'ina on women chronically exposed to polychlorinated pinenes, who had previously suffered "slight to moderate" poisoning. The findings are of interest because of the close structural relationship to toxaphene and the strong possibility of camphene/pinene rearrangements during chlorination. The cohort was compared with non-exposed controls (n=155). Reproductive effects examined were:

disturbed menstrual cycle, secondary infertility,

salpingitis. cervical erosion and uterine fibromata. Menstrual

334

disturbance was noted from the f i r s t month of exposure, increased i n frequency with duration, with data highly s i g n i f i c a n t f o r a l l variables compared.

Adverse neurologic e f f e c t s appeared t o p a r a l l e l gynecologic findings ( r e f . 116). Chlordane and Heptachlor

2.11

Chlordane (CloH6C18) and Heptachlor (CloHtjC17) belong t o the family of b i c y c l i c cyclodiene organochlorine i n s e c t i c i d e s discussed e a r l i e r (See under Aldrin).

Both compounds a r e highly toxic, readily

dI hlordan

8

8

1 2 5 6 7 gIoct chloroia#,3 .fa:t&ahydro-8.7-

methanoidane)

absorbed through t h e skin and other p o r t a l s ( e . g . , v i a d u s t , o r a l ingestion, e t c . )

Heptachlor follows the favored cyclodiene

transformation route t o the epoxide. i n which form i t may be stored i n adipose tissue. There i t may be f u r t h e r transformed t o more soluble chemical species and excreted mainly v i a the f e c a l route, Animals poisoned by chlordane, heptachlor and/or r e l a t e d compounds Repeated

show very marked l o s s of a p p e t i t e and neurologic symptoms. experimental exposure t o low doses of chlordane lead t o

hyperexcitability, tremors and convulsions, followed by marked anorexia and l o s s of weight f o r those animals t h a t survive long enough.

Chronic

exposure t o chlordane or heptachlor leads t o degenerative changes i n the l i v e r end kidney tubules. The accidental application of a 25% solution of chlordane (technical grade) t o a human caused symptoms within 40 minutes and death before medical a t t e n t i o n w a s obtained. Two p a t i e n t s died a f t e r tho ingestion of low o r a l doses of chlordane. Both showed severe f a t t y degeneration of t h e l i v e r ( r e f . 99, p. 550). Chlordane is reported t o increase the incidence of hepatocarcinoma i n rodents ( r e f , 117a). Both chlordane and heptachlor a r e c l a s s i f i e d as animal p o s i t i v e carcinogens by t h e IARC (ref. l l 7 b ) . Chlordane is excreted i n mammalian milk.

Rats fed 150 to 300 ppm

chlordane during and a f t e r gestation produced i n i t i a l l y normal pups t h a t l a t e r developed e x c i t a b i l i t y and tremors, i f nursed by t h e i r l a c t a t i n g dams.

However i f transferred t o untreated foster mothers they developed

normally ( r e f . 118). Mice treated throughout pregnancy and l a c t a t i o n

335 with 8 mg/kg/day chlordane produced young w i t h a d e f e c t i n t h e i r cellmediated immune response. t h e golden hamster on day

A s i n g l e o r a l dose o f 25 mg/kg chlordane i n

7, 8, or 9 p.c.* was t e r a t o g e n i c , b u t n o t

embryotoxic ( r e f . 119). However f e t a l d e a t h and c o n g e n i t a l anomalies-e . g . , c l e f t p a l a t e , webbed foot--occurred with high incidence a t t h e 50 mg/kg l e v e l . Both h e p t a c h l o r and chlordane have been s e v e r e l y r e s t r i c t e d i n r e c e n t y e a r s and t h e i r formulations are now mainly used f o r termite c o n t r o l (ref. 103. p. 2 ) and t h e d i p p i n g of roots or t o p s of non-food

Most r e g i s t e r e d products c o n t a i n i n g chlordane w e r e e f f e c t i v e l y

plants.

c a n c e l l e d or t h e i r a p p l i c a t i o n for r e g i s t r a t i o n denied by December 31,

1980.

A similar a c t i o n covers h e p t a c h l o r u s e as of J u l y

1,1983.

2.12

2.4-D, 2,4,5-T (2,4-dichlorophenoxy- and 2,4,5-trichlorophenoxyacetic a c i d s ) and t h e Dioxin Dilemma. 2.4-D and 2.4.5-T

are c h l o r i n a t e d phenoxy compounds of t h e g e n e r a l

chemical s t r u c t u r e :

,ax ( x = 1

tos)

1 H, N a , R , or R'NH, (R,R' = a l k y l )

They are widely used in s e v e r a l hundred commercial h e r b i c i d e formulations (Morgan, ref. 20. Chap. 6).

The chlorophenoxy a c i d s , salts and esters are moderately i r r i t a t i n g t o e y e s , s k i n , r e s p i r a t o r y tract and l i n i n g of the G I tract. Prolonged and/or r e p e a t e d dermal c o n t a c t may r e s u l t i n depigmentation. Chlorophenoxy compounds are absorbed across t h e g u t wall, s k i n and lungs.

Excretion times are r e l a t i v e l y s h o r t (hours t o days) p r i m a r i l y

v i a the urine.

They are n o t a p p r e c i a b l y s t o r e d i n body f a t .

When fed

in large doses t o experimental animals, 2,4-D caused vomiting, d i a r r h e a , u l c e r a t i o n s o f mouth and pharynx, a n o r e x i a , l o s s o f weight, and i n j u r y

to t h e kidneys, l i v e r and CNS. Some s p e c i e s developed myotonia o f t h e hind e x t r e m i t i e s . a t t r i b u t e d t o t h e demyelination observed i n t h e d o r s a l column of t h e cord.

EEQ changes i n d i c a t i n g d i s t u r b a n c e of b r a i n

f u n c t i o n were a l s o observed a t high dose. I n humans, t h e i n g e s t i o n of large amounts of t h e chlorophenoxy a c i d s *p.c.

- p o s t conception.

336

produced severe metabolic acidosis and electrocardiographic changes, muscle weakness, myotonia, myoglobinurea and elevated serum phosphokinase--all associated with injury to striated muscle.

In large

doses chlorophenoxy acids may result in hyperthermia since they can interfere with oxidative phosphorylation (ref. 20. p. 27). 2.12.1

Toxicology of Chlorodibenzo-p-dioxins

The teratogenic potential of chlorophenoxyacetic acid derivatives cannot be unambiguously evaluated without consideration of the dioxin contaminants formed from the monomers by a 2-step condensation at elevated temperatures:

Xlll

Langer et al. found that the corresponding octachlorodioxin formation was favored for the sodium pentachlorophenate but that the yield of 2,3,~.8-tetrachlorodibenzo-1,4-dioxin (TCDD, XIII) was low for the 2.4.5-trichlorophenate. They concluded that the formation of linear trimers and tetramers were favored over cyclization of the dimer in the presence of a labile meta chlorine, and that steric effects also played an important selective role (ref. 121a). The severe dermatologic effects of chlorinated dibenzodioxins were recognized as early as 1899. By the 1950s a rash of runaway reactions associated with 2.4.5-T production had caused serious outbreaks of chloracne among German workers and in the United States as well (refs. 121b and 133). Chick edema disease became a serious economic problem by the mid1950s. by which time millions of broilers had succumbed to it in the U.S. The problem was traced to toxic components in the unsaponifiable fraction of certain low cost feed fats introduced into the chick diet to increase the caloric intake (ref. 121c). Symptoms included fluid in the heart sack and abdoninal cavity. subcutaneous edema and liver necrosis. Injection of purified chick edema factor into fertile eggs resulted in lower hatch yield, embryonic desormities and edema. Unhatched embryos exhibited a variety of defects (malformed beaks, leg deformities. no development of the right mesencephalon. and eye defects). Hatched embryos were growth-retarded, with sparse and defective feathers. The isolated toxin was ultimately identified as 1.2.3.7.8.9-

337

hexachlorodibenzo-1,Q-dioxin. Sparschu et al. reported the embryotoxicity of TCDD in rats (1970) (refs. 122a.b). Data are summarized for rats and mice in Table 5. The three major effects observed were:

intestinal hemorrhages (rat fetuses)

and increased incidence of cleft palate and kidney abnormalities (mouse fetuses). TCDD in pg/kg doses has also been reported to cause embryotoxic effects in hamsters: eye abnormalities, reduction of mean fetal weight; GI hemorrhages, increased prenatal mortality. (ref. 123). TCDD appears to be an unusually specific teratogen for cleft palate and certain kidney abnormalities. It is also notable for the very low doses (1 to 10 pg/kg) of TCDD required to induce both teratogenic and fetolethal effects in rats and mice. At threshold doses, TCDD potentiates the teratogenicity of 2.4,5-T. itself a weak teratogen (Neubert et al.. Fig.3).

Limited data available

are suggestive as well of a correlation between pronounced chloracne potency and embryotoxicity (121b). The study of Moore, Gupta et al. clearly showed that exposing pregnant mice to TCDD during fetal metanephric kidney formation results in a dose-dependent hydronephrotic kidney development (ref. 124).

If

the pups were also nursed by a TCDD-treated mother, the incidence of hydronephrosis increased. Pups born of untreated mothers, but fosternursed by treated mothers also developed hydronephrotic kidney disease. Hence the presence of TCDD in the dam's milk can play a significant role in determining the extent of kidney damage. 2.12.2 Ubiquity of the Dioxins The chlorophenoxy herbicides are used in the maintenance of rights of way, roadsides and rangelands, and to destroy plants toxic to livestock, including ragweed and poison ivy. By far their most important application, however, is in farming, where the need for ploughing and discing is either reduced o r eliminated by the use of potent weed killers. Between 1966 and 1981 farm use of herbicides had increased 280% to 625 million lbs., e.g.. more than the total insecticide use. Through run-off, precipitation, sublimation, etc., entire ecosystems, from aquatic algae and fish, land plants and animals to man, all imbibed these substances via the food chain. In 1961 the U.S. Army began a highly controversial defoliation and crop destruction program in South Vietnam, in collaboration with the South Vietnamese government, and focussed on areas of major Viet Cong activity. The principle defoliant used was Agent Orange--a mixture of

338

2.44 and 2,4,5-T. At first the visible ecologic effects of this program were limited to the denuding and possibly permanent destruction of huge forest areas. But the economic effects soon became evident, as rubber plantations and food crops were destroyed, and the civilian population began to experience severe nutritional privation. By 1969 reports leaking out of the country told of severe skin rashes, nausea, numbness of hands and feet and, more alarming, the birth of deformed infants in large numbers in the areas sprayed (ref. 126). NCI contracted with the Bionetics Research Laboratory (BRL; Kensington, MD) to screen pesticides for carcino-, muta- and teratogenicity. BRL found that 2.4.5-T--a major component of Agent Orange--did in fact produce marked fetal deformities in rats and mice. However, further investigation pointed to a contaminant of the chlorophenoxy acids as the main culprit--namely the dioxin TCDD. The list of animal embryotoxicities of dioxins continued to grow to include rabbits, guinea pigs and dogs (Schwetz et al., ref. 121b). The symmetrical 2,3,7,8-tetrachlorodibenzodioxin is now recognized as the most toxic of the dioxins and one of the most toxic chemical compounds known (refs. 121b.e). The guinea pig was the most sensitive mammal tested. 2.12.3 Epidemiology Reports associating herbicides and birth defects in humans first appeared in Vietnamese newspapers in 1969. These led to a survey of birth defects, conducted by Dr. Cutting of the U.S. Army medical research team with the cooperation of the South Vietnam ministry of health. Over 112 million obstetrical records from 22 maternity hospitals located in 16 cities were examined for the years 1960-69. They showed no significant increase in stillbirths or malformations over prior years. Unfortunately Cutting’s data came largely from capital area hospitals not serving the population from highly sprayed rural regions: hence this cohort was markedly under-represented. When the original data were analyzed excluding the largely unexposed capital region, the more heavily exposed areas showed increased rates of stillbirths and malformations from 1965 on. The review was carried out by a special commission sent to Vietnam by the M A S . headed by Constable, Meselson and Westing (ref. l27a). Hospital records for the province of Tai Ninh. serving the population living along the rivers draining the area of heaviest defoliation, showed a stillbirth rate approximately twice the average for other districts for which comparable

339 d a t a were obtained. The AAAS commission found an i n c r e a s e d incidence o f malformations

(spfna bfjfda, c l e f t p a l a t e ) among c h i l d r e n admitted t o t h e Saigon C h i l d r e n ' s Hospital for c o r r e c t i v e surgery.

The i n c i d e n c e o f spfna

bfjfda had i n c r e a s e d from 0.7% (1959-65) to 2.1% (1967-68); c l e f t p a l a t e , from 0.5% (1959-65) to 2.6% (1966-68).

These d a t a are i n accord

with animal experiments discussed i n t h e preceding s e c t i o n . The U.S.

A i r Force "Ranch Hand" study ( r e f . 128b) compared 1206

v e t e r a n s who flew h e r b i c i d e spraying missions with 778 v e t e r a n s t r a n s p o r t i n g a i r cargo i n South E a s t Asia.

S e v e r a l h e a l t h problems

occurred more f r e q u e n t l y i n t h e Ranch Handers' cohort than i n t h e controls.

There was a l s o a s t a t i s t i c a l l y s i g n i f i c a n t i n c r e a s e i n b i r t h

d e f e c t s among Ranch Handers' o f f s p r i n g as compared with c o n t r o l s , a f t e r adjustment f o r 5 confounding v a r i a b l e s .

More s i g n i f i c a n t was t h e

c o n s i s t e n t l y g r e a t e r r i s k of undesirable pregnancy outcomes f o r 6 o u t of

7 types o f outcomes and 9 o u t o f 12 types o f b i r t h d e f e c t s . Kidney and l i v e r ailments ( o t h e r than c i r r h o s i s , h e p a t i t i s or jaundice) a l s o exceeded t h e c o n t r o l s .

Cancer rates f o r t h e Ranch

Handers, while c o n s i s t e n t l y h i g h e r , were n o t considered t o be s i g n i f i c a n t l y so a t t h e time of t h e study. I n January, 1983 a panel of s c i e n t i s t s from 21 c o u n t r i e s examined t h e claims o f l o n g e r term d e l e t e r i o u s e f f e c t s on l a n d , w i l d l i f e and humans o f Vietnamese wartime exposure t o h e r b i c i d e s ( r e f . 128c).

The

b i r t h d e f e c t s r e p o r t e d most f r e q u e n t l y were those a l s o a s s o c i a t e d with

2.4.5-T animal experiments.

They included cleft p a l a t e , h a r e l i p and

missing limbs, e.g. muscular-skeletal d e f e c t s , and incomplete c l o s u r e of embryonic t i s s u e l e a d i n g t o n e u r a l and s p i n a l d e f e c t s ; I n a case-control study of molar pregnancies (Huong and Ngoc) 48 of

85 women who presented had been exposed t o h e r b i c i d e s p r a y s compared with 27 o f 176 women p r e s e n t i n g with normal pregnancies.

Another study

by t h e same workers compared t h e h e a v i l y sprayed v i l l a g e of Thanh Phong with t h e 1 0 t h District of Ho Chi Minh C i t y (formerly Saigon).

Only 83

of t h e c i t y cohort had been exposed, compared with a l l of t h e v i l l a g e r s . I n o r d e r to o b t a i n a comparison between completely exposed and unexposed c o h o r t s , t h e c h i l d r e n of t h e 8%-exposed c i t y cohort were e l i m i n a t e d from the analysis.

The sprayed v i l l a g e had from 2 t o 3 times t h e d e f e c t rate

found i n t h e 1 0 t h d i s t r i c t (unexposed) c o h o r t .

Two s t u d i e s compared o f f s p r i n g of t h e North Vietnamese army v e t e r a n s who were exposed t o h e r b i c i d e spray o p e r a t i o n s with t h o s e o f unexposed--

340 or l i g h t l y exposed--veterans.

Defect rates found were 2.5% (exposed

f a t h e r s ) and 0.46% (unexposed f a t h e r s ) . Nguyen Can et al. (ref. 1 2 7 ~ )found s i g n i f i c a n t l y higher rates of miscarriage, molar pregnancy and congenital defects i n children whose f a t h e r s had served i n South Vietnam when compared with those whose f a t h e r s had not.

A number of s t u d i e s of adults reported increased disease r a t e s i n those exposed t o herbicides.

Do Thuc Trinh e t al. ( r e f . 127d) compared

350 individuals with a t least one exposure t o herbicide spray with an unexposed control group (200). A s i g n i f i c a n t l y higher percentage of those exposed suffered from neurasthenia, g a s t r i t i s and chronic hepatitis.

Ton That Tung's studies indicated a higher r i s k f a c t o r f o r

l i v e r cancers i n s o l d i e r s who had been sprayed with herbicides (ref. l27e).Tung's findings on l i v e r cancer were confirmed by Do Duc Van who matched l i v e r cancer cases with 2 sets of controls. More recently three cases of r a r e thoracic s o f t t i s s u e sarcomas were reported ( r e f . 129).

Case-control studies from Sweden reported a 5- t o

6- f o l d increased incidence of s o f t t i s s u e sarcoma i n lumberjacks exposed t o phenoxyacetate herbicides ( r e f . 129).

Erickson e t al.

assessed Vietnam veterans' r i s k s f o r fathering babies with major s t r u c t u r a l b i r t h defects i n a case-control study ( r e f . 130). Questionnaires r4 Vietnam military service were administered t o both parents i n case and control groups and f u r t h e r information w a s obtained by a review of military records.

These workers concluded t h a t "Vietnam

veterans i n general did not have an increased r i s k combined; RR estimate, 0.97).

..

.I'

( a l l types

This included those with greater EOI* f o r

Agent Orange (AO). However, the estimated r i s k s f o r fathering spfna btltda babies w a s s i g n i f i c a n t l y higher f o r Vietnam veterans with greater EOI scores. This was a l s o t r u e f o r babies with c l e f t l i p with or without c l e f t palate, and f o r those with a number of neoplasms a s c l a s s i f i e d i n the study (e.g., dermoid and epidermoid cysts (26 cases) ; teratomas (14 c a s e s ) ; lipomas ( 9 ) ; hamartomas (5); CNS tumors (5); Wilma' tumors ( 3 ) ; hepatoblastomas (1) rhabdomyosarcoma (1) and miscellaneous benign tumors ( 2 4 ) ) . A s i g n i f i c a n t l y greater number of birth-defective s i b l i n g s w a s born a f t e r the index baby t o f a t h e r s i n the AO-exposed category. I n a c r i t i q u e of the Erickson e t a l . study, S t e r l i n g and Arundel observed t h a t the study was designed primarily t o determine whether the *Exposure Opportunity Index.

341

children of veterans serving in Southeast Asia exhibited a higher incidence of birth defects.

Since there were no strong reasons to

suspect an increase in risk for birth defects in all 2.6 million veterans who served there, they concluded that both the emphasis and expense of the study were not justified. The question at issue (and the related litigation by veterans) concerned the increased risk of defects among veterans exposed to AO.

Nevertheless, Erickson et al. did obtain

information on possible exposure to A0 during these interviews, and were able to relate the specific risks of spina b t j t d a and cleft palate to dioxin-2.4.5-T

exposures.

Sterling emphasized the importance of these

findings to teratologists and epidemiologists. in view of their specific replication of animal studies--specificity following exposure to a substance being a strong indication that the substance is a teratogen (ref. 131). In 1978 EPA issued an WAR* for 2.4,5-T, following the occurrence of a cluster of 8 miscarriages in Alsea. Oregon, near heavily sprayed forest areas (ref. 126b).

The U.S. Forest Service was temporarily

prevented from spraying 2.4.5-T by an emergency suspension of its use on rights of way. and the EPA funded a reproductive study at Colorado State University and the University of Miami Medical School.

The study showed

an unusually high miscarriage rate around Alsea correlated with both time of spraying and degree of exposure (refs. 126b and 132).

Neither

this nor other studies cited in a NIOSH document (ref. 133) were deemed sufficiently conclusive to ban the use of 2.4,5-T, and products containing the herbicide may continue in use only on rice crops. rangelands and a number of restricted non-food crop areas (ref. 103. p.

25). Perhaps the most catastrophic industrial accident involving dioxin occurred in SBveso, Italy in July, 1976. Here an entire community surrounding a trichlomphenol feedstock plant was contaminated: individuals were in the maximum exposure zone;

4699

736

were in a less

exposed zone, and 31,800 individuals were in the zone of least exposure. There were four spontaneous abortions and thirty voluntary interrupted

pregnancies.

The dose-related increase in chloracne occurred, but the

spate of voluntary abortions obscured the teratogenicity data. Because of the risk of contamination with TCDD, 2.4.5-T registration was cancelled October 18, 1983 (48FR48434), but the distribution of existing stocks allowed for another year.

This allowance included

*Rebuttable Presumption Against Registration.

342

products sold for use on rice, but was otherwise confined to non-food crop areas. Silvex (2.4.5- trichlorophenoxypropionic) acid received similar treatment (ref. 103, pp. 19 and 25). 2.13

Polychlorinated Biphenyls (PCBs, chlorodiphenyls, C , ~ H ~ O - ~ C ~ ~ ) Polychlorinated biphenyls were manufactured in the U.S. as early as 1929. Their low flammability and generally inert properties soon brought them into wide industrial use. Domestic U.S. manufacture peaked in 1970 at 85 million pounds, then plummeted after the uses of PCBs were sharply restricted (ref. 103, p. 17). PCBs are obtained by the catalytic chlorination of the parent biphenyl whose structure is that of two linearly linked equivalent aromatic rings:

4

XIV Biphenyl: Ring numbering convention Table 6 lists the number of isomers and percent chlorine content in each of the ten classes of chlorinated biphenyls. In all, 209 isomers are theoretically possible, about half of which had been synthesized and characterized by 1976 (refs. 135a.b). Hence commercial PCB formulations may be expected to have significant concentrations of only a fraction of the isomers possible. Industrially important PCB mixtures are called Aroclors in the U.S., followed by a &digit number, the last two digits (usually) indicating proximate chlorine content. In addition there are a number of trade names f o r products containing PCBs (See Table 7).

PCBs are thermally and chemically stable, e.g.. resist high temperatures, oxidants. acids and bases. They are not readily biodegradable, hence persist in the environment. Exposure to sunlight

343

(action spectrum above 290 nm) does however promote photodechlorination. PCBs dissolve in most common organic solvents and in lipids, but are only slightly soluble in polar solvents, e.g.. water, glycerol and glycols. When pure, PCB isomers are colorless crystals at room temperature. Physical and chemical properties of single isomers vary, depending on degree of substitution and position of the chlorine(s). Water solubilities range from .OO7 to 5 mg/L, and vapor pressures from to 10-3 mm Hg at 20' (ref. 135b). Commercial PCB mixtures have depressed melting points and can vary in viscosity from mobile oils to viscous liquids or tacky resins. PCB formulations are mixtures designed to fulfill unique specifications (color, density, dielectric constant, fire and flash point, percent chlorine, etc.) Such mixtures may vary from batch to batch. There is some evidence that the presence of trace quantities of chlorinated napthalenes and dibenzofurans in commercial PCBs may be of toxicologic significance (ref. 134. p. 52)

.

2.13.1 Uses of PCRs The chemical and thermal stabilities of PCBs, their nonflammabilities and excellent dielectric characteristics led to their wide use as capacitor and transfer fluids. Other significant uses of PCBs included heat exchangers and hydraulic fluids. Prior to controls PCBs were also used in adhesives, coatings, plasticizers and inks; for microencapsulating dyes for carbonless duplicating paper; as extenders in pesticide formulations and catalyst carriers in olefin polymerizations; to impart hydrophobicity to materials and surfaces; in bactericide formulations (combined with insecticides), and in immersion oil for microscopes. Mixed with chloronaphthalenes, PCBs were also used in wire and cable insulation in the mine and shipbuilding industries (ref. 80, p. 455). The fluids in both large and small capacitors were essentially 100% PCBs. Capacitors in common household appliances, e.g., fluorescent fixtures, air conditioners, TV sets, used between 0.1 and 0.6 lb. of PCB per appliance, with an estimated minimum use lifetime of 10 years. According to EPA estimates, approximately 10% of these small capacitors were retired annually, lizing about 350 million units still in use as late as 1984. Large capacitors (>3 lb. PCBs) were predominant in electrical substations, buildings and on utility poles. There were still about 3.3 million of these capacitors in service in 1981 (CIB 45. P. 3 ) .

344 Dielectrics i n transformers are usually composed of 60-70% PCBs and up t o 40% chlorinated benzenes (ref. 1 3 5 ~ ) . The generic name of askarels is applied t o t h i s broad class of nonflammable synthetic chlorinated hydrocarbon insulating liquids.

Prominent among askarels @

formulated i n the U.S. are Inerteen.@Noflamol and Pyranol

7).

QD

(see Table

The quantities of f l u i d contained i n these transformers is large,

ranging f r o m 40 t o 1500 gallons.

They have been used primarily i n areas

where electrical equipment i n close proximity to people, property or both necessitated t h e use of f i r e - r e s i s t a n t d i e l e c t r i c s .

EPA estimates

i n d i c a t e t h a t approximately lO7.OOO PCB transformers were i n use or stored f o r re-use i n 1984.

About 77,600 of these were located near

commercial and public buildings, e.g.. o f f i c e buildings, shopping centers, hospitals, schools, e t c . ( r e f s . 137b,c). Under TSCA ( r e f . l38a) the P A was authorized t o control the production and use of chemicals i n the U.S. I n 1978 the agency exercised its authority (under section 6(e) of TSCA) t o prohibit “the manufacture, processing, d i s t r i b u t i o n i n commerce and use of PCBs” a f t e r January 1, 1978 (CIB 45, p. 3). This prohibition waa l i f t e d re e l e c t r i c a l equipment by a f i n a l EPA r u l e issued i n 1982. permitting the use of PCBs i n c e r t a i n electrical equipment ( s m a l l and l a r g e capacitors, and transformers) t o continue f o r t h e i r remaining useful l i v e s under specified conditions ( W f . 137a). A f i n a l rule with respect t o electrical transformers was issued by the EPA i n 1985 prohibiting the use of high secondary voltage network PCB transformers i n or near commercial buildings a f t e r October 1, 1990. Low secondary voltage network and high secondary voltage r a d i a l PCB transformers i n or near commercial buildings are required t o be equipped with enhanced e l e c t r i c a l protection devices by t h a t date (ref. 1 3 7 ~ ) . 2.13.2

R i s k s of Exposure t o PCBs and Related Compounds

The major r i s k s of exposure under current constraints a r e fire-

a) PCB-containing electrical equipment exposed to s u f f i c i e n t l y high temperatures t o release PCBs from equipment casing; related.

These include:

b) formation of soots containing PCBs and r e l a t e d products during burning, and t h e d i s t r i b u t i o n of t h i s contaminated carbonaceous material i n the environment. PCB. polychlorinated dibenzofurans (PCDFs) and dibenzodioxins (PCDDs) have a l l been i d e n t i f i e d following fires involving electrical equipment. The f i r e - r e l a t e d release of PCBs through pressure relief s a f e t y valves has a l s o been documented i n overheated transforners. Here hot PCB vapors can e n t r a i n l i q u i d PCBs

345

forming a fine aerosol that is in turn distributed via air convection. The OSHA PELS* for chloridiphenyls (42% C1) are 1 mg/m3. and 0.5 mg/m3 for products containing 54% C1. Allowable concentrations (WAS)** are based on 1968 figures for 8 hours (ACGIH), adopted to prevent liver injury to exposed workers (ref. 138d). MACs of toxicants for the population at large are usually reduced by a factor of 100 to 1000. 2.13.3 Toxicity of PCBs In their acute toxic effects on the skin and liver PCBs resemble the chlorinated naphthalenes. Acute yellow atrophy is produced in the liver and enhanced in the presence of CHC13 (synergism). Toxicity increases with increase in chlorine content of the PCB, and with oxide formation. Skin lesions (chloracne) consist of small pimples and dark pigmentation of exposed areas. Later comedones and pustules develop. With systemic intoxication, progressive symptoms are nausea, vomiting, weight loss, jaundice, edema, abdominal pain, and, where liver damage is severe, it is followed by coma and death ( S a x , 3d ed., p. 551). 2.13.4 Metabolism of PCBs A comprehensive review of the metabolism of PCBs was published in 1976 by Sundstrom et al. (ref. 139a) confirming the importance of degree of substitution and location of halogens on toxicity. The lesser chlorinated biphenyls are more readily metabolized. The presence of at least two adjacent hydrogens--preferably in positions 3, 4, 5 or 3'. 4 ' , 5'--is required for the rapid metabolism of PCBs. This requirement is satisfied by all mono-, di- and trichlorobiphenyls, and by the tetrachlorobiphenyls with the exception of the 3, 3', 5, 5'-chlorinated PCB. This compound was reported particularly toxic to monkeys, and the intermediate formation of chlorinated dibenzofuran was postulated to account for this toxicity (ref. 139~). No metabolism has been demonstrated for the decachlorobiphenyl ( N I O S H , ref. 136, p. 29). This and other highly chlorinated PCBs not readily metabolized may persist in the tissues for years following

exposure. Some PCBs lacking the adjacent hydrogens required for rapid metabolism can be slowly metabolized by hydroxylation and oxidative dechlorination. Since arene oxide intermediates may also be involved, there is the risk of chronic exposure to compounds of high carcinogenic activity (ref. 136. p. 30). ~

*PEL-Permissible exposure limit. *I TWA-Time weighted average.

346 PCBs are readily absorbed from the digestive t r a c t and probably as readily from the respiratory tract ( r e f . 136, p. 28).

Amounts excreted

i n animal feces, milk and h a i r depend on chlorination pattern and Differences i n

degree; only trace amounts are excreted i n the urine.

PCB metabolism between mammaliirn species are more quantitative than q u a l i t a t i v e f o r mice, rabbits, monkeys, cows, goats and pigs.

Excreted

metabolites i n urine, bile-and milk are conjugated with glucuronic or Metabolism of PCBs is usually v i a

s u l f u r i c acids t o varying degrees.

hydroxylation through an arene oxide intermediate ( r e f , 80, p. 456).

Lucier et a l . (1978) reported some marked differences between adult end f e t a l metabolism i n a t least one mammal--the rat.

Here, while

adults and newborns were found t o s t o r e many PCBs i n adipose t i s s u e , biphenyl analogs containing 1, 2. not stored.

4, or 6 chorines w e r e

readily cleared,

R a t fetuses, by contrast, stored high concentrations of

these analogs i n the i n t e s t i n e , but cleared them rapidly a f t e r p a r t u r i t i o n ( r e f . 139b).

One explanation is t h a t hydroxylated PCB

crosses the placenta and is conjugated t o the glucuronide i n the l i v e r . Since i t is unable t o cross the placenta i n t h i s form, the conjugate accumulates i n the f e t a l i n t e s t i n e where it may re-form a hydroxymetabolite.

I n the hydroxy form the metabolite may be recirculated t o

the l i v e r for enterohepatic recycling.

This lack of a f e t a l mechanism

f o r exogenous removal of polar conjugates r e s u l t s i n a potentially harmful accumulation of the PCB metabolites i n the fetus. 2.13.5 A

Reproductive and Related Effects of Animal Exposure t o PCBs

1963 report of embryotoxic and teratogenic e f f e c t s of Aroclor 1242

anticipated the later findings of PCBs as environmental pollutants by f i v e years.

When McLaughlin et a l . injected the Aroclor i n t o the yolk

sacs of 20 f e r t i l i z e d eggs prior t o incubation, only one chick hatched-and it died within two days ( r e f . 140).

Embryos examined showed beak

deformities, edema and a retarded growth pattern. Placental transfer of PCBs has been established f o r the mouse, r a t , rabbit and monkey ( r e f . 80. pp. 457-458).

However, because of high PCB

l i p o s o l u b i l i t y , the transfer v i a milk i s much greater.

This was

demonstrated f o r the KanechlorB with the mouse and rat. the pig (Aroclor 1242) and the monkey (Aroclor 1248; r e f . 80, pp. 458-460).

Lucier e t

a l . observed a s t r u c t u r e a c t i v i t y relationship (SAR) f o r the PCB

transfer v i a milk, and a positive correlation between chlorine content and degree of transfer ( r e f . 139b).

The high r a t e of transfer by the

milk route makes t h i s by f a r the most important source of PCB exposure

347

both in the newborn and infant, regardless of the species tested and time of exposure of the dam (e.g., before or after parturition). The half life of PCBs is very long in adult adipose tissue and milk is the main excretion route in nursing dams. Hence the prenatal effects of PCBs may be less significant than their postnatal developmental toxicity Like the organochlorine pesticides, PCBs affect endocrine and gonadal function. Male mice fed a diet containing 0 to 400 ppm of

.

Aroclor 1254, for two weeks, showed significantly increased liver weight at all levels of PCB, and decreased weight of seminal vesicle (50%) and testes (18%)at 400 ppm. Total sperm number and concentration were also significantly reduced (40% and 3O$, respectively). At 200 ppm a significant reduction in the sperm concentration was still evident (refs. 141a,b). PCBs resemble diary1 organochlorine pesticides in their effect on androgen and estrogen behavior. Erythrocyte production, which is androgen-dependent in the rat. was reported to decrease significantly when male rats received i.p. injections of Aroclor 1254 (10. 20. or 50 mg/kg) (ref. 141~). Similar effects were observed in the estrus cycles of female mice injected i.p. with 20 mg/kg of Clophen A60 (60%Cl). Orberg et al. (1972) reported a mean prolongation of the first postinjection estrus cycle from 5.5 days prior to injection to 6.6 days. Comparable results were obtained when a peanut oil solution of the Clophen A60 was fed daily (.025 mg/d. for 62 days) to 11 females. Treated females produced fewer implanted ova on mating (ref. 141d). While estrus cycle data on rats appeared to be negative, there were significant dose-related reductions in plasma progesterone levels on 36week diets containing 75 to 150 ppm Aroclor 1242. Rat ovaries showed characteristic changes in stromal cells and reduced follicle numbers. At the higher dose (150 ppm) reproduction was totally inhibited after 36 weeks (ref. 141e). Rhesus monkeys fed a diet containing 2.5 or 5 ppm Aroclor 1248 showed clinical signs of toxicity after two months--progressive weight loss, alopecia, acne and swollen lids. Later, cycle lengths and duration of menstrual bleeding increased. Reproduction was greatly impaired after 7 months on this regimen (ref. 80, p. 462).

In general the adverse reproductive effects of PCBs on fertility are evident sooner in the female of a species, and at lower doses. At subtoxic doses, PCB effects on reproduction can span several generations.

348 An i n t e r e s t i n g phenomenon observed i n some of t h e offspring of mice

exposed (prenatally, 32 mg/kg/d) to tetrachlorobiphenyl (3,4,3'4 ' ) , was

a form of' hyperactivity known as the "Spinning Syndrome"--a jerking or r o t a t i o n of the head often followed by rapid c i r c l i n g . Those offspring affected exhibited slower growth rates than unaffected s i b l i n g s (ref. 143a). had impaired forelimb g r i p strength and found crossing a w i r e rod d i f f i c u l t . Spinners a l s o had long l a t e n c i e s i n a one-way avoidance test and poor v i s u a l placement response. Hyperactive s i b l i n g s without the spinning syndrome were a l s o d e f i c i e n t i n the wire rod and avoidance t e s t s (143b). Dopamine agonists and antagonists modified spinning behavior (amphetamine, apomorphine), or inhibited i t e n t i r e l y (haloperidol). Neurologic studies i n spinners indicated a biochemical l e s i o n of dopaminergic pathways.

Further histologic and u l t r a s t r u c t u r a l CNS

s t u d i e s showed a l e s i o n consisting of CNS projections i n t o ventral, dorsal and (some) c r a n i a l nerve m o t s .

Such l e s i o n s never appeared i n

the controls ( r e f . 143a). Miniature pigs fed Amclor 1254 (1, 10 or 30 mg/kg/d) beginning 21 days prior t o breeding, and continued throughout pregnancy and l a c t a t i o n , showed dose-related decreases i n l i v e litter s i z e and number of pregnancies, and an increase i n post-natal mortality.

A t 10 mg/kg

malformations (syndactyly, c l e f t p a l a t e s ) appeared; a t 30 mg/kg, c l e f t palates and patent fontanelles ( r e f . 1 4 3 ~ ) . Dogs fed 0.25, 1 or 5 mg/kg/d Aroclor 1254 throughout pregnancy and l a c t a t i o n had l e s s pregnancies and reduced l i t t e r s i z e a t the higher dose, as well as increased resorptions and post-natal mortalities.

Some

pups had c l e f t palates, enlarged fontanelles and additional phalanges (ref. 143d).

Rhesus monkeys fed a d i e t containing 2.5 or 5.0 mg/kg/d

Aroclor 1248 had a high incidence of abortion.

Offspring weighed 20%

l e s s , showed poor postnatal growth and had c h a r a c t e r i s t i c hyperpigmentation. Of 6 offspring produced, 3 died a f t e r 2 months' exposure t o PCB-tainted mother's milk (ref. 143e). Summarizing, the main e f f e c t s of.prenata1 exposure t o PCBs i n the species studied were low b i r t h weights, high peri- and postnatal mortalities and poor growth r a t e s of the offspring. Exposure t o PCBs very e a r l y i n pregnancy could i n h i b i t implantation. Offspring exposed t o PCBs excreted i n dam's milk had impaired reproductive function (mouse, r a t ) . Prenatal exposure t o tetrachlorobiphenyl produced a severe neurological disorder (spinning

349

syndrome) in the mouse, attributed to resultant lesions in dopaminergic pathways. Hydronephrosis in the mouse was also observed with the tetrabichlorobiphenyl. Cleft palate, enlarged fontanelle and poly- and syndactyly (dog, mini-pig) were observed after administration of Aroclor 1254. The hyperpigmentation and low birth weights observed in monkeys when exposed to Aroclor 1254 prenatally is paralleled in humans under comparable conditions. 2.13.6 Reproductive and Related Effects of Human Exposure to PCBs Extremely favorable physical and chemical characteristics made PCBs ideal vehicles for widely diverse industrial uses and formulation (see section-Uses). Soon after their industrial production by Monsanto and others (1929) their wide commercial application in products and processes resulted in extensive environmental contamination throughout the world--in air. soil and water. Virtually no living creature is free of PCB contamination, since it has been incorporated by now into all levels of the food chain from the lowliest unicellular creature to man (ref. 142). Table 8 gives PCB concentrations measured in blood sera of 616 residents of urban and rural areas of South Carolina in 1972 (ref.

136. p. 36). The GLC technique used (e-capture with Ni-63, after dehydrochlorination) was of limited sensitivity, hence the poor detection of lower PCB levels. Data correlated with race and residence and appeared to be independent of sex and age. Mean concentrations of PCBs found in maternal and cord blood samples (Tokyo, Japan, Dec. 1973 through Feb. 1974) were 2.8 and 1.1 ppb, respectively, calculated on a whole blood basis (Akiyama et al., 1975). Transfer of PCB from the mother to the fetus appeared to be non-selective (ref. 143f). Table 9 gives PCB concentrations found in seven second- and third-trimester fetuses, calculated on both whole tissue and fat bases.

Concentrations

reported in 19 first trimester fetuses (5-8weeks) were less than 2 ppb (ref. 136, P. 37). In February 1977 PCB analyses of 384 human milk samples from 40 states were reported to NIOSH. Of these, only 5 samples were not positive; 112 samples from 27 states contained measurable amounts of PCBs--up to 12.6 ppm(fat basis). Systematic worldwide studies of PCB accumulation in humans is limited. The average PCB level in adipose tissue of Europeans is ca. 1

-

ppm (range 0.3 9 ppm), with occasional reports in the hundreds of ppm. In spite of efforts to control PCB contamination it appears that PCB

350 residence i n humans i s slowly increasing ( r e f . 80, p. 473).

Plasma

l e v e l s i n Americans, Japanese and Europeans is estimated a t 3 t o 30 ppb, but mean occupational levels found were much higher ( N 800 ppb; Wassermann, r e f . 142) , with individual analyses as high a s 1900 ppb. Fishbein e t a l . (1979) reported a high incidence of toxic symptoms among workers i n two f a c t o r i e s producing capacitors i n the U.S. ( r e f . 1 4 4 ) . The danger t h a t weight l o s s may release these lipid-stored PCBs i n t o the blood, r a i s i n g PCB l e v e l s there by factors up t o 103 is a serious consideration. Mean PCB l e v e l s i n breast milk reported were high worldwide, with l e v e l s i n the milk f a t averaging between 1 and

15 ppm. Mean l e v e l s i n

t o t a l milk samples collected throughout Europe ranged from 10 ppb (Norway) t o 100 ppb (Qermany) and 390 ppb (Poland). Rogan e t a l . (ref

88) analyzed PCB d a t a from the 1975 EPA survey of chlorinated hydrocarbon pesticides by Savage ( r e f . 145a) and found t h a t less than 1% (9 out of 1038 samples) had no PCB contamination, 69% (720) had detectable levels below 50 ppb, and 30% (309) were a t l e v e l s above the quantifiable l i m i t of 50 ppb, calculated on a whole milk basis.

About

20% of the l a t t e r 309 samples had PCB levels above 10 ppb (0.1 ppm; r e f .

88). Data f o r the pesticides and PCBs a r e summarized i n Table 10. Measurements of PCB l e v e l s i n whole breast milk were made i n Osaka, Japan between 1972-77.

Mean values of 32-40 ppb (range: 10-240 ppb)

remained s t a b l e f o r the

5 years of the study.

Blood PCB l e v e l s

correlated well with those of milk. but the latter were 10 times as An inverse correlation found between maternal PCB l e v e l s and the

high.

number of children w a s evidence t h a t the excretion of PCBs v i a milk was

a major route f o r the mother and the main source of PCB ingestion by t h e infant. Blood PCB l e v e l s i n occupationally exposed women could be 10 t o 100 times higher than f o r those not so exposed. Their offspring too had much higher PCB blood levels. Since these l e v e l s were higher the longer the nursing time, and lower f o r those infants maintained on formula, i t indeed appears t h a t the mother is the main PCB source f o r the child. Beyond a nursing period of three months, the i n f a n t ’ s blood l e v e l may

well surpass t h a t of the mother. I n the Middle E a s t , non-exposed Israeli women a l s o had high PCB milk l e v e l s with the colostrum l e v e l about half t h a t found i n t h e milk l a t e r on. (ref.

This may be explained by the lower f a t content of the colostrum

80, p. 474).

351 A serious episode of PCB poisoning associated with the consumption

of PCB-contaminated rice bran oil occurred in Japan in 1968. By September of 1973 over 1200 "Yusho" or rice bran disease cases had been registered, most of them from the Fukuoka and Nagasaki prefectures (approximately 450 cases in each). Hiroshima (80 cases), Kochi (45) and Yamaguchi (40)prefectures were also seriously affected. Seventeen other prefectures reported from 1 to 25 cases each. The source of contamination was a PCB-containing heat exchanger used in deodorizing the rice bran oil at reduced pressure. Analysis of rice bran oils by infrared spectrophotometric and GLC methods showed Kanechlor 400 to be the principal contaminant. By May of 1975 the number of Yusho patients had risen to 1291 (ref. 136, pp. 40ff). Common symptoms of toxicity were the characteristic acnei form eruption and eye discharges, along with swelling of the upper eyelids previously described, hyperemia of the conjunctiva, hyperpigmentation of skin, mucous membranes and nails (ref. 146). Attempts were made to bracket the PCB concentrations in oil shipments over time. In analyses that were based solely on chlorine content, oil shipped February 5, 1968 had a PCB content of ca. 3000 ppm. Subsequent shipments decreased rapidly, and oils produced after February 19 had PCB traces only (NIOSH Criteria , p. 41). PCDF at NO.5% of % C1 content), traces total PCB concentration, low bromine levels ( ~ 2 of of chlorinated naphthalenes, and evidence for other unspecified chlorinated contaminants are also noted in the PCB literature references

...

cited in the NIOSH document containing 302 references (ref. 136). Discharges from the acneiform eruptions of two patients analyzed at 32 and 45 ppm PCBs. An 18 year old male showed ca. 75 and 13 ppm in subcutaneous fat samples taken from his face and abdomen, respectively. GLC patterns similar to those in contaminated rice oils were found in the human samples examined, including those from fetal and placental tissues. Tissues from a stillborn infant (October 1968) were preserved for later analysis. These had PCB concentrations in liver, skin and fat of 1.8. 1.2 and 0.1 ppm, respectively. The pregnant mother had been diagnosed as a severe case of YUP~Q. First trimester PCB concentrations reported for 19 embryos were low (<2ppb). Second and third trimester were successively higher (Table 9). Sputum samples collected'from 13 patients between December 1969 and May 1970 all contained PCBs. Contamination was highest in December, with detection less common by May, and PCB levels were lower. Autopsy

362

data obtained from 3 of 5 patients' body f a t and other t i s s u e s are given i n Table 11. The cause of death was given a s h e a r t f a i l u r e (4) and a ruptured l i v e r (1). Organs examined for PCBs included the brain, heart, kidney, l i v e r and skin, with highest PCB concentrations generally found i n the h e a r t and l i v e r ( r e f . 147). The infants of Yusho mothers were called "black" or "cola" babies due t o t h e i r skin pigmentation which persisted post partum f o r some Even offspring born as long as 5 years a f t e r maternal ingestion of the contaminated o i l showed some pigmentation. Other abnormalities

months.

found i n a study of four infants included retarded i n t r a u t e r i n e growth

(3). f a c i a l edema and exopthalmy (3), dentition ( Z ) , c a l c i f i c a t i o n on s k u l l and a wide, open s a g i t t a l s k u l l suture (3) at b i r t h . Postnatal development i n Yusho children however appeared normal ( r e f , 148a)

.

Of 13 infants born t o exposed women, two were stillborn, ten had the c h a r a c t e r i s t i c pigmentation of skin and gums, 8 were jaundiced a t b i r t h

9 had

conjunctivitis ( r e f . 80, p. 476).

T a k i e t al. found t h a t a l l 13 of the neonates exhibited a grayish dark brown skin, and gingival and n a i l staining. The l i v e offspring had a skin desquamation resembling parchment. A l l were below the mean weight f o r gestational age (G.A.); of these 5 were c l a s s i f i e d 88 "sma1l"for t h e i r G.A. The health e f f e c t s of occupational exposure t o PCBs are tangential t o the purpose of t h i s chapter, hence have been only b r i e f l y discussed. They are treated i n some d e t a i l i n r e f . 136, pp. 49-65 and references c i t e d therein. Of those e f f e c t s mentioned, the complaint of sexual impotence encountered with other chlorinated organics (e.g., DBCP. Kepone, etc.) is noted. Also. the higher than expected incidence of melanoma and pancreatic cancers i n one study is cause f o r concern ( r e f . and

149). 2.13.7 Summary Polychlorinated biphenyls are ubiquitous worldwide and l e v e l s are slowly increasing i n human tissues. Of p a r t i c u l a r concern are the high PCB l e v e l s ( ~ 1 0 0ppb) found i n human breast milk and the r i s k t h a t human nurslings w i l l ingest mounts i n excess of the maximum allowable intakes. Milk PCB l e v e l s i n occupationally exposed women may exceed those of the population a t large by f a c t o r s of 10 t o 100. This source of exposure is viewed as a greater r i s k t o the infant than that transferred v i a the placenta during the second and t h i r d trimesters ( r e f . 80, p . 478). Women exposed to high PCB levels may experience menstrual problems.

353 The ingestion of PCB-contaminated cooking oil by pregnant women produced Yusho disease and their offspring were born with a characteristic dark grayish-brown discoloration that affected skin, nails and gums, fading slowly after birth. Mortality was higher among infants of Yusho mothers, and survivors were initially handicapped by low birth weights and retarded development. Within 2 to 3 years however the gap between

them and unexposed offspring appears to have been closed. While the surviving offspring did not show permanent structural malformations, PCBs did have a marked effect on both fetal and post-natal development, growth and mortality.

In view of the possible relationship between

malignant melanoma and exposure to PCBs. long-term follow-up studies should be pursued on the surviving offspring of highly exposed mothers as well as on the mothers themselves. One study of nine post-Yusho offspring exposed to PCB via breast milk reported apathy, enervation, hypotonia and a lack of endurance in three of these children for more than 5 years (ref. 151). PCBs are classified as animal carcinogens and viewed as potential human carcinogens as well (ref. 152). Three NIEHS-funded reproductive toxicity studies were scheduled for fiscal year 1985 (ref. 162~). 2.14 Polybrominated Biphenyls (PBBs, C12 H ~ O B-r,)~ The polybrominated biphenyls are analogs of the PCBs reviewed in the previous section. In view of their chemical similarities and current restrictions on the uses of PBBs, it is clear that future chemically related substances bear closer scrutiny prior to commercial production. 2.14.1 Background Polybrominated biphenyls are solids at room temperature, insoluble in water and soluble to varying degrees in other aromatic hydrocarbons-e.g, benzene and in organic solvents of appropriate (low) polar characteristics. Of the large number of PBBs theoretically possible, only three have been commercially produced: the hexa-, octa-, and decabromobiphenyls

(2.2'- ,-4,4 ' - , 5,5' -hexabromo-1,1'- ; ar ,ar,artar ar ' ,ar ' ,ar' ,ar ' octabromo-1.1'-, and 2.2',3.3',4,4'.5.5',6.6'-decabromo-l,l'-biphenyl). Michigan Chemical Company was the sole manufacturer of PBBs sold in the U.S. prior to their discontinuance in 1974 (ref. 153). 2.14.2 Uses of PBBs Like the PCBs, PBBs were used primarily where low flammability and/or chemical reactivity of the product was a desirable

354

characteristic.

A mixture of PBBs i n which the hexabromo derivative was

the main ingredient was sold a s a fire retardant. nFiremastern BP-6 contained t h e penta-, hexa-, and heptabromo-1.1'-biphenyls. with the hexabromo compound a s t h e main component, and 2% added calcium trisilicate ( r e f . 152, p. 169). PBBs w e r e a l s o widely used as flame retardant additives i n polymer formulations. e.g., synthetic f i b e r s , molded p l a s t i c s and p l a s t i c housings; also i n the manufacture of polycarbonates, polyesters, polyolefins and polystyrenes. Mixed ABS polymers ( a c r y l o n i t r i l e butadiene styrene), plastics, coatings and lacquers a l s o contained added PBBs t o enhance fire-retardancy. PBBs may be used as s t a r t i n g materials i n the synthesis of biphenyl esters. i n a modified Wllrtz synthesis and as color activators i n

-

-

s e n s i t i z e r s ; a l s o , t o control the molecular weights of polymers, e.g., i n polybutadienes. Other possible uses include wood preservation and as voltage s t a b i l i z e r s i n e l e c t r i c a l insulation ( r e f . 80, p. 438). Commercial production of PBBs dates from 1970. By 1974 ca. 11 million lba of hexabromobiphenyl had been manufactured and marketed under t h e "Firemaster" trade name (BP-6 and FF-1). Production of some PEPS w a s discontinued i n the late '70s. but the 1980 decabromobiphenyl production i n t h e U.S. w a s s t i l l reported as more than 10,000 lb. An unspecified quantity of t h e hexabromobiphenyl produced by a s i n g l e manufacturer is l i s t e d i n the Chemical Substances Inventory of 1979 ( r e f . 152. footnote, p. 170). 2.14.3 Risks of Exposure t o PBBs According t o the FDA, the p o t e n t i a l f o r human exposure t o PBBs i s largely through the ingestion of foods containing PBB residues. Present sources of PBB contamination are i n areas where products containing PBBs were formerly produced, processed, or manufactured. The National Hazard Survey of 1974 estimated t h a t approximately 4900 workers were p o t e n t i a l l y exposed t o PBBs, e i t h e r by skin contact and inhalation, o r v i a inadvertent ingestion.

PBB concentrations found i n worker's sera

ranged from 1.1 t o 1729 ppb of the hexabromo derivative (HBB); 0.51 t o 581 ppm were detected i n workers' adipose t i s s u e . I n 1973 about 2000 l b of P'BBs were accidentally mixed with livestock feed a t the Michigan Farm Bureau feed m i l l i n Battle Creek, Michigan--the r e s u l t of packaging mix-up of "Firemaster" and "Nutrimaster", a sweetening agent (MgO) used i n c a t t l e feed. Thousands of animals sickened and died. Some 30,000 c a t t l e , along with thousands

355

of other farm animals were quarantined and had to be destroyed. Livestock and poultry on hundreds of farms were contaminated with the fire retardant. Between 1973-4 an estimated 8000 to 12.500 Michigan residents were exposed to contaminated meat, milk and eggs. Later a population survey conducted in Michigan showed that only 10% of the population did not have detectable blood levels of PBBs (ref. 152, p.

169). Since PBBs were known to be biologically stable and eliminated very slowly, significant body burdens of the compounds were expected to persist throughout the lifetimes of exposed individuals. 2.14.4 The Role of Serendipitous Sleuthing in Discovery of the Mix-up Farmers whose herds (and families) were among the early victims of PBB poisoning were initially unaware of the merging statewide pattern of illness. Were it not for the perseverance and unusual background of one dairy farmer, the true cause of the problem might never have been discovered. Certainly it would have taken much longer to end the mischief caused by the mix-up. This dairy farmer, Frederic Halbert by name and the recipient of what was probably the most contaminated feed consignment from the Farm Bureau Services feed mill. just happened to have a chemical engineering degree and 3 years' experience with the Dow Chemical Company before his return in 1971 to the family farm. Halbert also proved unusually resourceful and persistent in his determination to track the cause of the devastation of his animals and his onceflourishing dairy farm, whose milk production before the end of September 1973 had been outstanding. Thereafter production began to fall off, had declined 40% by mid-October, and his cows were eating less and showing symptoms of illness: weight loss, hoof defects, "rheumy eyes and runny noses" (ref. 153, p. 241). Veterinariaos consulted were at a loss, though blood samples of ailing cows were analyzed and the carcasses of dead animals autopsied. Halbert next turned to the feed; he w a s aware of the possibility of pesticide contamination, but early analysis ruled out the usual culprits --DDT, dieldrin and PCBs, all of which peak early in gas chromatographic analysis. At this point Halbert's dairy farm was at stake. Scientists at Michigan's Department of Agriculture also failed in their search for a chemical clue, so Halbert turned to the USDA's National Animal Disease Center at Ames. Iowa. Here the accidental failure to switch off the GC apparatus during a lunch break revealed a "Rocky Mountain Range" of late peaks. At this critical point the bureaucratic genius of the Animal and Plant Health Inspection Service called off the investigation for lack of

356

H a l b e r t , f r u s t r a t e d but undeterred, s e n t a sample of

earmarked funds.

h i s feed to s c i e n t i s t Qeorge F r i e s a t USDA's Reeearch Center a t Fortunately F r i e s was one of t h e few s c i e n t i s t s

B e l t s v i l l e , Maryland.

a b l e to recognize PBBs on a aC a t t h a t time--the r e s u l t of having analyzed a f r e e sample obtained from Michigan Chemical Company a few y e a r s previously.

When Halbert a l l u d e d t o t h e late-merging peak i n a

telephone conversation with F r i e s , t h e l a t t e r observed t h a t PBB e x h i b i t s t h i s GC behavior. made PBB?

H a l b e r t , i n t u i t i v e l y asked whether Michigan Chemical

F r i e s , s u r p r i s e d , asked why Halbert had asked--and w a s t o l d

t h a t t h e company made Nutrimaster. Once Halbert made t h e c r i t i c a l a s s o c i a t i o n between Nutrimaster and Firemaster, t h e mystery was solved.

By A p r i l 29. 1974 F r i e s had

e s t a b l i s h e d v i a both Qc and MS (mass spectrometry) t h a t H a l b e r t ' s feed d i d indeed contain PBB. Some weeks later FDA i n v e s t i g a t o r s and Farm Bureau people found a p a r t l y f i l l e d bag of Firemaster a t t h e feed m i l l .

Within t h e month (May

1974) a c t i o n ( t o l e r a n c e ) l e v e l s were e s t a b l i s h e d by t h e FDA f o r PBB contamination.

The Michigan Department o f A g r i c u l t u r e began

q u a r a n t i n i n g contaminated farms--a process t h a t went on u n t i l t h e end of

1975. Another s i x months saw t h e o r i g i n a l MACs f o r PBBs f u r t h e r lowered t o 0.3 ppm f o r meats and d a i r y products, and 0.05 ppm f o r eggs and feed, as t h e t o x i c e f f e c t s i n animals were noted a t lesser concentrations, and t h e r o u t i n e d e t e c t i o n o f PBBs a t t h e s e lower c o n c e n t r a t i o n s became feasible. I n t h e absence of p r e c i s e t o x i c o l o g i c d a t a , i t is not unusual f o r t h e concentration l i m i t s set to be determined by t h e s e n s i t i v i t y of t h e a n a l y t i c a l methods develqped.

When d e a l i n g with highly t o x i c

substances, such a c r i t e r i o n poses obvious r i s k s , p a r t i c u l a r l y where d i e t a r y s t a p l e s are involved f o r large populations.

I n t h e elapsed

i n t e r i m between t h e i n i t i a l d e l i v e r i e s of contaminated feeds t o farmers and t h e quarantine a c t i o n o f May 1974, s e v e r a l thousand farm f a m i l i e s i n Michigan had consumed considerable q u a n t i t i e s of' PBB-contaminated meats and d a i r y products.

The non-farm Michigan population was also exposed,

but t o a lesser e x t e n t , because milk from v a r i o u s sources was mixed and homogenized before s a l e , d i l u t i n g t h e contamination. The Michigan Department of P u b l i c Health r e p o r t e d t h a t none of t h e many complaints of i l l n e s s examined could be unequivocally a t t r i b u t e d t o PBB i n t o x i c a t i o n , b u t both t h e medical and epidemiologic conclusions of MDPH have come under s t r o n g criticism by W.D.

Meester, a c l i n i c a l

357

t o x i c o l o g i s t a t Grand Rapids' Blodgett Memorial H o s p i t a l .

Meester

argued t h a t , with 70% of t h e c o n t r o l group showing d e t e c t a b l e PBB blood Studies a t

l e v e l s , t h e r e was no c r e d i t a b l e b a s e l i n e i n t h e MDPH study.

t h e l a b o r a t o r i e s of du Pont de Nemours r e v e a l i n g l i v e r enlargement i n

rats had persuaded t h a t company t o cancel p l a n s f o r t h e use o f PBBs i n flame-resistant clothing.

Also, r a t - f e e d i n g s t u d i e s by both f e d e r a l and

state agencies (October 1974) l e d t o t h e conclusion t h a t , while both PCBs and PBBs caused "dramatic a l t e r a t i o n s " i n normal b i o l o g i c a l processes, t h e l a t t e r compound(s) were t h e more t o x i c . FDA o f f i c i a l , " t h e weight of t h e

evidence

According t o one

. . . indicates

t h a t PBB

caused g r e a t e r responses a t lower l e v e l s than PCB and ( i t s t o x i c i t y ) may be up t o f i v e times (greater)" ( r e f . 153, p. 242). Typical of t h e h e a l t h e f f e c t s r e p o r t e d were t h o s e o f t h e Cole family, revealed i n an open l e t t e r t o t h e Michigan l e g i s l a t u r e .

Mr.

Cole and f o u r c h i l d r e n , age 5 t o 10 f e l t " s i c k and miserable", each s u f f e r i n g from one or more maladies, e.g., "extreme l e t h a r g y , s e v e r e headaches, stomach discomfort, and s t i f f or swollen j o i n t s " .

Their

i l l n e s s was a t t r i b u t e d t o pork from p i g s f a t t e n e d on PBB-contaminated g r a i n , obtained from t h e i r l o c a l Farm Bureau e l e v a t o r i n Chippewa County.

A f a t sample taken from t h e e l d e r Cole showed 0.15 ppm of PBB

contamination and t h e pork e a t e n was r e p o r t e d l y only l i g h t l y contaminated.

No mention i s made of milk consumed--particularly by t h e

children. The PBB contamination i n c i d e n t had a d e v a s t a t i n g e f f e c t on t h e Michigan economy.

Long before a complete accounting w a s a v a i l a b l e , t h e

l o s s o f farm animals reported was 29.800 c a t t l e , 5,920 hogs, 1,470 sheep and ca. 1.5 m i l l i o n chickens.

Thousands o f cattle were hauled t o a

remote 20-acre b u r i a l s i t e ("Animal Auschwitz") i n c e n t r a l Michigan by Farm Bureau S e r v i c e s . By late 1975, 335 o f 650 claims f i l e d a g a i n s t Michigan Chemical Company and t h e Michigan Farm Bureau had been s e t t l e d a t a cost o f $22.5 million.

F r e d e r i c H a l b e r t ' s claim was among t h o s e s e t t l e d e a r l y i n t h e

proceedings.

Among t h e l i t i g a n t s with cases s t i l l pending w e r e many

seeking compensation f o r damage t o farm animals contaminated with "sub a c t i o n l e v e l s " o f PBBs, based on FDA criteria.

It w a s argued t h a t such

animals could n o t i n good conscience be marketed f o r meat or used for commercial milk production.

Hence t h e l i t i g a n t s w e r e faced with t h e

prospect of t o t a l f i n a n c i a l l o s s e s estimated ( u n o f f i c i a l l y ) a t $50 m i l l i o n or more. A l t e r n a t e l y they faced a long drawn-out legal b a t t l e

358

that many less affluent farmers could ill afford. Insistence by Farm Bureau Services and Michigan Chemical that the compensation for animals with below-action level PBB residues be reduced to reflect their "salvage value" resulted in a march on Lansing, Michigan by several hundred outraged farmers, demanding that the governor and legislature opt for greatly reduced official PBB action levels. This one costly human error had a considerable effect on the Congress, just then in the process of hammering out certain provisions of TSCA--The Toxic Substances Control Act of 1976. In particular those sections dealing with the premarket testing of hazardous chemicals, their labeling and distribution were affected (ref. 154). 2.14.5. Metabolism of PBBs

A review of the absorption, distribution and metabolism of PBBs in animals--mainly cattle and rodents--is already extant and will not be covered here (See DiCarlo et al, ref. 155). Suffice it to say that excretion rates of PBBs are exceedingly low, hence their biological half-lives long. Continued exposure leads to the build-up of PBBs in body fats. A major excretion route is via the lipid fraction of breast milk. Toxic effects observed in a number of species are similar, and include impaired appetite, weight loss, enlarged liver and a number of adverse reproductive effects. Despite the low levels at which these toxic effects are evident, lethal doses are relatively high. Although a number of experiments have established the placental transfer of PBBs in the rat and cow, post-partum experiments with rat pups born to controls but nursed by dams fed 50 ppm PBBs, end those born to PBB-exposed dams but nursed by unexposed dams, established the greater importance of PBB transfer via milk compared with placental transfer. 2.14.6 Endocrine and.Reproductive Effects of PBBs in Animals Testicular atrophy in cattle was first reported by Jackson and Halbert, who maintained a bull aged 18 months on a PBB-contaminated diet for six weeks. Semen examination showed many headless and tail-less sperm and no sperm motility. The animal died within three weeks. Autopsy revealed massive liver abscesses (ref. 156a). Later experiments by other workers gave similar results. In addition, organs infiltrated by lymphocytes included the liver, lung, kidney and small intestine (ref. 80, p.

439).

359 An adult male rhesus monkey maintained on a d i e t containing 25 ppm

PBB died a f t e r 25 weeks, during which t i m e he had l o s t 35%of h i s i n i t i a l weight and consumed a l i t t l e over 1 gram of PBB. Autopsy revealed alopecia and dry, scaly s k i n . marked edema of the l i d s with l o s s of eyelashes, and subcutaneous edema.

Internal organic damage

included an enlarged heart, severe ulcerative c o l i t i s , hyperplastic g a s t r o e n t e r i t i s , hyperplasia of the b i l e duct epithelium, hypoactive seminiferous tubules, and keratinized h a i r f o l l i c l e s ( r e f . 156b).

In an

experiment with seven female rhesus monkeys, maintained on a 7 month d i e t containing 0.3 ppm

PBB, the same workers observed a w e i g h t l o s s After 6 months, four of the seven females had longer menstrual cycles and altered ("flattened") serum progesterone peaks. A n average of 10.4 mg of PBB had been ingested by averaging ca. 7% of i n i t i a l weight.

these monkeys during the experimental period ( a s compared with 1000+ mg f o r the male monkey over a 25-day period). Animal studies of the e f f e c t of PBB exposure on pregnancy have been carried out on the cow, monkey, mouse and rat.

A number of these

studies employed acceptable teratological methods t o determine PBB teratogenicity ( r e f . 80, pp. 440ff).

These a r e described i n some d e t a i l

i n Barlow and Sullivan, and w i l l be discussed only b r i e f l y here.

When

pregnant female mice were fed 200 ppm PBBs on days 4-16 and 8-16, the incidence of f e t a l mortality and resorption w a s greater f o r the 4-16 cohort, with reduced f e t a l body weight i n the 8-16 cohort.

Live litter

s i z e w a s a l s o reduced a t lOOppm i n the 8-16 cohort. A significant increase i n swollen hepatocytes and focal necrosis was

observed i n pregnant mice when fed a d i e t containing 1000 ppm of PBBs from days

7

t o 18.

No l i v e r observations were reported a t lower levels

(50 and 100 ppm). but a s i g n i f i c a n t dose-related decrease i n f e t a l weight w a s observed, a t t a i n i n g 14 percent below t h e mean f o r controls i n the lo00 ppm cohort. One c l e f t palate occurred a t 50 ppm and 5 cases of exencephaly (3 a t 100, 2 a t 1000 ppm of PBB). These malformations were significant when compared with pooled data from h i s t o r i c a l controls, but ambiguous when compared with the simultaneously run controls ( r e f .

1 5 6 ~ ) . In a similar experiment w i t h r a t s . no malformations w e r e observed, but dose-related mean f e t a l weight reduction occurred. higher dose range (100. 1O00,

lo4 ppm.

At a

days 6-15). anasarca and

g a s t m s c h i s i s (one f e t u s each) were observed at the two highest doses

(ref. 156d). A t the low dose end (from 0.25 mg t o 10 mg/day) with f i v e groups of

360

6-8 rats per dose and 30 controls. maternal l i v e r weight increased significantly at 1.5 and 10 mg/d. but f e t a l weight and crown rump length were significantly reduced only a t the 0.25 mg/d level, and appeared t o correlate with lower food and water intake and the maternal weight loss observed i n t h i s cohort. The same workers (Harris e t a l . ) carried out a second experiment feeding cohorts of eight r a t s 0-10 mg PEE per day (days 7-15). Dams delivered and suckled t h e i r own young. Significantly lower weights were observed i n the PEE-exposed pups from 3 through 60 days, when the study ended. Post-natal mortality w a s also higher (controls 1.53, exposed

14.3%). Vaginal opening w a s s l i g h t l y delayed i n exposed female pups. Harris et al. carried out yet another experiment, designed t o d i f f e r e n t i a t e between pre- and postnatal e f f e c t s of PBEs. Here pups were cross-fostered with groups of 8 dams given zero or 10 mg/d of PEB (days 7-15). Greatest body-weight reduction occurred i n pups born t o , and nursed by PEE-exposed dams. PBB pups nursed by control dams and control pups nursed by PEE dams exhibited an intermediate weight reduction pattern when compared w i t h t o t a l l y exposed and t o t a l l y non-exposed control pups and dams. The e f f e c t of the fostering procedure i t s e l f on weight loss was not examined Males showed greater weight reduction.

(ref. 157a). Beaudoin studied the teratogenicity of single high

(40.

200. 400, 800 mg/kg by gavage).

p8B

doses i n rats

Resorption rates increased a t 200 13 of pregnancy.

mg/kg f o r some females exposed on days 6 , 8 or

Maternal deaths (S2/group) occurred at 400 and 800 =/kg levels. except f o r dams exposed on day 7: the l a t t e r yielded 5 mortalities out of 6 dams. Resorption a t the two highest levels were dose-related. and significantly higher than for controls. Major malformations observed

were c l e f t palates and herniated diaphragms. Maternal weight gain w a s also reduced at the highest PEE dose. Beaudoin confirmed t h a t the e f f e c t s on f e t a l weight, resorption and malformation were indeed those of PBB and not the result of reduced food and water consumed. by pairfeeding another group of controls, w i t h rats given 800 mg/kg PBB on. day 12 (ref. 157b). PBBe strongly induced hepatic enzyme a c t i v i t y i n pre-weaned rats,

even at very low levels (0.2 pg/pO.&b) independently of whether PEE exposure w a s pre- or postnatal (ref. 80, pp. 443-444). Dams were also affected, but t o a lesser degree. Pups suckled by dams exposed t o l@pm PEE exhibited mixed-type microsomal induction of l i v e r

361

enzymes--increased cytochrome P-450, benzo(a)pyrene hydroxylation, etc. The enzyme induction following pre- and/or post-natal PBB exposure can significantly affect response to other environmental chemicals o r drugs (synergism). Of

7 rhesus females fed PBB for 7 months prior to and after

breeding, two had persistent implantation bleeding. One of them aborted a mummified fetus at 146d; the other infant was still-born at 154d. Five low-weight but otherwise normal-appearing offspring were delivered after 156-165d gestation. PBB toxicity in the rhesus monkey closely parallels that of PCBs in many respects: alopecia and swollen eyelids, low birth weight offspring and menstrual disorders in the dam (ref. 156b). The work of Jackson and Halbert with cattle was briefly mentioned earlier (ref. 156a). Among the reproductive effects of PBBs were: evidence for early embryonic resorption, delayed parturition. large calves, frequently stillborn, negligible milk production, and dystocia. Prewitt et al. reported similar findings in a field study of contaminated animals; namely, food consumption and milk production were reduced by one-half, cattle with more than 20 ppm of PBBs in their milk fat produced still born o r short-lived calves, had dystocia. and retained placentas were common, as was metritis. Similar symptoms appeared in cows with only 1 ppm of PBBs in their milk fat (ref. 158a). Other studies of PBB-dosed cattle were reported by Durst et al. (ref. 158b). Six-heifer cohorts received 0.25 mg. 0.25 g or 25 g/d of PBB for 60 days (or until death at the maximum dose) following diagnosis of pregnancy. Three of 6 heifers aborted 30, 33 and 39 days following maximum dosing; the others had dead fetuses when autopsied on days 33,

39 and 40. Fetuses were edematous and hemmorrhagic. Necrosis of the placental cotyledons and uterine hemorrhage were also observed, as were other indications of toxicity prior to autopsy. No toxic effects were seen at lower doses, nor was any gross histopathology evident at autopsy in the lower-dosed cohorts (ref. 158~). 2.14.7. Endocrine and Reproductive Effects of PBBs in Humans The Firemaster episode of 1973-4 resulted in widespread PBB contamination of dairy products and meats, the quarantining of more than 500 Michigan farms, and the destruction of some 23,000 dairy cattle, 1.6

million chickens and

5 million eggs.

By 1975 the body fats of most

residents of the state had detectable amounts of PBBs (refs. 155 and 158d). An in-depth study of the exposed farm population was carried out

362

by a team from the Environmental Sciences Laboratory, M t . S i n a i School of Medicine (I.J. Selikoff, Director) + Comparison of a Michigan cohort with a matched Wisconsin population showed t h a t the former had s i g n i f i c a n t l y more neurologic, musculo-skeletal and skin symptoms then the Wisconsin group.

Chief neurologic symptoms reported were extreme fatigue, a marked reduced work capacity, both physical and i n t e l l e c t u a l , and an excessive sleep requirement--frequently double t h e usual 6 t o 7 hours required ( r e f . 159).

Women were more neurologically affected than

men. A cohort of

4545 individuals were selected t o be examined

periodically f o r the long-term effects of PBBs by t h e Michigan Department of Public Health, i n cooperation with t h e CDC, FDA, NIH and EPA.

The cohort contains four groups:

quarantined-farm residents,

recipients of farm produce, PBB-exposed chemical workers and t h e i r

families, and a control ( p i l o t study) group. After four years the most frequent symptoms were still headache. fatigue, j o i n t pain and paresthesia. Serum PBB measurements (1~3639)ranged from 0-1900 ppb, with 106 values greater than 100 ppb. Serum PBB values i n males were s i g n i f i c a n t l y higher than i n females, with chemical workers and t h e i r ,families the highest of a l l , and residents of quarantined farms second. The mean PBB change i n 148 subjects was (-)16 ppb from years 1974-7, a t t e s t i n g t o i t s biologic persistence and s t a b i l i t y .

PBB l e v e l s i n f a t

samples obtained from 221 subjects averaged 363 times higher than those i n serum. Chloracne occurred i n 21 of 1029 subjects studies i n Grand Rapids, Michigan ( r e f . 155). Serum samples from PBB-exposed women examined a t p a r t u r i t i o n between

1973-9 had a mean value of 26.2 ppb, but ranged widely, from the The cord serum of 58 i n f a n t s

detection l i m i t of <1 ppb t o 1150 ppb.

delivered during t h a t period ranged from the detection l i m i t t o 104 ppb (mean = 3.2). For 13 p a i r s studied, the mean maternal/fetal r a t i o found was 7.04, indicating t h a t while PBB transfer does occur across the placenta, the l a t t e r does function as a b a r r i e r t o some extent, i n a

similar manner t o the placenta with PCB analogs ( r e f . 80, p. 449). Carefully randomized sqmples of breast milk obtained from women residing i n the upper and lower Michigan peninsula (U.P., L.P.) were examined f o r PBBs. A l l samples were derived f r o m d e l i v e r i e s occurring during August 1976.

Ninety-six percent of t h e U.P. women (51/53) and

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43%of the L.P. women (18/42) had detectable levels of PBBs. Based on their data the investigators concluded that between 8-9 million of the

L.P. population harbored detectable levels of PBBs. The ratio of body fat/milk fat was close to 1 (0.88) for 10 women in the cohort studied (ref. 160). In a follow-up fertility study after the Michigan accident. the Mt. Sinai research team examined the seminal fluids of the three groups of men: 1) 41 farmers and other consumers of produce from contaminated farms; 2) 11 employees of Michigan Chemical. manufacturer of PBBs; and

3) an unexposed group of 52 graduate students from Michigan University. The first two groups were medically selected to exclude those with a history of thyroid and liver disease, cancer, diabetes, myocardial infarction, and renal or urinary tract infections. The control (unexposed) group merely excluded Michigan residents. Blood samples from groups 1 and 2 were all PBB-positive. All but one of the control subjects (group 3) were PBB-negative. Semen samples were first counted and examined for motility, after which a fixed specimen was examined for morphology. Sperm counts, motilities and morphologies'were within normal ranges for all three groups. The FSH. LH, and testosterone levels measured on 16 exposed subjects and 16 controls were considered "valueless", either because results were below detection levels (FSH, LH), or because of the methodology used (ref. 80, p. 450). Other criticisms of this study included the late date of the survey (4 years after initial exposure), and medical exclusions in the exposed groups that may have missed the PBB effects in those subjects most severely affected

.

2.14.8. Summary Studies of PBBs in animals and humans have established their longterm accumulation in body lipids and very slow metabolism, hence prolonged storage in animals and man. While PBBs do cross the placental barrier, their transfer via nursing is considered to be of greater importance. Rats and mice both exhibited endocrine and other reproductive changes when exposed to nonlethal doses of PBBs via diet (1000ppm) or gavage (50 ppm). Toxic doses were embryolethal and in one case

.

teratogenic (rat, single dose 2400 mg/kg) Toxic PBB-contaminated diets fed to cattle caused gross tissue pathology, reduction or absence of sperm and damage to seminiferous tubules: milk production and food consumption were reduced, and

364

resorptions increased.

Prolonged gestations, s t i l l b i r t h s and deaths of

neonates may bb secondary t o the occurrence OF dystocia reported. Rhesus monkeys on a d i e t containing 0.3 ppm PBB had lengthened menstrual cycles, increased f e t a l loss. low b i r t h weights and poor postnatal growth of neonates. I n humans, PBB l e v e l s i n breast milk exceed those i n plasma by a f a c t o r of ca. 100, and breast milk i s considered the main PBB excretion path.

While PBBs have been shown t o cross the human placenta, the lower

fetal plasma l e v e l s are evidence f o r a t least p a r t i a l placental b a r r i e r action.

Results of a 1978 study of blood and l i p i d t i s s u e samples collected from a cross-section of the PBB-exposed Michigan population showed t h a t nearly a l l of the s t a t e ' s population w a s contaminated ( r e f s . 159a, 161). Subsequent studies indicate t h a t the PBB l e v e l s have not decreased s i g n i f i c a n t l y a f t e r t h a t sampling.

Wolff et al. has pointed out t h a t

the health e f f e c t s of p e r s i s t i n g body burdens of PBBs a r e as yet unknown ( r e f . 1 5 9 ~ ) . Animal studies have shown these substances t o be damaging t o the l i v e r , as well a s neuro- and immunotoxic ( r e f s . 159d and 161). T-cell suppression i n PBB-exposed Michigan dairy farmers has been observed, and later r e s u l t s suggestive of a dose-response relationship a r e further causes f o r concern ( r e f . 161, p. 276; r e f . 163). This chronically impaired immune function, and t h e evidence of PBB-induced cancer i n animal studies. point t o the need f o r extended monitoring of the PBB-exposed population, " i n view of the carcinogenesis l a g time of up t o two or three decades" (Roberts, r e f .

159e).

The PBB category potentially comprises 200-300 chemicals, and is subject t o a special TSCA 8 ( a ) reporting rule.

The FDA regulates PBBs

a s unavoidable environmental contaminants under section 406 of the Federal Food, Drug and Cosmetic Act.* The long-term health e f f e c t s of acute PBB exposure are monitored by the FDA i n cooperation with the CDC and the Michigan Public Health Department ( r e f . 152, p. 70; r e f . 162a). A n immunologic t o x i c i t y study of PBBs w a s scheduled f o r completion during f i s c a l year 1985 ( r e f . 162b).

*Federal Food, Drug and Cosmetic Act a s amended. 21 USC 346a Sec. 406 "Toleraffce f o r Pesticide Chemicals i n or on Raw Agricultural Cododities

.

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3. THE HALOALKANES AND RELATED PESTICIDES 3.1 Dibromochloropropane (DBCP) The dilemma of a toxicologist, employed by a prestigious university while consulting for the pesticide industry, was highlighted during four days of hearings on DBCPI, precipitated by the high incidence of sterility and low sperm counts among exposed workers (refs. 23b,c). In the course of the hearings it became clear that a joint industry-academic study in 1961 had already shown severe testicular atrophy and cancer in test animals at 5 ppm. Without further testing, an allowable DBCP concentration of 1 ppm was then recommended. Later in-house tests showed infertility at exposures possibly as low as 0.3 ppm. DBCP was suspended by the EPA (Sept 1977) when it was found to cause sterility and low sperm counts "in more than 100 workers" in Alabama, Arkansas. California and Colorado, in addition to severe testicular atrophy and cancer in test animals (ref. 234. In all there have been six published studies of men exposed to DBCP with consistent reduction in sperm count, including some cases of sterility (refs. 24a-f). One of these reported a higher rate of miscarriage in wives of DBCP applicators (ref. 24e). Following the hearings, work by Whorton et el. (ref. 24a) showed that reversibility of the azoospermia experienced by exposed workers was probably dose-dependent and e function of individual sensitivity. OSHA then reduced the MAC to 1 ppb (ref. 25). See table on p. 167 of ref. 47 for reproductive effects on males. All registrations of end use products except for use on pineapples in Hawaii have been cancelled (EPA, ref. 103, p. 3).

3.2 Ethylene Dibromide (EDB) Successor t o DBCP was the equally suspect ethylene dibromide

(EDB). (ref. 26) widely used as a fumigant on fruits and vegetables. Based on the National Cancer Institute's finding of carcinogenicity of EDB the Environmental Defense Fund petitioned for cancellation of EDB registration. The EPA responded with an RPAR** notice in December 1977. Three years later (Dec. 1980) the agency announced its preliminary decision to cancel EDB registration for use on stored *Conducted by the California State Dept. of Industrial Relations. Oct. 1977; Donald Vial, Director. **WAR Rebuttable Presumption Against Registration.

-

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grain immediately and on citrus and tropical fruits as of July 1, 1983. In the interim (1981) the compound was used to fumigate citrus in California to control the Mediterranean fruit fly infestation. At stake was the citrus export to Japan, valued at about $100 million (ref. 27). EDB is highly toxic, oncogenic. mutagenic and severely damaging to the sperm of bulls. Hens fed grain containing 10 to 15 ppm of EDB lay fewer and smaller eggs. At higher concentrations of EDB, egg laying is irreversibly inhibited with continued exposure. In a controlled experiment, hens showed a striking reduction in fertilization rates when fed grains containing 100 ppm EDB. Two fertilized eggs obtained contained dead embryos (ref. 26a). Similarly. rats exposed to 31.6 ppm EDB had significantly lower implants and live fetuses per dam when compared with unexposed controls (ref. 26a. p. 94). Fetuses from pregnant mice and rats exposed to EDB during days 6-15 of gestation differed significantly from controls. Rats showed costal anomalies and hydrocephaly: in mouse fetuses, additional anomalies occurred in other ossification processes (ref. 26a, p. 112). The use of EDB was finally discontinued in 1984 (ref. 28). Three more grain fumigants used as EDB substitutes were removed in 1985 (ref. 2ga): carbon tetrachloride (CCl4). carbon disulfide and ethylene dichloride. Remaining stocks of these may not be used after June 30. 1986 and all food residue exemptions are to be revoked by that date. All four of the organohalides discussed are classified as carcinogens by the EPA. based on NCI findings (refs. 29b.d). Ethylene dichloride has also been reported to cross the placental barrier in rats, accumulate in placental and fetal tissues and to cause abnormal fetal development (ref. 29~).

4.

MISCELLANEOUS HALOGENATED AND OTHER ALKANES AND ALKENES OF INDUSTRIAL IMPORTANCE

blost lipophilic compounds with a molecular weight below 600 o r 700 can cross the placenta (Brix. ref. 25. p, 577). Hence the halogenated hydrocarbons as a class must all be viewed as potential embryotoxins and teratogens. The following section deals with halogenated alkanes and alkenes of secondary importance as pesticides but of major industrial importance as petrochemical intermediates, solvents, degreasing agents, propellants, refrigerants, etc.

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4.1 Monohalomethanes (MeCl, MeBr, MeI) are alkylating agents, hence potential carcinogens and mutagens. All have been shown to be directacting mutagens in the Ames assay and carcinogens in rats o r mice (ref. 30). 4.1.1 Monochloromethane (Methyl chloride, CH3C1) produced heart defects in the offspring of pregnant mice exposed to the vapor at 500 and 750 ppm. hence it is viewed as a potential occupational teratogen (refs. 30 and 3la,b). In addition., male rats exposed to 1000 ppm methyl chloride by inhalation showed degeneration and atrophy of the seminiferous tubules (ref. 33). The chloride is used to manufacture silicones, tetramethyl lead and triptane (2,2.3 trimethylbutane). Lesser uses include the manufacture of butyl rubber, higher halogenated methanes, methyl cellulose, quaternary ammonium compounds, methyl mercaptan, methionine, fungicides and pesticides (primarily the Me-arsenate herbicides). Recently the chlorinated fluorocarbons have replaced CH3C1 as high volume refrigerants and propellants (ref. 32).

Tables

12 and 13 list the chemical and physical properties and potential numbers of workers exposed to the monohalomethanes. 4.1.2 Methyl Bromide (CH3Br) is used as a soil and spore fumigant: also as a disinfectant, rodenticide. methylating agent, and a wool degreaser. A relatively low ionization potential led to its use in ionization chambers as well. Exposure data on CH3Br are largely obtained from its use as a fumigant to control nematodes, fungi and weeds. The compound is applied to soil under plastic sheets or in space fumigation under tarpaulins. 4.1.3 Methyl Iodide (CH31) is used primarily as a methylating agent. Occupational exposure in the work place is estimated as relatively low

(400workers). This however does not consider the much greater number of potential exposures of individuals in university and pharmaceutical laboratories where methylations are routinely carried out. Occupational permissible exposure levels (PELS) to the monohalomethanes are intended to protect against their neurotoxic effects. Long term studies on the bromide and iodide are still in progress. (ref. 30, pp. 7-8) In view of their carcinogenic and mutagenic behavior, the teratogenicity of the chloride, their neurotoxicity and potential for crossing the placental barrier, and the generally suspect status of chloroalkanes, all three

368

monohalomethanes should probably be treated as potential teratogens for the present.

4.2 Methvlene Chloride (dichloromethane, CH2C12 ). Among the many uses of methylene chloride is that of an "inert ingredient" in over 1750 pesticide formulations. It is a powerful solvent, also used as a degreaser, paint remover and aerosal propellant. The EPA is currently (1985) engaged in a full scale study of this compound under TSCA (ref. 34). It is known to cause malignant liver and lung tumors in mice and benign mammary tumors in rats. Dichloromethane is widely used as a solvent in analytical laboratories, both in routine extraction procedures and in high pressure liquid chromatography (HPLC) separations. In 1984 domestic production of CH2C12 was estimated at 584 million lbs. with another 44 million lbs imported. Unlike food additives, which must be banned by the FDA if they produce cancer in animals, the dichloride is subject to EPA regulation under TSCA; hence economic factors must be considered along with health effects. Metabolism of CH2C12 produces CO in humans, increasing carboxyhemoglobin in the blood. Acute toxicity involves the CNS and liver in test animals. The biological half-life of CO is greatly prolonged in the presence of CHzC12 (2 to 5 times: ref. 35). Pregnant rats and mice exposed to 1250 ppm of CH2C12 (gestation days 6 to 15, 7 hr. daily) showed a lower incidence of lumbar ribs than controls, and increased incidence of delayed ossification. A significant number of mouse pups had an extra center of sternal ossification (ref. 36). Exposure of rats to 4500 ppm of the dichloride for the 21 days prior to, and seven days during gestation altered environmental habituation rates. Preliminary observations indicate a possible behavioral effect on progeny of dams exposed to dichloromethane (ref. 37).

4.3 Chloroform (trichloromethane,CHC13). Chloroform was first used as an anaesthetic in 1847 and its narcotic effects on the central nervous are well documented (ref. 41a). It has important applications as an intermediate in the chemical synthesis of a large number of industrial chemicals: chlorofluorocarbons, dyes. drugs and pesticides. Its powerful solvent properties and low boiling point (61'C) have made it a favorite for extractive and purification operations in preparing antibiotics, alkaloids, flavors and vitamins.

369

In the laboratory it ranks with methylene chloride as a favorite solvent. Until 1976 chloroform was used in cough and cold preparations, mouthwashes, dentifrices, etc., when these uses were prohibited by the FDA. It is listed by the EPA as a carcinogen (ref.

48). The toxicology of chloroform is similar to that of related volatile halo-organics and will not be reviewed in depth here. A more detailed discussion, including the citation of review articles, is available in ref. 35 (pp. 282-290)and in the CIB No.

9 (ref. 41a).

As with other volatiles. inhalation is viewed as the main route of entry for chloroform. Its absorption and distribution to all organs is rapid. Except for some C02 production most of it is exhaled unchanged. The carbon dioxide conversion rate appears to vary with both port of entry and species. When human volunteers of both sexes were administered 500 mg of CHC13 orally, from 20 to 60% of it continued to be exhaled unchanged for 40 to 120 minutes (ref. 38). The hepatic and renal toxicities of chloroform are selectively modified by induction of the drug-metabolizing enzyme systems in those organs (ref. 39) and the production of phosgene is strongly indicated (ref. 40). Chloroform is carcinogenic in rats and mice (refs. 4la,b,c). It has been detected in cord blood at concentrations comparable to maternal levels. It is not teratogenic to rabbits and rats when administered by gavage at near-lethal levels. However, at anaesthetic concentrations and exposures up to one hour during organogenesis, chloroform was extremely embryotoxic (ref. 35. p. 291). SpragueDawley rats exposed to 30, 100 and 300 ppm

(7 hr/day) on gestation days 6-15 exhibited high fetal resorption rates, retarded development, embryotoxicity and evidence of teratogenicity. Inhaled chloroform also interfered with implantation in the mouse, and produced some fetal malformation (ref. 42). Chloroform is listed as a teratogen in the NIOSH Registry (ref. 5 0 ) .

4.4 Carbon Tetrachloride (tetrachloromethane,CCl4) Carbon tetrachloride has been used in grain fumigation, as a rodenticide, an industrial solvent and fire extinguisher. Absorption of CCl4 occurs through the lungs, skin and GI tract. It is highly liposoluble. hence maximum concentrations are found in the lipid tissues. The tetrachloride is also found in the liver and bone marrow. Elimination of unchanged CCl4 in mammals is largely via the

370

lungs. Biotransformation is to chloroform and C02; and, possibly, to the dimeric hexachloroethane and the highly toxic phosgene (ref. 35, p. 292ff.) , The latter products indicate free radical formation, presumably via lipid peroxidation. Hence the biotoxicity of CCl4 is determined largely by MFO system activation and may be influenced through inhibition or activation of the enzymes involved. Acute effects are to kidney and liver function. with tubular necrosis found in both organs. Alcohol acts synergistically with CCl4. Although CCl4 was found negative in in vttro mutagenicity testing, the irreversible binding properties of its metabolites (to DNA. lipids and proteins) indicate the likelihood #at it can form intermediates that are carcinogens (ref. 43). Using CCl4 as a positive control Weisburger (ref. 44) found a high yield of hepatocellular carcinomas in male and female mice, and an increase in adrenal tumors not seen earlier. The tetrachloride also yielded neoplastic nodules and some liver carcinomas in rats, but at lower than expected incidence. Reported cases of excess cervical, lung and skin cancers and excess leukemia in exposed laundry workers, and of delayed hepatomas in man after cCl4 poisoning, all indicate that CCl4 should be viewed as a buman carcinogen. Studies of teratogenicity of tetrachloromethane have lagged behind those of carcino- and mutagenicities. Nevertheless, experience with lower molecular weight lipophilic organochlorine derivatives (ref. 25) indicate a potential risk that CCl4 is both fetotoxic and teratogenic to humans. Thus, Dowty’s et al. study of the volatile organics (ref. 45) would at least indicate the possibility of selective Ccl4 transfer to the fetus. Female rats administered high doses of CCl4 (0.3m1/100g) incurred marked injury to placental tissue especially the chorionic epithelium of the labyrinth (ref. 46a). Pregnant rats receiving 300 and 1000 ppm carbon tetrachloride (7 hr/day during gestation days 6-15) showed some retarded fetal development, e.g.. delayed sternal ossification but no embryotoxicity. despite high maternal toxicity. Pregnant mice receiving 150 mg of CCl4 toward the end of pregnancy showed higher fetal mortality, due to liver damage with concomitant placental damage (ref. 46b).

4.5 Carbon Disulfide (CSz) has been used as a fumigant and insecticide, replacing the banned DBCP and EDB, along with cC14 and

371 It is a recognized neurotoxin, resembling o t h e r s o l v e n t s and

EDC.

halohydrocarbons i n t h i s r e s p e c t .

Its neurotoxic e f f e c t s a t lower

exposures are s u f f i c i e n t l y s u b t l e t o have been missed c l i n i c a l l y a t

first.

The following is a summary of conclusions drawn from an

e x t e n s i v e l i t e r a t u r e review by Tuttle et a l . ( r e f s . 49a.b). 1) The earliest s i g n s o f CS2 poisoning appear t o be

psychologic/behavioral.

Symptoms a r e :

headache, f a t i g u e , insomnia.

r a p i d mood changes, i n t e l l e c t u a l and s l i g h t psychomotor impairment. 2 ) The o n s e t of c l i n i c a l symptoms o f n e u r o l o g i c a l damage is preceded by slowed p e r i p h e r a l nerve conductor v e l o c i t y and abnormal electromyographic t r a c i n g s .

3) More advanced s t a g e s of CS2 poisoning produce changes (e.g.. abnormal r e f l e x a c t i o n s ) t h a t are less u s e f u l t o its e a r l y d i a g n o s i s , and n o t as r e l i a b l e as t h e EMG or conduction v e l o c i t y measurements.

4)

Cardiovascular e f f e c t s of chronic CS2 exposure i n c l u d e :

high

d i a s t o l i c and s y s t o l i c blood p r e s s u r e , a t h e r o s c l e r o s i s and increased l i k e l i h o o d o f death from coronary d i s e a s e .

5) Chronic exposure to CS2 l e a d s t o h e p a t i c enlargement and d i s t u r b a n c e of l i v e r a n t i t o x i c f u n c t i o n , with p o s s i b l e s y n e r g i s t i c i n t e r a c t i o n s with d i e t or drugs; a l s o t o i n c r e a s e d r e t i n a l arterial p r e s s u r e and r e t i n a l microaneurysms.

There i s some evidence of

h e a r i n g impairment over time.

6) Occupational exposure of women t o low ambient c o n c e n t r a t i o n s of CS2 r e s u l t e d i n numerous d i s o r d e r s of menstrual and o v a r i a n function.

I n h a l a t i o n of somewhat h i g h e r ambient c o n c e n t r a t i o n s (

gppm) r e s u l t e d i n an i n c r e a s e d incidence o f a b o r t i o n and premature births.

7 ) I n men, occupational exposure (13-26 ppm) produced asthenospermia. teratospermia, decreased l i b i d o and impotence ( r e f .

47. Table p. 165). The 1979 s u b f i l e of RTECS* lists CS2 as a t e r a t o g e n .

4.6

The Chloroethanes There are n i n e p o s s i b l e chloroethanes ( F i g . 4 ) o f which t h e d i - .

tri- and t e t r a c h l o r o e t h a n e s e x i s t i n two isomeric forms. Monochloroethane is a gas a t room temperature, t h e d i - t o p e n t a c h l o r i n a t e d ethanes are l i q u i d s . and hexachloroethane, a s o l i d t h a t sublimes a t 1 8 7 ' ~ . Like t h e halomethanes. t h e chloroethanes a r e *RTECS:

R e g i s t r y of Toxic E f f e c t s o f Chemical Substances (NIOSH).

372 excellent solvents and degreasing agents. They are also used as fumigants, cutting fluids, and as feedstocks in the manufacture of other chemicals, plastics and textiles (ref. 51). Of the nine chloroethanes, the 1.2-dichloride (EDC) poses the highest human exposure risk, by virtue of its high production volume (ref. 54). Most of the EDC produced provides the feedstock for vinyl chloride monomer (VC). Dispersive uses and estimated environmental releases of EDC are shown in Fig. 5. Table 14 gives the estimated 1977 consumption pattern and growth projections through 1982. All of the chloroethanes produce physiologic symptoms characteristics of chloro-organics and lipid solvents: CNS depression (intoxication), abnormal weakness, restlessness and irregular respiration, incoordination and unconsciousness. Chloroethanes are generally irritating to skin and eyes and damaging to the kidneys and/or liver. Table 15 summarizes the reported adverse effects (ref. 51). Four of the chloroethanes were carcinogenic in rats and mice under experimental conditions (Weisburger. ref. 44: see also ref. 51). They are: 1,2-dichloro- (ref. 29d), l,l,2-trichloro- and hexachloroethane. Carcinogenicity test results for the 1.1,ltrichloroethane and 1,l-dichloroethane were ambiguous and to be repeated. Some of the chloroethanes and their metabolites have also been reported mutagenic in bacterial systems (refs. 51 and 55). Elovaara et al. found a clear dose-response relationship both in survival time and fetal malformation when fertilized chicken eggs were injected with 1,l.l-trichloroethane (25 pmol/egg; days 3 or 6) (ref. 52)* Earlier inhalation experiments on rodents were negative. Female rats exposed to methylchloroform during pregnancy produced offspring of reduced weight, but otherwise normal. However, if dams were also exposed prior to mating, increased incidence of skeletal and soft tissue variations were observed in the fetuses. In the rat, ethylene dichloride (EDC) has been reported to cross the placental barrier, accumulate in the placental and fetal tissues and cause abnormal fetal development (ref. 29c). The 1,l-isomer is listed as a teratogen and suspect carcinogen in the 1979 update of RTECS (ref. 53).

4.7 Selected Pesticide-Related Chemicals The compounds discussed in the following section are either

373

components in pesticide formulations, feedstocks in pesticide syntheses, propellants, o r have some limited use as a pesticide. All have other important uses as well, e.g., as starting materials in the manufacture of pharmaceuticals, plastics, etc.. Hence they pose appreciable exposure risks in the workplace, and often to the public at large, through the use of commercial preparations. 4.7.1 The Vinyl Halides (haloethenes or haloalkenes) Vinyl bromide (VB) and chloride (VC), I (X = B r or Cl), vinylidine chloride (VDC, II), trichloroethylene (TCE. 111) and tetrachloroethylene (IV) are the haloalkenes of greatest commercial importance:

H H H-k= C-X I

1;1

CI

H-C= II

I H

k-ci cl-8=bcl 111

CI-~!=~!CI IV

Discovery of the carcinogenicity of VC presents a classic example of serendipity (ref. 22). In 1970 Dr. P.L. Viola of the Regina Elena Institute of Cancer Research (Rome) found tumors of the skin, lung and bones while investigating acroosteolysis in rats (ref. 57). The latter study was undertaken because of a problem of hand bone loss encountered among meat packagers using heat-sealing techniques on PVC wrap. Viola's finding alerted the international industrial community and led to a meeting (Washington, D.C.. Nov. 18. 1971) of representatives from the U.S.. Canada, and European firms. It was here that Solvay et Cie reported further studies by Professor Cesare Maltoni (Instituto di Oncologia, Bologna) demonstrating angiosarcoma in rats. By 1974 Goodrich Chemical had reported four deaths from angiosarcoma of the liver within 5 years, 16 identified cases among VC workers had been found in the US, and 26 world-wide. Angiosarcoma is a sufficiently rar(? cancer that only about one hundred cases had been reported altogether up to that time. Such a lack of ambiguity is rare indeed, and is a strong argument for minimizing exposure to all industrial chemicals, given our limited information on the health effects of most of them. Vinyl chloride is mutagenic in Salmonella Typhfmurfm and

Escherichfa colt (ref. 58, p . 3 ) ; also in the yeast mutation assay, the Drosophfta recessive lethal test and in the host-mediated assay

314 (loc. c i t . ) According t o Bartsch et a l . and Simmons, VB a l s o induced mutations i n Salmonella ( r e f . 58, p. 3). Vinylidene dichloride induced mutations i n Salmonella T. and

Escherichia c . (loc. c i t ) . Inhalation exposure studies on VC. VB and VDC showed t h a t a l l three compounds produced angiosarcoma of the l i v e r . Other reported adverse health e f f e c t s of vinyl halides include CNS and cardiovascular; respiratory, skin, s k e l e t a l , and l i v e r or spleen abnormalities. Cytogenetic s t u d i e s have demonstrated a s i g n i f i c a n t increase i n the frequency of chromosomal aberrations i n t h e lymphocytes of workers exposed t o VC (ref. 58).

Further evidence f o r the mutagenicity of VC

was gleaned from s t u d i e s showing increased f e t a l l o s s among wives of male workers a f t e r exposure t o VC ( r e f s . 59a.b). Also reported: retarded f e t a l growth, bleeding during pregnancy, premature and prolonged rupture of amniotic membranes, abruptto placentae and

placentae p r e v f a , f e t a l and neonatal deaths, increased incidence of S.1.D..

syndrome, and long-term l a g i n physical growth of children

with possible behavioral cognitive defects. 4.7.2 Trichloroethylene (TCE) is a powerful solvent f o r f a t s , greases and waxes and one of the most important solvents f o r degreasing and dry cleaning operations.

It is a colorless, v o l a t i l e l i q u i d (b.p.

87'c) of high density (4.45), insoluble i n water but miscible with organic solvents (EtOH. CHC13. Et20). volatile oils.

It dissolves most fixed and

More than 90% of the TCE produced is used i n

degreasing and dry cleaning, but i t is a l s o an ingredient i n lacquers and varnishes, adhesives, paints and p r i n t i n g inks.

Minor quantities

of TCE go t o i n t o t h e production of pesticides, chemicals and miscellaneous commercial products. A pharmaceutical grade of TCE was formerly used i n surgical and

o b s t e t r i c procedures a s a d i s i n f e c t a n t , and as an analgesic i n the treatment of trigeminal neuralgia ( r e f . 62a).

It has a l s o been used

as an analgesic during dental extractions and f o r a v a r i e t y of minor surgical procedures ( r e f . 62b).

TCE has been used t o e x t r a c t caffeine

i n t h e preparation of decaffeinated coffee.

The predominant physiological response to W E is one of CNS *S.I.D.-Sudden Infant Death.

375

depression. Confusion, fatigue, nausea and visual disturbances may also occur. In industrial operations incoordination may pose a safety hazard. Repeated immersion of the hands into the solvent caused finger paralysis (NIOSH CIB #2, p. 2). TCE is absorbed by intact skin and readily absorbed from the GI tract. In the latter case it can lead to respiratory failure, cardiac arrest, and death. Anesthetic doses of TCE cause tachycardia, bradycardia and tachypnea. and cardiac arrhythmias are common. The inhalation of moderate concentrations of TCE induces a state of euphoria and may lead to addiction (ref. 63a). In pregnant women, the inhalation of TCE results in its rapid diffusion across the placenta (ref. 63b). Human carcinogenicity data on TCE are conflicting (ref. 35, p. 298). An excess of cervical, lung and skin cancers, and a slight excess of leukemia and liver cancers in 330 laundry and dry cleaning employees was reported by Blair et al. (1979;ref. 64a). However, a study by Tola and coworkers (1980)found no increase in cancer mortality among 2117 exposed workers (ref. 64b). Weisburger (ref.

44)

reported an increase in hepatocellular carcinomas in mice but not in rats. The most consistent and predominant epidemiologic findings in studies of TCE and miscellaneous anesthetic exposures were an increase in spontaneous abortions and in congenital malformations among the children of exposed females and males (ref. 65a. p. 29). Since TCE readily crosses the placental barrier, it may be responsible for respiratory problems encountered in newborn infants. When used as an anesthetic, TCE reduced uterine motility. Increased maternal and fetal mortality were associated with its use as an analgesic (ref. 35, p. 299). 4.7.2.1 Metabolism of TCE The biotransformation of TCE in humans is carried out by the liver microsomal enzymes, hence requires NADPH and oxygen. Oxidation products found were chloral hydrate, trichloroacetic acid and trichloroethanol. The acid is excreted unchanged in the urine: the ethanol is first converted to the glucuronate (ref. 65a).

4.7.3 Tetrachloroethylene (Perchlorethylene,PCE) Tetrachloroethylene is a volatile liquid whose odor is detectable at ca. 50 ppm. It is an excellent solvent, and is widely used in dry

376

cleaning. degreasing. and fabric finishing, etc. In 1978 NIOSH (ref. 66a) estimated that approximately 500,000 workers in the U.S. were at risk of exposure to PCE, and that production of PCE was about 700 million pounds. Because of its excellent cleaning and recycling properties and low flammability, PCE is used by 75% of the dry cleaners. About 15% of the domestic consumption of PCE occurs in metal cleaning processes when cold cleaning and degreasing can result in high worker exposure. Tetrachloroethylene is also an intermediate in the synthesis of the trichlorotrifluoro-, dichlorotetrafluoro-and chloropentafluoroethanes (fluorocarbons, 113, 114, and 115, resp. ) PCE has been demonstrated to be carcinogenic in mice, both male

.

and female, producing a significant increase in hepatocellular carcinoma over the controls (ref. 66a.b). Rat experiments were ambiguous due to early mortalities. However, a high incidence of kidney damage was observed in both species. Inhalation of PCE is followed by prolonged urinary excretion of metabolites, primarily TCA. At more than 10 mg/l of urinary TCA. workers may show some signs of toxicity. The finding of both di- and trichloroacetic acids in human urine following exposure to PCE has led to the suggestion of an oxirane as the metabolic intermediate (ref, 67b). A variety of pathological changes of the liver occur with

repeated exposures of rats, rabbits,guinea pigs and dogs to PCE. Hepatotoxicity is increased in rats pretreated with aroclor or phenobarbital. This observation as well as the urinary excretion of chlorinated metabolites points to the liver as a probable oxidation site (ref. 67). In man, acute intoxication has generally resulted from industrial degreasing operations. 4.7.3.1 Reproductive Effects Hepatonephritis and pulmonary edema were reported as causes of fetal death. The presence of PCE in breast milk was the cited reason for obstructive jaundice in a 6-week old infant (ref. 35, p. 303). A study by Schwetz et al. (ref. 68) indicates that PCE may be teratogenic. Delayed skull-bone ossification and split sternbrae were observed in mice, as well as increased fetal resorption, decreased fetal body weight and fetal subcutaneous edema.

5. MISCELLANEOUS INSECTICIDES: FUMIQANTS

Fumigants are insecticides that may be applied as solids, liquids or gases. Of the 18 chemicals listed in Table 16. nine have been discussed in the preceding sections dealing with alkyl and alkenyl halides. p-Dichlorobenzene is an arylhalide and is discussed in the section dealing with DDT-related and haloaromatic pesticides. is a condensed aromatic compound obtained 5.1 Naphthalene (Cl&) from coal tar. It has a relatively low melting point (80.2'C; b.p. 217.9"), sublimes readily on warming, and exerts sufficient vapor pressure at room temperature to be readily detectable by its characteristic odor. It is a chemical intermediate o r feedstock in the synthesis of a large number of derivatives (e.g., phthalic, anthranilic, hydroxy-. amino- and sulfonyl-), compounds used in the production of the coal tar dyes. Naphthalene's use as a fumigant was largely confined to that of moth repellency (ref. 69). Its main route of entry is by inhalation of the dust o r vapor. It is also a primary irritant and causes erythema, contact dermatitis and allergic dermatitis in sensitized individuals. Direct eye contact may lead to cataracts. Repeated inhalation o r ingestion can result in serious systemic sequelae (CNS, blood, kidneys), many of the symptoms mimicking those reported for organic solvents, haloalkenes and other petrochemicals. A chronic toxicology/carcinogenicity study of naphthalene was still underway at

the end of FY 1984 (ref. 70).* 5.2

Acrylonitrile (vinyl cyanide, CHz=CH-C=N;AN) Acrylonitrile resembles VC, a carcinogen, in structure. It is a

flammable, explosive liquid (b.p. 77'C. V.P. 80 mm at 20'C). AN is a component of acrylic and modacrylic fibers produced by copolymerization with other monomers, e.g., with methyl acrylate, Memethacrylate, vinyl acetate, VC and VDC. Other major uses of AN include copolymerizations with butadiene and styrene to produce ABS polymers, and with styrene to yield SAN resins which are used in the manufacture of plastics. Nitrile elastomers and latexes are also made with AN, as are a number of other chemicals, e.g. acrylamide and adiponitrile. Acrylonitrile is also used as a fumigant. In 1977 NIOSH was informed by duPont of excess lung and colon cancers associated with occupational exposure to AN. A rat study *The study had not been completed by the end of FY/85 (ref. l72a, p.101).

378 (ingestion) by the Manufacturing Chemists' Association (MCA) confirmed these findings, showing t h a t the animals developed stomach papillomas, CNS tumors and zymbal gland carcinoma not present i n controls. Inhalation studies on r a t s by MCA showed similar r e s u l t s (ref. 71, p.

3). with increased ear canal tumors and mammary masses. Toxic e f f e c t s of AN resemble those produced by cyanide poisoning. The e f f e c t s of AN inhalation include CNS, kidney, l i v e r and lung damage, and embryotoxicity. Murray. Schwetz et al. ( r e f . 72) exposed pregnant Sprague-Dawley

rats t o AN by ingestion and inhalation from days 6 t o 15 (0,10, 25 and 65 mg/kg/day) A t t h e highest ( o r a l ) l e v e l embryotoxic e f f e c t s included an increased incidence of f e t a l malformations, e.g., missing

.

vertebrae, right-sided a o r t i c arch and shortened t a i l and trunk.

At

25 mg/kg (by gavage) o r at 80 ppm of AN by inhalation, the magnitude of these e f f e c t s was reduced.

Oral doses of lO/mg/kg/day or

inhalation exposure of 40 ppm produced neither embryotoxic or teratogenic e f f e c t s . Mutagenesis/genetic t o x i c i t y studies of AN were scheduled t o be i n i t i a t e d i n FY 85 (NIEHS, r e f . 70. p . 40).

5.3 Dioxane ( l , b d i o x a n e , 1 , b d i e t h y l e n e oxide; c4H802) Dioxane i s a symmetrical cyclic diether (mol w t 88.10, b.p.

H$iiH H

H

0 1,4-Dioxane

750 mm; d=l.03372{). It is a water-miscible colorless l i q u i d a t room temperature, with an appreciable vapor pressure (40mm @25.2'C)

lOl'C,

and a penchant f o r forming explosive peroxides--a c h a r a c t e r i s t i c of oxygen ethers on storage.

Its primary use is t h a t of solvent f o r a

large number of i n d u s t r i a l products, e.g. c e l l u l o s e a c e t a t e , dyes, f a t s , greases and waxes; paints, lacquers and varnishes, e t c . Specific applications include:

use as a wetting and dispersing agent

i n t e x t i l e processing, a paint and varnish s t r i p p i n g agent, i n dye baths, s t a i n and printing composition, and i n the preparation of

379 histologic slides. Is has also been used as a fumigant (ref. 69, p.

461). The main route of entry of dioxane is either through inhalation or percutaneous absorption. The liquid and vapor are somewhat irritating to eyes, nose and throat. Exposure to the vapor causes drowsiness, dizziness, headache, loss of appetite, nausea and vomiting, gastrointestinal pain, liver and kidney damage and death (ref. 73). Severe drying and cracking of the skin results from prolonged exposure to the solvent. There is sufficient evidence for the carcinogenicity of 1.4dioxane in experimental animals (refs. 74a.b) (See also ref. l09ff). to

73, pp.

In humans the data are less clear but an unpublished report

NIOSH of four cancer deaths i n one dioxane unit is suggestive.

(ref. 73, P. 115) Franceschini studied the effect of dioxane on the growth of chick embryo tibia1 buds. He found hypertrophic and vacuolized chondroblasts in diaphysis and a reappearance of mitosis in metaphysis of the tibia. Another study by Schwetz et al. showed a few terata in rats and mice when about 3.5% of dioxane was added to 1.1,ltrichloroethane. The results are ambiguous in the latter case and of questionable relevance to humans in the former (chick) study (ref. 73. p. 117). Dioxane is one of the industrial chemicals for which teratogenicity data have been evaluated (ref. 80, pp. 283-286; ref.

75). It was scheduled for genetic toxicity and biochemical studies in FY 1985 by NIEHS and FDA, reap. (ref. 70, p. 49 and 51 of the Toxicology Testing Section).

5.4 Ethylene Oxide (1.2-epoxyethane. oxirane, C2H4O) Ethylene oxide is listed among the 25 chemicals of highest production volume in the U.S.. whose production capacity is estimated at 6.1 billion lb/yr. This is about 43% of world production capacity (refs. 76a, b). At room temperature and atmospheric pressure ethylene oxide (ETO) is a colorless gas. Is has a characteristic odor, generally described at ether-like, whose detection threshold varies widely in humans. The mean detection threshold is estimated at 700 ppm (1260 mg/m3). It is miscible with water, alcohol, ether and most other organic solvents. ETO is chemically reactive and potentially explosive when heated o r exposed to active catalysts or to alkali metal hydroxides. When diluted with C02 o r halocarbons. or in aqueous solutions, it is

380

r e l a t i v e l y stable.

Hence, when w e d as a s t e r i l a n t or fumigant, it is

often d i l u t e d to reduce explosion hazard, e.g., 1O%A Rl'O/gO% CO2 or 12% EM/88$ halocarbon. E3O's majob use is aa s t a r t i n g material f o r ethylene glycol (antifreeze) production, and as an intermediate f o r polyester b o t t l e s , f i b e r s and films.

Secondarily

finds use i n production of non-

i o n i c surface active agents f o r industry and formulation of heavy duty home laundry/dishwashing agents. Qlycol e t h e r solvents f o r surface coatings, and ethanol amines (soaps, detergents, t e x t i l e chemicals) c o n s t i t u t e the 3rd and 4th l a r g e s t uses of EM. used i n a v a r i e t y of ways:

The remaining EM is

as a p e s t i c i d e (fumigant) and

antimicrobial s t e r i l a n t ; i n medical products manufacture; i n research laboratories, l i b r a r i e s and museums; i n beekeeping and fumigation of seasonings, spices and black walnut meats; as

4

s t e r i l a n t i n cosmetics

and packaged dairy products; i n animal and p l a n t quarantine services

a t p o r t s of entry: i n the fumigation of transportation vehicles, e.g., a i r c r a f t , buses and railroad c a r s , and of clothing, f u r s and furniture.

For the i n d u s t r i a l worker t h e g r e a t e s t r i s k of exposure is during loading and unloading of tanks f o r shipping, product sampling, and equipment maintenance, as ETO chemical reactions a r e generally carried out i n sealed vessels, often located out of doors i n recognition of

its explosion p o t e n t i a l through peroxide formation. Occupational exposure p o t e n t i a l bears an inverse relationship t o the amount of EM used i n one's work. Thus, health care and medical i n d u s t r i e s consume less than 1/4%(0.25%)of annual EM production, with s t e r i l i z a t i o n of hospital equipment accounting f o r less than 0.1 of t h e latter amount, e.g., 0.02% of production. Yet approximately 75000 health care workers i n s t e r i l i z a t i o n areas are a t risk. and improper engineering and/or administrative controls were found t o account for another estimated 25000 workers unnecessarily exposed t o

ETO

.

Based largely on an industry-sponsored study showing t h a t EM is carcinogenic t o animals, NIOSH recommends t h a t it be t r e a t e d as a p o t e n t i a l occupational carcinogen.

The study showed dose-related

increased leukemia i n female rats and treatment-related (33 and 100 ppm) peritoneal mesotheliomas i n male rats ( r e f . 77a). Limited epidemiologic investigation a t two work sites revealed excess cancer mortality i n the cohort studied ( r e f s . 77b,c).

There is widespread

381

recognition that EM is also a mutagen (ref. 78).

A mouse study showed adverse reproductive effects (ref. 79) and the potential for transplacental effects induced by EM was also indicated. When female mice were given ETO (i.v.) at daily doses of 0, 75 and 150 mg/kg during gestation periods on days 4-6,6-8. 8-10, 10-12. there was significant reduction of mean body weight (dam) at the highest dose compared with controls (except for d. 6-8). and a significant increase in malformed fetuses/litter for the highest dose administered during the second and fourth periods. Approximately 19% of fetuses/litter with no signs of toxicity had some kind of malformation, chiefly in the cervical and thoracic skeletal regions. Although the dams showed no toxicity at highest dose for gestation period 6-8. the high mortality for the other periods at this dose complicates the teratogenicity picture in this study. A critical summary of animal and human reproductive data on ETO appears in Barlow and Sullivan (ref. 80,p. 316-325). Relevant animal data include a) pharmacology and toxicology; b) endocrine and gonadal effects; c) fertility; d) pregnancy; e) mutagenicity, and f) carcinogenicity. While clear mutagenic effects were observed both in vivo and fn vitro. the two animal teratology studies reported were derived from abstracts, hence inconclusive. Human (workplace) studies revealed significant increases in two gynecological disorders as well as spontaneous abortions for exposed over unexposed female workers. Unfortunately, inadequate accounting for other possible factors in the workplace led the authors to conclude that the human data were also insufficient for conclusive evaluation of reproductive and teratogenic effects of EI'O (ref. 80,p. 321-324). The 1984 NTP listing for ethylene oxide indicates that a high priority reproductive toxicology study was to have been completed in FY-84 (ref. 81a). An OSHA report based on the study was circulated for external review (ref. 81b). In it OSHA recommended a long term exposure standard (1 ppm over 8 hrs) and a prudent short term limit (10 ppm). based on findings of sister chromatid exchanges and evidence for an increased incidence of spontaneous abortons among 1000 exposed female workers reported in a Finnish study (ref. 81c). Objections from the Budget Office. Union Carbide (chief US manufacturer of EM) and the Health Industry Manufacturers Association, persuaded the agency to withdraw its short term limit recommendation, despite strong support from within the agency itself and from Johnson and Johnson, based on a study of its

382

own employees (loc. cit., p. 393). Ethylene oxide is listed as a teratogen in the 1979 NIOSH subfile of RTECS (ref. 81e).

6. ORQANOPHOSPHORUS PESTICIDES AND RELATED COMPOUNDS Most organophosphorus insecticides derive from phosphoric acid, as shown in I:

' I A more gen raliz d structure (11) takes into account phosphonic cid derivatives such as Trichlorfon (111):

R' ,R"=alkyl alkox;

I1

.

0 OH 2 l-{-CC13

I11 Trichlorfon

R' and R"

are usually methyl, ethyl or the corresponding alkoxyl R may be an alphatic or cyclic moiety forming a labile bond with phosphorus (P). Table 17 lists some organophosphorus pesticides (OPPs) arranged according to the ligands attached to P. OPP Alkylation characteristics have been examined in some detail as a consequence of their biological significance. It is clear that preferential attack on the carbon of an alkyl group (R' or R" in 11) favors an alkylation reaction while the attack on phosphorus, followed by cleavage of the P-0 bond, favors a phosphorylation reaction. Unfortunately the analytical test used to detect alkylation--the Preussman reaction with 4 (4-nitrobenzyl) pyridine-does not yield conclusive in viuo evidence as to the extent of the OP-DNA alkylation reaction. Dichlorvos was the main OPP used to examine the in u t t r o alkylation of DNA. The compounds listed in Table 17 include those whose in vfvo and fn v f t r o effects on cellular systems have been studied most frequently. groups.

383

Studies are reviewed in some detail by Moutschen-Dahmen et al. (ref. 2b, sec 3.2ff). They include the following summary observations of interest: (a) eight of 17 OPPs induced sister chromatid exchange (SCE) in Chinese hamster V79 cells cultured in vivo; (b) nine of 10 OPPs tested also induced SCE in Chinese hamster ovary (CHO) cells; (c) oxygen was more effective than S in SCE induction, and (d) SCE induction appears to be a common property of OPPs. Of two types of in vivo tests carried out on mammals--chromosome damage in bone marrow or testes--only the intratesticular injection of Parathion in the guinea pig yielded strongly positive (clastogenic) effects on spermatogonia (ref. 2b, p. 157).

6.1 Uses The organophosphorus pesticides are used primarily as insecticides and acaricides. Some of the OPPs of commercial importance are listed in Table 18 and in Table 24 at the end of this chapter. More detailed information (LD50s, etc.) may be obtained from references listed in the introduction, e.g., the Pesticide Index (ref. 14) and the Agrochemicals Handbook (ref. 15). The annual Pesticide Use Report(s) of the State of California list current agricultural and environmental usage of all classes of pesticides both as to commodities treated and the names and quantities of pesticides applied (ref. 165). 6.2 Toxicoloav Organphosphorus compounds are hydrolytically unstable:

-

OP compound phosphoric acid diester -. monoester [ + alcohol, thiol. or phenol, etc.] [ + ROH/RSH]

-

phosphoric acid.

Hence OP pesticides are much less environmentally persistant than are the organochlorines. However their chemical reactivity frequently renders them more acutely toxic than the organochlorine pesticides. Organophosphates are characterized by their similar mechanism of toxic action in insects and mammals, resulting in the irreversible inhibition of the enzyme cholinesterase, and the accumulation of acetylcholine at nerve endings (synapses). The primary mechanism is phosphorylation of the enzyme critical to normal transmission of nerve impulses from fibers to innervated tissues. A critical fraction of tissue enzyme must be inactivated before the symptoms of toxicity appear. At sufficient dose, the loss of enzyme function results in

384 the accumulation of acetylcholine at cholinergic neuroeffector junctions (muscarinic effects), at skeletal myoneuraljunctions and in autonomic ganglia (nicotinic effects). Organophosphates also impair nerve impulse transmission in the brain, disturbing behavioral, motor, respiratory and sensor functions. The usual cause of death in OPP intoxication is depression of respiration. The recovery from OPP poisoning depends on the generation of new enzyme (Morgan, ref. 20). OPPs are readily absorbed by all routes: inhalation, ingestion, skin penetration, eyes--and even more readily absorbed where cuts, abrasions and/or dermatitis are present. (Straub, ref, 69, Pesticides chapter). The toxicity of a particular OPP will depend on the rate at which it is metabolized t n vivo, principally by hydrolysis in the liver, as this limits its availability for attack in other tissues. Many OPPs undergo ready in vtvo conversion from thions to oxons (P=S-P=O). The P-S-+P=Oconversion occurs environmentally in the presence of sunlight. Physiologically it is driven primarily by the liver microsomes. The end products of hydrolysis at the ester linkage are alkyl phosphates and phenols, readily excreted and of relatively low toxicity. Depending a n the specific organophosphate, some phosphorylated enzyme nay be reactivated ("dephosphorylated") by certain oxime antidotes from one to two days after OP absorption. Thereafter a change in the nature of the enzyme-phosphoryl bond occurs, rendering the inactivation irreversible and necessitating the generation of new enzyme. A less frequent kind of neurotoxicity produced by OPPs is characterized by damage to the myelin substance of peripheral nerves, and leads to prolonged peripheral neuropathy with numbness, pain and weakness in the extremities persisting for months or years (delayed neurotoxicity). The OPPs associated with this kind of chronic illness include some with low acute toxic potential. There is no apparent correlation between acute toxicity and the potential for a chronic neurophathy. The phenylphosphonothioates cyanofenphos, EPN, leptophos and EPBP are neurotoxic agents in this category. Others known to induce delayed neurotoxicity include Cerbophenthion, DMPA, Haloxon, Merphos, Mipafox, M C P and Trichlorfon. Organophosphorus compounds known to induce delayed neurotoxicity are listed in Table 19. All but TOCP are used as insecticides and acaricides. The tri-o-cresyl phosphate is used as a plasticizer in wood lacquers. The delayed

386

neurotoxicity or paralysis induced by these substances is not the result of cholinesterase inhibition but stems from inhibition of yet another enzyme linked to neural function (ref. 164, p. 7 3 7 ) . Unusual properties of some OPPs render them more hazardous than suggested by their toxicity data. Thus. malathion on long storage can produce by-products that greatly inhibit the enzymes essential to this compound's catabolism, magnifying its toxicity. Also, some OPPs have a strong affinity for lipid tissue, where their storage prolongs antidote requirement as the stored OPP is released. The possibility that other factors modify the toxicities of OPPs cannot be ruled out, as

synergistic interactions between substances are well known. Dose and dose intervals of OPP ingestion will both affect the

time of initial onset of toxic symptoms. A delay of 12 hours after termination of exposure without symptoms implies that a toxicant other than an OP may be involved (and/or that appropriate precautions have been taken to avoid continued exposure from contaminated hair, clothing, shoes, etc.). It should be noted that both plasma and red blood cell (RBC) cholinesterase activity may be low from other causes--e.g.. liver o r other disease(s). However the cholinesterase inhibition induced by

OPP poisoning is

so much greater that plasma o r RBC cholinesterase activity remains a reliable test for OPP exposure (ref. 164. p. 736).

6.3 Frequent Symptoms Associated with OPP Poisoning Early symptoms of acute OPP poisoning are usually apparent during exposure or within 4 to 12 hours. They may include headache, fatigue, vertigo. incoordination, blurred vision, weakness, tremors, abdominal cramps, diarrhea, nausea and vomiting, salivation and excessive sweating. These are also symptomatic of many unrelated illnesses--e.g., gastroenteritis, influenza, heat stroke or heat exhaustion. They are considered indicative of mild OPP intoxicaton. Moderately severe OPP poisoning may include all of the above symptoms plus chest discomfort (tightness, wheezing), a productive cough, pulmonary edema, a marked constriction of the pupils (miosis) muscular twitching, and the inability to walk. These symptoms could be mistaken for encephalitis, myocardial infarction and pneumonia. Severe OP-poisoning is evidenced by the rapid onset of unconsciousness, local or generalized seizures, incontinence and other manifestations of a cholinergic crisis. Further indications of severe intoxication may include a slow heartbeat, tearing, toxic psychosis

386

with manic o r b i z a r r e behavior (misdiagnosed as alcoholism) and r e s p i r a t o r y depression, which may be f a t a l .

Slow h e a r t b e a t may

( r a r e l y ) p r o g r e s s to complete s i n u s arrest. The d i a g n o s t i c test f o r a n t i c h o l i n e s t e r a s e poisoning is a t r o p i n e refractoriness.

I n t h e absence of OPP poisoning t h e e a r l y signs of

a t r o p i n e t o x i c i t y develop r a p i d l y (dry mouth, d i l a t e d p u p i l s , f l u s h i n g , and increased h e a r t r a t e ) .

There are a l s o a number of

simple b u t crude "Acholest" screening tests a v a i l a b l e f o r r a p i d c l i n i c a l t e s t i n g , but more p r e c i s e and r e l i a b l e r e s u l t s are obtained by plasma and RBC c h o l e s t e r a s e determinations. Standard treatment f o r OPP poisoning is i . v . i n j e c t i o n with a t r o p i n e s u l f a t e t o p r o t e c t t h e muscarinic end-organs from t h e accumulation of excessive a c e t y l choline c o n c e n t r a t i o n s .

Diagnostic

t e s t i n g , o r treatment with a t r o p i n e must be used c a u t i o u s l y i n p a t i e n t s with glaucoma, i n view of t h e r i s k of increased i n t r a o c u l a r p r e s s u r e from t h e drug. Treatment f o r Parathion poisoning has been improved by t h e a v a i l a b i l i t y of t h e oxime 2-PAM (2-pyridine aldoxime methiodide) ( r e f .

69, P., 455). As i n s e c t r e s i s t a n c e t o t h e organochlorine d e r i v a t i v e s ( e , g . , chlordane, d i e l d r i n , DDT) have increased with time, t h e use of

organophosphorus compounds h a s e s c a l a t e d .

They have t h e advantage of

less p e r s i s t a n c e i n t h e environment and do n o t p r e s e n t t h e obvious ( d e t e c t a b l e ) problem of body burden of t h e organochlorines. Unfortunately t h e OPPs are "responsible f o r more deaths than any o t h e r group o f compoundsn, with Parathion c i t e d as t h e OPP to which most of t h e s e f a t a l i t i e s may be a t t r i b u t e d (M. Moses, r e f . 164, p. 736). Documentation f o r f a t a l i t i e s and permanent nerve damage goes back t o 1930, when some 15000 TOCP poisonings occurred i n t h e U.S. from i n g e s t i o n of an a l c o h o l i c d r i n k known as Jamaica Ginger, o r "jake", a d u l t e r a t e d with about 2% of t r i - o - c r e s y l phosphate.

Those a f f e c t e d

developed a progressive p o l y n e u r i t i s i n many i n s t a n c e s with u l t i m a t e p e r i p h e r a l motor nerve, a n t e r i o r horn c e l l and pyramidal t r a c t degeneration.

There have been s e v e r a l outbreaks s i n c e then, one of

t h e most s e r i o u s occurring i n Morocco (1958) where s e v e r a l thousand consumers of a TOCP-adulterated e d i b l e oil were poisoned, many of them

l e f t with permanent p a r a l y s i s .

The e d i b l e o l i v e oil had been

d e l i b e r a t e l y mixed by purveyors with a TOCP-containing l u b r i c a t i n g o i l t o extend t h e much more remunerative e d i b l e product (Sax, r e f .

99, p .

387

1184).

Clinical symptoms from TOCP intoxication were similar: first

symptoms occurred about 1 to 3 weeks following ingestion of the poison usual1.y with calf pain. This progressed within days to weakness, followed by ataxia and distal paralysis. Proximal paralysis and sometimes hand and forearm muscle involvement, occurred in more severe cases. Delayed neurotoxicity from an OPP was first reported in 1953. Two chemists investigating the insecticidal properties of Mipafox developed weakness and unsteady gait about two to three weeks after their recovery from an acute poisoning episode. This progressed to bilateral foot drop in one victim, who ultimately did recover. The other was less fortunate, progressing to a persistent and flaccid paralysis of his lower extremities, with no improvement after two years (ref. 167).

6.4 Reproductive Effects and Teratonenicity Reports of teratogenicity of organophosphorus pesticides on avian embryos are numerous and will be only briefly summarized here. For detailed references to the following reports see the citations at the end of chapter 3 in ref. 2b. Compounds tested with positive results on chick embryos include Azodrin (Schom et al. 1979). Bidrin (Roger et al. 1969). Diazinon (Khera, 1966; Ceausescu et al.. 1978; Eto et al., 1980); Dichlorvos (Khera, 1966; Upshall et al. 1968; Roger et al.. 1969); Dicrotophos. (Eto et al. 1980), Ethylpirimiphos (Eto et al., 1980); Ethylparathion (Khera, 1966; Upshall et al. 1968; Roger et al. 1969; Reis et al. 1971; Yamada 1972; Meiniel 1973); Fenitrothion (Paul and Vadlamudi. 1976); Methylazinphos (Upshall et al. 1968; Roger et al. 1969); Methylpirimphos (Eto. et al. 1980): Malathion (Greenberg and LaHam, 1969; Walker, 1971); Phosdrin (Roger et al. 1969). Teratogenicity tests were also positive on duck embryos with Diazinon, Dichlorvos and Ethylparathion (Khera, 1966); on quail treated with Azodrin (Schom et al. 1979); Bidrin (Meiniel, 1976), and Ethyl parathion (Meiniel, 1973); also on partridge with Azodrin (Schom et al. 1979). and Ethylazinphos (Lutz and Lutz-Ostertag, 1971). A few negative results were reported: Malathion-chicks (Upshall et al. 1968; Roger et al. 1969), quail (Meiniel, 1977). Mevinphoschicks (Upshall et al. 1968); Salithion-chicks (Eto et al. 1980). Teratogenic studies of OPPs on fish were also positive on the following species: Serfola quinqueradfata (Fenitrothion and Trichlorfon); medaka fish (Malathion and Ethylparathion), and

388 k i l l i f i s h (Ethylparathion).

T e s t r e s u l t s on k i l l i f i s h with malathion

were negative. Teratogenicity tests with Dichlorvos on mammals (mice, rats) were negative.

Similarly male and female pigs withstood longterm exposure

t o dichlorvos without. v i s i b l e e f f e c t s on offspring. A multigeneration study with r a t s fed 30,100 or 300 ppm

Chlorfenvinphos (Ambrose et al

. 1980) observed dose-related decreases

i n l i t t e r s i z e , but no gross abnormalities i n fetuses born dead or alive. Methylparathion administered (ip) on the 10th day p.c. gave negative r e s u l t s at 20 mg/kg, but induced an increased number of c l e f t palates a t 60 mg/kg (Tanimura et el. 1967). Ethylparathion appeared t o be more embryotoxic than teratogenic i n mice, where a single ( i . p . ) dose (12mg/kg) on the 8th. 9th or 10th day p.c. produced 27% of in u t e r o f e t a l deaths. given on days 12, 13 or

I f injections were

14 P.c.. mortality increased t o 90%.

Pregnant r a t s showed embryotoxic and teratogenic resistance t o Diazinon, whereas Beagles showed a high incidence of s t i l l b i r t h s a t 1, 2. or 5mg/kg/day administered per 0s. Mice injected with Fenthion i n a single dose (40 or 60mg/kg on days

7 t o 12 P.c.) produced an increased number of malformed fetuses

and f e t a l weight was reduced. Dimethoate was not teratogenic i n mice or rats.

Cats produced an

increased number of polydactyls when fed 12 mg/kg/day dimethoate. Trichlorfon given by gavage t o the golden hamster a t 400mg/kg ( 3 times/day 7 t o 11 P.c.) induced teratogenic e f f e c t s not observed a t

Wistar rats given a single o r a l dose (80mg/kg) on day 9 or 13 p.c. exhibited both embryotoxic and teratogenic e f f e c t s not lower doses.

observed on a low dose regimen (8mg/kg/day) throughout the gestation period (Martson and Voronina, 1976).

Pregnant rats receiving low

inhalation dose of trichlorfon throughout pregnancy produced offspring with s k e l e t a l defects.

A t higher doses (0.2 and 9mg/m3) placental

changes were observed (Qofmekler and Tabakova, 1970).

A single

teratogenic study with Ruelene on pregnant cows did not produce any f e t a l anomalies (Rumsey e t al.. 1974, r e f . 169).

6.5 Reoroductive Effects and Teratorrenicitv of OPPs i n Humans Gordon e t al. (1981) examined the correlation between f i r s t trimester f e t a l exposure in utaro t o agricultural chemicals during t h e i r peak use periods and the incidence of c l e f t l i p or palate.

The

389 correlation was found to be stronger for insecticides and/or herbicides than for all other agricultural chemicals combined. The evidence, while not conclusive, was viewed as an indication that further research was needed (ref. 170).

Deichman (1970) quoted

Adebahr's report (1966) of the adverse effects of Parathion on the ovaries of women examined post mortem following acute intoxication (ref. 116.p. 23). In 1974 Nakazawa (loc cit) reported more than 50 cases of infertility and/or menstrual disturbances among female applicators of large quantities of OPPs. Also women who lived and/or worked in those fruit growing areas experienced earlier menopause than did women from areas not applying OPPs to their fields.

Data were adjudged inadequate in the summary available to Zielhuis et al. Il'na (1978) examined 306 women aged 18-40 for reproductive effects of pesticide exposure, including OPPs, in the presence of cyclic organochlorine pesticides. Depending on the nature of the combination, effects on menstrual cycles in the exposed group were from 10 to 30 percent, while control's cycles varied between 2 to 6 percent (P <.001). The exposed cohort also exhibited other functional irregularities--e.g. liver and nervous system function and bile production. In an earlier study (1977) Il'na had observed an increased incidence of infertility, cervical erosion and salpingitis. along with menstrual disturbances in women exposed to OPPs and cyclic organochlorine pesticides (OCPs) (ref. 116. pp. 24-5).

6.6 Summary Organophosphates made their appearance during World War I1 research on nerve gases. Their insecticidal properties were soon appreciated, and they are now used in massive quantities in large scale agriculture particularly where monoculture makes comercial crops more vulnerable to insect attack. Unfortunately OPPs kill insects and humans by the s.ame mechanism of cholinesteSase inhibition. Their more polar characteristics than the organochlorines (OCs) enhance aqueous phase solubility; hence they have increased reaction rates. These characteristics have given the OPPs the dubious distinction of being the most frequent causative agents in cases of acute human toxicity and death. As yet there is little firm information on the reproductive effects of OPPs in humans beyond the studies already noted. Parathion and Phosdrin are the leading causes of severe pesticide poisoning and death among California farmworkers (ref. 171). The

390 incidence of childhood cancers and birth defects also appears to be high among farmworkers' families exposed to the pesticides. The illnesses of nine children living within a six block area of McFarland, California have been diagnosed as cancer (ref. l7la). The water supply of McFarland is reported contaminated by pesticides. presumably from surface drainage of nearby pesticide-treated fields. Ten of the 20 pesticides known to be teratogenic (Table 20) in animals are OPPs (starred). None is listed for teratologic studies in the latest published NTP Annual Plan and NTP Review of the National Toxicology Program (1986). A few, including Parathion are scheduled for neuro-behavioral, and/or pharmaco-kinetic/metabolism studies, but at relatively low (D) priority (ref. 172a,b). Tri-o-cresyl phosphate, not classified as a pesticide, is the only organophosphate for which testing and a final report were to have been completed in 1986. One of the TOCP studies under the auspices of CDC/NIOSH, and with an A completion priority, was a reproductive/developmental toxicity study. However, it is unclear from the TOCP listings (ref. 17.2~1. Table 23) whether either the reproductive study or one of the neurologic/behavioral studies for M C P w a s completed and reported in 1986. In a tentative listing of pesticides with teratogenic potential (revised 6/10/85), the California Department of Food and Agriculture included only two OPPs (Dimethoate and Metasystox R) (ref. 173). UFW has claimed that government agencies have been ineffectual in dealing with toxicity and teratoginicity issues of OPPs and pesticides in general, in response to pressure from agribusiness and chemical industry. The low testing priorities assigned to these compounds and the paucity of teratogenicity testing for this category lends some credence to the claim.

7. CARBAMATE PESTICIDES AND RELATED COMPOUNDS The carbamate pesticides are derivatives of carbamic acid and/or related thio- and dithio-acids:

Carbamic acid itself does not exist independently. The ethyl ester of

391 carbamic a c i d , u r e t h a n e , is a known mammalian carcinogen. A more g e n e r a l i z e d formulation o f t h e carbamate p e s t i c i d e is:

where R ' and R" hydrogens.

may be a l k y l groups--usually methyl, e t h y l , or

The R may be aromatic, h e t e r o c y c l i c , or r e l a t e d m o i e t i e s ;

and one or both oxygens may be replaced by s u l f u r , r e s u l t i n g i n t h i o -

or dithiocarbamate d e r i v a t i v e s .

7.1 H i s t o r y N a t u r a l l y o c c u r r i n g carbamates from t h e f r u i t of t h e African v i n e

(Physostigma venenoswn) known as t h e Calabar or Esc?re bean were used by West African n a t i v e s i n t h e i r a d m i n i s t r a t i o n o f j u s t i c e .

The

accused w e r e o f t e n spared from f a t a l poisoning by an emetic substance p r e s e n t i n t h e seed h u l l ( r e f .

174). The bean c o n t a i n s a number o f

a l k a l o i d s , physostigmine and e s e r i n e (or g e n e s e r i n e ) being t h e most important among them. I n t h e mid-19th century t h e Calabar bean w a s s e n t t o Scotland and t h e two p r i n c i p a l a l k a l o i d s were e x t r a c t e d i n a number o f European laboratories.

There t h e formulae were determined and t o x i c and

medicinal p r o p e r t i e s i n t e n s i v e l y s t u d i e d .

By t h e e a r l y 20th century

t h e formula f o r physostigmine (ClgH2102N3.1) and t h e presence o f two tertiary

N-CH3 groups were e s t a b l i s h e d .

The t h i r d n i t r o g e n was

hydrolyzed t o methylamine and carbon d i o x i d e , hence is d e r i v e d from a urethane group : CH

CH,

.

CH,

PhysosllOmlno (I)

L

6% Physoollgmol (111)

CH ,NCO

I .-

CH,

LH,

Esorollno (11)

392 Zinc dust distillation of I yielded the 1- and 2- methylindoles. The milder degradation of eseroline (11) of the ethyl ether (IV) to the Physostigmol verified the presence of the indole nucleus in the original structures. Once the medicinal properties of I and I1 were appreciated, the inevitable synthesis of carbamate analogs followed. The anticholinesterase activity of physostigmine- and eserine-related synthetics suggested their possible use as insecticides; but tests of early compounds failed, due to the quaternary ammonium barrier to penetration of the insect cuticle present in them. In 1940 Dimetan, the first lipid-soluble carbamate derivative, was synthesized. Later (1953) Sevin (Carbaryl V) was synthesized and marketed after publication (1957):

OCONH CH,

7.2

rn

Carbaryl: 1-naphthyl methylcarbamate V

Carbamate pesticides are used as (1) insecticides, (2) fungicides and (3) herbicides. Insecticides are generally derived from carbamic acid; fungicides, from thiocarbamic acid. The herbicide carbamates are a more complex class of compounds. Tables 21 and 22 list some commercial carbamate pesticides in approximate order of decreasing toxicity. It should be noted that the relative classification of 'highly' and 'moderately' toxic is no measure of the relative carcino-

, muta- or teratogenicities of these carbamates, since it is based solely on acute LD50 data (Morgan. ref. 20). The most widely used insecticides among the carbamates are Carbaryl (1-naphthyl methylcarbamate, Table 22) and Carbofuran (2.3dihydro-2.2- dimethyl-7-benzofuranyl methylcarbamate, Table 21). Because carbamates are readily obtained in pure crystalline form, their chemical and biochemical properties have been studied extensively (ref. 175).

7.3 Metabolism The carbamates exhibit relatively low toxicities in mammals because they are rapidly metabolized by them. Initially the MFOs are involved in an oxidative transformation. In the aryl methyl

393 carbamates this is generally an aryl hydroxylation reaction and the metabolites are excreted as conjugates of glucuronic acid. Carbaryl is oxidized in the mammalian liver to naphthyl N-hydroxymethyl carbamate and the bhydroxy- and 5-hydroxy- isomeric Nmethylcarbamates. followed in large part by glucuronide conjugation. The methylcarbamates metabolize to water-soluble species with the carbamate moiety undisturbed. Resistant insect species absorb less and excrete a larger fraction of the absorbed pesticide. This is attributed to thelr higher levels of oxidative enzymes dependent on NADPH. Although OPPs and carbamates exhibit very similar modes of action in various animal species, i.e. acetylcholinesterase inhibition in the CNS with resulting paralysis--there is an important difference between the two classes of pesticides. Carbamates do not require metabolic conversion prior to exhibiting their toxicity. Furthermore the enzyme activity may at times be rapidly regenerated by reversal of inhibition. The kinetics of the inhibition (carbamoylation) reaction have been well studied: in it electrophilic carbamoyl moieties form covalent bonds with enzyme esteratic sites. This is followed by carbamate transfer of an acidic group to the site to yield the acetylated enzyme complex (ref. 176)-

7.4

Toxicolonv Carbamates effect the reversible carbamylation of

acetylcholinesterase, permitting accumulation of acetylcholine at cholinergic neuroeffector junctions (muscarinic effects), at the myoneural junctions of skeletal muscle, and in the autonomic ganglia (nicotinic effects). CNS function is also impaired. However the relatively large dissociation constant of the carbamyl-enzyme complex indicates that it dissociates more readily than does the organophosphate-enzyme complex, mitigating the toxicity of the carbamate pesticides. The reversibility of the carbamyl-enzyme complex affects (limits) the utility of blood enzyme measurements as a diagnostic tool. Symptoms of carbamate intoxication develop earlier than those of OPP poisoning. Hence the exposed worker is more likely to associate his or her symptoms with the pesticide and take earlier evasive action. The antidote of choice for carbamate poisoning is atropine, as with the OPPs. However, the use of PAM is not recommended here, as it may actually prove to be deleterious in some instances (ref. 164,

394

P. 738). The fungicides Maneb and Zineb are dithiocarbamates of low acute toxicity but with troublesome contaminant and degradation problems from ethylene thiourea, a carcinogen. The neurotoxic metabolite, carbon disulfide, is another potential hazard of their use. Carbamates are most frequently absorbed by inhalation, ingestion, o r dermal penetration, and actively metabolized via the liver. Their degradation products are egcreted by both the kidneys and liver. For the few carbamate insecticides whose formulations contain methanol ("wood alcohol"), the toxicology of the latter is an important consideration. Methanol ingestion by any route can cause severe gastroentritis, acidosis, CNS damage and neuropathy. The most frequent indications of poisoning by the carbamates themselves are reported to be: abdominal pain, diarrhea, nausea, and vomiting. salivation, profuse sweating and blurred vision. Other common symptoms include: headache, dyspnea, muscle twitching and tremors, and ataxia. Temporary paralysis of the extremities has also been reported. But most illnesses attributed to the carbamates are reported to be of a shorter duration and in general to afford a more favorable prognosis for the patient than does organophosphate poisoning (ref. 20, pp. 9-10). When the intoxication is severe, respiratory depression should be anticipated, as well as pulmonary edema and convulsions. Constant exposure to carbamates at levels too low to precipitate an acute reaction may lead to anorexia, weakness and protracted malaise--symptoms resembling those of influenza (Morgan, ref. 20). While the depression of plasma and/or RBC cholinesterase may be detected after exposure to very large amounts of carbamates, enzyme activity usually recovers rapidly--within minutes to hours. Hence these tests can be misleading unless one of the rapid methods for testing cholinesterase activity has been employed. A more sensitive and specific absorption test for several of the carbamate pesticides is the measurement of their metabolites in the urine within 48 hours of exposure. Carbamate pesticides are sufficiently acutely toxic that those attending the victim must avoid contact with contaminated apparel o r vomitus, and should wear rubber gloves during decontamination of hair and skin of the victim.

7.5 Reproductive Effects and Teratoaenicity The teratogenic effect of Carbaryl was initially reported in

396 b i r d s (Khera. 1966).

Doses ranging from 10 t o 1 0 W / e g g were

teratogenic f o r both chick and duck embryos.

Eto e t a l . a l s o obtained

similar r e s u l t s f o r white Leghorn eggs i n 1980. al.

However, Tos-Luty e t

(1973) found no e f f e c t ( i n surviving embryos) i f the Carbaryl w a s

i n j e c t e d i n t o the chick egg a l l a n t o i c cavity a f t e r the 10th day of development. The observation of a high incidence of abnormalities i n Medaka f i s h by Solomon e t al. (1979)--also i n Sertota quinqueradiata by Baba

e t a l . (1975)--was noted i n the previous section on OPPs.

A number of

long-term rat s t u d i e s with Carbaryl discussed by Moutschen-Dahmen e t a l . ( r e f . 2b, pp. 182-183) gave equivocal r e s u l t s . (1972-73) fed r a t s between 2.5

-

Thus Weil e t al.

200 mg/kg/day per os, or

3

t o 100

mgfday by intubation and observed n e i t h e r embryotoxic nor teratogenic effects.

Collins e t e l . (1971) found a ( s l i g h t ) decrease i n the

l i t t e r s i z e of Osborne-Mendel s t r a i n r a t s when fed a d i e t containing 5000 ppm of Carbaryl.

were g r e a t l y decreased.

A t twice t h a t dose the f i r s t generation l i t t e r s

There were none i n the second generation.

Shtenberg e t al. (1971) oboerved enhanced numbers of s t i l l b i r t h s i n r a t s t r e a t e d with low doses of Carbaryl ( 2 t o 5 mg/kg/d.).

Golbs e t

(1975) reported only s l i g h t teratogenic e f f e c t s with Carbaryl (200 t o 350 mgfkg) when given 3 x per 0s a t various stages of f e t a l development. I n a developmental experiment (P.c. days 1-7, 5-15, 19al.

20) a t doses of 20,100 and 500 mgfkgfday Carbaryl w a s reported by Weil

e t a l . (1972) t o be neither embryotoxic nor teratogenic.

See

references 2b and 86 (Shepard) f o r c i t a t i o n s . Rao and Schwetz i n Chambers and Yarborough ( r e f . 84b) have commented on the appreciable c o n f l i c t between Soviet workers' r e s u l t s reported i n rat experiments with Carbaryl and those of Wesf;ern workers, e.g..

Collins, Guthrie. Weil and t h e i r teams.

The former

(Orlova e t al.. 1968; Rybakova, 1966; and Vashakidze. 1968) reported changes i n gonadotropins, the neuroendocrine system, and response t o estrogens i n unmated r a t s .

Also, reduced reproduction was reported i n

r a t s itubated d a i l y with Sevin (Carbaryl) a t doses of 5 t o 50 mg/kg/day over several months.

It is not c l e a r t o what extent the

differences i n observations resulted from impurity variations with confounding reproductive e f f e c t s , or the extent t o which variations i n t e s t animals and/or experimental techniques played a r o l e ( r e f . 178a). I n 1982 the World Health Organization (WHO) reviewed animal experiments carried out with Carbaryl (Sevin) focussed on reproductive

396 effects (ref. 177).

The estrow cycles of rats were affected when fed

a relatively high dose of the insecticide (100 mg/kg/day) for 90 days. The dose threshold was bracketed between 7 to 14 mg/kg/day in a 12month study. A four generation study at 5 mg/kg/day for 90 days decreased the fertilities of the 2nd and 4th generations. The excretion of cholesterinase inhibitors through breast milk was not investigated (Zielhus, ref. 116, p. 24). Carbaryl experiments with guinea pigs were inconclusive. Robens reported slight embryotoxicity with vertebral malformations at 300 mg/kg/day, p.c. days 11 to 20. Weil et al. (1973) found neither embryotoxic nor teratogenic effects by oral feeding (100, 200 and 300 mg/kg/day) , or by intubation (30, 100 and 200 mg/kg/day) P.C.. days 10 to 24. Murray et al. (1979) reported an increase in the occurrence of omphalocele in New Zealand rabbits (200 mg/kg/day) p.c. days 6 to 18. Robena (1969) had observed no embryotoxic or teratogenic effects on New Zealand rabbits in a comparable experiment. Robens (1969) found Carbaryl both embryotoxic and teratogenic in golden hamsters (250) mg/kg) P.C. day

7 or 8, but not at 125 mg/kg,

p.c. day 6, 7. or 8. Miniature swine also exhibited embryotoxicity, and with 4, 8 and 16 mg/kg/day Carbaryl a high incidence of resorptions occurred (Earl et al., 1973). Beagles fed Carbaryl in the diet at five dose levels (3.125 to 50 mg/kg/day) throughout gestation, exhibited teratogenic responses at all levels except at the lowest doses. Smalley et al. (1968) reported abdominal-thoracic fissures, brachygnathia, ecaudate pups, failed skeletal formation and extra phalanges. Dougherty et al. (1971). experimenting with a small cohort of Maccacca Mutatta monkeys, found increased abortions but no malformations with Carbaryl (2mglkglday and 20 mg/kg/day; p e r 178b).

08,

ref.

7.6 Dithiocarbamateg. The fungicidal dithiocarbamates Maneb and Zineb are the manganese and zinc salts, respectively of ethylene -1,2- bisdithiocarbamic acid:

397 In addition to the degradation, contaminant and metabolite problems (ethylene thiourea, CS2) mentioned earlier (see Toxicology), the dithiocarbamates are reported to affect the male reproductive tract in rats. When given in daily doses (20 mg/kg/d) for 5 to 6 months, testicular atrophy occurred, and both sperm motility and viability decreased (Shtenberg, et al., 1973). Chronic feeding of Zineb sterilized the rats (Korte, 1972), and administration of Zineb to rats for 30 days (100mg/kg/d.) produced pathologic testicular changes with extensive tubular degeneration (Raizada et al., 1979, ref. 178a). Makletsova (USSR, 1979) examined 162 pregnant women occupationally exposed to Zineb and found an increased r i s k of abortion, delivery complications and puerperium. Controls were 148 pregnant women.

Zielhuis (ref. 116. p. 32) found the data

inconclusive because of the absence of dose information and a relatively high incidence of pregnancy and delivery complications in the controls.

7 . 7 Disulfiram (tetraethylthiuram disulfide; bis(diethylcarbamoy1) disulfide) is a fungicide, an accelerator used in vulcanizing during the manufacture of rubber polymer, and a prescription drug (Antabuse) used as an alcohol deterrent (ref. 179):

s

s

CH3CH2, II I1 ,CH2CH3 ,N-C-S-S-C-N, CH3CH2 CH2CH3 Disulfiram VII Rats fed Disulfiram (100 mg/d.) from p.c. day 3 had 88% fetal resorption by day 13. Copper chelation is postulated as the probable mechanism of embryotoxicity (Robens, 1969, ref. 118, abstr. 397). Favre-Tissot and Delatour (1965;loc'cit.ref. 118. abstr.) reported two offspring with club feet and one spontaneous miscarriage among five women medicated with Disulfiram and tranquilizers during pregnancy. In addition to its powerful synergistic action with alcohol by the inhibition of aldehyde dehydrogenase. Disulfiram exerts an equally strong synergistic toxic effect in the presence of ethylene dibromide (EDB. ref.

179). Laboratory rats exposed to 20 ppm EDB (inhalation)

398 while fed a diet containing .05$ of the dithiuram (Disulfiram) exhibited high mortality rates and tumor incidence, including hemangiosarcomas of the liver, spleen and kidney. At the end of 13 months of a proposed 2-year study, 45 of 48 males and 47 of 48 females exposed simultaneously to EDB and Disulfiram had either died or been terminated, dying from tumors. Table 23 gives survival ratios for the rats exposed to the chemicals separately and in concert, compared with controls. The significance of the data in Table 23 for workers exposed to Disulfiram and EDB. itself a carcinogen, sterilant and teratogen with potentially serious effects on major organs--cannot be overemphasized. Similarly a worker under treatment for alcoholism with Disulfiram is at risk, at the very least, of becoming violently ill in the presence of alcohol vapors. At higher alcohol concentrations unconsciousness o r death may result. Approximately 7O.OOO workers were estimated by NIOSH to be exposed to Disulfirarn in 1978, with an additional estimated 100,000individuals on Disulfiram therapy for alcoholism. Exposure to EDB in the workplace involves a much larger number of workers because of its many industrial uses (see organochlorines section, under EDB and ref. 179). Disulfiram is listed among the chemicals selected for in vitro mutagenicity testing with mouse lymphoma cells (ref. 172, Table 6) during fiscal year 1986-eight years after publication of the NIOSH warning of the synergistic toxic interactions of this fungicide with EDB, itself a highly toxic fumigant and insecticide (CIB #37, ref. 26b). Disulfirarn was not scheduled for NTP reproductive testing in fiscal year 1986.

7.8 Ethvlenethiourea (2-mercaptoimidazoline: imidazolidine-2-thione : imidazoline-2-thiol, VIII) is a water-soluble white crystalline solid used extensively i n curing elastomers (rubbers, e.g., polychloroprenes, polyacrylates, etc.) It is also present as an impurity in the ethylene bisdithiocarbamates widely used as fungicides. When the fungicides are present as a contaminant in heated foods, they may be converted to the ethylenethiourea (ref.

180).

Ethylenethiourea VIII

399

There is sufficient evidence for the carcinogenicity of ETU in experimental animals (refs. 181a,b). Given ETU in the diet, rats developed thyroid cancers and liver neoplasms (ref. 181b). The compound is also a known goitrogen. 7.8.1

Uses Ethylenethiourea has a wide variety of uses in addition to vulcanization, a principal application since 1948. The curing process converts most of the ETU to other compounds, but traces of it are still found in the rubbers. Neoprene (polychloroprene) is found largely in automotive parts, wire and cable insulation, construction and adhesives. Consumer products containing neoprenes include container seals (e.g.. aerosol dispensers) and shoes. It is also an intermediate in the manufacture of antioxidants, dyes, fungicides, insecticides, pharmaceuticals, synthetic resins, and a constituent of plating baths. A NIOSH National Occupational Hazard Survey conducted between 1972-4 estimated that approximately 3500 workers in the rubber industry alone were potentially exposed to ETU. ETU is also a manufacturing and processing component, and metabolic product of the ethylenebisdithiocarbamate family of fungicides, e.g.. Mancozeb (a mixture of Mn and Zn salts), Metiram and Zineb. ETU is taken up by plant roots and appears as a stable residue in fruit and vegetable crops treated with the fungicides. Levels of

0.18 to 0.44 mg/kg of ETU have been found in commercial apples. Studies have shown that ETU is present in twenty-eight different commercial ethybenebisdithiocarbamate products (ref. 182a)

.

7.8.2 Reproductive Effects and Teratogenicity of ETU In the course of a NIOSH Special Occupational Hazard Review on ETU. the high risk of teratogenesis, particularly to the nervous

system, became apparent from the literature review. The NIOSH study showed ETU to be both a carcinogen and a teratogen in rats, "with supportive studies in other species". In addition ETU produced myxedema (a drying and thickening effect on the skin, associated with a diminution in physical and mental capacities), goiter and general effects related to decreased output of thyroid hormone. Stula et al. reported marked teratogenic effects when a 20% solution of ETU in DMSO was applied to the skin of pregnant Sprague-Dawley rats (50 mg/kg. days 12 and 13 P.c.). Malformations were observed in all (73)

400

fetuses. The same dose administered earlier (d. 10 and 11, P.c.) produced only 5/83 fetuses with malformations. Controls (40) produced one abnormality. Pregnant rats similarly exposed to ETU (25 mg/kg,days 10 and 11, P.c.) produced no abnormal fetuses; hence it was concluded that both dose and p.c. time of exposure were critical (ref. 183a). Earlier work by Ruddick and Khera (1975) examined this fungicide degradation product during several periods of organogenesis at doses of 10 to 80 &@/day. Above 10 mg/kg they found neural tube closure defects, aa well as hydrocephalus and other malformations of the brain; also tail and limb deformities. Decreased brain weight was found in rabbits exposed to 80 mg/kg (ref. 183~). Ruddick et al. (1976) studied metabolism and distribution of ETU in pregnant rats (ref. 183d). Later Ruddick et al. (1976) attempted to correlate structure and teratogenicity in 16 ETU-related compounds. Only one (4-methylethylenthiourea) was teratogenic (240 mg/kg, day 12 or 13 p.c./rat) (ref. 1836). The others showed only minor skeletal changes. Induction of teratogenic activity appeared to depend on the presence of an imidazolidine ring plus sulfur in the 2-position. Lu et al. (1978) reported defect6 in the rat fetus even after thyroparathyroidectomy of the mother and proposed that the effect of El'U on the maternal thyroid was not involved in the teratogenic action on the fetus (ref. 183f). (See also ref. 72b, pp. 141-142, abstr.

443). 7.9 SfchloroallulYIbio- and Dithiocarbamates (S-(2,3-dichloroallyl) diisopropylthiocarbamate, Avadex (IX); S- 2,3,3-trichloroallyl) diisopropythiocarbamate, Avadex BW ( X ) ; 2-chloroallyl-N,Ndiethyldithiocarbamate, Sulfallate(X1))

.

H ( (CH3)2CH)2N~-S-CH2-~~~1

0 c1 Diallate (Avadex)

IX c1

I

( (CH3)2CH)2NC-SCH2-C=C-C1

II

1

0 c1 Triallate (Avadex BW) X

401 (CH3CH2)2N-C-S-CH2-C'CH2

4'

I

c1

Sulfallate (Vegadex)

XI The S-chloroallylthiocarbamates exist in cis and trans configurations, by virtue of their ally1 moiety. Commercial mixtures of the isomers have been used extensively as pre-emergence herbicides in growing vegetable and grain (wheat, barley) crops. The di-, tri-, and sulfallates were classified as potent mutagens in the Ames assay with TA 100 and TA 1538 (base-pair substitution mutants), with metabolic activation required (1978).

More recent in

vftro testing (1981)of di- and triallate with S. tgphfmurium (strains TA1535,-100. and -98) showed dose-related increases without metabolic activation, but greatly enhanced mutagenicities in the presence of Aroclor 1254-induced rat liver S-9 fraction. These tests indicated that both the di- and triallates can induce base pair substitution and frame shift mutations. Similarly, in vftro tests with CHO cells (with activation) caused an increased frequency of chromosome-damaged cells and SCEs and doserelated decreases in colony formations. In a large number of fn vftro tests reviewed by Fishein (ref. 184a), diallate was the more active compound of the two. The ultimate mutagen postulated is 2chlorocrolein formed via a series of sulfoxidation, rearrangement and 1. 2-elimination reactions:

2-Chloroacrolein XI1

The 2-haloacroleins are strongly mutagenic, regardless of the mechanism(s) of their formation from parent compounds, and 2chloroacrolein itself is a potent (direct acting) mutagen with TAlOO in comparison with the cis-or trans-diallates. The cis-diallate structure is the stronger mutagen, presumably because it gives rise to the 2-chloroacrolein more readily (ref. 184b) The haloacroleins were all much stronger mutagens sans metabolic

.

402

activation than was any other aldehyde studied by Roam et al. (1966). Conversely S-9 activates the chloroallyl alcohols, again pointing to the aldehydes as the ultimate mutagens (ref. 184c). In 1982 diallate was relegated to a restricted commercial use category by the EPA (47 FR 27209. June. 1982).

8. M I S C W M I U S PESTICIDES

(4.6 -dinitm-o-cresol) is one of a group of dinitmphenol 8.1 and dinitrocresol herbicides that are highly toxic to both humans and animals. Most compounds in this class are well absorbed from the GI tract, via the skin and by the lung (as fine droplets). 8.1.1 Toxicology Other than in sensitive individuals, the aromatic n i t m compounds are only moderately irritating to the skin, but very toxic to the liver, kidneys and nervous system. The basic mechanism of toxicity is stimulation of oxidative metabolism in cell mitochondria through interference with the normal coupling of carbohydrate oxidation to phosphorylation (ADP to AW). The increased oxidative metabolism leads to pyrexia, tachycardia, dehydration and the ultimate depletion oP fat stores. The most severe toxicity occurs when workers are concurrently exposed to hot, humid environments. Pyrexia and direct action on the brain cause cerebral edema, clinically evidenced by toxic psychosis and, at times, convulsions. Degenerative changes occur in the liver parenchyma, and renal tubules, and clinical signs of renal injury appear (albuminuria, hematuria. pyuria, increased

BUN). Following large doses of dinitrophenol, humans have developed agranulocytosis. Chronically intoxicated laboratory species have developed cataracts (not observed in humans). Excretion of nitrated phenols and cresols is via the kidneys, with some hepatic excretion into the bile. Elimination of nitrophenols is nearly complete within 3-4 days, unless exposure was extremely high or kidney function is impaired. An early sign of exposure may be yellow staining of skin and hair. If urine o r sclerae are stained, absorption of toxic amounts should be assumed. Common early symptoms include headache, profuse

sweating, lassitude, malaise and thirst. More serious indications are: warm flushed skin, tachycardia, and fever. Apprehension, restlessness and anxiety, manic behavior or unconsciousness indicate

403

severe cerebral injury. The most severe cases involve convulsions. Individuals chronically poisoned with low doses lose weight. For this reason dinitrophenol was used as a weight control agent during the 1930s. (The practice has been discontinued). DNOC was the first of its class to be patented as a selective herbicide, but his'highly toxic class is gradually being displaced by less toxic products. 8.1.2

Reproductive Effects and Teratogenicity Osipova (USSR, 1971; WHO 1982) examined nine women exposed to DNOC for 3 months in a M o m painted with a DNOC-containing paint. Adverse effects on the autonomic and central nervous systems and evidence of liver toxicity were reported after one month of exposure. (See DNOC, refs. 116 and 177). Goldman and Yakovic (1964) produced fetal grown inhibition with dinitrophenol in rat fetuses after maternal doses of 8 to 40 mg/kg (P.c. days 9, 10, or 11) (ref. 118, abstr. 385). The high toxicities of the nitro phenolic herbicides add to the difficulty of obtaining reliable teratogenicty data and probably account for the paucity of relevant studies in this area. However, studies of the hair dyes--l,2- and 1,4-diaminonitrobenzenes--revealed embryotoxicities and teratogenicities in this series (e.g. cleft palates, intrauterine growth retardation, resorption, blood vessel anomalies, reduced maternal and fetal weights, etc. (ref. 118, abstr. 751 and 752).

8.2 Biwridvls (Diquat (1,l'ethylene-2, 2'-dipyridylium dibromide) ; Paraquat (1, 11-dimethyl-4,4'-bipyridinium dichloride))

-

-

Q-Q \

.

c-c

/

Diquat XI11

-

2Br-

404

Paraquat XIV

The quaternary salts of bipyridyls a r e used as contact herbicides.

Diquat, the less toxic of the two shown, is used largely Paraquat is b e t t e r known f o r its use

i n the control of aquatic weeds. i n marihuana destruction.

8.2.1

Toxicology These herbicides damage e p i t h e l i a l t i s s u e s , e.g., cornea, n a i l s ,

skin, kidney, l i v e r and l i n i n g s of the G I and respiratory t r a c t s . More serious i n j u r i e s involve peroxidation of i n t r a - and e x t r a c e l l u l a r phospholipids and i n h i b i t i o n of surfactant synthesis by lung tissue. The pulmonary reaction following paraquat ingestion is frequently f a t a l or permanently injurious. Occupational contact with concentrated Paraquat solution may cause skin f i s s u r i n g of the hands with cracking, discoloration and/or

loss of fingernails.

Eye contact with the concentrate may lead to

.

permanent corneal damage (opacity) Most systemic paraquat poisonings r e s u l t from its ingestion, but excessive dermal contact may a l s o lead t o the same end r e s u l t . Inhalation of d i l u t e paraquat m i s t i s i r r i t a t i n g t o the upper respiratory t r a c t and causes nosebleed.

On ingestion i t causes severe

inflammation of the mouth and G I tract leading t o ulceration i n 1 t o 4 days.

Once absorbed, damage t o l i v e r parenchymal c e l l s and kidney

tubules follows.

These i n j u r i e s may be survived; but Paraquat

concentrates i n the pneumocytes of lung t i s s u e and these c e l l s d i e

after several days. followed by rapid p r o l i f e r a t i o n of connective t i s s u e , f i l l i n g the alveolar spaces of the lung. Once t h i s degree of lung damage is sustained, death from asphyxia usually occur8. survivors, recovery of lung function is very slow.

For

Occasionally

pulmonary edema and myocardial damage have been observed from ingestion of the Paraquat. I n Diquat poisoning the main t a r g e t organs are the G I t r a c t , kidneys and l i v e r .

Fatty l i v e r and acute renal tubular necrosis may

405

result.

In animals cataracts have been observed.

In lung t i s s u e

Diquat produces punctuate hemorrhagic lesions, but does not appear t o concentrate i n the lung tissue.

Brain hemorrhages a f t e r diquat

ingestion have a l s o been reported.

For symptoms, diagnosis and

treatment of poisoning, see Morgan, r e f . 20, chapter 7. 8.2.2

Reproductive Effects and Teratogenicity In a dominant l e t h a l study on mice (LD5O doses) both of the above

dipyridyls exhibited a n t i f e r t i l i t y e f f e c t s .

Diquat e f f e c t s occurred

-

with e a r l y and late premeiotic spermatocytes. while the Paraquat

induced i n f e r t i l i t y involved postmeiotic l a t e spermatids ( r e f . 84, p.

155) Khera e t al. (1970) a l s o reported reproductive studies with Diquat.

Pregnant r a t s were injected with

7 or 1 4 mg/kg on one of

several days during organogenesis. (Higher doses frequently resulted i n maternal death).

Skeletal sternum defects and non-ossification or

absence of one of the auditory o s s i c l e s were noted in some fetuses ( r e f . 118, abstr.

395).

Paraquat (40 ppm) i n the drinking water fed t o hens yielded eggs containing 0.1 ppm of the herbicide.

The treated group contained a

small but s i g n i f i c a n t increase i n the number of abnormal eggs.

The

nature of the defect w a s not described. Khera e t al. reported a s m a l l increase i n c o s t a l c a r t i l a g e defects i n the offspring of r a t s injected with 0.5 mg/kg/day Paraquat ( r e f . 118, a b s t r . 785). Dipyridyl, a chelating agent s t r u c t u r a l l y related t o Diquat and Paraquat, w a s administered t o r a t s ( i . p . 60 t o 75 mg/kg. p.c. days

11.5

- 14.5).

Skeletal defects were found by Dohira et al. (1978,

r e f . 118, abstr. 394).

9. SUMMARY Unlike other chemical pollutants of the environment, pesticides a r e purposeful environmental contaminants added t o achieve s p e c i f i c goals i n agriculture. i n d u s t r i a l production, public health, forestry,

road maintenance and construction, e t c .

Hence the term "economic

poisons" o r i g i n a l l y employed, but l a t e r substituted by the less pejorative npesticides".

Pesticides are c l a s s i f i e d commercially

FIFRA Oct 21. 62169$-396(9-$0-78).

PL 2 28-75; an%

1972). as m d d by PL 94-140 (11-

FIFRA-The Federal Insecticide, F'ungicide. and Rodentici.de Act.

406

according t o t h e i r intended uses, but there is considerable overlap. Ninety percent of a l l agricultural uses f a l l i n t o three categories: insecticides, herbicides and fungicides. Their economic and environmental importance hae increased enormously between 1950 and 1980 as a consequence of a 10-fold expansion i n t h e i r agriculture application. It is estimated t h a t the U.S. pesticide industry itself uses some 1400 a c t i v e ingredients i n formulations produced by 4600 companies a t 7200 plants. These account for the approximately 35.000 brand-name formulations registered with the EPA. encompassing some 60,000 pesticide products on the market. Of a world production now exceeding 4 b i l l i o n lba, about 1/2 is used i n agriculture, with a mere hundred

or so pesticides dominating the a g r i c u l t u r a l use category (Schardein. r e f . 185). By 1971 U.S. agriculture alone consumed 0.5 b i l l i o n l b s of pesticides, of which 228 million l b s (M)* were herbicides, 170M insecticides. 42M fungicides and 15M rodenticides. Seventy percent of these pesticides were used on three crops: cotton, corn and soybeans. About 18OM of the Sumigants produced i n the U.S. are used annually i n rodent and insect control f o r food storage ( g r a i n ) , s o i l treatment, and i n pest control on food imports and exports (Moses, r e f . 164). Classes of chemicals used as pesticides a r e summarized i n Table 24. Inorganics and organometale are included i n the table t o r e f l e c t the f u l l range of chemicals used. I n the public health area, the phenomenal but short-lived successes of DDT in controlling disease vectors w a s noted. I n 1955 t h e WHO had embarked on a program t o eradicate malaria. However by the '70s it was evident t h a t t h e resistance of anophotes to organochlorine pesticides had c l e a r l y foiled t h i s plan. 1962 w a e a peak year f o r insecticide application i n malaria control (130M DDT, 8M Dieldrin, and 1 M Lindane) Currently the world ecosystem remains heavily contaminated with synthetic organohalogens highly r e s i s t a n t to biodegradation. and toxic to species a l l along the food chain. The legacy of our ecologic indiscretions is p a r t i c u l a r l y w e l l documented f o r endangered avian and estuarine species. The destruction of beneficial i n s e c t s and plants by pesticides is also a serious concern t o farmers, and an incentive t o the development of an integrated pest management (XPM) approach--as

.

*M-million pounds/annum.

407

are economic considerations. For, as insect pests evolved to meet the challenge of the new petrochemically derived pesticides, increasing quantities of costly chemicals were used to overcome insect resistance. Eventually the law of diminishing returns set in, and many a once prosperous American farm enterprise was foreclosed. no longer able to obtain needed farm credit advanced o r bank loan extensions". Organochlorine pesticides are nerve poisons in both insects and mammals. Action mechanisms are complex and not yet fully understood. They have been shown to have estrogen-like effects (ref. 84a). to inhibit testicular growth and secondary sex characteristics in cockerels and mice (DDT), to induce persistent estrus in rats, and to affect fertility, gestation, lactation and survival times. Evidence is similar for humans but limited, and includes male sterility, spontaneous abortions in human females, premature human fetuses, severe neurologic and CNS effects, blood dyscrasias, hepatotoxicity, accumulation of organohalogen pesticides in human lipid tissue--and, perhaps even more important, their presence in human breast milk, whence they can continue to exert influences on growth. development and hormonal, CNS and enzyme systems. Aldrin, dieldrin, chlordane. chlordecone (Kepone), heptachlor epoxide, hexachlorobenzene (HCB) and Mirex are all excreted via breast milk in the human female. This is also true for the related PCBs and PBBs that resist biodecomposition and maintain persistent residence in mammalian tissues. For them, excretion via breast milk may constitute the main--if not sole--elimination route. Most of the cyclic organohalogen pesticides studied are known o r suspect animal carcinogens. The alkyl halide fumigants (methyl bromide, EDB, DBCP) are alkylating agents and mutagens, with adverse reproductive effects as well. Hexachlorobenzene (HCB) is known to cross the rat placenta and accumulate in the fetus. Deaths of breast fed infants and an epidemic of skin sores and porphyria cutanea tarda in Turkey resulted from the accidental consumption of HCB-contaminated seed grain. The "The picture is much more complex, involving once-inflated farmland values used as collateral to finance equipment and fertilizer purchases by farmers, encouraged by lenders and often by county agriculture representatives, themselves influenced by the heavy pesticide promotion of manufacturers' representatives. The result has been consolidation of former family-size farms into much larger units, managed fn absentta by owner- corporations, and the rapid growth of agribusiness in the U.S.

inhabitants of a small Louisiana community also experienced an epidemic of illness, traced to accidental HCB ingestion. Hexchlorophene (HCP) is readily absorbed via the skin and is highly neurotoxic, especially to newborns. Clusters of similar malformations were observed in the offspring of workers exposed to HCP detergent washes. Infants exposed to a 6% HCP powder showed brain stem vacuolizations similar to that induced experimental animals. A Lindane formulation (mixture of BHC isomers) is used as a termiticide. The 1% shempoo,lotion or cream (Kwell) is also used as an ovacide. The dz-isomer is a CNS stimulant of high acute toxicity, and caused serious illness including convulsions in a patient when administered aa a vermifuge. Applications of lindane preparations have resulted in seizures in young children. Because of their skin-penetrating power, the topical use of lindane preparations is contraindicated in pregnant women. A 1980 study of premature labor and abortions in India found significantly higher pesticide concentrations in the blood and placental tissues of affected women compared with their full-term counterparts (ref. 103). The widely used chlorophenoxy herbicides are chemical teratogens-as are their byproduct chlorodibenzodioxins. The symmetrical tetrachloro compound TCDD is perhaps the most toxic chemical known. It enhances the teratogenic effect of 2.4.5-T by orders of magnitude, even when present at trace (nanogram) levels (synergism). Dioxins are now ubiquitous, thanks to the widespread popularity of 2.44 and 2.4.5-T herbicides for weed control in agriculture and the massive use of Agent Orange in a defoliation and crop destruction program in Vietnam. Between 1966-81 farm use of herbicides had increased 280% to 6251, exceeding total insecticide use. As organochlorine pesticides fell into disfavor the use of organophosphorus pesticides (OPPs) multiplied and with them a concomitant and increase in morbidity and mortality--particularly among sprayers and fa- workers. The OPPs--especially Parathion and Phosdrin--account for more deaths than any other class of pesticides (Moses, ref. 164). OPPe are acetylcholinesterase inhibitors with potentially disabling neurotoxic effects. The teratogenicity of OPPS in avian species and fish is well documented. Mammalian data indicate more fetotoxicity than teratogenicity. Still, 10 of the 20 animal teratogena listed in Table 20 are OPPa.

409

Studies of reproductive and teratogenic effects of OPPs on humans are few. Gordon et al. (1981)found stronger correlations of cleft lip and palate malformations for insecticides and/or herbicides than for all other agrichemicals combined, The post mortem examination of women's ovaries following acute intoxication revealed adverse ovarian effects from parathion; and both infertility and menstrual disturbances were observed in female applicators of OPPs. Also, women from fruit growing areas exposed to OPPs experienced earlier menopause, infertility and other functional irregularities--e.g., in the liver and nervous system and in bile production. In addition to the most popular chlorophenoxy herbicides, the group includes a variety of other chemical classes--e.g.. amides, bipyridyls, carbamates. dinitrophenols. substituted ureas and triazines. Most of the chemicals tested are animal teratogens, as are many of the fungicides in this miscellaneous group (ref. 185. p. 578 and 586). Carbamates are also used as insecticides and t'ungicides. Their mode of action--acetylcholinesterase inhibition--while similar to that of the OPPs, does not require prior metabolic conversion, and carbamates are more rapidly metabolized. .As with OPPs carbaryl was found teratogenic in birds and fish. Rat studies were somewhat more ambiguous (1.12.5). A WHO review of animal experiments reported affected estrous cycles in rats and decreased fertilities of offspring in a &generation study. Other reproductive and teratogenic effects reported included omphalocele in rabbits, embryotoxicity and teratogenicity in golden hamsters, resorption and embryotoxicity in miniature swine. Beagles exhibited the greatest variety of abnormalities among mammals studied. Dithiocarbamates affected the male reproductive tracts in rats, decreased sperm motility and viability and caused testicular atrophy. Zineb acted as a sterilant in rats. Disulfiram appeared to act synergistically with tranquilizers, causing spontaneous miscarriages and/or malformations in the fetuses of five women. It also exerts powerful synergistic action with alcohol by inhibition of the enzyme of aldehyde dehydrogenase and acts similarly with EDB to magnify the toxicity and oncogenicity of the latter compound. Ethylenethiourea, a widely present impurity in the dithicarbamate fungicides, is a known animal carcinogen (liver, thyroid) and

410 goitrogen. It also poses a high risk of teratogenesis, particularly of the nervous system. The S(chloroally1)thio- and dithiocarbamates and the d -haloacroleins are potent mutagens. The extreme toxicities of the nitrophenolic herbicides probably accounts for the paucity of teratogenic studies in this class of herbicides. Rat studies of the related hair dyes 1.2- and 1.4diaminonitrobenzenes revealed extensive reproductive anomalies. Nine women exposed to a room painted with a DNOC-containing paint showed evidence of liver toxicity and adverse CNS effects. The dipyridyl-baaed contact herbicides (Diquat, Paraquat) exhibit antifertility effects on spermatocytes and cause fetal malformations. In addition these compounds are severely damaging to lungs, kidneys, liver, heart and/or QI tract, and can be permanently disabling when not lethal. While commercial agrochemicals constitute the largest segment of the pesticide market, home and garden use products made a significant economic contribution to the otherwise lackluster years of 1982-3, (Fig. 6) with an estimated volume of 97M: 45% fungicides, 30% herbicides, 24% insecticides, 1% fumigants (C&EN, 4-9-84, p.36). In 1984 the largest selling herbicide for home use was still 2.4-D. with Sevin, malathion and diazinon constituting the three chief insecticides used. All three are neurotoxins and either structurally related to or per 8e carcinogens, mutagens and/or teratogens. The professional home pest control business accounted for about $2.5 billion in 1985 (ref. 186b). Further information dealing with public health concerns and regulatory issues may be found in refs. lO,ll,12ab,l03,164,187-195. 10. ACKNOWLEDGMENTS Thanks are due the following colleagues for their cooperation in

providing essential documentation and data not readily accessible through the open literature: Mr. Tom Alexander, Director, Univprsity of California Public Health Library (Berkeley, CA). Mr. Frank Brucato, Deputy Iigriculture Commissioner, Contra Costa County (Concord, CA). Mr. James Lim. Supervising Industrial Hygienist, CAL-OSHA (Berkeley, CA) .

411

Mr. Melvin Okawa, Consulting Industrial Hygienist, Federal Employee Occupational Health, NIOSH/PHS (San Francisco, CA)* Dr. Peter Kurtz, Senior Medical Coordinator, Medical Toxicology Branch, California Department of Food and Agriculture, Division of Pesticide Management. Environmental Protection and Worker Safety

.

(Sacramento, CA) Dr. Keith Maddy, Chief Toxicologist and Head of the Above Division of Pesticide Management (Sacramento, CA). Dr. Donald Mengle. Research Scientist, Epidemiological Studies Section, California Department of Health Services (Berkeley, CA). Dr. Marion Moses, Medical Director, National Farm Workers Health Group (Salinas, CA). Most of all. I am deeply indebted to Professor Vera Kolb Meyers. without whose invaluable assistance this chapter could not have been completed. 11. ABBREVIATIONS ADI-Allowable daily intake BRL-Bionetics Research Laboratory CEEEN-Chemical and Engineering News CAS-Chemical Abstracts Service CDC-Center for Disease Control CDD-Chlorodibenzodioxin CDF-Chloradibenzofuran CEQ-Council on Environmental Quality CFR-Code of Federal Regulations CIB-Current Intelligence Bulletin CNS-Central Nervous System d. -Day(s) DCB-Dichlorobenzene DDT-Dichlorodiphenyltrichloroethane

DOE-Department of Energy EDB-Ethylene dibromide EHP-Environmental Health Perspectives EOI-Exposure Opportunity Index EPA-Environmental Protection Agency ETO-Ethylene oxide FDA-Food and Drug Administration *Currently. Environmental Scientist with the EPA Water Management Division, Policy and Standards Section in San Francisco.

412

FIFRA-Federal Insecticide Fungicide and Rodenticide Act FR-Federal Register GAO-Government Accounting Office GC-Gas chromatography HCB-Hexachlorobenzene HCP-Hexachlorophene HHS-Health and Human Services M-Million pounds per year MAC-Maximum allowable concentration MCA-Manufacturing Chemists' Association MS-Mass spectrometry NCI-National Cancer Institute NIEHS-National Institute of Environmental Health Sciences NIH-National Institutes of Health NIOSH-National Institute of Occupational Safety and Health NPR-National Public Radio OPP-Office of Pesticide Programs (EPA) OSHA-Occupational Safety and Health Administration OTS-Office of Toxic Substances p.c.-Post conception PBBs-Polybrominated biphenyls PCBs-Polychlorinated biphenyls PCDD-Polychlorinated dibenzodioxin PCDF-Polychlorinated dibenzofuran PCP-Pentachlorophenol PEL-Permissible Exposure Level PHS-Public Health Service PL-Public Law QC-Quality control RPAR-Rebuttable Presumption Against Registration RTECS-Registry of Toxic Effects of Chemical Substances RTP-Research Triangle Park TCDD-2,3,7,8-Tetrachlorodibenzo-1,h-dioxin TCDF-2,3,7,8-tetrachlorodibenzofuran TCE-Trichloroethylene TIC-Toxic Information Center TSCA-Toxic Substances Control Act TWA-Time weighted average UFWA-United Farmworkers of America USDA-United States Department of Agriculture

413

Table 1.

Cyclic Organochlorlnr Pesticides

A . DDT Analogs

C

-

-

I

CI

8. Condensed Rlng (unsaturated)

~

DDT ~

-y

~CI C I & j l

Aldrln

CI

CI

H

Dleldrln Endrln

6 c$Q

Heptrchlor

CI CI

C

l

-C

~II

CI

CI “&CI ~

Chlordane

CDDEI CI

CI -c-CI H

CI

(Telodrlne)

CI CI CI

dl C. Miscellaneous Chlorinated Pesticides

& CI

Llndanr

(71,2,3.4,5,6

-

hexachlorocyclohrxane)

“@=O

CI

Paradlchlorobrnzenr

-C

Endorullan

0 . Condensed Rlng 1Saluraled)

CI

Polychlorinated Terpene(s)

CI O

CI

I CI

TABLE 2

Proximate Excretion Times and Relative Human Toxicities for Some Common Organochlorine Pesticidesa. Pesticide

Excretion Time (Prox)

8-Benzene Hexachloride

Toxicityc T

DDT Kepone/Mirex

Very long/Months to years Endrin VT; others, T

Aldrin, Dieldrin, Endrin

VT

Hexachlorobenzene (HCB)

T

Heptochlor

Oxychlordane

Long/Weeks to months

Chlordane Chlorobenzilate Dicofol Endosulfan Lindane (Oammexane) Methoxychlor Terpene Polychlorinates Toxaphene %organ

T VT T T

T VT T T Short/3 to 4 days

T

(ref. 20. p. 15).

because of their lipophilicity, organochlorine pesticides are also excreted in the milk of lactating women. --Toxic. %-Very

toxic

TABLE 3

Organohalide P e s t i c i d e s i n Human B r e a s t Milka Substance

Typical Levelsb bpb)

Dieldrin Heptachlor epoxide

1-6 8-30

PCBs

40-100 DDT (including 50-200 metabolites )

aRef. 88:

FDA Action Levels f o r Cow's MilkC

7.5 7.5

Allowable Daily Intake

Daily Intake of Breast-Fed Infantd

0.1 0.5

0.8

62.5

1

50

5

4 14 28

Rogan e t al. (1980).

b v e l s considered t y p i c a l i n whole milk i n t h e United S t a t e s . cAssuming 2.5 percent f a t . FDA Action l e v e l s represent t h e l i m i t a t or above which FDA w i l l t a k e legal a c t i o n a g a i n s t a product t o remove it from the market. dIntake of a 5-kg i n f a n t drinking 700 m l of milk p e r day. based on high values given under t y p i c a l l e v e l s .

Levels are

416 TABLE 4A Kepone Reproductive Effects (Animal)a Species (and sex)

Route

Sheepshead minnow

In water

Japanese quail (M)

Oral

Rat (F)

Rat (F)

Fxposure Dose and Time

Effect

Reference

Concentration of 0.08-24 pg/liter for 28 days before spawning

Embryotoxicity ; malformat ions ; decreased length and some scoliosis in juvenile fish

Hansen et a1

Dietary concentration of 200 ppm, 0-42 days

Structural deterioration of testes; enlargement and atrophy, apparently depressed spermatogenesis

Eroschenko

Gastric intubation

2-10 mg/kg on days 7-16 of gestation

Fetal toxicity, reduced fetal weight, reduced ossification, edema , undescended testis, enlarged renal pelvis, enlarged cerebral ventricles

Chernoff and Rogers 1976

Gastric intubation

2-4 mg/kg/day on days 2-21 of gestation

Fetotoxicity; stillbirths and abortions; strong evidence of CNS impairment in the perinatal rats

Rosenstein et al. 1977

Oavage

15 mg/kg/day on days 14-20 of pregnancy

Persistent Qellert and vaginal Wilson 1979 estrus , anovulation, and toxic levels of serum estradiol in female offspring

1977

1978

417

TABLE 4 A (Continued)

Rat

Oral

Dietary concentration of 25 ppm fob 3 months before mating

Reproduction i n females completely inhibited (partially restored i n 2 months) ; hyperplasia of adrenal cortex; no effect i n males

Cannon and Kimbrough

Oral

Dietary concentration of 30 ppm f o r 7 weeks before mating

Smaller litters s i r e d by treated males ; females i n constant estrus; low estradiol; decreased luteinizing hormone levels; increased uterine weights; decreased ovarian weights

Hammond e t al. 1978

Gastric intubation

2-12 mg/kg on days 7-16 of gestation

Increased fetal mortality and clubfoot

Chernof f and Rogers

Dietary concentration of 10 ppm f o r 1 month before mating

Decrease i n s i z e and numbers of litters

Good e t a l .

30 ppm

Constant estrus; reduced luteinizing hormone, which prevented normal ovulation

Haber 1965

(M and F)

(6)

Rat

(M and F)

(7)

Mouse ( F )

(8)

Mouse (F)

Mouse (F)

Oral

Oral

aRef. llla-Adapted from Appendix. pp. 220-221. see ref. 47.

1979

1976

1965

For complete c i t a t i o n s

Kepone Reproductive Effects a Exposure

Effect

DOSWF

Reference

Occupational, men working at manufacturing plant

Not specified

Reproductive failure

Langford. 1978

Occupational, 148 men working at manufacturing plant

unknown

Substantial reduction in sperm motility in 13 workers

Taylor et al.

a

Ref.

Nisbet-Karch. App., p. 173.

See ref.

1978 ( r e f , lllb)

47 for complete citations.

419

TABLE 5 Evaluation of the published teratogenic (embryotoxic) effects induced by TCDD in rats and micea Dose Hg/ kg Time Teratogenic TCDD effect Winimal-ED50b given, tested Species Strain (system) days Rat

Intestinal hemorrhage

Mouse

0.125

=o.5?

Route ReferencesC Oral

Sparschu et al. Courtney & Moore

CD

Kidney 0 -5 abnormality

>

1

6-15

sc

CD-I

CP

> 3

6-15

sc

1-3

6-15

sc

11

3

> 3

6-15

sc

II

Kidney 3 abnormality

> 3

6-15

sc

II

3

> 3

6-15

sc

65

Kidney 3 abnormality

< 3

6-15

sc

NMRI

CP

3

6-15

Oral

Neubert & Dillman

9

9

<9

9-13

Oral

I1

15

40

13

Oral

Neubert et al.

5

15

ii

Oral

1

3 Kidney 1 abnormality

DBA/ZJ CP

C57Sl/ CP

6.5

(ref. 121d)

aTbe smallest dose with which a significant teratogenic effect was produced is indicated. Where only one dose level was tested, it is not necessarily the smallest dose from which a teratogenic effect could result. Routes were both oral and subcutaneous (SC). An attempt was also made to estimate the ED,, from the few data available. bED50: dose required to produce effect in 50% of animals. CComplete citations in ref. 121d. Ref. Neubert et al. in

EHp#5

(ref. 121d, p.70).

420

TABLE 6

Number of Isomers and Percent Chlorine for the 10 Chlorobiphenyl (PCB) Classesa

Weight % C1

Chlorobiphenyl

Empirical Formula

No. of Isomers

mono

C 12HgC1

3

18.79

di

C 12H8C1 2

12

31.77

tri

c 1 2 ~ 7 ~3 1

24

41.30

tetra

C 12H6C1

42

48.56

penta

c

46

54.30

hexa

C 12H4C1 6

42

58.93

hepta

C 12H3C1 7

24

62.77

octa

C 12H2C1 8

12

65.98

nona

C 12H C1 9

3

68.73

deca

c

1

71.18

aAdapted from ref. 136.

4

1 2 ~ 5 ~5 1

12 c1 10

421 TABLE 7 Tradenames for Products Containing PCBs .a Tradename

Tradename Owner

Aroclor

Monsanto Company St. Louis, MO

Chlorextol

Allis-Chalmers Milwaukee, WI

Clophen

Farbenfabricken Bayer OmbH Germany

Dykanol

Federal Pacific Electric Co. Newark. NJ

Fenclor

Caffaro S.P.A. Italy

h e r teen

Westinghouse Electric Corp. Pittsburgh, PA

Kanechlor

Kanegafuchi Chemical Industry Co., Ltd. Japan

Nof lam03

Wagner Electric Corporation Newark, NJ

Phenoclor

Prodelec

Pyralene

Prodelec France

Pyranol

General Electric Co. Schenectady. NY

Santotherm

Mitsubishi-Monsanto Japan

Therminol

Monsanto Co. St. Louis. MO.

BTherminol products now formulated in the U.S. do not contain PCBs.

Ref: CIB#7

422

TABLE 8 PCB Concentrations in Blood Serum by Race and Residence Race and N o . in Residence Sample

PCBs Measureable In No. x

PCB Cpncentrations Ave" Max

Rural black

107

5

4.67

9.45

20.6

Urban black

151

57

37.75

5.22

29.0

Rural white

192

119

61.98

5.12

16.6

Urban white

166

89

53 * 61

4.38

22.0

*Average of measureable concentrations. NIOSH. Criteria Ref. 136.

...

TABLE 9 Concentrations (ppb) of PCBs in Tissues of Human Fetuses. Tissue Analyzed Age of Placental Contents

Basis Cerebrum Liver

Kidney

2nd trimester

Whole Fat

6-20 17-83 60-1.900 550-1.300

3rd trimester

Whole '2 Fat 270*

2-23 2-33 150-60 230-800

*One sample. NIOSH, Criteria

Skin

25-90 6-10 48-769 1,000-1,300 420-470 880-1,400

. . . Ref:

136, p.

37.

423 TABLE 10 P e s t i c i d e s and PCB Levels i n Breast Milk i n t h e United S t a t e s Finding

Dieldrin"

Heptachlor* Oxychlordane" Epoxide

PCB' sa

parts/billionb

1436

No. of samples %, d e t e c t a b l e

Mean

83

61

74

30

164

91

96

87

16-2050

13-5700

50-4091

14-12,300

Range

"Mean and range a r e given on samples with >1 p a r t p e r b i l l i o n detectable. aMean and range are given on samples with >5O p a r t s p e r b i l l i o n detectable. bOn a whole-milk b a s i s Ref.

88: Rogan e t al. (1980).

TABLE 11 PCBs and PCDFs (ppm) I n Fat from Three Yusho P a t i e n t s a t Autopsy

Year of Death

a

PCBs

a

PCDFs

Adipose

Liver

Adipose

Liver

1969

3.4

4.7

0.03

2.3

1969

8.5

5.6

0.04

1.1

1972

2.1

3.5

0.01

0.3

NIOSH Criteriaref.

136, p. 45.

424

TABLE 12

Chemical and Physical Properties of the Monohalomethanesa Chemical Identity

Methyl Chloride

Methyl Bromide

Methyl Iodide

C A S ~Registry NO.

74-87 3

74-83-9

74-88-4

RTECSC Accession No.

PA6300000

PA4900000

PA9450000

Empirical Formula

CH,C1

CH3Br

CH3 I

Formula Weight

50.49

94.95

141.95

Physical Form

Gas

Gas

Liquid

Boiling Point, 'C

-24.2

3.5

42.5

Freezing Point, 'C

-97.7

-93.7

-66.1

Vapor Pressure

5 atm at 22.0'c

2 atm a t 23.3'

0.5 atm a t 25.3.C

Color

Colorless

Colorless

Odor

Faint, sweet odor which is not noticeable a t dangerous concentrations

Chloroform l i k e Pungent odor a t high concentrations

Specific Gravity

0.973 (-10.C)

1.736 (-10.C)

Flammability

Flammable, forms explosive mixture with air a t 8-17%

Nonflammable i n Nonflammable a i r , burns i n oxygen

-

.

%f: CIB #43 (monohalomethanes) bChemical Abstract Service. CRegistry of Toxic Effects of Chemical Substances.

Colorless, turns brown when exposed to light

2.279 (20'C)

425

TABLE 13 Number of Workers Potentially Exposed to Monohalomethanesa SICb Code

07 13 15 16 17 20 21 22

23 24 26 27 28 29 30 31 33 34 35 36 37 38 39 41 44 45 48 49 50

53

54 55 58 65 73 78 79 80 89

CH3Br

Agriculture Services and Hunting Oil and Gas Extraction General Building Contractors Heavy Construction Contractor Special Trade Contractors Food and Kindred Products Tobacco Manufacturers Textile Mill Products Apparel and Other Textile Products Lumber and Wood Products Paper and Allied Products Printing and Publishing Chemicals and Allied Products Petroleum and Coal Products Rubber and Plastics Products, NEC Leather and Leather Products Primary Metal Industries Fabricated Metal Products Machinery, Except Electrical Electrical Equipment and Supplies Transportation Equipment Instruments and Related Products Miscellaneous Manufacturing Industries Local and Interurban Passenger Transit Water Transportation Transportation by Air Communication Electric, Gas. and Sanitary Service Wholesale Trade Retail General Mrchandise Food Stores Automotive Dealers & Service Stations Eating and Drinking Places Real Estate Miscellaneous Business Services Motion Pictures Amusement and Recreation Services Medical and Other Health Services Miscellaneous Services TOTALS aRef: CIB #43 (monohalomethanes). bStandard Industrial Classification Code.

5 t 922 129 934

-

1,936 4,356 108 237 52 471 1,270

80

4.859 11

89 38 44 65

357 345 643 174 34 27 1.047 11,496 10,069 4,713 1.356 1,481

-

17,958 4.665 12,600 597 4.147 12,015 354 104,679

CH3I

426

TABLE 14 a

Estimated U S . Consumption Pattern for EDC, 1977

Pounds

%Total Consumption

Projected annual growth rate 1977-1982 ( X I

9,460

85

5 to 8

1,1,l-Trichloroethane

473

4

4 to 5

Ethyleneamines

299

2

-2 to -4

VDC

213

2

5 to 7

PCE

191

2

0 to 2

TCE

205

2

-2 to 3

Lead scavenger

196

2

-15

Miscellaneous

11

<1

-

11,048

100

( lo6)

vc

Total a

5 to 6

Adapted from data in Chemtcat econontco handbook, SRI International (1979)* Ref, 54 : Swirsky-Gold

427

TABLE 15 Adverse Effects of Chloroethanes on Human Organs and

CHEMICAL monochloroethane

0

0

1,l-dichloroethane

0

0

1,2-dichloroethane

0

0

l,l,l-trichloroethane

0

0

1,1,2,2-tetrachloroethane

0

0

hexachloroethane

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0 0

0 0

0

Badverse human health effects have not been reported to NIOSH for 1.42 trichloroethane. 1,1,1,2-tetrachloroethane, end pentachloroethane. hef. 51:

CIB#27.

TABLE 15A Specific Adverse Effects of Chloroethanes on Humans, By System Chemical

system

Adverse Effect

monochloroethane

neurologic

other

central nervous system depression, headache, dizziness, incoordination feeling inebriated. unconsciousness abdominal cramps respiratory tract irritation, respiratory failure cardiac arrhythmias, cardiac arrest skin irritation, frostbite, allergic eczema eye irritation, death

1.1-dichloroethane

neurologic respiratory dermatologic

central nervous system depression respiratory tract irritation skin burn

1,2-dichloroethane

neurologic

headache, dizziness, unconsciousness, vertigo, hand tremors, generalized weakness, sleepiness, nervousness, mental confusion liver function abnormalities, cellular damage, toxic chemical hepatitis, jaundice, liver enlargement

gastrointestinal respiratory cardiovascular dermatologic

hepatic

1,l.l-trichloroethane neurologic

hepatic gastrointestinal cardiovascular

hematologic dermatologic other 1,1,2-trichloroethane

central nervous system depression, headache, dizziness,,incoordination feeling inebriated, unconsciousness impaired perceptual speed, manual dexterity and equilibrium; increased reaction time. lightheadedness. drowsiness, sleepiness. generalized weakness, ringing sound in ears, unsteady gait, burning and/or prickling sensation in hands and/or feet cellular damage, liver function abnormalities nausea, vomiting, diarrhea, drop in blood pressure (hypotension). decrease in heart rate (bradycardia), cardiac arrhythmias blood clotting changes dryness, cracking, scaliness, inflammation eye irritation, fatigue, death

NIOSH is unaware of reports of adverse occupational exposure (see Table 7, ref. 51)

429

TABLE 1 5 A (continued)

l,l,l,Z-tetrachloroethane

NIOSH is unaware of reports of adverse occupational exposure (see Table 7 , ref. 51)

1.1.2.2-tetrachloroethane neurologic

hepatic

gastrointestinal

urologic respiratory cardiovascular hematologic dermatologic other

central nervous system depression, headache, feeling inebriated, unconsciousness, drowsiness, unsteady gait, vertigo, hand tremors, numbness in limbs, prickling sensation of fingers and toes, pain in soles of feet, loss of knee jerk, paralysis of some muscles of the hands and feet, inflammation of the peripheral nerves, slight paralysis of the soft palate, loss of the gag reflex, irritability, mental confusion, delirium, convulsions, stupor, coma liver function abnormalities, massive cell damage, jaundice, toxic chemical hepatitis, liver enlargement, sensation of pressure in the liver area abdominal pain, nausea, vomiting, unpleasant taste in the mouth, loss of appetite (anorexia), vomiting of blood (hematemesis), increased flatulence, diarrhea, constipation, pale stools kidney damage, presence of bile pigments, albumen, and casts in the urine excessive fluid in the lungs (pulmonary edema), respiratory paralysis fatty degeneration of the heart muscle (in lab animals) anemia, increase in white blood cells (and blood platelets), dryness, cracking, scaliness, inflammation, purpuric rash insomnia, general malaise, fatigue, excessive sweating, weight loss

NIOSH is unaware of reports of

pentachloroethane

adverse occupational exposure (see Table 7. ref. 51) hexachloroethane

Ref.:

NIOSH CIB #27

neurologic

inability to close eyelid, eye irritation, tearing of eyes, inflammation of delicate membrane lining the eye, visual intolerance to light, (photophobia)

430

TABLE 15B Some Adverse Effects of Chloroethanes Reported in Animal Studies (ref. 51) Chemicals

Species

Adverse Effect

monochloroethane

unspecified

kidney damage; fatty changes in liver, kidney, and heart

1.1-dichloroethane

cat dog rat

kidney damage liver injury liver injury; retarded fetal development

1,2-dichloraethane

bacterium cat

mutagen retarded growth rate, fatty changes in liver; heart dilation; lung hyperemia corneal clouding; fatty changes in liver liver enlargement; weight loss mutagen fatty changes in liver; liver enlargement; weight loss fatty changes in liver weight loss; fatty changes in liver: hypotension; respiratory paralysis; EKG changes; anemia; bone marrow changes; liver dysfunction, hemorrhage and degeneration; kidney degeneration and dysfunction embryotoxin; pulmonary congestion; fatty changes in liver

dog fruit fly guinea pig monkey rabbit

rat

1.1.1-trichloroethane cat dog guinea pig mouse monkey rat

neuromuscular reflex changes sudden death; respiratory failure fatty changes in liver; lung irritation cardiac arrythmias; liver dysfunction; pulmonary congestion cardiac arrythmias; myocardial depression; respirtory failure; staggering gait; tachycardia; tremors; cardiac failure; pulmonary congestion; pneumonitis; staggering gait; weakness: respiration; semiconsciousness; respiratory failure

1,1.2-trichloroethane dog guinea p i g

1.1,1.2-tetrachloroethane rabbit rat

liver and kidney injury liver and kidney injury

embryotoxin embryotoxin; liver dysfunction; mutagen (Continued)

431 TABLE 158 (continued)

1,1,2,2-tetrachloroethane bacterium dog

guinea pig monkey mouse rabbit

rat

pentachloroethane

hexachloroethane

mutagen ascites; diarrhea; jaundice; liver enlargement; intestinal hemorrhage convulsions; weight loss; death anorexia; diarrhea; blood cell fluctuation; weight loss staggering gait; breathing difficulty; fatty degeneration of liver and kidney; death altered immune system; altered blood chemistry; liver and kidney degeneration fatty degeneration of liver and kidney; corneal reflex changes; liver enlargement; paralysis; death blood cell changes; fatty degeneration of liver; liver dysfunction: death

sheep

liver, kidney, and lung changes fatty degeneration of liver; kidney and lung injury liver dysfunction

cattle mouse rat sheep

liver liver liver liver

cat dog

and kidney damage and kidney damage and kidney damage and kidney damage

TABLE 16 Fumigantsa Acrylonitrile Carbon Disulfide Carbon Tetrachloride p-Dichlorobenzene Dioxane Ethylene Dibromide Bthylene Dichloride Ethylene Oxide Hydrogen Cyanide a

Ref. 69. p. 461

Methyl Bromide Methylene Chloride Methyl Formate Napthalene Perchloroethylene Propylene Dichloride Sulfur Dioxide Tetrachlorethane Trichloroethylene

432

Organophorphorur P.rtlcld*r,

Table 1Z A

- PhOaDhaIrr and

relalad compounds

8.

arranged by P

- Llgandr

Phorphorolhlonrlrr

0. Phorphorolhlolalrr 0 (C,H,

Kllerln

O), b'-S-CH,

P

(CH, 0 ),P-0-CH,-

CH,-S-

FH CH -CNHCH,

Vamldothlon

0

R

, - CH,-N, ? I

,c-0

(cn, 0 ) P-8

A

(CH, 01, P-S-CH,-C-

If (CH,O), P-8-CH,-E-N,

I

N=E-OCH,

P

Malhldalhlon

f

(CH,O), P-S-CH,-W,-S-

?f

C, H , O x y d ~ m ~ l o n - m ~ l h y l

E. Phorphorrmldrtr NHCH,

'05 Cm,

Dlmelhorlr

Formothlon

ci F. Phorphonrlr 0

e,O):!+

-a, OH

Rrl:

Moulrchrn

-

[khmrn m d Dagrarvr, mi. 2b.

Trlchlorlon

433

Some commerclally Important Orgnophoaphorus Insectlcldes 4€

Table 18.

ElhlonlAcarlclde, Insoctlcldo AbatellnsectIClde

(CH,

9 O ) , - b - 0 - CH = CCI,

,

S

(CH 0), - : - O n

SCH, CH,

DDVP(DlchlorvOa, Vapona)l Insecllclde wlth lumlgant ectlon

Fenthlon(Bayler)lAcarIclde,

n

0

(C* H, 0);

'

J

c- 0

Insect.,Blrd

N

I'-\NJCH(CH,

), I

Diazinonllnsecliclde

CI Gardona(TetrachIorvlnphos)/lnsectlclde

(CH, O),--bl-O

0

s

QNO,

(CH, O),-P-S-CH-

t(-O-C,H,

&I2-c-oc, H,

CI

8

DiCapthonllnSecliCide

MaIalhlonllnsec1IClde

Dimethoate (Cygon)lAeariclde, Insecticide

sII (C, H , O ) , - P - 0

cln

(CH, O),-

tP-

0-

7 $1'

C - C - CI I I Br Br

Naled(D1brom)llnsect.. Acar.

CI

Methyl or Ethyl Paralhionllnsecl

E PNIAcarlClde. Insecllclde

4k Adapted lrom rBfS. 14 and 69

434

rp w rp

Organ0 phosphorus Pestlcldes Associated with delayed Neurotoxicity

Table 19.

Z

0

CN

c_'z

Q 0-P

- OC, H,

Cyanofenphos: rothionate

II

0-(4-cyanophenyl) 0-ethyl phenylphospho.

S

N

0

2

EPN:

O-(Cnitrophenyl) 0-ethyl phenylphosphorothionate

7.

OC,

O

z

!-O

Y

0

"5

"2

n

I

0

EPBP (S-Seven) 0-(2,4-dIchlorophenyI) 0-ethyl phenylphosphorothionate

I

"6"

Leptophos: 0-(4 bromo-2,5-dichlorophenyl) 0-Methyl phenylphosphorothionate

Uipstox: N.N-bit(l-nmthyiethyI)

phesplmrdamllllc fluorid.

Trlchlorlon: dimelhyl .2.2,2-trichioro-i-hydroxyethyl

,d

OCH

phosphonate

DMPA: 0.(2,4-dichlorophenvI) 0-Methyl (I-methylethyl) PhosPhoramidolhioa1e

Merphos(de1olianl): lIi(butyi1hio)phosphorus

Haloxon: 3-chloro-Fhydr0xy-4-mothyl-bis(2-chlor~lhyl) C

O

~

phOSph*O n

P 01 W

436

TABLE 20 Pesticides Reported to be Teratogenic In Animals

Fndrln

Aldrln Azinphosmethyl" Captafol Captan Carbaryl Dlazlnon* Dlchlorvos" Dicrotophos" Dieldrin Dimethoate"

EPN"

Folpet Maneb Parathion' Phosmet" 2,4I54' Thiram Trichlorfon" Trithion"

*OrpmophosphOru8 pemtioides Adaptad from ref. 160.

CH,-S

-

I

Oxarnyl (Vydala):

(BCirklde. Carbolursn InSKIklde. (Furadan) nemrllclde)

(CH3)2N-CO * C=NOCO NH-CH,

QjLJ2 0

OCO-NH CH, Melhornyl(Lannsle, Nudrln) onseeitchre)

CH, FINOCO -NHCH S-CH,

, e O C O N H C H ,

Amlnocrrb (Mslacll) Vnstcllcld*. mollusclclde)

0

0 - ' c H 3 ) '

Oimelllsn (Snip Fly Bands)

CH,

I

(CH,)? N-CzO

aAdeptad f r o m refa. 14 and 20. bAcuta oral LDojo <WW/K#(rat), l i s t e d in spproxlmate order of decreuine toxicity. "?hisis a eya$amic. 1.0.. tdean up by tha plant and tranalocated to f o l i w and sonatimam to fruit (Worran, mi. 20, p. 9 ) .

437 Table 22. Moderat*ly TOXIC Commerclal Carbamate

Pesticides*

-

3-Me-5 (1 MethyWhyl)phenyl methylcarbarnate

OCO NHCH,

YelhloClrb

-

YCONHCH,

(Merurol. Drare)

3.5-dlmethyl 4 methylcarbemale

-

- (mathylth1o)phenyl

-

2 (1 malhylethoxy) phony1 methylcarbnmale

2

- (dlmrthylarnlno).

5, 6

. dlmOthyl

-

.

4 pyrlmldlnyl dlrnalhylcarbamate

Bufencarb (Bur) (InseCIICldsJ

OOCONHCH3 3 3

.(1 - Othylpropyl) + - (1 . metnylbutyu)

phenyl molhylcarbarnale

0-CONHCH, Cerbnryl (Sevln) (IrSbcllcM.)

'See footnotes lor Table 21

1

- naphlhyl methylcarbemale

TABLE 23

Rat Survival Ratios: Treatment Cohort (48 i n each")

EDB, Disulfiram and EDB/Disulfiram* survival Ratio Male Female

none/controls

48/48

45/48

Disulfiram alone

45/48

46/48

EDB alone

33/48

39/48

3/48

1/48

EDB/Disulfiram

*Adapted f r o m data in ref. 179, p.3.

439 TABLE 24 Classes of Chemicals Used as Pesticides (ref. 164) Chemical Classification

Uses

Examples

Aliphatic acids Arsenic-inorganic Arsenic-organic Carbamates Bisdithiocarbamates Methyl carbamates Thiocarbamates Chlorinated Hydrocarbons bis (diphenyl) aliphatics Cyclodienes

Herbicides Herbicides Herbicides

Dalapon, TCA Sodium arsenite MSMA, Cacodylic Acid

Fungicides Insecticides Herbicides

Maneb, Zineb, Ziram Carbaryl, Methomyl EPTC, Butylate

Insecticides Insecticides

DDT, Methoxychlor Dieldrin, Toxaphene, Chlordane Hexachlorobenzene Lindane ( f-hexachlorocyclohexane)

Chlorinated benzene Cyclohexane Coal Tar Copper-inorganic Halogenated aliphatics Nitrogen compounds Benzimidazoles Bipyridyls Pyridine Anilides Nitroanilines Nitriles Phenylureas Triazines Triazole Uracils Organophosphorous compounds Phosphates Phosphorothioates Phosphorodithioates Phosphonates Phosphoroamidates Phosphonothioates Heterocyclic derivatives Organotins Petroleum oils Phenol derivatives Chlorinated

Nitro compounds Phenoxyaliphatic acids Phthalates Phthalimides Pyrethroids Sulfur

Fungicide Insecticide Wood preservative Fungicide Fumigants

Creosote Bordeaux Mixture. Paris Green Methyl Bromide, EDB, DBCP

Fungicides Herbicides Herbicide Herbicide Herbicides Herbicide Herbicides Herbicides Herbicide Herbicides

Benomyl. Thiobendazole Paraquat, Diquat Picloram Alachlor. Propanil Trifluralin, Benefin Dichlorobenil, Bromoxynil Monuron. Chloroxuron Atrazine, Simazine Ami trole Bromacil. Terbacil

Insecticides Insecticides Insecticides Insecticides Insecticides Insecticides Insecticides Fungicides Herbicides

Mevinphos. Phosphamidon Parathion, Fenitrothion Malathion, Ethion Trichorfon Crufomate Leptophos. EPN Chlorpyrifos, Diazinon Brestan. Du-Ter Flit, Kerosene

wood Preservative Fungicide, Molluscicide Herbicides Herbicides Herbicides Fungicides Insecticides Fungicide

Pentachlorophenol DNOC, Dinoseb 2,4-D, Silvex, 2.4.5-T Endothal. DCPA Captan. Folpet Allethrin , Decamethrin Sulfur

441

OVER-ADDITIVE EFFECT

fetuses affected per litter

1

[

CONTROLS

2.5-

2,4.5-T TCDD

(PPm

60

60 2

2

(33)

60 60 0.2 0.2

100

100

100 100 0.02 0.02

0.1 0.1

(3.3)

(0.2)

(1)

Fig. 3a. Cleft palate frequency in mice produced by a cornbination of TCDD and 2,4,5T. Both drugs were given in the doses indicated ( m g k g for 2,4,5-T and p g k g for TCDD) during days 6-15 of pregnancy, once daily by stomach tube. In each group 20 litters were evaluated. Data a r e given as number of fetuses per litter (M). The effect produced by 60 m g k g 2,4,5-T + 2 p g k g TCDD is highly significant; that produced by 100 m g k g 2,4,5T t 0.1 p g k g TCDD, just significant (P=O.Ol). Ref. 121d, Neubert e t al., EHP #5, p. 76.

OVER-ADDITIVE EFFECT

,',2h/

fetuses aftected per litter

[

1

CONTROLS

2.5-

Fig. 3b. Cleft palate frequency in mice produced by a combination of TCDD and 2,4,5-T. Experimental conditions as in Fig. 3a. The effects observed with both 15 m g k g 2,4,5-T + 2 p g k g TCDD and with 30 m g k g 2,4,5-T + 2 p g k g TCDD a r e highly significant (P < 0.0027).

H-i-i-Cl CNoroethane (Ethyl chloride)

c1 H-IF-C-Cl A 61 l,l,l-R~cNoroethane (Methyl chlomform)

.-“pi B 1

1,l ,-DicNoroethane

c 1- p 9 C l 1,2-DicNoroethane (Ethylene Dtchloridef

C1 -z-z:H 1,1,2-Trichloroethane

1,1,1,2-TetracNoroethane

c1 1 C l - k - E-Cl 61 1

1,1,2,2-Tetrachloroethae

Figure 4. Chloroethanes.

Pentachloroethane

HexacNoroethane

11,OOomillionIbs \

\

LOSS TO AIR 100 million lbdyr

LOSS TO WATER

-

LEAD SCAVENGER

-

INGASOLINE 196 million Wy

PESTICIDE 2mi~ionlbslyr

>11 million Ibs/yr

1 I

LOSS TO SOLID WASTE >60million lbdy

OTHER ---m

Fig. 5. Estimated environmental release of E X , 1977, based on information contained in Auerbach Associates (1978); Storm (1978); Drury and Hammons (1979h and SRI International (1979); E. Fry (pers. comm.); P. Williams (pers. eomm.) Ref. 54: Swksky-Gold.

444

Total

1983 volume: 97 million

Figure 6.Peslicides: Home Use. Ref. Slorck, 186a.

Ib

445

REFERENCES 1 2

Flint, M.L.. and R. van den Bosch, Introduction to Integrated Pest ManaRement, Chapter 4, "A History of Pest Control." pp. 51-81. Plenum Press. NY (1981). xv + 240 p. Kirsch-Volders, M. Carcinogenicity, MutaRenicity and Teratogenicity of Industrial Pollutants, M. KirschVolders, (Ed.) , Plenum Press, NY (1984) XIV + 336 pp. Moutschen-Dahmen, J. and M. DeGraeve. Chap. 3, Insecticides, in 2(a). Balandrin, M.F., J.A. Klocke. E. Syrkin Wurtele and W.H. Bollinger, "Natural Plant Chemicals: Sources of Industrial and Medicinal Materials," Science 228, No. 4704. 1154-60 (June 7. 1985) 68 refs. Crosby, D.G., pp. 1-16 in: Natural Pest Control Agents, D. 0 . Crosby (Ed.), Am. Chem. SOC.. Washington, D.C. (1966). See also: Agricultural Handbooks 154 and 461, U.S. Dept. of Agriculture/Agricultural Research Service. Washington, D.C., (1958 and 1975, resp.). 2 Reviews of literature: Insecticides from Plants, 1941-53 and 1954-71, resp. Levy, L.W.. "A Large Scale Application of Tissue Culture: The Mass Propagation of Pyrethrum Clones in Ecuador", Environ. Exp. Botany 21, pp. 389-395 (1981). LOC cit. ref. 2b. Putnam. A.R., "Allelopathic Chemicala," Chem. Eng. News, 61, No. 14, 34-45 (April 4, 1983) 16 refs. Mellor. J.W. and R.H. Adams. Jr... DD. - - -17-19. . - - . Pesticides. in : "Feeding the Underdeveloped World," Chem. Eng. News .62, No. 17. 32-39 (April 23, 1984). Hileman, B., "The Global 2000 Report to the President," Environ. Sci. Technol. 16. No. 3. 151A-155A (1982). Carson, R., Sf lent Spring, Houghton Mifflin, Boston (1962) XI + 368 pp. Rachel Carson, aquatic biologist, w a s born May 27. 1907 and died of cancer on April 14. 1964. Odum, E.P.. "The Strategy of Ecosystem Development." Science 164, 262-270 (April 18. 1969). Based on an address originally delivered to the Ecological SOC. of America, University of Maryland, Aug. 1966. Hardin. G.. "The Traaedv of the Commons." DD. . _ - 250-263 in: Exploring New Ethics-f& Survival: Voyage of the Space Ship Beagle, G. Hardin (Ed.), Viking Press, NY (1972) 273

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w.

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460

67

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71 72

73

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Rhesus Monkeys," Toxicol 6, 331-340 (1976) Akiyama, K.. 0 . Ohi, K. Fujitani, H. Yagyu, M. Ogino, and T. Kawana, "Polychlorinated Biphenyl Residues in Maternal and Cord Blood in (the) Tokyo Metropolitan Area." Bull. Environ. Contamin. Toxicol., 14. 588-92 (1975). As cited in ref. 136. p. 177. Fishbein, A., M.S. Wolff. R. Lilis, J. Thornton and I.J. Selikoff, "Clinical Findings Among PCB exposed Capacitor Manufacturing Workers,' Ann. N.Y. Acad. Sci. 320, 703-15 (1979)* Savage, E.P., "National Study to Determine Levels of Chlorinated Hydrocarbon Insecticides in Human milk, 1975-6 and Supplementary Rept. 1975-6. NTIS Springfield, VA ( 19771* Kuratsune, M.. T. Yoshimura, J. Matsuzaka and A. Yamaguchi. t'Epidemiologic Study (on) Yusho, A Poisoning caused by Ingestion of Rice Oil contaminated with a Commercial Brand of Polychlorinated Biphenyls," Environ. Health Perspect., Exp. Issue No. 1, pp. 119-28 (Apr. 1972). Kikuchi, M. and Y. Masuda, "The Pathology of Yusho" pp. 6986 in: PCB Poisoning and Pollution, K. Higuchi (Ed). Academic Press, New York (1976). Funatsu, I., F. Yamashita, Y. Ito, S. Tsugawa, T. Funatsu. et al. "Polychlorbiphenyls (PCB) Induced Fetopathy--I. Clinical Observation," Kurume Med. J. 19, 43-51 (1972). Cited in ref. 136. Taki, 11, S. Hisanaga and Y. Amagase, "Report on Yusho (Chlorobiphenyls Poisoning) (in) Pregnant Women and Their Fetuses," Fukuoka Acta Medica 60, pp. 471-4 (1969). Cutler. S.J.. and J.L. Young, Jr., "Third National Cancer Survey--Incidence Data," Monograph 41, pp. 10-24, US/DHEW/PHS/NIH/NCI ( M a r . 1975). IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, Vol. 18. pp. 43-103, IARC, Lyon, France (1978) 140 p. Op Cit., Supp. 4, pp.217-219, (1982), 292 pp. Miller, R.W., "Pollutants in Breast Milk," J. Pediat. 90(3) ~p.510-511 (1977)* Fourth Annual Report on Carcinogens, 1985 Summary, pp. 1702, National Toxicology Program, US-DHHS/PHS. NTP 85-002 (1985)* Carter, L.J.. "Michigan's PBB Incident: Chemical Mix-up Leads to Disaster," Science 192, 240-243 (Apr. 1976). PL 94-469, Toxic Substances Control Act, Section 6, "Regulation of Hazardous Substances and Mixtures," 90 STAT. 2020-2025 incl. (Oct. 11, 1976). Di Carlo, F.J.. J. Seifter and V.J. DeCarlo, "Assessment of the Hazards of Polybrominated Biphenyls," Environ. Health Perspect 23, 351-365 (1978) Jackson, T.F. and F.L. Halbert, "A Toxic Syndrome Associated with the Feeding of Polybrominated Biphenylcontaminated Protein Concentrate to Dairy Cattle," J. Amer. Veterinary Med. Assoc. 165 (5). 437-442 (1974) Allen, J.R.. L.K. Lambrecht and B.A. Barsotti, "Effects of Polybrominated Biphenyls on Non-human Primates," fbfd. 173(11) 1485-1489 (1978). Corbett. T.H., A.R. Beaudoin, R.Q. Cornell, M.R. Anver. R. Schumacher, J. Endres and M. Szwabowska, "Toxicity of Polybrominated Biphenyls (Firemaster "-6) in Rodents I I' Environ Res. 10, 390-396 (1975). 9

153 154 155

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(1973) Durst, H.I., L.B. Willett, F.L. Schanbacher and P.D. Moorhead. "Effects of PBBs on Cattle, I. Clinical Evaluations and Clinical Chemistry." EHP 23, 83-89 (1978). "Effects of PBBs Moorhead. P.D.. L.B. -and F.L. -, on Cattle, 11. Gross Pathology and Histopathology." loc. c L t . , pp.111-118. Dunckel. A.E.. "An Updating on the Polybrominated Biphenyl Disaster in Michigan." J. Am. Veterinary Med. Assn. 167,

838-841 (1975). Anderson, H.A., R. Lilis. I.J. Selikoff. K.D. Rosenman, J. A. Valciukas and S. Freedman, "Unanticipated Prevalence of

(el

160

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643-646 (1978). 161 162

Garmon, L.. "The State of PBB Contamination." Science News lZl(l7), 276 (Apr. 24, 1982). Review of Current DHHS. DOE and EPA Research Related to Toxicology, FY 1985. Toxicology Testing/NIEHS, p. 22-NTP-

85-056

(Mar.

1985).

Michigan Dept. of P.H.. PBB Epidemiology Study funded by the FDA Center for Food Safety end Applied Nutrition. Scheduled for testing during FY 1985 (Status B) Clinical Toxicology/Epidemiology, p. 52, NTP-85-056. Mt. Sinai School of Medicine, Immunologic Toxicity Study, NIEHS Contract NOl-ES-g-OO04 (Status A/1985) toc cLt. NIEHS, p. 22. East Carolina Univ. Reproductive/Developmental Toxicity Contract NOl-ES-0-0005 (Status B/l985): (2) Durham Women's

460

163

164

165 166

167

168

169 170

173

174 175 176

177

Clinic/NOl-ES-1-5006; (B/1985); (3) Wake Area Health Education Center/NOl-ES-0-0006 (811985) Bekesi, J.G., J. Roboz, A.S. Fischbein, J.P. Roboz, S. Solomon and J. Greaves, "Immunological. Biochemical and Clinical Consequences of Exposure to Polybrominated Biphenyls, I' pp. 393-406 in: Target Organ Series : 3 J . H . Dean, , (Ed.), Raven Press, New York (1985). Moses, M.. "Pesticides", pp. 731-750, in: Maxcy-Rosenau, Public Health and Preventive Medicine, 11th edn., John M. Last, M.D., D.P.H., (Ed.), Appleton/Century/Crofts, New York (1980). Pesticide Use Reports, Published annually by the California Department of Food and Agriculture, 1220 N. St.. Sacramento, CA, 95814. NIOSH Criteria f o r a Recommended Standard Occupational Exposure during the Manufacture and Formulation of Pesticides, DHEW (NIOSH) No. 78-174 US-GPO, Washington, DC (1978). 429 pp.. 343 refs., 5 appendices. Bidstrup. P., J . A . Bonnell and A. Beckett, "Paralysis following Poisoning by a New Organic Phosphorus Insecticide (Mipafox)". B r i t . Med. J . ( l ) 1068-1072 (1953). As c i t e d i n ref. 164. Agricultural Chemicals and Pesticides. A Subfile of the Registry of Toxic Effects of Chemical Substances, NIOSH, Cininnati, OH 45226 (July 1977). US-GPO, Washington, D.C. 20402. See chapter 3 of r e f . 2b, pp. 178-183 and detailed l i t e r a t u r e references a t the end of t h a t chapter. Qordon, J . E . and C.M. Shy, "Agricultural Chemical Use and Congenital Cleft L i p and/or Palate, " Arch. Envtron. Health 36, 213-221 (1981). Moses. M.. "Parathion and Phosdrin" in: Ford and J u s t i c e United Farm Workers, pp. 13-14 (Oct. 1985). t b t d , Feb/March 1986, pp. 4-6. National Toxicology Program, 1986 Annual Plan, USD/HHS/PHS, NTP 86-086 (May, 1986) 354 pp. ( 2 App., Chemical and CAS indices. 41 Tables, 5 Fig.) NTF' Review of Current DHHS, DOE and EPA Research Related t o Toxicolo , RTP Pub. Information Off., Res. Triangle Pk., N.C. 277%, Pub. No. NTP 86-087 (May, 1986), 132 pp. narrative and 201 p. Chem. Tables and 12 pp. App. "Selected Pesticides f o r Which There Have Been Some Concerns about a Teratogenic Potential." CA. Department of Food and Agriculture, Div. of P e s t Management, 1220 North S t . , Sacramento, C A . , 95814. HS-1091 (Rev. June 10, 1985). Oilman's Organic Chemistry: An Advanced Treatise, Vol. 11. "Physostigmine" pp. 1230-1232. H. Oilman et al., (Eds.), John Wiley and Sons, New. York and London, 2nd edn. (1944). Kuhr, J., and H.W. Dorough, Carbanate Insecticides: Chemistry Biochemistry and Toxicology, CRC Press (1976). Ooldstein, A., L. Aronow, and S.M. Kalman, Principles of Drug Action: The B a s i s of Pharmacology, Chapter 1, pp. 8 f f . John Wiley and Sons, Inc., New York (1974). 854 pp. WHO, Recommended Health-Based L i m i t s i n Occupational Exposure t o Pesticides, WHO Technical Rept. Series No. 677 (1982). See ref. 84b, p. 162 f o r the complete c i t a t i o n s . See the end of Chapter 111. ref. 2 f o r complete c i t a t i o n s . NIOSH Current Intelligence Bulletin 23, "Ethylene Dibromide

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180 181

182

183

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and Disulfiram Toxic Interaction," USDHEW/PHS/CDC/NIOSH (Apr. 11, 1978) ~ P P . NIOSH CIB 22. "Ethylene Thiourea," p . 1 USDHW/PHS/CDC. NIOSH Pub. No. 78-144 (Apr. 11. 1978). ii and 8pp. IARC, Monographs on the Evaluation of the Carcinogenic Risks of Chemicals to Humans. pp. 128-130, Supp. 4, Lyons, France (1982) 292 pp. Weisburger. E.K.. M.U. Eorge. J. Nam. J.J. Gart and J.H. Weisburger. "Carcinogenicity Tests of Certain Environmental and Industrial Chemicals," J. Natl. Cancer Inst., 67, pp. 75-88 (1981) National Toxicology Program, Fourth Annual Report on Carcinogens, "Ethylenethiourea. p. 109. NTP 85-002,USDHHS/PHS (1985) Summary, 333 PP. Newsome, W.H., Determination of Ethylene Thiourea Residues in Apples, J. Agr. Food Chem. 2 0 , 967-969 (1972). Stula, E.F., and W.C. Krauss. "Embryotoxicity in Rats and Rabbits from Cutaneous Application of bide-Type Solvents and Substituted Ureas," Toxic01 and App. Pharmacol. 41, 3555 (1977). Khera, K.S., and L. Tryphonas, "Ethylenethiourea-Induced Hydrocephalus; Pre- and Postnatal Pathogenesis in Offspring from Rats given a Single Dose During Pregnancy," ibid. 42, 85-97 (1977). As cited in ref. 180. Ruddick, J . A . , and K.S. Khera, "Pattern of Anomalies Following Single Oral Doses of Ethylenethiourea to Pregnant Rats," Teratology 12. 277-282 (1975). -, D.T. Williams, 'L. Hierlihy, and K.S. Khera. (C-14) Ethylene Thiourea, Distribution, Excretion and Metabolism in Pregnant Rats," fbtd, 13, 35-39 (1976). -, W.H. Newsome and L. Nash, "Correlation of Teratogenicity and Molecular Structure: Ethylenethiourea and Related Compounds,n i b i d . 13, 263-266 (1976). Lu, M.H. and R.E. Staples, "Teratogenicity of Ethvlenethiourea and and Thvroid Function in the Rat" Teratology 12, 171-178 (19$). Fishbein. L., "An Overview of the Structural Features of Some Mutagenic and Teratogenic Pesticides." in ref. 84. pp. 177-209. Schuphan. I., J.D. Rosen and J.E. Casida, "Novel Activation Mechanism for the Promutagenic Herbicide Diallate," Science 205, 1013-1015 (1979) Rosen. JID., Y. Segall and J.E. Casida, "Mutagenic Potency of Haloacroleins and Related Compourids, Mutat, Res., 78, 113-119 (1980). .~ Schardein, J.L. Chemically Induced Birth Defects, Chap. 22, "Pesticides", 577-617, Marcel Dekker. Inc.. N.Y. and Easel (.1985 1 . .. Storck. Wm.J.. "Pesticides Head for Recovery," in: PESTICIDE REPORT. Chem. Eng. N - 8 , 35-39 (Apr. 9, 1984). "Demand for Home and Garden Pesticides Spurs New -, Products." ibtd. 11-17 (Apr. 6. 1987). Zwerdling. D., "Pesticides." NPR Weekend Edition (Jan. 31 1987)* , o p . c i t . , NPR All Things Considered (Feb. 12, 1987 =, op. c i t . , NPR Morning Edition (Feb. 13. 1987). -, op. c i t . , NPR Morning Edition ( M a r . 7, 1987). -, o p . c i t . , NPR All Things Considered (May 20, 1987)I . -, op. c i t . , NPR Morning Edition (June 15, 1987). Zwerdling, et a1 "Chlordane" Tape AT-870122.01/01-C NPR

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~

185 186

187

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(1987). , "Pesticides. Effectiveness & Health Risksv', Tape AT830725 .Ol/Ol-C NPR (1983) Tapes are available for $24.90, mailing included, from Instructional Communications Systems, NPR Customer Service, Univ. of Wisconsin-Extension, Old Radio Hall, 975 Observatory Drive, Madison, WI 53706 (non-technical investigative reports.) Moses, M.. "Captan and Dinoseb". Pesticides: Toxics Report, United Farmworkers of America (1986). *'Captan", pp. 13-14, in: Food and Justice, 2(1) "Deadly Dozen" Pesticide Series, UFW (Jan. 1986). Moses, M., "The Poisons in our Food", fbfd, 3(4), pp. 12-13 (May. 1986). Anon., "FDA is Failing,", f b f d , 4(2). 3-5 (Feb., 1987). Anon., "Almost Slavery," fbfd, $(4), 15 (Apr., 1987). Sun, M.. IlEPA Proposal on Alachlor Nears," Science, 1143-4 (Sept. 12, 1986). Marshall, E., "The Rise and Decline of Temik," Ibfd, 229, 1369-71 (SePt. 27, 1985). Anon., "Melon Contamination: Toxic Effects Raise Pesticide Issue," Chem. Eng. News, 3-4 (July 15, 1985). Dillon, S., "The Food Biz: pesticides A Little Light," Food Monitor. no. 40. 15 (Spring, 1987). Anon. "Pesticides: Uniform food residue standard urged," Chem. Eng. News, a(21), 4-5 (May 25, 1987). Norman, Colin, "Regulating Pesticides: The Delaney Paradox," Science, 1054-5 (May 29. 1987). Abrams. L., ItAn Alar Apple a Day May be One Too Many," Health Letter, vol. 2, no. 3, Public Citizen Health Research Group, Dr. Sidney M. Wolfe. Editor (July/August, 1986). fbld, g(4) (Sept./Oct., 1986). Tufts University Diet and Nutrition Letter, 4(7), 7-8 (Sept. 1986). NRDC Newsline, vol. 5(2), (Apr./May. 1987). Oovernment Concentrates, "WA intends to reduce Alar residue levels,1vChem. Eng. News, &(3)19 (Jan. 19, 1987). Zurer, P a s , ,"Misconduct in Research, fbtd, @(15), 10-17 (Apr. 13, 1987). NRDC Newsline, 3(4), 3 (Oct./Nov. 1985). QAO, "Report to Congressional Requesters," PESTICIDES: Need to Enhmce FDA's Ability to Protect the Public from Illegal Residues, QAO/RCED-87-7 (Oct 1986) 58pp. -, "Report to the Honorable Frank Horton, House of Representatives," PESTICIDES: Better Sampling and Enforcement Needed on Imported Food, GAO/RCED-86-219 (Sept. 1986) 56pp. U.S. General Accountiw Office, P.O. Box 6015. Qaithersburg, MD 20877. Tel. 202-275-6241 (First 5 copies free; additional ccs $2.00 ea.. 25% discount for 100 or more ccs. Make checks or money orders out to the Superintendent of Documents). Anon.. "1985: The Environment in Review," EcoAlert, p. 1, Environmental Task Force (Winter, 1985). BHOPAL REPORT," A C&EN Special Issue, Chem. Eng. News, Q(16). pp. 14-65, (Feb. 11, 1985); Heylin. M., loc. cit., 3. 14-15; Lepkoweki, W., 'I. Appropriate Response ," 16-26; Worthy, W., "Methyl Isocyanate, The Chemistry of a Hazard," 27-33; Dagani. R . , "Data on MIC's Toxicity are

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a,

...

s,

...

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..

...

463

. . . 37-40; Weber. W., "Settlement or Litigation? . . 47-60;Ember, L.R.. "Technology in India: An Uneasy Balance of

Scant

.It

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Progress and Tradition." 61-65. Lepkowski, W. , "Ch&nical Safety in the Developing (C) Countries: The Lessons of Bhopal, fbfd, Q(14), 9-14 (April 8, 1985). Storck, W.J. and D. Webber, "Carbide's Anderson Explains Post-Bhopal Strategy," ibfd. Q, 9-15 (Jan. 21, 1985). Anon., Bhopal Update, loc. cft., 4-6. Lepkowki, W., Bhopal, fbfd, a(48) 18-32 . (Dec. 2, 1985). Mitra, A., "The Bhopal Disaster,*'New Internationalist,no. 144, 4 (Feb. 1985). Anon., "Bhopal: One Year Later," NRDC Newsline, 3(5). 1-2 (Dec./Jan. 1986) Baum, R . , "Cleanup Order for Polluted Reservoir Put on Hold," ZOC. cft. ( a ) , 18-20. Lewin. R., "Parkinson's Disease: An Environmental Cause?* Science, a(4710). 257-8 (July 19, 1985). Symposium on MPTP, Uniformed Services, U. of Health Sciences, Bethesda. MD (June 6-7. 1985). The 8th Int. Symposium on Parkinson's Disease, New York. (June 9-12, 1985). As cited in 194a. Worthy. W.. "Pesticide Chemists are Shifting Emphasis from Kill to Control," Chem. Fng. News, 62(30),22-26 (July 23, 1984). Anon., "EPA t o regulate inert pesticide ingredients." ibid. a(17) 5-6 (Apr. 27, 1987).

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466

SUBJECT INDEX Acrylonitrile, -, as a fumigant, 377 -, reproductive effects of,

-. 378

toxicity of. 377.378

Addictive drugs as neurobehavioral teratogens, -, alcohol, 275.276 -, cannabinoids. 275 -, opiates. 275 Agent Orange. 337.338 -, epidemiology of, 338, 339.340.341 -, teratogenicity of, 338 Aldrin, 329,330

Carbaryl, 392.393 -, metabolism of, 393

-.

Carbon disulfide, 370,371 reproductive hazards in men, 371 -, teratogenicity of, 371 - , toxicity of, 371

-.

Carbon tetrachloride, 369,370 toxicity of, 370

-.

Chemical exposure, at TLV(thresho1d limit values )levels, 244,245 -, census study on, 266 of students in undergraduate general chemistry laboratories,

-.

Animal models for human teratogenesis, 42.43

247 -. ofScandinavian working women in the countries.

Animal teratogenicity data, -, predictive values for the human situation , 42,241, 243,244 quantitative correlations with human data, 241

242,243 -, to exhaust fumes, 266 -, to metals, 266 -, to polycyclic aromatic hydrocarbons, 266 -, to solvents, 266 -, to textile dust, 266

-.

Arochlors , 342,346,347,348 Askarels, 344 Behavioral teratology. -, methodological aspects of, 296 -, tent batteries for, 298.299.300,301,302.303 Benzenehexachloride (BHC),

325.326.327.328

-, persistence in -,

environment. 328 toxicity of isomers, 328

Carbamate pesticides. 390 -, histom of. 391 -, metabolism of, 392,393 modes of absorption of,

-. 394

-

-,

symptoms of intoxication with. 393,394 teratogenicity of,

394 395.396 -, toxicology of, 393 t

-, uses of, 392

Chlordane. 334 - * toxicity of, 334

-. -.

Chlorinated benzenes, 325 benzenehexachloride (BHC), 325,326 327 328 dichlombenzenes (DCBs), 325 I 326 - , o-dichlorobenzene, 325 -, p-dichlorobenzene, 325 I

I

Chlorodecone (Kepone), see Kepone Chloroethanes, 371,372 -, toxicity of, 372 Chloroform. 368,369 -, toxicity of, 369 Cincinnati Behavioral Teratology Test Batteries, 299

466

Classification of workers by job exposure based on, -, personnel records of the local employees, 265 -, population census, 264 -, union records, 264 Collaborative Behavioral Teratology Study (CBTS), 299 2.4-D. 335 , toxicity of, 335,336

-

Data bases on teratology/teratogenicity,

6.7.8 -, bibliographic, 32

-.

computerized searching of, 14 -, for on-line computer systems, 21.24 -, RTECS data base, 43,44 -, scanning data base, 15 -, substructural searching of, 14 -, with peer-reviewed evaluations, 42

- , methylchlor, 324,325 Dibromochloropropane (DBCP), see DBCP Dichloromethane , 368 -, toxicity of, 368 Dieldrin, 329,330 Diquat ,

-, as herbicide, 403 -, reproductive effects of, 405 -, teratogenicity of, 405 , toxicology of, 403,404

-

Dioxane ,

-, as a fumigant, 378 -, reproductive effects of, 379

Dioxins , 336,337,338 -, dermatologic effects of,

336 -, epidemiology of, 338,339,340,341

-, in Seveso accident, Data extraction file in teratology, 15 file identifiers. 16

-. -.

DBCP (dibromochloropropane), as cause of low sperm count in humans, 365 -, as cause of sterility in males. 365

341.342

-, teratogenicity of, 337 339 -, use of, as defoliant South Vietnam, 337 t

Disulfiram, 397,398 -, as a fungicide, 397 reproductive hazards of,

-. 397

DDA, 320,324

-,

-.

-,

DDD, 318.324 environmental persistance of, 319 DDE, 320.324 DDT. 317,318,322 -, biochemistry of, 319,320 -, environmental persistance of, 319 estrogen-like activity, 322 -, insect resistance to, 319 metabolism of, 320 -, reproductive effects of, 322.323 teratogenicity of, 322

-. -.

-.

DDT analogs, 324 , methoxychlor, 318,324,325

-

in

synergistic effect with alcohol, 397 synergistic effect with ethylene dibromide,

397 398 I

Dithiocarbamates, 396,397 -, reproductive hazards of, to females. 397 -, reproductive hazards of, to males, 397 DNOC (4.6-dini tro-o-cresol), -, reproductive effects of, 403 -, toxicology of, 402,403 Drug-related teratogenicity, -, human risks data base, 19 -, of chemotherapeutic agents, 21,265,266

467

EDB (ethylene dibromide), 365 -, as a cause of sperm damage, 366 reproductive effects of,

-. -, .

Fumigants. 376.377 Haloalkanes of industrial importance. 365,366,367,372

366

toxicity of, 366

Endrin 329,330 Environmental Carcinogen Information Center:15

.

Environmental Mutagen Information Center (EMIC) 13.14 Environmental Teratology Information Center (ETIC),

8.46 -, key publication sources of. 9.10

Haloalkenes of industrial importance. 373,374 Heptachlor, 334 -, toxicity of, 334 Hexachlorophene (HCP), 326,327 Hexachlorobenzene (HCB). see Benzenehexachloride Hospital Discharge Register, -, data on spontaneous abortions, 262,263 -, Finnish. 262 -, pregnancy data, 263

Ethylene dibromide (EDB). see EDB Ethylene oxide (E") -, as a fumigant, 379,380 -, reproductive effects of,

380,381 -, toxicity of, 380,381 'Ethylenethiourea (ETU) , 398 -, reproductive effects of,

399.400 -, teratogenicity of, 399 400 toxicity of, 399 -, uses of, 399

-.

I

FPIC. see hvironmental Teratology Information Center

Insecticide classification, 317 -, carbamates, 317,390 organochlorines, 317 organophosphates,

-.-.

317.382

Inorganic pesticides, -, arsenic, 315 -, sulfide(s) of arsenic,

315 Japan Information Center of Science and Technology's On-Line Information System (JOIC). 15 Kepone (Chlorodecone),

330v 331 e 332 333 contamination with,

Em. see Ethylenethiourea Fetal accumulation of, -, alcohol, 279 -, metals, 278 -, therapeutic drugs, 278 Fetal alcohol syndrome (FAS).

275. 276 Food additives a neurobehavioral teratogens, -, lecithin, 273, 274 -, monosodium glutamate MSQ), 273,289,292 Firemaster,

-, BP-6, 354 FF-1, 354 - 1

331,332

kepone shakes, 331 reproductive hazards of,

332 as neurobehavioral teratogen, 272,289,290,

291 levels in the immature brain. 278 Lindane, 327,328 Long-term effects of chemicals on. -, behavior, 271 -, developing brain, 271

468

Male reproductive toxicology, 3

-, pathological e f f e c t on eyes, 332

Maneb,

-, t o x i c i t y

of,

394

Medical Literature Analysis and Retrieval System (MEDLAE1s). 15.25 -, MEDLARS on-line (MEDLINB) , 32,43 MEDLARS, see Medical Literature Analysis and Retrieval System

Naphthalene, -, as a fumigant, 377 -, t o x i c i t y of, 377 Natural pesticides, -, e a r l y h i s t o r y o f , 315,

316

-, e x t r a c t

of d e r r i s root, 315 -, pyrethrins. 315 -, rotenones, 315 -, tobacco e x t r a c t , 315

Mercury,

-, exposure t o , i n the undergraduate general chemistry laboratories, 250 251 I

Neurobehavioral teratology, -, methoaological aspects o f , 296 -, test b a t t e r i e s for. 298 299,300.301,302,303 I

Methodological issues in neurobehavioral teratology. -, choice of proper control, 297 choice of statistical u n i t , 296 -, dose-effect rel’ations, 297 mode of fostering of PUPS, 296 -, role of cagemate behavior, 297 -, r o l e of maternal s t r e s s , 297 -, r o l e of placebo treated group, 297 -, r o l e of pup-dam interactions, 296 -, r o l e of untreated group, 297

-. -.

Methyl bromide, 367 -, uses o f , 367 Methylene chloride, see Dichloromethane Methylmercury, -, as cause of Minamata disease, 272 -, as neurobehavioral teratogen, 272,278,287. 290 295 t 299 -, concentration i n the f e t u s , 278 -, concentration i n the i n f a n t , 278 MiEx e 332 t 333

NLM. see National Library of

Medicine National Library of Medicine

8.43 Occupational exposure. -, census study on, 266 -, d a t a from company records, 260 -, data from union records, 260,264 -, interview d a t a on, 260 -, relationship with pregnancy outcome, 260 Occupational hazards, -, a s r e l a t e d , t o the t r a d i t i o n a l female occupations, 242 -, f o r women vs men, 242 -, i n smaller enterprises vs large industry, 264

OPPs, see Organophosphorus pesticides

-. -.

Organochlorine insecticides, chlorinated benzenes. 325 -, DDD, 318 DDT, 317.318 -, DDT analogs, 324 , hexachlorophene, 326,327 -, metabolism of, 320,321

-

469

-, modes of action of, 319 * 320 -, reproductive effects of, 322 teratogenicity of, 322

-.

Organophosphorus pesticides (opps), 382 -, absorption of. 384 - , neurotoxicity of, 384,385 -, reproductive effects of,

-. 387.388

reproductive effects of, in humans, 388,389 symptoms associated with poisoning by, 385,386,387 -, teratogenicity of,

-.

387.388 -, teratogenicity of, in humans, 388,389 toxicology of * 383,384,385

-*

humans, 361.362

-, toxicity of, as compared to PCBs, 357

-.

uses of, 353,354

PCBs (polychlorinated biphenyls), absorption of, 346 -, as a cause of "Spinning Syndrome", 348 as neurobehavioral teratogens, 273 -, environmental contamination by, 349,350 -, industrial names of, 342 -, levels of, in milk, 350 -, metabolism of, 345,346 -, photodechlorination of,

-. -.

343

-, poisoning by, 351 -, reproductive effects of, in animals, 346,347,348

Paraquat, -, as herbicide, 403 reproductive effects of, 405 -, teratogenicity of, 405 - , toxicology of, 403.404

-.

Passage of chemicals into the fetus, 277. 278 Passage of chemicals into the infant, -, via ingested mother's milk, 278 -, via undeveloped bloodbrain barrier, 278 PBBs (polybrominated biphenyls) ,

353

-, reproductive effects of, in humans, 349

-, risks of exposure to,

344 1345

-, toxicity of, 345.347.351.352

-, toxicity of, as compared to PBBs, 357 -, uses of, 343,344 PCDDs (polychlorinated dibenzodioxins) , 344 PCE (perchloroethylene), 375 -, reproductive effects of, 376 -, toxicity of, 376 Pentachlorophenol (PCP), 325

-, endocrine effects of, in animals. 358,359

Pesticides classification, 317

-, endocrine effects of, in

-. -. 362,363

humans, 362,363 gas chromatographic analysis of, 355.356 levels of, in human milk,

metabolism of, 358 -.-, poisoning by. in Michigan. 354,355,356.

357.358 -, reproductive effects of, in animals, 358,359,360,361 -, reproductive effects of, in humans, 362,363 -, toxic effects of, in

Pesticide information, -, Agrochemical Handbook, 317 -, sources, 317 -, The Pesticide Index, 317 Placental permeability to, -, lipophilic chemicals,

277

-, nonionized chemicals, 277

-, therapeutic drugs, 278 Polybrominated biphenyls (PEES). see PBBs

410

Polychlorinated biphenyls (PCBs), see PCBs Pregnancy outcome of, , butchers , 267 -, laboratory assistants, 267 -, nurses, 265 -, weavers, 267 -, workers caring for furbearing animals, 267 -, workers i n occupations related to cutting and sewing fabric, 267 -, workers i n the pharmaceutical industry, 268,269 workers i n the p l a s t i c industry , 267 ,268

-

-.

Psycho-active substances as neurobehavioral teratogens , alcohol, 275,276,277 -, caffeine, 276 , tobacco smoke, 276,277

-

Register of Congenital Malformation. Finnish. 262,263

-.

Register of Health Care Personnel, Central, -, Finnish, 264 Registry of Toxic Effects of Chemical Substances (RTECS), -, computer search of, 43 -, key words used f o r searching of teratogens,

-,

43

subfile on teratogens, 43

Reproductive epidemiology, 240 -, environmental studies, 240 -, food poisoning studies, 240 -, occupational studies, 240,241,260 -, studies of exposure i n hospitals, 241 Reproductive hazards, -? a f t e r b i r t h , 239 -, during pregnancy, 239,240 -, i n industry, 239 -, preconceptional, 239 Reproductive toxic effects, -, e f f e c t s on embryo or

fetus.

-, e f f e c t s -, e f f e c t s

44

on f e r t i l i t y , 44 on newborn, 44 -, maternal e f f e c t s , 44 -, paternal e f f e c t s , 44 -, specific developmental abnormalities, 44 Reproductive toxicity , -, mechanism o f , 239 -, of laboratory solvents, 240,243 Reproductive Toxicology Center, 20 RTECS, see Registry of Toxic Effects of Chemical Substances Safe handling of teratogenic chemicals , 256 -, general safety procedure. 256 , i n laboratories , 256,257 -, i n the community, 259 -, i n the industrial operations, 258

-

S(Chloroallyl)dithiocarbamates, 400,401 , toxicity of, 401,402

-

S(Chlomally1) thiocarbamates, 400,401 , toxicity o f , 401.402

-

Silvex. 342 Structure-Activity Relationship (SAR) of teratogens, -, computer-assisted multivariate SAR. 42 -, quantitative methods, 42 Synthetic pesticides -, ecological concerns about the use o f , 316 -, social concerns about the use o f , 316 2.4.5-T. 335 -, as a cause of miscarriage, 341 , toxicity o f , 335,336

-

TCDD, 336 -, embryotoxicity o f ,

337.338

47 1

-, teratogenicity o f , 337,338,339 Teratogen Information System, -, of the Food and Drug Administration, 20,21 -, of the University of texas Health Science Center a t Dallas. 20 Teratogenic behavioral developmental e f f e c t s o f , alcohol, 287,288 alpha-me thyldopa , 286,289 aluminum. 292 amphetamine, 289,290,292 barbiturates , 292 benzodiazepines , 287 cannabis, 291 chlorpromazine , 289,290, 292 clomipramine, 285,289,291 clonazepam, 290 Clonidine , 285,286, 289.292 diazepam, 287,288,290 haloperidol, 290 heroin, 287 imipramine, 290,291 kanamycin, 289 meprobamate, 289,292 methadone, 287,288,290 methylmercury , 287,288, 289 morphine, 292 phenobarbital, 289,290 reserpine, 289,292 mc. 291 theophylline, 286,287 Teratogenic brain developmental derangements, e f f e c t s on biochemical measures of brain cell growth and maturation, 280 e f f e c t s on brain elect~hysiological a c t i v i t y , 283 e f f e c t s on brain receptors and neurocheais t r y , 282,283 e f f e c t s on brain structure, 280,281,282 e f f e c t s on prenatal motility. 284 endocrine e f f e c t s influencing neuronal development, 284

Teratogenic e f f e c t s of chemicals on, -, food and water intake, 295,296 -, sexual behavior, 294 social behavior, 294

-.

Teratogenic e f f e c t s of chemicals on development o f , -, a c t i v i t y and exploration, 289 -, coordination, 288 , neuromo t o r capacity , 288 -, reflexes, 288 , sensory capacity, 288

-

Teratogenic e f f e c t s of chemicals on learning behavior i n , -, active avoidance, 293 -, appetitive learning, 290 aversive learning, 292 -, conditioned t a s t e aversion. 293,294 -, maze behavior, 291 passive avoidance, 293 Skinnerbox performance, 292 -, water maze learning. 294

-. -.-.

Teratogenic e f f e c t s on learning behavior o f , amphetamine, 292 -, chlorpromazine, 292.293 clomipramine, 292 -, delta-g-THC, 293 -, ethanol, 293 -, haloperidol, 292 imipramine. 294 -, lead, 293 meprobamate, 293 -, methadone, 293 -, naloxone, 294 pargyline, 293 , phenobarbital, 293 , pyridos tigmine, 293 -, reserpine, 293 -, vitamin A

-. -. -.

-. -.

-

Teratogenic e f f e c t s on sexual behavior o f , , alpha-methyldopa, 295 clomipramine, 295 -, clonidine, 295 -, delta-9-THC -, pargyline, 294 , pyridost i p i n e , 294,295 -, reserpine, 294 , tes toeterone

--.

-

472

Teratogenic effects on social behavior of, -, clonazepam, 295 -, diazepam, 295 lorazepam, 295 -, methadone, 295 -, methylmercury, 295

-.

Tetrachloroethylene, see PCE Therapeutically used drugs as neurobehavioral teratogens. -, anesthetics, 275 , anticonvulsants, 274 -, antihypertensive agents,

-

274

Teratogenic neurobehavioral effects on, -, human fetus, 271,272 -, human infant, 271,272 -, laboratory animals,

271,272 Teratogens, in undergraduate general chemistry laboratories,

247,249,252 list of names,

1.4,17.18,43,45~ 6 ~ 4 7 238 literature-sourceson, primary, 9,lO literature sources on, secondary, 21,22,23 reference books on,

1,2,3,33,34

- , barbiturates, 274 - , benzodiazepines, 274

-, betamethasone, 275 -, caffeine. 275 -, corticosteroids, 275 -, diethylstilbestrol (DES), 274 -, morphine, 292 - , neuroleptics, 274 -, neuropeptides, 275 - , thalidomide, 274

-, theophylline. 275 -, tricyclic

antidepressants, 274 Toxaphene. 333 -, environmental persistence of, 333 -, teratogenicity of, 333 , toxicity of, 333,334

-

with low safety margins,

244 Teratogens. neurobehavioral, addictive drugs, 275 combination of various chemicals, 277 food additives, 273 in polluted environment,

272

in polluted food, 272 lead, 272,289,290,291 methylmercury,

272,278,287,290 polychlorinated biphenyls, 273 psycho-active substances, 276,277 therapeutically used drugs, 274 vitamin A, 273 Teratology Information Services,

34 135

-, California Teratogen -

-, -,

Registry, 34,35 European Information Services, 35.36 Genetic Amniocenteqis Office of the University of Michigan, 35

Toxicology Information On-Line

(TOXLINE), a,15,3o -, searching ETIC on, 36.37.38.39 TOXLINE, see Toxicology Information On-Line Trichloroethylene, 374,375 -, metabolism of, 375 -, reproductive hazards of,

375

-, toxicity of, 375 Vinyl halides, 373,374 , toxicity of, 373,374

-

Vitamin A ,

-, as neurobehavioral teratogen. 273,292 Zineb,

-, reproductive effects of, 397 toxicity of, 394 - 1