ACRYLONITRILE - who.int · This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of

This report contains the collective views of an international group of experts and does notnecessarily represent the decisions or the stated policy of the United Nations EnvironmentProgramme, the International Labour Organization, or the World Health Organization.

Concise International Chemical Assessment Document 39

ACRYLONITRILE

Please note that the layout and pagination of this pdf file are not necessarily identital tothose of the printed copy

First draft prepared by G. Long and M.E. Meek, Health Canada, Ottawa, Canada, andP. Cureton, Environment Canada, Ottawa, Canada

Published under the joint sponsorship of the United Nations Environment Programme, theInternational Labour Organization, and the World Health Organization, and produced within theframework of the Inter-Organization Programme for the Sound Management of Chemicals.

World Health OrganizationGeneva, 2002

The International Programme on Chemical Safety (IPCS), established in 1980, is a joint ventureof the United Nations Environment Programme (UNEP), the International Labour Organization (ILO),and the World Health Organization (WHO). The overall objectives of the IPCS are to establish thescientific basis for assessment of the risk to human health and the environment from exposure tochemicals, through international peer review processes, as a prerequisite for the promotion of chemicalsafety, and to provide technical assistance in strengthening national capacities for the sound managementof chemicals.

The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) wasestablished in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO,the United Nations Industrial Development Organization, the United Nations Institute for Training andResearch, and the Organisation for Economic Co-operation and Development (Participating Organiza-tions), following recommendations made by the 1992 UN Conference on Environment and Developmentto strengthen cooperation and increase coordination in the field of chemical safety. The purpose of theIOMC is to promote coordination of the policies and activities pursued by the Participating Organizations,jointly or separately, to achieve the sound management of chemicals in relation to human health and theenvironment.

WHO Library Cataloguing-in-Publication Data

Acrylonitrile.

(Concise international chemical assessment document ; 39)

1.Acrylonitrile - toxicity 2.Risk assessment 3.Environmental exposure4.Occupational exposure I.International Programme on Chemical Safety II.Series

ISBN 92 4 153039 1 (NLM Classification: QV 633) ISSN 1020-6167

The World Health Organization welcomes requests for permission to reproduce or translate itspublications, in part or in full. Applications and enquiries should be addressed to the Office of Publications,World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information onany changes made to the text, plans for new editions, and reprints and translations already available.

©World Health Organization 2002

Publications of the World Health Organization enjoy copyright protection in accordance with theprovisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.

The designations employed and the presentation of the material in this publication do not imply theexpression of any opinion whatsoever on the part of the Secretariat of the World Health Organizationconcerning the legal status of any country, territory, city, or area or of its authorities, or concerning thedelimitation of its frontiers or boundaries.

The mention of specific companies or of certain manufacturers’ products does not imply that they areendorsed or recommended by the World Health Organization in preference to others of a similar naturethat are not mentioned. Errors and omissions excepted, the names of proprietary products aredistinguished by initial capital letters.

The Federal Ministry for the Environment, Nature Conservation and Nuclear Safety, Germany,provided financial support for the printing of this publication.

Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10

iii

TABLE OF CONTENTS

FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1. EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

3. ANALYTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

4.1 Natural sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64.2 Anthropogenic sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64.3 Production and use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION . . . . . . . . . . . . . . . . . . . . . . 7

5.1 Air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75.2 Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75.3 Soil and sediment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75.4 Biota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85.5 Environmental partitioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

6.1 Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96.1.1 Ambient air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96.1.2 Indoor air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96.1.3 Surface water and groundwater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96.1.4 Drinking-water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106.1.5 Soil and sediment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106.1.6 Food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106.1.7 Multimedia study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

6.2 Human exposure: environmental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106.3 Human exposure: occupational . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS ANDHUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . . . 14

8.1 Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148.2 Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

8.2.1 Skin irritancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148.2.2 Eye irritancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148.2.3 Respiratory tract irritancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148.2.4 Sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

8.3 Short-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148.4 Medium-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158.5 Long-term exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

8.5.1 Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158.5.2 Drinking-water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16


iv

8.5.3 Gavage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208.6 Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

8.6.1 In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208.6.2 In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

8.7 Reproductive toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218.8 Neurological effects and effects on the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228.9 Mode of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

8.9.1 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228.9.2 Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

9. EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

10.1 Aquatic organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2510.2 Terrestrial organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2610.3 Microorganisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

11.1 Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 11.1.1 Hazard identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

11.1.1.1 Effects in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2711.1.1.2 Effects in experimental animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

11.1.2 Dose–response analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2911.1.2.1 Effects in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2911.1.2.2 Effects in experimental animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

11.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 11.1.4 Uncertainties and degree of confidence in human health risk characterization . . . . . . . . . . . . . . . . . . . . 3211.2 Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

11.2.1 Assessment end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3311.2.1.1 Aquatic end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3311.2.1.2 Terrestrial end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

11.2.2 Sample environmental risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3311.2.2.1 Aquatic organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

11.2.2.2 Terrestrial organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3411.2.2.3 Discussion of uncertainty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

APPENDIX 1 — SOURCE DOCUMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

APPENDIX 2 — CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

APPENDIX 3 — CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

RÉSUMÉ D’ORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

RESUMEN DE ORIENTACIÓN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

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FOREWORD

Concise International Chemical AssessmentDocuments (CICADs) are the latest in a family ofpublications from the International Programme onChemical Safety (IPCS) — a cooperative programme ofthe World Health Organization (WHO), the InternationalLabour Organization (ILO), and the United NationsEnvironment Programme (UNEP). CICADs join theEnvironmental Health Criteria documents (EHCs) asauthoritative documents on the risk assessment ofchemicals.

International Chemical Safety Cards on therelevant chemical(s) are attached at the end of theCICAD, to provide the reader with concise informationon the protection of human health and on emergencyaction. They are produced in a separate peer-reviewedprocedure at IPCS. They may be complemented byinformation from IPCS Poison Information Monographs(PIM), similarly produced separately from the CICADprocess.

CICADs are concise documents that provide sum-maries of the relevant scientific information concerningthe potential effects of chemicals upon human healthand/or the environment. They are based on selectednational or regional evaluation documents or on existingEHCs. Before acceptance for publication as CICADs byIPCS, these documents undergo extensive peer reviewby internationally selected experts to ensure theircompleteness, accuracy in the way in which the originaldata are represented, and the validity of the conclusionsdrawn.

The primary objective of CICADs is characteri-zation of hazard and dose–response from exposure to achemical. CICADs are not a summary of all available dataon a particular chemical; rather, they include only thatinformation considered critical for characterization of therisk posed by the chemical. The critical studies are,however, presented in sufficient detail to support theconclusions drawn. For additional information, thereader should consult the identified source documentsupon which the CICAD has been based.

Risks to human health and the environment willvary considerably depending upon the type and extentof exposure. Responsible authorities are stronglyencouraged to characterize risk on the basis of locallymeasured or predicted exposure scenarios. To assist thereader, examples of exposure estimation and riskcharacterization are provided in CICADs, wheneverpossible. These examples cannot be considered asrepresenting all possible exposure situations, but areprovided as guidance only. The reader is referred to EHC

1701 for advice on the derivation of health-basedguidance values.

While every effort is made to ensure that CICADsrepresent the current status of knowledge, new informa-tion is being developed constantly. Unless otherwisestated, CICADs are based on a search of the scientificliterature to the date shown in the executive summary. Inthe event that a reader becomes aware of new informa-tion that would change the conclusions drawn in aCICAD, the reader is requested to contact IPCS to informit of the new information.

Procedures

The flow chart on page 2 shows the proceduresfollowed to produce a CICAD. These procedures aredesigned to take advantage of the expertise that existsaround the world — expertise that is required to producethe high-quality evaluations of toxicological, exposure,and other data that are necessary for assessing risks tohuman health and/or the environment. The IPCS RiskAssessment Steering Group advises the Co-ordinator,IPCS, on the selection of chemicals for an IPCS riskassessment, the appropriate form of the document (i.e.,EHC or CICAD), and which institution bears theresponsibility of the document production, as well as onthe type and extent of the international peer review.

The first draft is based on an existing national,regional, or international review. Authors of the firstdraft are usually, but not necessarily, from the institutionthat developed the original review. A standard outlinehas been developed to encourage consistency in form.The first draft undergoes primary review by IPCS andone or more experienced authors of criteria documents toensure that it meets the specified criteria for CICADs.

The draft is then sent to an international peerreview by scientists known for their particular expertiseand by scientists selected from an international rostercompiled by IPCS through recommendations from IPCSnational Contact Points and from IPCS ParticipatingInstitutions. Adequate time is allowed for the selectedexperts to undertake a thorough review. Authors arerequired to take reviewers’ comments into account andrevise their draft, if necessary. The resulting second draftis submitted to a Final Review Board together with thereviewers’ comments.

1 International Programme on Chemical Safety (1994)Assessing human health risks of chemicals: derivation ofguidance values for health-based exposure limits. Geneva,World Health Organization (Environmental Health Criteria170).


2

SELECTION OF HIGH QUALITYNATIONAL/REGIONAL

ASSESSMENT DOCUMENT(S)

CICAD PREPARATION FLOW CHART

FIRST DRAFTPREPARED

REVIEW BY IPCS CONTACT POINTS/SPECIALIZED EXPERTS

FINAL REVIEW BOARD 2

FINAL DRAFT 3

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

SELECTION OF PRIORITY CHEMICAL

1 Taking into account the comments from reviewers.2 The second draft of documents is submitted to the Final Review Board together with the reviewers’ comments.3 Includes any revisions requested by the Final Review Board.

REVIEW OF COMMENTS (PRODUCER/RESPONSIBLE OFFICER),PREPARATION

OF SECOND DRAFT 1

PRIMARY REVIEW BY IPCS (REVISIONS AS NECESSARY)

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A consultative group may be necessary to adviseon specific issues in the risk assessment document.

The CICAD Final Review Board has severalimportant functions:

– to ensure that each CICAD has been subjected toan appropriate and thorough peer review;

– to verify that the peer reviewers’ comments havebeen addressed appropriately;

– to provide guidance to those responsible for thepreparation of CICADs on how to resolve anyremaining issues if, in the opinion of the Board, theauthor has not adequately addressed all commentsof the reviewers; and

– to approve CICADs as international assessments.

Board members serve in their personal capacity, not asrepresentatives of any organization, government, orindustry. They are selected because of their expertise inhuman and environmental toxicology or because of theirexperience in the regulation of chemicals. Boards arechosen according to the range of expertise required for ameeting and the need for balanced geographicrepresentation.

Board members, authors, reviewers, consultants,and advisers who participate in the preparation of aCICAD are required to declare any real or potentialconflict of interest in relation to the subjects underdiscussion at any stage of the process. Representativesof nongovernmental organizations may be invited toobserve the proceedings of the Final Review Board.Observers may participate in Board discussions only atthe invitation of the Chairperson, and they may notparticipate in the final decision-making process.


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1. EXECUTIVE SUMMARY

This CICAD on acrylonitrile was prepared jointlyby the Environmental Health Directorate of HealthCanada and the Commercial Chemicals EvaluationBranch of Environment Canada based on documentationprepared concurrently as part of the Priority SubstancesProgram under the Canadian Environmental ProtectionAct (CEPA). The objective of assessments on PrioritySubstances under CEPA is to assess potential effects ofindirect exposure in the general environment on humanhealth as well as environmental effects. Data identifiedas of the end of 31 May 1998 (environmental effects) andApril 19981 (human health effects) were considered inthis review. Other reviews that were also consultedinclude US EPA (1980, 1985), IPCS (1983), ATSDR (1990),IARC (1999), and EC (2000). Information on the nature ofthe peer review and availability of the source document(Environment Canada & Health Canada, 2000) ispresented in Appendix 1. Information on the peer reviewof this CICAD is presented in Appendix 2. This CICADwas approved as an international assessment at ameeting of the Final Review Board, held in Geneva,Switzerland, on 8–12 January 2001. Participants at theFinal Review Board meeting are listed in Appendix 3. TheInternational Chemical Safety Card on acrylonitrile (ICSC0092), produced by the International Programme onChemical Safety (IPCS, 1993), has also been reproducedin this document.

Acrylonitrile (CAS No. 107-13-1) is a volatile,flammable, water-soluble liquid at room temperature. Thelarge majority of acrylonitrile in Canada is used as afeedstock or chemical aid in the production of nitrile-butadiene rubber and in acrylonitrile-butadiene-styreneand styrene-acrylonitrile polymers. Estimated worldcapacity in 1993 was about 4 million tonnes. Major areasof production are the European Union (>1.25 milliontonnes per year), the USA (approximately 1.5 milliontonnes per year), and Japan (approximately 0.6 milliontonnes per year).

Acrylonitrile is released into the environment pri-marily from chemical production and the chemical andplastic products industries (>95% in the samplecountry). There are no known natural sources.

Acrylonitrile is distributed largely to the environmentalcompartments to which it is principally released (i.e., airor water), with movement to soil, sediment, or biotabeing limited; reaction and advection are the majorremoval mechanisms. In limited surveys in the countryon which the sample risk characterization is based (i.e.,Canada), acrylonitrile has been detected in the generalenvironment only in the vicinity of industrial sources.

Occupational exposure to acrylonitrile occursduring production and its use in the manufacture ofother products; potential for exposure is greater in thelatter case, where the compound may not be as easilycontained. Based on recent data for countries in theEuropean Union, time-weighted-average (TWA) expo-sures are #0.45 ppm (#1 mg/m3) during production and#1.01 ppm (#2.2 mg/m3) in various end uses.

Acrylonitrile is rapidly absorbed via all routes ofexposure and distributed throughout examined tissues.There is little potential for significant accumulation inany organ, with most of the compound being excretedprimarily as metabolites in the urine within the first 24–48h following administration. Available data are consistentwith conjugation to glutathione being the major detoxifi-cation pathway, while oxidation to 2-cyanoethyleneoxide is considered an activation pathway.

Available data from studies in animals indicate thatacrylonitrile is a skin, respiratory, and severe eye irritant.Acrylonitrile may cause allergic contact dermatitis, butthe available data are inadequate to assess its sensitiza-tion potency. With the exception of developmental tox-icity, for which effects (fetotoxic and teratogenic) havenot been observed at concentrations that were not toxicto the mothers, available data on other non-neoplasticeffects in experimental animals are inadequate to charac-terize exposure–response. In the few studies in humanpopulations in which non-neoplastic effects of acrylo-nitrile have been systematically investigated, only acutedermal irritation has been reported consistently.

Based on studies in animals, cancer is the criticalend-point for effects of acrylonitrile on human health. Arange of tumours in rats — including those of the centralnervous system (brain and/or spinal cord), ear canal,gastrointestinal tract, and mammary glands — has beenconsistently observed following both ingestion andinhalation. In almost all adequate bioassays, there havebeen reported increases in astrocytomas of the brain andspinal cord, which are rarely observed spontaneously;these have occurred at highest incidence consistentlyacross studies. Increases have been statistically signifi-cant, and there have been clear dose–response trends.Tumours have sometimes been reported at non-toxicdoses or concentrations and at periods as early as7–12 months following onset of exposure. Tumours have

1 New information flagged by the reviewers or obtained in aliterature search conducted prior to the Final Review Boardmeeting has been scoped to indicate its likely impact on theessential conclusions of this assessment, primarily to establishpriority for its consideration in an update. More recentinformation not critical to the hazard characterization orexposure–response analysis, considered by reviewers to add toinformational content, has been added.

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also been observed in exposed offspring of a multigener-ation reproductive study at 45 weeks.

Increases in cancer incidence have not been con-sistently observed in available epidemiological studies.However, the meaningful quantitative comparison of theresults of these investigations with those of studies inanimals is precluded by inadequate data on mode ofinduction of brain tumours, relative paucity of data onexposure of workers in the relevant investigations, andthe wide range of the confidence limits on the standard-ized mortality ratios for cancers of possible interest inthe epidemiological studies.

In numerous studies on the genotoxicity of acrylo-nitrile involving examination of a broad spectrum of end-points both in vitro, with and without metabolic activa-tion, and in vivo in mice and rats, the pattern of resultshas been quite mixed, while the metabolite, cyanoethyl-ene oxide, is mutagenic. Although direct evidence is notavailable, based on available data, it is reasonable toassume that induction of tumours by acrylonitrileinvolves direct interaction with genetic material. Theweight of evidence for other potential modes of induc-tion of tumours is inadequate. Acrylonitrile or its epoxidecan react with macromolecules.

Cancer is considered the critical end-point forquantification of exposure–response for risk characteri-zation for acrylonitrile. The lowest tumorigenic concen-tration (TC05, the concentration that causes a 5%increase in tumour incidence over background) (humanequivalent value) was 2.7 ppm (6.0 mg/m3) for thecombined incidence of benign and malignant tumours ofthe brain and/or spinal cord in female rats exposed byinhalation. This equates to a unit risk of 8.3 × 10–3 permg/m3.

Although limited, available data are consistentwith air being the principal medium of exposure of thegeneral population to acrylonitrile; intake from othermedia is likely to be negligible in comparison. The focusof the human health risk characterization is populationsexposed through air in the vicinity of industrial sources.Based on the margins between carcinogenic potencyand limited available data on predicted and measuredconcentrations of acrylonitrile primarily in the vicinity ofpoint sources in the sample risk characterization, risks inthe vicinity of industrial point sources are >10–5.

In the sample environmental risk characterization,levels in treated industrial wastewaters are less than theestimated no-effects value (ENEV) for the most sensitiveaquatic organism, and predicted maximum levels (near achemical industry processing plant) are less than theENEV for the most sensitive terrestrial organism.

2. IDENTITY AND PHYSICAL/CHEMICALPROPERTIES

Acrylonitrile is also known as acrylic acid nitrile,acrylon, carbacryl, cyanoethylene, fumigrain, propene-nitrile, 2-propenenitrile, propenoic acid nitrile, propylenenitrile, VCN, ventox, and vinyl cyanide. Its ChemicalAbstracts Service (CAS) number is 107-13-1, its molecu-lar formula, C3H3N, and its relative molecular mass, 53.06.The molecular structure of acrylonitrile is presented inFigure 1.

C C

NC

HH

H

Fig. 1: Chemical structure of acrylonitrile.

The physical and chemical properties of acrylo-nitrile are presented in Table 1. At room temperature,acrylonitrile is a volatile, flammable, colourless liquidwith a weakly pungent odour (IPCS, 1983). Acrylonitrilehas two chemically active sites, at the carbon–carbondouble bond and at the nitrile group, where it undergoesa wide variety of reactions. It is a polar molecule becauseof the presence of the cyano (CN) group. It is soluble inwater (75.1 g/litre at 25 °C) and miscible with mostorganic solvents. The vapours are explosive, withcyanide gas being produced.

Acrylonitrile may polymerize spontaneously andviolently in the presence of concentrated caustic acid,on exposure to visible light, or in the presence ofconcentrated alkali (IPCS, 1983). Hence, it is storedaccordingly, often as an acrylonitrile–water formulationthat acts as a polymerization inhibitor (Kirk et al., 1983).Spontaneous polymerization during storage andtransport can also be prevented by the addition of aninhibitor, typically hydroquinone methyl ether (NICNAS,2000).

3. ANALYTICAL METHODS

The most common method for analysis of acrylo-nitrile is gas chromatography. Method S156 of the USNational Institute for Occupational Safety and Health(NIOSH, 1978, 1994) specifies sampling with activatedcharcoal sorption tubes, rinsing with methanol, andsubsequent analysis by gas chromatography with anitrogen–phosphorus detector. The working range ofthis method is 0.5–31 ppm (1–68 mg/m3) for a 15-litresample. The estimated limit of detection is 0.02 ppm


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Table 1: Physical and chemical properties of acrylonitrile.a

Property Mean (range) Reference

Density at 20 °C (g/litre) 806 American Cyanamid Co., 1959

Melting point (°C) !83.55 Riddick et al., 1986; Budavari et al., 1989

Boiling point (°C) 77.3 Langvardt, 1985; Howard, 1989

Water solubility at 25 °C(g/litre)

75.1 Martin, 1961; Spencer, 1981; Langvardt, 1985; Howard, 1989;DMER & AEL, 1996

Solubility Miscible with mostorganic solvents

American Cyanamid Co., 1959

Vapour pressure at 25 °C (kPa) 11 (11–15.6) Groet et al., 1974; Riddick et al., 1986; Banerjee et al., 1990; BG-Chemie, 1990; Mackay et al., 1995

Henry’s law constantb at 25 °C(Pa@m3/mol)

11 (8.92–11.14) Mabey et al., 1982; Howard, 1989; Mackay et al., 1995

Log organic carbon/waterpartition coefficient (log Koc)

1.06 (!0.09 to 1.1) Koch & Nagel, 1988; Walton et al., 1992

Log octanol/water partitioncoefficient (log Kow)

0.25 (!0.92 to 1.2) Collander, 1951; Pratesi et al., 1979; Veith et al., 1980; Tonogai etal., 1982; Tanii & Hashimoto, 1984; Sangster, 1989; DMER & AEL,1996

Log bioconcentration factor(log BCF) in fish

0.48–1.68 Barrows et al., 1980; Lech et al., 1995

Half-life (t ½)

air (h) 55 or 96 (4–189)96 (13–198)

Callahan et al., 1979; Cupitt, 1980; Atkinson, 1985; DMER & AEL,1996 Atkinson et al., 1992

water (h) 170 (30–552) Going et al., 1979; Howard et al., 1991

soil (h) 170 (30–552) Howard et al., 1991

sediment (h) 550 DMER & AEL, 1996c

a Conversion factors between concentration by weight and concentration by volume: 1 mg/m3 = 0.4535 ppm (20 °C, 101.3 kPa); 1ppm in air = 2.205 mg/m3.

b Vapour pressure (at given temperature) × molar mass/water solubility (at same temperature).c No specific sediment value was found in the literature; this is based on the assumption of slower reactivity compared with soils

(DMER & AEL, 1996).

(0.04 mg/m3). The US Occupational Safety and HealthAdministration specifies a similar method of samplingwith charcoal tubes, desorption with acetone, andsubsequent analysis with gas chromatography using anitrogen–phosphorus detector. The detection limit forthis method is 0.01 ppm (0.026 mg/m3) (OSHA, 1982,1990). Health and Safety Executive (1993, 2000) specifiesadditional methods using porous polymer adsorptiontubes and thermal desorption with gas chromatographicanalysis.

A method has been developed for monitoring ofexposure to acrylonitrile by determination of the adduct,N-(2-cyanoethyl)valine, formed in the reaction ofacrylonitrile with the N-terminal group of haemoglobin(Bergmark et al., 1993; Osterman-Golkar et al., 1994;Tavares et al., 1996). The method is based on a modifiedEdman procedure and detection with selected ion monit-oring by gas chromatography–mass spectrometry. The

limit of detection is about 0.1–1 pmol/g globin (Tavareset al., 1996; Licea Perez et al., 1999).

4. SOURCES OF HUMAN ANDENVIRONMENTAL EXPOSURE

Data on sources and emissions primarily from thesource country of the national assessment on which theCICAD is based (i.e., Canada) are presented here as anexample. Sources and patterns of emissions in othercountries are expected to be similar, although quantita-tive values may vary.

4.1 Natural sources

Acrylonitrile is not known to occur naturally, andthere are no known reactions that could lead to in situ

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formation of this substance in the atmosphere (Grosjean,1990a).

4.2 Anthropogenic sources

The total release of acrylonitrile in Canada in 1996was 19.1 tonnes (97.3% to air and 2.7% to water)(Environment Canada, 1997). The major source ofreleases was the organic chemicals industry (97.4%)(namely, the chemicals and chemical products industriesand the plastic products industries), while municipalwastewater treatment facilities accounted for 2.6% ofreleases. Although accounting for at most 1% of thereleases to air from chemical industries in Canada,incineration of sewage sludge represents another poten-tial source of acrylonitrile release to air. Use ofacrylonitrile polymers as conditioners for wastewatertreatment is another potential source, although this isalso considered to be minor in relation to industrialsources in Canada.

There is also potential for long-range transport ofacrylonitrile (up to 2000 km from its source) based on itshalf-life in air of between 55 and 96 h (see Table 1).

Acrylonitrile has also been used in some countriesas a pesticide. Its registration as a fumigant for storedgrain in Canada ceased in 1976 (J. Ballantine, personalcommunication, 1997).

Environmental tobacco smoke is a potentiallyimportant source of acrylonitrile indoors (Miller et al.,1998).

4.3 Production and use

World production of acrylonitrile exceeded 3.2 mil-lion tonnes in 1988, with later production increasingslowly (IARC, 1999). The estimated world capacity in1991 was 4.2 million tonnes, while world demand in 1993was 3.846 million tonnes (PCI, 1994). Major areas ofproduction are the European Union (>1.25 million tonnesper year), the USA (approximately 1.5 million tonnes peryear), and Japan (approximately 0.6 million tonnes peryear). The large majority of acrylonitrile is used as afeedstock or chemical aid in the production of nitrile-butadiene rubber (68% of 1994 imports in the samplecountry) and in acrylonitrile-butadiene-styrene andstyrene-acrylonitrile polymers (30% of 1994 imports inthe sample country).

5. ENVIRONMENTAL TRANSPORT,DISTRIBUTION, AND TRANSFORMATION

5.1 Air

Acrylonitrile emitted to air reacts primarily withphotochemically generated hydroxyl radicals (@OH) inthe troposphere (Atkinson et al., 1982; Edney et al., 1982;Munshi et al., 1989; US DHHS, 1990; Bunce, 1996). Theatmospheric half-life, based on hydroxyl radical reactionrate constants, is calculated to be between 4 and 189 h(Callahan et al., 1979; Cupitt, 1980; Edney et al., 1982;Howard, 1989; Grosjean, 1990b; Kelly et al., 1994).Modelling of environmental partitioning (section 5.5) isbased on a mean half-life for acrylonitrile in air of 55 h.

The reaction of acrylonitrile with ozone and nitrateis slow, because of the absence of chlorine and bromineatoms in the molecule, and is not likely to constitute amajor route of degradation (Bunce, 1996).

The reaction of hydroxyl radicals with acrylonitrileyields formaldehyde and, to a lesser extent, formic acid,formyl cyanide, carbon monoxide, and hydrogen cyanide(Edney et al., 1982; Spicer et al., 1985; Munshi et al.,1989; Grosjean, 1990a).

5.2 Water

Acrylonitrile in water can be biodegraded by accli-matized microorganisms or volatilized (Going et al., 1979).In water, half-lives of 30–552 h are estimated based onaqueous aerobic biodegradation (Ludzack et al., 1961;Going et al., 1979; Howard et al., 1991). Modelling ofenvironmental partitioning (section 5.5) is based on amean half-life for acrylonitrile in water of 170 h (7 days).The half-life based on volatilization is 1–6 days (Howardet al., 1991). The hydrolysis of acrylonitrile is slow, withhalf-lives under acidic and basic conditions of 13 and188 years, respectively (Ellington et al., 1987).

Acrylonitrile has an initial inhibitory effect onactivated sludge systems and other microbialpopulations and does not meet the criteria ofOrganisation for Economic Co-operation andDevelopment (OECD) Test Method 301C for readybiodegradability (Chemicals Inspection and TestingInstitute of Japan, 1992; AN Group, 1996; BASF AG,1996). However, acrylonitrile will be extensivelydegraded (95–100%) following a short acclimation periodif emitted to wastewater treatment plants (Tabak et al.,1980; Kincannon et al., 1983; Stover & Kincannon, 1983;Freeman & Schroy, 1984; Watson, 1993).


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5.3 Soil and sediment

Acrylonitrile is biodegraded in a variety of surfacesoils (Donberg et al., 1992) and by isolated strains of soilbacteria and fungi (Wenzhong et al., 1991). Concentra-tions of acrylonitrile up to 100 mg/kg were degraded inunder 2 days (Donberg et al., 1992). Similar breakdownby microbial populations present in sediment is likely(DMER & AEL, 1996; EC, 2000). Results of experimentalstudies (Zhang et al., 1990) or soil sorption coefficientscalculated by quantitative structure–activityrelationships (Koch & Nagel, 1988; Walton et al., 1992)or based on water solubility (Kenaga, 1980) indicate littlepotential for adsorption of acrylonitrile to soil orsediments.

A half-life of acrylonitrile in soil of 6–7 days hasbeen reported (Howard et al., 1991; Donberg et al., 1992)(see Table 1). Based on biodegradability and the soilpartition coefficient (EC, 1996), the half-life ofacrylonitrile in soil was classified in the category of300 days (EC, 2000). Modelling of environmentalpartitioning (section 5.5) is based on a mean half-life foracrylonitrile in soil of 170 h (7 days). The half-life in theoxic zone of sediment can be assumed to be similar.

5.4 Biota

Bioaccumulation of acrylonitrile is not anticipated,given experimentally derived values of the octanol/waterpartition coefficient (log Kow) ranging from !0.92 to 1.2(mean 0.25) (Collander, 1951; Pratesi et al., 1979; Veith etal., 1980; Tonogai et al., 1982; Tanii & Hashimoto, 1984;Sangster, 1989) and a log bioconcentration factor (logBCF) of 0 calculated from the water solubility ofacrylonitrile (EC, 2000).

Log BCF values were 0.48–1.68 in bluegill (Lepomismacrochirus) (Barrows et al., 1980) and rainbow trout(Oncorhynchus mykiss) (Lech et al., 1995). Theexperimentally derived log BCF of 1.68 reported byBarrows et al. (1980) in whole-body tissue of bluegill maybe an overestimate, due to uptake of 14C-labelleddegradation products in addition to acrylonitrile and tocyanoethylation of macromolecules (EC, 2000).

5.5 Environmental partitioning

Fugacity modelling was conducted to characterizekey reaction, intercompartment, and advection (move-ment out of a compartment) pathways for acrylonitrileand its overall distribution in the environment. A steady-state, non-equilibrium model (Level III fugacity model)was run using the methods developed by Mackay (1991)and Mackay & Paterson (1991). Assumptions, inputparameters, and results are presented in DMER & AEL(1996) and summarized here. Values for input parameters

were as follows: molecular mass, 53.06 g/mol; watersolubility, 75.5 g/litre; vapour pressure, 11.0 kPa; log Kow,0.25; Henry’s law constant, 11 Pa@m3/mol; half-life in air,55 h; half-life in water, 170 h; half-life in soil, 170 h; half-life in sediments, 550 h. Modelling was based on anassumed default emission rate of 1000 kg/h into a regionof 100 000 km2, which includes a surface water area (20 mdeep) of 10 000 km2. The height of the atmosphere wasset at 1000 m. Sediments and soils were assumed to havean organic carbon content of 4% and 2% and a depth of1 cm and 10 cm, respectively. The estimated percentdistribution predicted by this model is not affected bythe assumed emission rate.

Modelling indicates that when acrylonitrile iscontinuously discharged into a specific medium, most ofit (84–97%) can be expected to be present in that medium(DMER & AEL, 1996). More specifically, Level IIIfugacity modelling by DMER & AEL (1996) predicts that:

# when released into air, the distribution of mass is92.8% in air, 6.4% in water, 0.8% in soil, and 0.0%in sediment;

# when released into water, the distribution of massis 2.5% in air, 97.3% in water, 0.0% in soil, and 0.1%in sediment; and

# when released into soil, the distribution of mass is4.4% in air, 11.9% in water, 83.7% in soil, and 0.0%in sediment.

The major removal mechanisms in air, water, andsoil are reaction within the medium and, to a lesserdegree, advection and volatilization. Abiotic and bioticdegradation in the various compartments result in lowpersistence overall and little, if any, bioaccumulation.

Owing to the paucity of data on concentrations ofacrylonitrile in environmental media, fugacity modellingwith version 4 of the ChemCAN3 model (Mackay et al.,1995) was also conducted with the conservative assump-tion that all known releases in 1996 (EnvironmentCanada, 1997) in Canada occurred in southern Ontario.Release to air was considered to be approximately19 tonnes per year, with simultaneous release to water of0.53 tonnes per year. Since the half-life of acrylonitrile inair is the major determinant of its fate in the environment,the model was run using the minimum, median, andmaximum half-life values (4, 55, and 189 h) under summer,winter, and year-round conditions. Modelling predicteddistribution primarily to air (41.9–78.1%) and water(21.6–57.9%).

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6. ENVIRONMENTAL LEVELS ANDHUMAN EXPOSURE

Data on concentrations in the environment primar-ily from the source country of the national assessmenton which the CICAD is based (i.e., Canada) arepresented here as a basis for the sample riskcharacterization. Patterns of exposure in other countriesare expected to be similar, although quantitative valuesmay vary. Detection of acrylonitrile in the generalenvironment is restricted primarily to the vicinity ofindustrial sources.

6.1 Environmental levels

6.1.1 Ambient air

Maximum predicted rates of emission of acrylo-nitrile during any half-hour period were 0.003, 0.018, and0.028 g/s for stacks 14, 17, and 11 m high, respectively,near the site of the largest user in Canada (a Sarnia,Ontario, plant), based on dispersion modellingconducted in 1998 (H. Michelin, personal communica-tion, 1999). Predicted concentrations at 11, 25, 41, and1432 m from the stacks under the assumption thatinversion occurs just above stack height and the plumeis therefore forced to the ground were 6.6, 2.2, 0.4, and0.1 µg/m3. Predicted concentrations at 11, 35, 41, and3508 m under the assumption of close to stable or neutralatmospheric conditions were 9.3, 2.9, 0.6, and 0.1 µg/m3.Accuracy testing indicates that the model may overpre-dict actual values by as much as 2 orders of magnitude.

In six samples taken on 2 different days in the vic-inity of a nitrile-butadiene rubber production plant inSarnia, Ontario, 5 m outside the company fence line,2 m above ground, and directly downwind of the stacks,acrylonitrile was not detected (detection limit 52.9 µg/m3)(B. Sparks, personal communication, 1997; M. Wright,personal communication, 1998).

Levels of acrylonitrile in ambient air sampled for6 days near a chemical manufacturing plant in Cobourg,Ontario, ranged from 0.12 to 0.28 µg/m3. Measurementsfrom stacks of the facility in 1993 ranged from <251 to100 763 µg/m3 (Ortech Corporation, 1994). The concen-tration at point of impingement estimated on the basis ofdispersion modelling of these data was 1.62 µg/m3.

At six urban stations in Ontario in 1990, concentra-tions of acrylonitrile in 10 of 11 samples were below thedetection limit of 0.0003 µg/m3. In this study, the maxi-mum and only detectable concentration of acrylonitrilewas 1.9 µg/m3 in one sample (OMOE, 1992a).

Levels of acrylonitrile were <0.64 µg/m3 in all sevensamples of ambient air taken in the industrialized area ofWindsor, Ontario, in August 1991 (Ng & Karellas, 1994).

Ambient air samples were collected from down-town (n = 16) and residential (n = 7) areas of Metropol-itan Toronto, Ontario, during a personal exposure pilotsurvey. The air samples were obtained at 1.5 m aboveground for 12 consecutive hours. Acrylonitrile was notdetected (detection limit 0.9 µg/m3) in any sampleanalysed (Bell et al., 1991).

Air samples were collected within the inhalationzone by a personal unit for 1–2 h while the participantswere commuting to and from work (n = 19) and whilethey were spending the noon-hour period (n = 8) indowntown Toronto, Ontario, from June to August 1990.Acrylonitrile was not detected (detection limit 0.9 µg/m3)in any sample analysed. Acrylonitrile was also notdetected (detection limit 0.9 µg/m3) in four special com-posite samples collected during the same study; the firsttwo samples were collected while the participants wereattending meetings, the third was collected while theparticipants were at a barbecue, and the fourth was anoverall composite sample of the afternoon and morningcommutes and the overnight residential indoor air (Bellet al., 1991).

6.1.2 Indoor air

Environmental tobacco smoke appears to be asource of acrylonitrile in indoor air (California AirResources Board, 1994).

Acrylonitrile was not detected in samples collectedovernight (duration up to 16 h) from June to August1990 in four different residences near Toronto, Ontario(detection limit 0.9 µg/m3) (Bell et al., 1991).

6.1.3 Surface water and groundwater

Acrylonitrile has been detected only in waterassociated with industrial effluent; it has not beendetected in ambient surface water in Canada (detectionlimit 4.2 µg/litre).

Of the effluents sampled from five companiesusing acrylonitrile and discharging to the environmentin 1989–1990 in Ontario, the compound was detected in12 of 256 samples (OMOE, 1993). Daily concentrationsranged from 0.7 to 3941 µg/litre; annual site averagesranged from 2.7 to 320 µg/litre. Intake water at the 26organic chemical manufacturing plants sampled overthe same period did not contain detectable amounts ofacrylonitrile (207 samples; detection limit 4.2 µg/litre)(OMOE, 1992b). Biological treatment reactors haverecently been introduced for two of the five companies


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with remaining commercial activity involving acrylo-nitrile, and levels from both sites are below 4.2 µg/litre(Y. Hamdy, personal communication, 1998).

In a large study of Canadian municipal watersupplies in 1982–1983, acrylonitrile was not detected inany of the 42 raw (and 42 treated) water samples fromnine municipalities on the Great Lakes (detection limit5 µg/litre) (Otson, 1987). Acrylonitrile was not detected(detection limit 2.1 µg/litre) in groundwater samplesdowngradient of a wastewater treatment pond at anOntario chemical industry site (Environment Canada,1997).

6.1.4 Drinking-water

Acrylonitrile was monitored in municipal watersupplies at 150 locations in Newfoundland, Nova Scotia,New Brunswick, and Prince Edward Island over theperiod 1985–1988. It was detected at a trace concentra-tion (0.7 µg/litre) in only one sample of treated water inNova Scotia in June 1988 (detection limit 0.5–1.0 µg/litre)(Environment Canada, 1989a,b,c,d).

Acrylonitrile was not identified in treated (or raw)water at facilities near the Great Lakes in 1982–1983 (n =42; detection limit 5 µg/litre during the initial samplingand <1 µg/litre during later sampling after the techniquewas modified) over three sampling periods (Otson, 1987).Analyses were by gas chromatography–massspectrometry.

6.1.5 Soil and sediment

Significant concentrations of acrylonitrile are notexpected in soil or sediment based on the releasepatterns and the environmental partitioning, behaviour,and fate of the substance (section 5.3).

Significant levels of acrylonitrile have not beendetected in Canadian soils. Levels in 18 soil samples atan Alberta chemical blending plant were below thedetection limit of 0.4 ng/g (G. Dinwoodie, personalcommunication, 1993). Significant quantities ofacrylonitrile in soil at a LaSalle, Quebec, chemicalindustrial site have not been identified since regularmonitoring began at the site in 1992 (EnvironmentCanada, 1997).

Data on levels of acrylonitrile in sediment have notbeen identified.

6.1.6 Food

Acrylonitrile may potentially be introduced intofoodstuffs from acrylonitrile-based polymers used infood packaging. Page & Charbonneau (1983) measured

concentrations of acrylonitrile in five types of foodpackaged in acrylonitrile-based plastic containers,purchased from several stores in Ottawa, Ontario.Average concentrations of acrylonitrile (measured inthree duplicate samples of each food type by gaschromatography with a nitrogen–phosphorus-selectivedetector) ranged from 8.4 to 38.1 ng/g.

A survey of food packed in acrylonitrile-basedplastics containing up to 2.6 mg acrylonitrile/kg wasconducted in Ottawa, Ontario. The samples representedfive food companies and a variety of luncheon meats,including mock chicken, ham, salami, pizza loaf, andseveral types of bologna. Acrylonitrile was not identified(detection limit 2 ng/g). Analyses were by gas chroma-tography, with nitrogen–phosphorus-selective detection(Page & Charbonneau, 1985).

6.1.7 Multimedia study

In a multimedia study carried out for HealthCanada (Conor Pacific Environmental & Maxxam Ltd.,1998), exposure to several volatile organic chemicals,including acrylonitrile, was measured for 50 participantsacross Canada. Thirty-five participants were randomlyselected from the Greater Toronto Area in Ontario, sixparticipants from Liverpool, Nova Scotia, and nine fromEdmonton, Alberta. For each participant, samples ofdrinking-water, beverages, and indoor, outdoor, and per-sonal air were collected over a 24-h period. Acrylonitrilewas not detected in air (detection limit 1.36 µg/m3), water(detection limit 0.7 ng/ml), beverages (detection limit 1.8ng/ml), or food (detection limit 0.5 ng/g).

6.2 Human exposure: environmental

Point estimates of average daily intake (per kilo-gram body weight) were developed for the samplecountry (i.e., Canada), based on the few monitoring dataavailable and reference values for body weight, inhala-tion volume, and amounts of food and drinking-waterconsumed daily by six age groups (Environment Canada& Health Canada, 2000). Similar estimates weredeveloped based on the results of the ChemCAN3fugacity modelling (Environment Canada & HealthCanada, 2000). In view of the limitations of the data onwhich these estimates are based, however (i.e., lack ofdetection of acrylonitrile in most media in which it wasmonitored or fugacity modelling), these estimates areprimarily useful as a basis for identification of principalroutes and media of exposure.

Although it is uncertain, based on this limitedinformation, air (ambient and indoor) is likely theprincipal medium of exposure. Intakes from food anddrinking-water are likely to be negligible in comparison.This is consistent with the physical/chemical properties

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11

of acrylonitrile, which has moderate vapour pressure anda low log Kow, and the results of fugacity modelling(section 5.5). On the basis of the estimates derivedabove, intake from ambient and indoor air ranges from96% to 100% of total intake.

Exposures from ambient air may be substantiallyhigher for populations in the vicinity of point sources.Data presented above (see section 6.1.1) on concentra-tions in the vicinity of point sources indicate that popu-lations in the area might be exposed to levels of acrylo-nitrile in the range of tenths of µg/m3 (Ng & Karellas,1994; Ortech Corporation, 1994). Additional data from theUSA indicate that levels vary considerably in thevicinity of various point sources (Health Canada, 2000).

Limitations of the data preclude development ofmeaningful probabilistic estimates of exposure to acrylo-nitrile in the general population.

6.3 Human exposure: occupational

Exposure to acrylonitrile may occur during itsproduction and its use in the manufacture of otherproducts; potential for exposure is greatest in factorieswhere acrylonitrile is used to make other products, whereit may not be as easily contained (Sax, 1989). IARC (1999)indicates that approximately 35 000 workers in Europeand as many as 80 000 workers in the USA arepotentially exposed to acrylonitrile. These individualsinclude acrylic resin makers, synthetic organic chemists,pesticide workers, and rubber, synthetic fibre, and textilemakers. The primary routes of potential exposure in theoccupational environment are inhalation and dermal.

Based on data collected in 1995 for countries in theEuropean Union (EC, 2000), 8-h time-weighted-average(TWA) exposures for production and various end useswere as follows: production, #0.45 ppm (1 mg/m3); fibre,#1.01 ppm (#2.2 mg/m3); latex, #0.10 ppm (#0.22 mg/m3);acrylonitrile-butadiene-styrene polymer, #0.40 ppm(#0.88 mg/m3); and acrylamide, #0.20 ppm (#0.44 mg/m3).

For six European producers of acrylonitrile,average personal monitoring levels at the workplacevaried from <0.12 to 0.49 ppm (<0.26 to 1.1 mg/m3); themaximum recorded level was 5.5 ppm (12.1 mg/m3). Forproduction of acrylonitrile fibres, the average personalmonitoring levels were from <0.26 to 0.43 ppm (<0.57 to0.95 mg/m3), with a maximum value of 3.6 ppm(7.9 mg/m3). For production of acrylonitrile-butadiene-styrene polymers, the average levels for personalmonitoring were 0.08–0.3 ppm (0.18–0.66 mg/m3), with amaximum recorded value of 8.6 ppm (19.0 mg/m3). Thehigher levels in use were consistent with production ofacrylonitrile being initially in a closed system, whilemanufacture of, for example, acrylonitrile-butadiene-

styrene polymers is carried out in a partially closedsystem, with local exhaust ventilation and emission (EC,2000).

Recent information on the occupational exposurescenario for Australia (NICNAS, 2000) correlates wellwith the above data. Australia imports approximately2000 tonnes of acrylonitrile per year, 70% of which isused for the manufacture of styrene-acrylonitrile poly-mer, which is further compounded into plastic resins.The remainder is used in the manufacture of latex poly-mers (polymers dispersed in water) for adhesive andcoating applications. Of 187 breathing-zone air samplescollected in 1991–1999 during normal operations,68% were <0.1 ppm (<0.22 mg/m3), 95% <0.5 ppm(<1.1 mg/m3), and 97% <1 ppm (<2.2 mg/m3), expressed as8-h TWAs. Personal exposure levels were slightly higherin latex than in styrene-acrylonitrile polymer and plasticresin manufacturing plants.

Surveys of full-shift personal exposures in four USacrylonitrile production plants have also been reported(Zey et al., 1989, 1990a,b; Zey & McCammon, 1990).Mean 8-h TWA personal exposures for monomerproduction operators were 1.1 ppm (2.4 mg/m3) or lessfrom about 1978 to 1986, with some individual TWAlevels up to 37 ppm (82 mg/m3). In three of these plants,levels for maintenance employees averaged below0.3 ppm (0.7 mg/m3), but in one plant, the average TWAexposure for these workers was 1 ppm (2.2 mg/m3).Average 8-h TWA exposures for loaders of acrylonitrileinto tank trucks, rail cars, or barges varied from 0.5 to 5.8ppm (1.1 to 12.8 mg/m3). For some of the higher valuesfor production and maintenance workers and loaders inthese plants, respirator use was noted. Although therewere several changes introduced to reduce exposurelevels, no trends over the years were noted.

In three US fibre plants for which data for full-shiftpersonal samples were available between the years 1977and 1986, the average 8-h TWA exposures were between0.3 and 1.5 ppm (0.7 and 3.3 mg/m3), based on nearly 3000individual samples. The dope (viscous pre-fibresolution) and spinning operators had exposures averag-ing 0.4–0.9 ppm (0.9–2.0 mg/m3). The lower exposureoccurred in the plant that dried the polymer before thespinning operation, resulting in a lower monomercontent in the polymer. The other plant had acontinuous wet operation without the drying stage.Exposure of maintenance workers averaged 0.2 ppm (0.4mg/m3). Tank farm operators, who are also likely tounload acrylonitrile monomer from trucks, rail cars, orbarges, had homogeneous exposure levels (0.5 ppm [1.1mg/m3]) across plants (IARC, 1999).

Haemoglobin adduct measurement is an extremelysensitive method for monitoring exposure to acrylo-


12

nitrile. The level of N-(2-cyanoethyl)valine reflectsexposure during a 4-month period (i.e., the life span ofthe erythrocytes) prior to blood sampling. Licea Perez etal. (1999) reported levels of 0.76 ± 0.36 pmol/g globin in18 non-smokers (who claimed that they were notexposed to environmental tobacco smoke). Adductlevels in smokers range from 8 to a few hundred pmol/gglobin and are related to cigarette consumption. Adductlevels in 10 smoking mothers (92.5–373 pmol/g globin)and their newborns (34.6–211 pmol/g globin) werestrongly correlated and demonstrated that transplacentaltransfer of acrylonitrile occurs (Tavares et al., 1996).Adduct levels ranging from 20 to 66 000 pmol/g havebeen observed in occupationally exposed workers(Bergmark et al., 1993; Tavares et al., 1996; Thier et al.,1999). Polymorphism with respect to the glutathionetransferases GSTTI and GSTMI had little effect onadduct levels (Thier et al., 1999; Fennell et al., 2000).

7. COMPARATIVE KINETICS ANDMETABOLISM IN LABORATORY ANIMALS

AND HUMANS

Based on studies conducted primarily in laboratoryanimals, acrylonitrile is rapidly absorbed by all routes ofadministration and distributed throughout examinedtissues. In inhalation studies with volunteers, 50% ofacrylonitrile was absorbed (Jakubowski et al., 1987).However, there appears to be little potential for signifi-cant accumulation in any organ, with most of the com-pound being excreted primarily as metabolites in urine inthe first 24–48 h following administration (Kedderis et al.,1993a; Burka et al., 1994).

Acrylonitrile is metabolized primarily by two path-ways: conjugation with glutathione to form N-acetyl-S-(2-cyanoethyl)cysteine and oxidation by cytochrome P-450 to form remaining urinary metabolites (Langvardt etal., 1980; Geiger et al., 1983; Fennell et al., 1991; Kedderiset al., 1993a) (Figure 2). Oxidative metabolism ofacrylonitrile leads to the formation of 2-cyanoethyleneoxide, which is either conjugated with glutathione(Fennell & Sumner, 1994; Kedderis et al., 1995) to form aseries of metabolites including cyanide and thiocyanateor directly hydrolysed by epoxide hydrolase (Borak,1992; Kim et al., 1993). Recent data indicate thatcytochrome P4502E1 is the sole P-450 catalysing theoxidation of acrylonitrile (Sumner et al., 1999).

Available data1 are consistent with conjugation withglutathione being the major detoxification pathway ofacrylonitrile, while the oxidation of acrylonitrile to 2-cyanoethylene oxide can be viewed as an activationpathway, producing a greater proportion of the totalmetabolites in mice than in rats. Available data alsoindicate that there are route-specific variations inmetabolism (Lambotte-Vandepaer et al., 1985; Tardif etal., 1987). Based on studies in which 2-cyanoethyleneoxide has been administered, there is no indication ofpreferential uptake or retention in specific organs,including the brain (Kedderis et al., 1993b).

Liver microsomes from rats, mice, and humansproduced 2-cyanoethylene oxide at a greater rate thanlung or brain microsomes, indicating that the liver is themajor site of formation in vivo of 2-cyanoethylene oxide(Roberts et al., 1989; Kedderis & Batra, 1991). Studies insubcellular hepatic fractions indicate that there is anactive epoxide hydrolase pathway for 2-cyanoethyleneoxide in humans, which is inactive, although inducible, inrodents (Kedderis & Batra, 1993). Studies with inhibitoryantibodies in human hepatic microsomes indicate thatthe 2E1 isoform of cytochrome P-450 is primarilyinvolved in epoxidation of acrylonitrile (Guengerich etal., 1991; Kedderis et al., 1993c).

A physiologically based pharmacokinetic modelhas been developed and verified for the rat (Gargas et al.,1995; Kedderis et al., 1996), and work is under way toscale it to humans. In a recent, although incompletelyreported, study, Kedderis (1997) estimated in vivoactivity of epoxide hydrolase in humans based on theratio of epoxide hydrolase to P-450 activity in subcellularhepatic fractions multiplied by the P-450 activity in vivo.Human blood to air coefficients for acrylonitrile and 2-cyanoethylene oxide have also been recentlydetermined, although incompletely reported at present(Kedderis & Held, 1998). Research is in progress todetermine partition coefficients for other human tissues.

1 Including results of short-term toxicity studies in which theoxidative pathway has been induced prior to administrationwith acrylonitrile or antioxidants have been administeredconcomitantly with acrylonitrile.

Figure 2 Metabolic pathway of acrylonitrile (IARC, 1999)

GlutathioneAcrylonitrile S-transferase S-(2-Cyanoethyl)thioacetic acid

N-Acetyl-S-(2-cyanoethyl)cysteine

CytochromeP450

GlutathioneS-transferase

N-Acetyl-S-(2-hydroxyethyl)cysteine2-Cyanoethylene oxide

Cyanoacetic acid N-Acetyl-S-(2-carboxymethyl)cysteine

2-CyanoethanolN-Acetyl-S-(1-cyano-2-hydroxyethyl)cysteine Thiodiglycolic acid

H2C CH CN GS CH2CH2CN HCCH S CH2CH2CN

C

N

OOH

H COCH

2

3

2

COCHH

OOH

N

C

SHCCH CH2CH2OH

3

2

COCHH

OOH

N

C

SHCCH CH2COOH

3

HOOCCH2 S CH2COOHHCCH S CHCH2OH

C

N

OOH

H COCH

2

3

CN

GS CH2CHOH

CN

SCN_

CN_

GS CHCH2OH

CN

HOOC CH2 CN

HOCH2 CH2 CN

[CO CH2 CN]

H2C CH CN

O

HOOCCH2 S CH2CH2CN

13

8. EFFECTS ON LABORATORYMAMMALS AND IN VITRO TEST SYSTEMS

8.1 Single exposure

The acute toxicity of acrylonitrile is relatively high,with 4-h LC50s ranging from 140 to 410 ppm (300 to900 mg/m3) (Knobloch et al., 1971, 1972) and oral LD50sranging from 25 to 186 mg/kg body weight (Maltoni etal., 1987). Dermal LD50 values for various species were inthe range of 148–693 mg/kg body weight, with the ratbeing most sensitive (BUA, 1995). Signs of acute toxicityinclude respiratory tract irritation and central nervoussystem dysfunction, resembling cyanide poisoning.Superficial necrosis of the liver and haemorrhagicgastritis of the forestomach have also been observedfollowing acute exposure (Silver et al., 1982).

Acrylonitrile-induced neurotoxicity following acuteexposure via inhalation or ingestion has been describedas a two-phase phenomenon. The first phase, whichoccurs shortly after exposure and is consistent withcholinergic overstimulation, has been likened to toxicitycaused by acetylcholinesterase inhibition.Cholinomimetic signs in rats exposed to acrylonitrilehave included vasodilation, salivation, lacrimation,diarrhoea, and gastric secretion. These effects aremaximal within 1 h of dosing. The second phase oftoxicity is delayed by 4 h or more and includes signs ofcentral nervous system disturbance, such as trembling,ataxia, convulsions, and respiratory failure (TERA, 1997). 8.2 Irritation and sensitization

Available data indicate that acrylonitrile is a skin,respiratory, and severe eye irritant. It induces skinsensitization in guinea-pigs, but available data areinadequate to assess its sensitization potency.

8.2.1 Skin irritancy

Identified data on irritancy to the skin are restrictedto three studies in which acrylonitrile was applied to theshaved skin of rabbits (McOmie, 1949; Zeller et al., 1969;Vernon et al., 1990). In early periods followingadministration (e.g., 15 min), slight local vasodilation andoedema were observed; at longer periods (20 h), effectswere more severe, with necrosis reported.

8.2.2 Eye irritancy

Identified investigations of eye irritancy arerestricted to principally early unpublished studies(McOmie, 1949; BASF, 1963; Zeller et al., 1969; DuPont,1975). Results of these investigations were consistentwith those reported in the most recent study conductedby DuPont (1975), in which 0.1 ml of undiluted acrylo-nitrile was placed in the right conjunctival sac of each oftwo albino rabbits. After 20 s, the treated eye of one

rabbit was washed with tap water for 1 min. Acrylonitrileproduced moderate corneal opacity, moderate iritis, andsevere conjunctival irritation in the unwashed treatedeye. In the washed eye, there was slight temporarycorneal opacity, transient, moderate iritic congestion,and moderate conjunctival irritation. These effects werenot completely reversible in the unwashed eye; by wash-ing the eye, the effects were considerably lessened, aswas the duration of these ocular effects.

8.2.3 Respiratory tract irritancy

While not examined directly, in repeated-dosetoxicity studies, there has been evidence of irritanteffects on the upper respiratory tract, including nasaldischarge in rats acutely exposed (Food and DrugResearch Laboratories, 1985) and rhinitis and hyper-plastic changes in the nasal mucosa following chronicexposure (Quast et al., 1980b).

8.2.4 Sensitization

In a guinea-pig maximization test, animals chal-lenged with 0.5% and 1.0% acrylonitrile had a 95%positive sensitization rate. Exposure to 0.2% on chal-lenge caused an 80% sensitization rate (Koopmans &Daamen, 1989).

8.3 Short-term exposure

Available short-term inhalation studies arerestricted to a few investigations involving administra-tion of single dose levels and, for one, examination ofclinical signs only. Exposure–response has not, there-fore, been well characterized. There were effects onbiochemical parameters, clinical signs, and body weight,although no histopathological effects on principalorgans, following exposure of rats to 130 ppm(280 mg/m3) acrylonitrile (Gut et al., 1984, 1985).

In short-term studies by the oral route, effects onthe liver, adrenal, and gastric mucosa have beenobserved, with effects on the gastric mucosa occurringat lowest doses in all studies in which they wereexamined. Effects on the adrenal cortex observed inshort-term repeated-dose toxicity studies from onelaboratory have not been noted in longer-terminvestigations in animals exposed to higherconcentrations. In investigations by Szabo et al. (1984),effects on the non-protein sulfhydryl content in gastricmucosa and hyperplasia in the adrenal cortex have beenreported at levels as low as 2 mg/kg body weight per dayadministered by drinking-water and gavage,respectively, for 60 days. Effects on hepatic glutathionewere also observed by these authors at similar dosesadministered by gavage but not in drinking-water (2.8mg/kg body weight per day for 21 days), although Silveret al. (1982) noted only slight biochemical effects but nohistopathological effects in the liver at doses up to 70mg/kg body weight per day (drinking-water, 21 days).


14

Significant increases in proliferation in the forestomachbut no changes in the liver or glandular stomach havebeen observed at 11.7 mg/kg body weight (Ghanayem etal., 1995, 1997).

Gastric lesions in the rat have been accompaniedby a decrease of gastric reduced glutathione concentra-tion. It has been suggested that depletion and/orinactivation of critical endogenous sulfhydryl groupscause configurational changes of cholinergic receptorsand increase agonist binding affinity, which may lead togastric mucosal erosion (Ghanayem et al., 1985;Ghanayem & Ahmed, 1986).

Effects of pretreatment with inducers of the mixed-function oxidase system or antioxidants on toxicity inshort-term studies have been consistent with metabolismto the epoxide 2-cyanoethylene oxide being the puta-tively toxic metabolic pathway (Szabo et al., 1983).

8.4 Medium-term exposure

Results of identified subchronic toxicity studiesare limited to an early 13-week inhalation study in ratsand dogs that has not been validated (IBT, 1976) and apreliminary brief report of the results of a 13-weekNational Toxicology Program (NTP) gavage study inmice.1 Lack of validation and inadequate detail limit theutility of these studies for hazard evaluation orcharacterization of dose–response.

8.5 Long-term exposure andcarcinogenicity

Data on effects of long-term exposure to acrylo-nitrile are currently restricted to those conducted in rats,although an NTP bioassay in mice is under way (NTP,1998). In the descriptions of the following studies,tumour types are reported as described by the authors.However, it should be noted that the histopathology ofthe tumours may be unclear (see footnote on page 18 insection 8.5.2).

8.5.1 Inhalation

Quast et al. (1980b) conducted a bioassay in whichSprague-Dawley (Spartan substrain) rats (100 per sex pergroup) were exposed by inhalation to averageconcentrations of 0, 20, or 80 ppm (0, 44, or 176 mg/m3)acrylonitrile 6 h/day, 5 days/week, for 2 years. Non-neoplastic histopathological changes related to the

treatment were present in the nasal turbinates and thecentral nervous system of both males and females. In thebrain, the changes were characterized by focal gliosisand perivascular cuffing at the highest concentration.The inflammatory changes in the nasal turbinates wereconsidered to be due to acrylonitrile irritation. Theseeffects were not observed at 20 ppm (44 mg/m3), and thisdose is considered as a no-observed-effect level (NOEL)for inflammatory changes in the nasal turbinates. Therewas an early onset of chronic renal disease in the groupexposed to 20 ppm (44 mg/m3) based upon histopatho-logical examination. The renal effect was not apparent atthe high dose because of early mortality. The chronicrenal disease, which is commonly observed in older ratsof this strain, was considered a secondary effect causedby increased water intake, although there was no pair-fed control study, and clinical analyses were inadequateto confirm the cause. In males, mortality at 80 ppm(176 mg/m3) was consistently and significantly increasedfrom days 211–240 to the end of the experiment. Similarfindings were noted for females beginning at days 361–390.

In both sexes, there was an increase in the com-bined incidence of malignant and benign tumours of thebrain and spinal cord (Table 2) and benign and malignanttumours of the Zymbal gland at the high dose. In males,the combined incidence of benign and malignanttumours of the small intestine and the tongue wasincreased at the high dose. The incidence of adenocarci-noma of the mammary gland was increased at the highdose in females (Quast et al., 1980b).

Although Maltoni et al. (1977) reported anincreased incidence of tumours in the mammary gland,forestomach, and skin in Sprague-Dawley rats exposedto up to 40 ppm (88 mg/m3) for 52 weeks, low concen-trations of acrylonitrile, short exposure time, and smallgroup size (n = 30) limit the sensitivity of the study. In afollow-up study (Maltoni et al., 1987, 1988), 54 femaleSprague-Dawley rat breeders and offspring were admin-istered 60 ppm (132 mg/m3) by inhalation for 4–7 h/day, 5days/week. The breeders and some of the offspring wereexposed for 104 weeks, and the remaining offspring wereexposed for 15 weeks only. The non-neoplastictreatment-related changes included slight, butsignificant, increases in the incidence of encephalic glialcell hyperplasia and dysplasia in offspring exposed for104 weeks. The incidence of various tumours was

1 NTP (1996) The 13-week gavage toxicity studies of acrylo-nitrile. CAS No. 107-13-1. Unpublished and unaudited data.Research Triangle Park, NC, US Department of Health andHuman Services, National Toxicology Program.

Acrylonitrile

15

Table 2: Quantitative estimates of carcinogenic potency, derived for tumour incidencesreported in an inhalation bioassay with Sprague-Dawley rats a

Animal data HumanequivalentvaluesDose Incidence Parameter estimates

Males: Brain and/orspinal cord, benign andmalignant; excludinganimals dying or sacri-ficed before 6 months

control44 mg/m3 (20 ppm)176 mg/m3 (80 ppm)

0/984/97 (4 astrocytoma)22/98 (15 astrocytoma, 7 benign)

TC05b = 52 mg/m3

95% LCL c = 29 mg/m3

Chi-square = 0.73Degrees of freedom =1P-value = 1.00

TC05d =

8.9 mg/m3

95% LCL = 5 mg/m3

Males: Brain and/orspinal cord, benign andmalignant; excludinganimals dying or sacri-ficed before 10 months(TERA, 1997)


0/97e

4/93e

15/83e

TC05b = 51 mg/m3

95% LCL = 33 mg/m3


TC05d =

8.7 mg/m3

95% LCL = 5.6 mg/m3

Females: Brain and/orspinal cord, benign andmalignant; excludinganimals dying or sacri-ficed before 6 months


0/998/100 (4 astrocytoma, 4 benign)21/99 (17 astrocytoma, 4 benign)

TC05b = 35 mg/m3

95% LCL = 26 mg/m3


TC05d =

6.0 mg/m3

95% LCL = 4.5 mg/m3

Females: Brain and/orspinal cord, benign andmalignant; excludinganimals dying or sacri-ficed before 6 months(TERA, 1997)


0/99e

8/99e

21/99e

TC05b = 35 mg/m3

95% LCL = 26 mg/m3


TC05d =

5.9 mg/m3

95% LCL =4.4 mg/m3

a From Quast et al. (1980b).b For this study, the resulting TC05s were multiplied by [(6 h/day)/(24 h/day)] × [(5 days/week)/(7 days/week)] to adjust for intermittent to

continuous exposure.c 95% LCL = lower 95% confidence limit.d To scale from rats to humans, the TC05s were multiplied by [(0.11 m3/day)/(0.35 kg body weight)] × [(70 kg body weight)/(23 m3/day)],

where 0.11 m3/day is the breathing rate of a rat, 0.35 kg body weight is the body weight of a rat, 23 m3/day is the breathing rate of ahuman, and 70 kg body weight is the body weight of a human.

e These incidence data could not be verified in an examination of mortality data in Quast et al. (1980b).

increased in the exposed offspring, both males andfemales. These included mammary gland tumours infemales, Zymbal gland tumours in males, extrahepaticangiosarcoma in both males and females, hepatomas inmales, and encephalic gliomas in both males and females.The most pronounced acrylonitrile-related tumour wasencephalic glioma (in control and exposure groups,respectively: 2/158 and 11/67 in males; 2/149 and 10/54 infemales) in the offspring treated with acrylonitrile for 104weeks.

8.5.2 Drinking-water

Quast et al. (1980a) administered acrylonitrile indrinking-water to Sprague-Dawley rats for 2 years atdose levels of 0, 35, 100, or 300 mg/litre. There wastreatment-related hyperplasia and hyperkeratosis of thesquamous epithelium of the forestomach in females at alldose levels and in males at 100 and 300 mg/litre. In thebrain of females, there was a significantly increasedincidence of focal gliosis and perivascular cuffing in the35 and 100 mg/litre groups. Tumours (including astro-

cytomas) were observed as early as 7–12 months infemales in the high-dose group; in other dose groups,tumours appeared initially in the 13- to 18-month period.In both males and females, the combined incidence ofbenign and malignant tumours of the brain and spinalcord was significantly increased in a dose-relatedmanner at all levels of exposure (Table 3).

In a study conducted by Bio/Dynamics Inc.(1980a), Sprague-Dawley rats were administeredacrylonitrile at dose levels of 0, 1, or 100 mg/litre indrinking-water for 19 and 22 months. Non-neoplasticeffects included increased weight of kidney and testes.The concentration of 1 mg/litre can be considered as aNOEL and 100 mg/litre as a lowest-observed-adverse-effect level (LOAEL) for non-neoplastic effects. In high-dose males, increased incidences of squamous cellcarcinoma of the stomach and carcinoma of the Zymbalgland were observed. In high-dose females, astrocytomaof the brain and carcinoma of the Zymbal gland wereincreased. At the high dose, there was an increasedcumulative incidence of astrocytoma of the brain, carci-

16

noma of the Zymbal gland, and papilloma/carcinoma ofthe stomach in both sexes. In females, the incidence ofastrocytoma of the spinal cord was significantlyincreased at the high dose. The spinal cord tissue of themales was not examined. Dose spacing was poor in thisstudy.

These results are consistent with those of asecond bioassay by Bio/Dynamics Inc. (1980b), in whichexposure–response was better characterized. Fischer 344rats (200 per sex, control group; 100 per sex per dosegroup) were administered acrylonitrile in drinking-waterfor approximately 2 years. The dose levels were 0, 1, 3,10, 30, and 100 mg acrylonitrile/litre (0, 0.1, 0.3, 0.8, 2.5,and 8.4 mg/kg body weight per day for males and 0, 0.1,0.4, 1.3, 3.7, and 10.9 mg/kg body weight per day forfemales, as reported by US EPA, 1985). Serial sacrificeswere conducted at 6, 12, and 18 months (20 per sex percontrol group and 10 per sex per treated group). Toensure at least 10 rats per sex per group forhistopathological evaluation, all females were sacrificedat 23 months, owing to low survival. The males werecontinued on test until the 26th month.

The consistently elevated mortality in the highestdose groups was primarily a consequence of tumours.Other changes observed primarily in the highest expo-sure group included consistently lower body weights infemales and males and consistent reduction in haemo-globin, haematocrit, and erythrocyte counts in femalesthroughout the study. A decrease in water intake wasalso observed, while food consumption was comparablefor all groups (Bio/Dynamics Inc., 1980b).

An increase in the relative organ weights of theliver and kidney was noted at the highest dose levels;however, the mean absolute weights for these organswere either comparable to those in the controls or onlyslightly increased. At terminal sacrifice, the absoluteliver and heart weights were elevated in females exposedto 30 mg/litre, but body weight was comparable to that incontrols. The LOAEL is considered 100 mg/litre, thelowest-observed-effect level (LOEL), 30 mg/litre, and theNOEL for non-carcinogenic effects, 10 mg/litre. In bothmales and females, the incidences of astrocytoma of thebrain (Table 4) and of carcinoma of the Zymbal glandwere significantly increased at the two highest doselevels (Bio/Dynamics Inc., 1980b).

In a multigeneration reproductive study, 0, 100, or500 mg acrylonitrile/litre (0, 14, or 70 mg/kg body weightper day; Health Canada, 1994) was administered indrinking-water to breeders (F0) and the offspring ofCharles River Sprague-Dawley rats (Litton Bionetics Inc.,1980). Rats of the F1b generation in the high-exposuregroup had a significantly increased incidence ofastrocytomas and Zymbal gland tumours. For control,low-exposure, and high-exposure groups, the incidenceof astrocytomas was 0/20, 1/19, and 4/17 (P < 0.05),respectively, and the incidence of Zymbal gland tumours

was 0/20, 2/19, and 4/17 (P < 0.05), respectively. Thetumour incidence was low, but the exposure and obser-vation period (approximately 45 weeks) was alsorelatively short. Not all tissues were examined histo-pathologically.

More recently, Bigner et al. (1986) observed neuro-oncogenic effects in Fischer 344 rats administered 0, 100,or 500 mg acrylonitrile/litre in drinking-water (0, 14, and70 mg/kg body weight per day; Health Canada, 1994).Each exposure group consisted of 50 male and 50 femalerats. A fourth group of 300 rats (147 males, 153 females)was exposed to 500 mg acrylonitrile/litre. Although theprotocol of the study indicated that rats were exposedfor their lifetime, results were presented for an 18-monthobservation period. There was a dose-related significantreduction in body weight in both males and females at500 mg/litre. In rats exposed for 12–18 months,neurological signs such as decreased activity, paralysis,head tilt, circling, and seizures were observed in the 100and 500 mg/litre groups. In control, low-exposure, andtwo high-exposure groups, the incidence of neurologicalsigns was 0/100, 4/100, 16/100, and 29/300, respectively.Based on histopathological examination of 215 animals inthe 500 mg/litre group, there were 49 primary braintumours, which were difficult to classify.1 Other tumoursfrequently observed included Zymbal gland tumours,forestomach papillomas, and subcutaneous papillomas.No further details, however, were presented. The authorsreported that the increase in incidence of the primarybrain tumour in the highest exposure group wassignificant (P-values were not reported, data were poorlypresented). Other end-points were not examined. Theresults are inadequate, therefore, for establishing effectlevels for non-neoplastic effects or for characterizingexposure–response for tumours.

Gallagher et al. (1988) investigated the carcino-genicity of acrylonitrile administered via drinking-waterat 0, 20, 100, or 500 mg/litre (approximately 0, 2.8, 14, and70 mg/kg body weight per day; Health Canada, 1994) tomale Sprague-Dawley rats (20 per group) for 2 years.There was no survival in the 500 mg/litre exposure groupat 2 years. Ingestion of acrylonitrile at

1 “The brain tumours were remarkably similar from animal toanimal, regardless of their size or anatomical location withinthe brain. They were also similar to, and probably indistin-guishable from, a subset of spontaneously occurring rat-braintumours that have been generally classified as astrocytomas oranaplastic astrocytomas by light-microscopic evaluation ofH&E-stained slides. Despite this superficial similarity toastrocytomas, we have found no hard evidence on which toidentify any of the neoplastic cells as astrocytic in lineage orrelatedness” (Bigner et al., 1986).

Table 3: Quantitative estimates of carcinogenic potency, derived for tumour incidences reported in a drinking-water bioassay with Sprague-Dawley rats a

Animal data

Human equivalent valuesDose Incidence Parameter estimates

Males: Brain and/orspinal cord, benign andmalignant; excludinganimals dying or sacri-ficed before 6 months

control3.4 mg/kg body weight per day (35 ppm)8.5 mg/kg body weight per day (100 ppm)21.2 mg/kg body weight per day (300 ppm)

1/79 (1 astrocytoma)12/47 (8 astrocytoma, 4 benign)23/47 (19 astrocytoma, 4 benign)31/48 (23 astrocytoma, 8 benign)

TD05 = 0.84 mg/kg body weight per day95% LCL b = 0.68 mg/kg body weight perdayChi-square = 3.68Degrees of freedom = 2P-value = 0.16

TD05 = 0.84 mg/kg body weight per day95% LCL = 0.68 mg/kg body weight perday

Females: Brain and/orspinal cord, benign andmalignant; excludinganimals dying or sacri-ficed before 6 months

control4.4 mg/kg body weight per day (35 ppm)10.8 mg/kg body weight per day (100 ppm)

[25.0 mg/kg body weight per day (300 ppm)]

1/80 (1 astrocytoma)22/48 (17 astrocytoma, 5 benign)26/48 (22 astrocytoma, 4 benign)

[31/47 (24 astrocytoma, 7 benign)]

Parameter estimates excluding high-dosegroup:TD05

c = 0.56 mg/kg body weight per day95% LCL = 0.44 mg/kg body weight per dayChi-square = 4.77Degrees of freedom = 1P-value = 0.08

TD05c = 0.56 mg/kg body weight per day

95% LCL = 0.44 mg/kg body weight perday

a From Quast et al. (1980a).b 95% LCL = lower 95% confidence limit.c Excludes high-dose group. A dose-related increase in mortality was observed for females, resulting in a plateau in the dose–response function and lack of fit of the model to brain/spinal tumours. However,

when the model was refit excluding the highest dose group, this lack of fit was no longer apparent.

Table 4: Quantitative estimates of carcinogenic potency, derived for tumour incidences reported in a drinking-water bioassay with F344 rats a

Animal data

Dose Incidence Parameter estimates Human equivalent values

Males: Nervous system,combined incidence,astrocytoma and focal gliosis,excluding animals dying orsacrificed before 6 months

control0.08 mg/kg body weight per day (1 ppm)0.25 mg/kg body weight per day (3 ppm)0.84 mg/kg body weight per day (10 ppm)2.49 mg/kg body weight per day (30 ppm)8.37 mg/kg body weight per day (100 ppm)

5/182 (3 astrocytoma, 2 benign)2/90 (2 astrocytoma)1/89 (1 astrocytoma)2/90 (2 astrocytoma)10/89 (10 astrocytoma)22/90 (21 astrocytoma, 1 benign)

TD05b = 1.8 mg/kg body weight per day

95% LCL c = 1.2 mg/kg body weight perdayChi-square = 3.0Degrees of freedom = 3P-value = 0.39


Females: Brain and/or spinalcord, benign and malignant;excluding animals dying orsacrificed before 6 months

control0.10 mg/kg body weight per day (1 ppm)0.40 mg/kg body weight per day (3 ppm)1.30 mg/kg body weight per day (10 ppm)3.70 mg/kg body weight per day (30 ppm)10.90 mg/kg body weight per day (100ppm)

1/178 (1 astrocytoma)1/90 (1 astrocytoma)2/90 (2 astrocytoma)5/88 (4 astrocytoma, 1 benign)6/90 (6 astrocytoma)26/90 (24 astrocytoma, 2 benign)

TD05 = 2.0 mg/kg body weight per day95% LCL = 1.2 mg/kg body weight perdayChi-square = 1.8Degrees of freedom = 3P-value = 0.62


a From Bio/Dynamics Inc. (1980b).b The experimental length for this study was 23 months for females and 26 months for males, so the resulting TD05s for males were multiplied by (26 months/24 months) × (26 months/24 months) 2, where the

first term amortizes the dose to be constant over the standard lifetime of a rat (24 months) and the second factor, suggested by Peto et al. (1984), corrects for an experimental length that is unequal to thestandard lifetime.

c 95% LCL = lower 95% confidence limit.

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concentrations up to and including 100 mg/litre did notincrease mortality. There was a significant increase inZymbal gland tumours at 500 mg/litre (0/18, 0/20, 1/19,and 9/18 [P < 0.005] in control, low-, mid-, and high-dosegroups, respectively). No increase in tumours of otherorgans including brain was observed, although four ratsdeveloped papillomatous proliferation of the epitheliumof the forestomach in the high-exposure group.

8.5.3 Gavage

Groups of 100 male and female Sprague-Dawleyrats were exposed in a Bio/Dynamics Inc. (1980c) studyto acrylonitrile in water by intubation at 0, 0.1, or10 mg/kg body weight per day for 20 months. The non-neoplastic effects in the high-dose group includedhigher mortality (both sexes), decreased body weight(males), and increased relative liver weight (males). Thedose of 10 mg/kg body weight per day is a LOAEL,based upon decreased body weight and increased liverto body weight ratio in males, with 0.1 mg/kg bodyweight being the NOEL. In both sexes at the high dose,there was an increased incidence of astrocytoma of thebrain, squamous cell carcinoma of the Zymbal gland, andpapilloma/carcinoma of the stomach.

Maltoni et al. (1977) exposed 40 Sprague-Dawleyrats of each sex by gavage to acrylonitrile in olive oil at 0or 5 mg/kg body weight per day, 3 days/week for52 weeks. In females, the incidence of mammary glandcarcinomas was 7/75 and 4/40 in control and exposedgroups, respectively; the incidence of forestomachepithelial tumours was 0/75 and 4/40 in control andexposed groups, respectively. However, a high spon-taneous incidence of mammary gland tumours in thisstrain of rats, the single dose level, and the shortduration of exposure limit contribution of the study tocharacterization of exposure–response.

8.6 Genotoxicity and related end-points

8.6.1 In vitro studies

In the Salmonella assay, acrylonitrile has inducedreverse mutations in strains TA1535 (Lijinsky &Andrews, 1980), TA1535, and TA100 (Zeiger & Haworth,1985), but only when hamster or rat S9 was present.Weak positive results were also reported in severalEscherichia coli strains in the absence of metabolicactivation (Venitt et al., 1977).

In mammalian cells, acrylonitrile induced hprtmutations in human lymphoblasts without metabolicactivation (Crespi et al., 1985), but not in Chinesehamster V79 cells (Lee & Webber, 1985). In severalstudies, acrylonitrile was positive at the TK locus inmouse lymphoma L5178 TK+/! cells, either with orwithout rat S9 (Amacher & Turner, 1985; Lee & Webber,1985; Myhr et al., 1985; Oberly et al., 1985), and in mouselymphoma P388F cells with metabolic activation

(Anderson & Cross, 1985). It was also mutagenic at theTK locus in human lymphoblasts with metabolicactivation (Crespi et al., 1985; Recio & Skopek, 1988).

Acrylonitrile induced structural chromosomalaberrations either with or without metabolic activation inChinese hamster ovary cells (Danford, 1985; Gulati et al.,1985; Natarajan et al., 1985) and without metabolicactivation in Chinese hamster lung cells (Ishidate &Sofuni, 1985). Results for sister chromatid exchanges inChinese hamster ovary cells and human lymphocytesboth with and without metabolic activation are mixed(Brat & Williams, 1982; Perocco et al., 1982; Gulati et al.,1985; Natarajan et al., 1985; Obe et al., 1985; Chang et al.,1990).

Results of in vitro assays for DNA single strandbreaks (Bradley, 1985; Lakhanisky & Hendrickx, 1985;Bjorge et al., 1996) and DNA repair (unscheduled DNAsynthesis) (Perocco et al., 1982; Glauert et al., 1985;Martin & Campbell, 1985; Probst & Hill, 1985; Williams etal., 1985; Butterworth et al., 1992) were mixed but morecommonly negative in a range of cell types from rats andhumans, with and without activation. Cell transformationin mouse and hamster embryo cells has also beeninvestigated, with mixed results (Lawrence & McGregor,1985; Matthews et al., 1985; Sanner & Rivedal, 1985;Abernethy & Boreiko, 1987; Yuan & Wong, 1991).

Binding of 2-cyanoethylene oxide to nucleic acidshas also been reported in in vitro studies at highconcentrations (Hogy & Guengerich, 1986; Solomon &Segal, 1989; Solomon et al., 1993; Yates et al., 1993,19941). The formation of acrylonitrile–DNA adducts isincreased substantially in the presence of metabolicactivation. Under non-activating conditions involvingincubation of calf thymus DNA with either acrylonitrileor 2-cyanoethylene oxide in vitro, 2-cyanoethylene oxidealkylates DNA much more readily than acrylonitrile(Guengerich et al., 1981; Solomon et al., 1984, 1993).Incubation of DNA with 2-cyanoethylene oxide yields 7-(2-oxoethyl)-guanine (Guengerich et al., 1981; Hogy &Guengerich, 1986; Solomon & Segal, 1989; Solomon etal., 1993; Yates et al., 1993, 1994) as well as otheradducts. Compared with studies with rat livermicrosomes, little or no DNA alkylation by acrylonitrilewas observed with rat brain microsomes (Guengerich etal., 1981). DNA alkylation in human liver microsomes wasmuch less than that observed with rat microsomes(Guengerich et al., 1981); although there was noglutathione S-transferase activity in cytosol preparationsfrom human liver exposed to acrylonitrile, there wassome activity for 2-cyanoethylene oxide (Guengerich etal., 1981).

1 Yates et al. (1994) also reported single and double strandbreaks in plasmid DNA incubated with 2-cyanoethylene oxide.


18

8.6.2 In vivo studies

Limitations of the few in vivo studies conducted inwhich the genotoxicity of acrylonitrile has been investi-gated preclude definitive conclusions. Data from thesestudies are also inadequate for characterization of dose–response for comparison between studies or with thecancer bioassays.

Exposure to acrylonitrile in drinking-water resultedin increased frequency of mutants at the hprt locus insplenic T-cells (Walker & Walker, 1997). Five female F344rats were exposed to 0, 33, 100, or 500 mg/litre (0, 8, 21, or76 mg/kg body weight per day; Health Canada, 1994) indrinking-water for up to 4 weeks and serially sacrificedthroughout exposure and up to 8 weeks post-exposure.At 4 weeks post-exposure, the average observed mutantfrequency in splenic T-cells was increased in a dose-related manner (significant at the two highest doses).

Results of a range of assays for structural chromo-somal aberrations, micronuclei in bone marrow, andmicronuclei in peripheral blood cells have been negativeor inconclusive, although there was no indication in thepublished accounts of three of the four studies that thecompound reached the target site. These include studiesin Swiss (Rabello-Gay & Ahmed, 1980), NMRI (Leonardet al., 1981), and C57B1/6 (Sharief et al., 1986) mice and acollaborative study following exposure by multipleroutes in mice and rats (Morita et al., 1997).

Results of dominant lethal assays were inconclu-sive in mice (Leonard et al., 1981) and negative in rats(Working et al., 1987).

In assays for unscheduled DNA synthesis in rats,results were positive only for the liver (Hogy & Guen-gerich, 1986), equivocal in lung, testes, and gastrictissues (Ahmed et al., 1992a,b; Abdel-Rahman et al.,1994), and, notably, negative in the brain (Hogy &Guengerich, 1986). In these studies, however, unsched-uled DNA synthesis was measured by liquid scintillationcounting to determine [3H]thymidine uptake in the cellpopulation, which does not discriminate between cellsundergoing repair and those that are replicating. Resultsfor unscheduled DNA synthesis in rat liver and sperma-tocytes were negative when [3H]thymidine uptake inindividual cells was determined by autoradiography,which eliminates replicating cells from the analysis(Butterworth et al., 1992).

Urine from acrylonitrile-exposed rats and mice wasalso mutagenic in Salmonella typhimurium followingintraperitoneal administration of acrylonitrile to rats andmice (Lambotte-Vandepaer et al., 1980, 1981). In bothspecies, mutagenic activity occurred without activation.Mutagenic activity was also observed in urine of rats

administered acrylonitrile by stomach intubation(Lambotte-Vandepaer et al., 1985). Thiocyanate, hydroxy-ethylmercapturic acid, and cyanoethylmercapturic acidwere not believed to be responsible for urinarymutagenicity.

In in vivo studies in F344 rats administered 50 mgacrylonitrile/kg body weight intraperitoneally, 7-(2-oxoethyl)-guanine adducts were detected in liver (Hogy& Guengerich, 1986). Incorporation of acrylonitrile intohepatic RNA was observed following intraperitonealadministration to rats (Peter et al., 1983). However, noDNA adducts were detected in the brain, which is theprimary target for acrylonitrile-induced tumorigenesis, inthis or a subsequent study in which F344 rats received50 or 100 mg acrylonitrile/kg body weight bysubcutaneous injection (Prokopczyk et al., 1988). Incontrast, in three studies from one laboratory, exposureof SD rats to 46.5 mg [14C]acrylonitrile/kg body weight(50 µCi/kg body weight) resulted in apparent binding ofradioactivity to DNA from liver, stomach, brain(Farooqui & Ahmed, 1983), lung (Ahmed et al., 1992a),and testicles (Ahmed et al., 1992b). In each tissue, therewas a rapid decrease in radioactivity of DNA samplescollected up to 72 h following treatment.

It is not clear why acrylonitrile–DNA binding wasdetected in the brain in these studies and not in those byHogy & Guengerich (1986) or Prokopczyk et al. (1988).The DNA isolation protocols and method for correctingfor contaminating protein in the DNA sample used byHogy & Guengerich (1986) may have allowed a morestringent determination of DNA-bound material. Alter-natively, the methods used to achieve greater DNApurity might have caused the loss of adducts orinhibited the recovery of adducted DNA; more likely,however, 7-oxoethylguanine and cyanoethyl adducts areof little consequence in the induction ofacrylonitrile-induced brain tumours. Indeed,investigation of the role of cyanohydroxyethylguanineand other adducts in the induction of these tumoursseems warranted.

8.7 Reproductive toxicity

Consistent effects on the reproductive organs ofmale or female animals have not been observed inrepeated-dose toxicity and carcinogenicity studiesconducted to date. In a specialized investigation in CD-1mice exposed by gavage, however, degenerativechanges in the seminiferous tubules and associateddecreases in sperm counts were observed at 10 mg/kgbody weight per day (NOEL = 1 mg/kg body weight perday) (Tandon et al., 1988). Although epididymal spermmotility was reduced in a 13-week study with B6C3F1

mice, there was no dose–response and no effect uponsperm density at doses up to 12 mg/kg body weight per

Acrylonitrile

19

day by gavage, although histopathological results werenot reported (Southern Research Institute, 1996). In athree-generation study in rats exposed via drinking-water (14 or 70 mg/kg body weight per day), adverseeffects on pup survival and viability and lactationindices were attributed to maternal toxicity (LittonBionetics Inc., 1980).

In two studies by inhalation, developmental effects(fetotoxic and teratogenic) were not observed at concen-trations that were not toxic to the mothers (Murray et al.,1978; Saillenfait et al., 1993). In the investigation in whichconcentration–response was best characterized (fourexposure concentrations and controls with 2-foldspacing: 0, 12, 25, 50, and 100 ppm [0, 26.4, 55, 110, and220 mg/m3]), the LOEL for maternal toxicity and forfetotoxicity was 25 ppm (55 mg/m3); the NOEL was12 ppm (26.4 mg/m3) (Saillenfait et al., 1993).

Similarly, in two studies by the oral route, develop-mental effects have not been observed at doses thatwere not also toxic to the mothers (lowest reported effectlevel in the mothers was 14 mg/kg body weight per day)(Murray et al., 1978; Litton Bionetics Inc., 1980).Reversible biochemical effects on the brain but not func-tional neurological effects were observed in offspring ofrats exposed to 5 mg/kg body weight per day (a dosethat did not impact on body weight of the dams); dose–response was not investigated in this study (Mehrotra etal., 1988).

8.8 Neurological effects and effects on theimmune system

In recently published studies in rats exposed byinhalation to 25 ppm (55 mg/m3) acrylonitrile and abovefor 24 weeks, there were partially reversible time- andconcentration-dependent reductions in motor andsensory conduction (Gagnaire et al., 1998).

In the few identified investigations of the immuno-logical effects of acrylonitrile, effects on the lungfollowing inhalation (Bhooma et al., 1992) and on thegastrointestinal tract following ingestion (Hamada et al.,1998) have been observed at concentrations and dosesat which histopathological effects have also beenobserved. The effects on the lungs included an increasein the level of procoagulant activity in alveolarmacrophages (Bhooma et al., 1992). The effects on thegastrointestinal tract consisted of an increase in thenumber of IgA-producing cells in the duodenum,jejunum, and ileum, an increase in the number of cells inS-phase in the duodenum and ileum, and a decrease inthe response of splenocytes to mitogens (Hamada et al.,1998).

8.9 Mode of action

8.9.1 Cancer

Results of the few identified investigations inwhich the relative potency of acrylonitrile was comparedwith that of cyanoethylene oxide are consistent with theoxidative pathway of metabolism being critical in geno-toxicity. In an assay with two strains of S. typhimurium,cyanoethylene oxide was mutagenic without activation,whereas acrylonitrile required activation (Cerna et al.,1981). In one study, cyanoethylene oxide was approxi-mately 15-fold more mutagenic than acrylonitrile at theTK locus in cultured human lymphoblastoid cells (Recio& Skopek, 1988). In vitro, the formation of DNA adductsat high unphysiological concentrations is increasedsubstantially in the presence of metabolic activation.Under non-activating conditions, cyanoethylene oxidealkylates DNA much more readily than acrylonitrile(Guengerich et al., 1981; Solomon et al., 1984, 1993).

Data on the binding of acrylonitrile to DNA arepresented in section 8.6. However, available data areinadequate to implicate a particular adduct in theinduction of acrylonitrile-induced brain tumours.

There are some suggestions from in vitro studiesreported as abstracts that free radicals (@OH, O2@) andhydrogen peroxide may be directly implicated in theoxidation of acrylonitrile and DNA damage. Formation offree radicals may be partially related to the release ofcyanide or other mechanisms responsible for cellular andDNA damage (Ahmed et al., 1996; Ahmed & Nouraldeen,1996; El-zahaby et al., 1996; Mohamadin et al., 1996).

In more recent investigations, the results of whichhave been presented incompletely at this time, Prow etal. (1997) reported that acrylonitrile inhibited gapjunctional intercellular communication in a rat astrocytecell line in a dose-dependent manner, possibly throughan oxidative stress mechanism. Similarly, Zhang et al.(1998) assayed acrylonitrile with Syrian hamster embryocells, with and without an antioxidant, and concludedthat oxidative stress contributed to morphologicaltransformation in the cells. Jiang et al. (1998) assayedacrylonitrile with a rat astrocyte cell line and reportedoxidative damage (indicated by the presence of 8-hydroxy-2'-deoxyguanosine) at all concentrations tested.

Jiang et al. (1997) exposed male Sprague-Dawleyrats to 0 or 100 mg acrylonitrile/litre in drinking-water for2 weeks. End-points examined were levels of glutathioneand reactive oxygen species in brain and liver, presenceof 8-hydroxy-2'-deoxyguanosine (indicative of oxidativeDNA damage) in several tissues, and determination ofactivation of NF-KB (a transcription factor stronglyassociated with oxidative stress). Glutathione in brain


20

was decreased. (Whysner et al. [1998a] reported noeffects upon concentrations of glutathione in brain ofmale Sprague-Dawley rats exposed to 3, 30, or 300 mgacrylonitrile/litre in drinking-water for 3 weeks.) Reactiveoxygen species were increased 4-fold in brain. Levels of8-hydroxy-2'-deoxyguanosine were increased 3-fold inthe brain. Activation of NF-KB was also observed in thebrain.

In recently conducted studies, levels of 8-oxo-deoxyguanosine in the brain of rats exposed to acrylo-nitrile in drinking-water in each of the three followingprotocols have been examined (Whysner et al., 1997,1998a):

# In male Sprague-Dawley rats exposed for 21 daysto 0, 3, 30, or 300 mg/litre, there was a significantincrease in 8-oxodeoxyguanosine in brain nuclearDNA at the two highest doses. In the liver, nuclearDNA 8-oxodeoxyguanosine concentrations weresignificantly increased at the two highest doses(Whysner et al., 1998a). In a bioassay withcomparable dose levels, the incidence of brainand/or spinal cord tumours was significantlyincreased in male Sprague-Dawley rats exposed to35 mg acrylonitrile/litre (3.4 mg/kg body weight perday) and higher for 2 years (Quast et al., 1980a).

# In male F344 rats exposed for 21 days to 0, 1, 3, 10,30, or 100 mg/litre, there were no significantdifferences between groups for 8-oxodeoxy-guanosine in the brain (Whysner et al., 1998a).

# In male Sprague-Dawley rats exposed for up to94 days to 0 or 100 mg/litre, concentrations of 8-oxodeoxyguanosine in the brain were significantlyincreased after 3, 10, and 94 days of exposure(Whysner et al., 1998a). In the 2-year drinking-water bioassay with male Sprague-Dawley rats(Quast et al., 1980a), the incidence of brain and/orspinal cord tumours was significantly increased at100 mg/litre (8.5 mg/kg body weight per day).

The end-point for which changes wereconsistently observed in male Sprague-Dawley rats wasthe induction of oxidative DNA damage, including theaccumulation of 8-oxodeoxyguanosine in the brain. Theauthors drew correlations between these results and theincidence of brain/spinal cord tumours that had beenreported in carcinogenicity bioassays in which maleSprague-Dawley rats were exposed to acrylonitrile viadrinking-water.

Increased levels of 8-oxodeoxyguanosine occuronly in the anterior portion of the brain, which containsrapidly dividing glial cells (Whysner et al., 1998b).

8.9.2 Neurotoxicity

Neurotoxicity following inhalation by maleSprague-Dawley rats of 0, 25, 50, or 100 ppm (0, 55, 110,or 220 mg/m3) acrylonitrile for 6 h/day, 5 days/week, for24 weeks, followed by 8 weeks of recovery, was reportedby Gagnaire et al. (1998). Body weight at the high dosewas significantly reduced throughout exposure. Clinicalobservations at the mid and high doses included wet furand hypersalivation during exposure. The authors notedthat signs were similar to those associated with acuteacetylcholine-like toxicity. There were time- andconcentration-dependent reductions in motorconduction velocity, sensory conduction velocity, andamplitude of sensory action potential in tail nerve, whichwere partially reversible after 8 weeks of recovery (LOEL= 25 ppm [55 mg/m3]). The protocol did not includehistological examination.

9. EFFECTS ON HUMANS

In case reports of acute intoxication, effects on thecentral nervous system characteristic of cyanide poison-ing and effects on the liver, manifested as increasedenzyme levels in the blood, have been observed. Therehave also been reports that acrylonitrile is a skin irritantand skin sensitizer, the latter based on patch testing ofworkers (Balda, 1975; Bakker et al., 1991; EC, 2000; Chu &Sun, 2001).

In the few studies in which non-neoplastic effectsof acrylonitrile have been systematically investigated,only acute dermal irritation has been reported consis-tently. In a cross-sectional investigation of workersexposed in acrylic fibre factories to approximately 1 ppm(2.2 mg/m3), there was no consistent evidence of adverseeffects based on examination of a wide range of clinicalparameters, including liver function tests (Muto et al.,1992). However, there was an increase in subjectivesymptoms of acute dermal irritation, consistent withobservations in another cohort of acrylic fibre manufac-turing workers (Kaneko & Omae, 1992).

In a cross-sectional investigation of a smallergroup of workers producing acrylic textile fibres forwhich quantitative data on exposure were not reported,there was no evidence of induction of hepatic cyto-chrome P-450 or genotoxicity of urine (Borba et al., 1996).

Although there was some evidence in primarilyearly limited studies of excesses of lung cancer (Thiesset al., 1980), “all tumours” (Zhou & Wang, 1991), andcolorectal cancer (Mastrangelo et al., 1993), suchexcesses have not been confirmed in well conducted andwell reported recent investigations in four relatively large

Acrylonitrile

21

cohorts of workers (Benn & Osborne, 1998; Blair et al.,1998; Swaen et al., 1998; Wood et al., 1998). Indeed, thereis no consistent, convincing evidence of an associationbetween exposure to acrylonitrile and cancer of aparticular site that fulfils, even in part, traditional criteriafor causality in epidemiological studies.

Benn & Osborne (1998) reported results of ahistorical cohort study carried out in 2763 workers. Vitalstatus was traced from 1978 through 1991, and follow-upwas virtually complete. Only for lung cancer was thereany indication of excess risk, and that was in the morehighly exposed jobs and among the very young; how-ever, based upon detailed analyses, there was no consis-tent support for the hypothesis of a causal relationshipbetween exposure to acrylonitrile and lung cancer.Limited information on exposure levels, questionablequality of source records of work histories, and use ofnational rather than local rates for computing standard-ized mortality ratios (SMRs) compromise the inferencesthat can be drawn.

Swaen et al. (1998) conducted a historical cohortstudy in 2842 workers occupationally exposed to acrylo-nitrile. Extensive industrial hygiene assessments wereconducted to quantify past exposure to acrylonitrile. Thefollow-up between 1979 and 1995 was 99.6% complete; in99.3% of cases, the cause of death could be ascertained.Selected cause-specific SMRs in the exposed cohortwere as follows: lung, 109.8 (95% confidence interval [CI]= 81–146, number of observed cases [Obs] = 47); colon,126.0 (95% CI = 58–239, Obs = 9); leukaemia, 266.7 (95%CI = 54–390, Obs = 5); prostate, 83.3 (95% CI = 22–213,Obs = 4); bladder, 97.9 (95% CI = 20–286, Obs = 3); brain,173.9 (95% CI = 64–378, Obs = 6). Some of these resultsare suggestive of excess risks, but the evidence ofexcess for any specific type of cancer is not strong. Thedata appear to have been well collected and analysed,and follow-up was good. While this is a reasonably largestudy, the power to detect dose–response relationshipsis still limited. Smoking was not considered.

The largest and most statistically powerful of therecent cohort studies was that conducted by Blair et al.(1998), which included 25 460 workers from eight plantsproducing and using acrylonitrile. Estimates of exposureto acrylonitrile were based on information from produc-tion procedures at the plants, interviews with manage-ment and labour, monitoring data from the companies,and monitoring conducted by the investigators specifi-cally for the study. Vital status was successfully deter-mined for 96% of the cohort. There was a total of 545 369person-years of follow-up, of which one-third was inunexposed workers. This study had the most extensiveexposure assessment protocol and the most extensivedata on smoking. The mortality follow-up was complete,and the observation period was lengthy. There was a

small (non-significant) excess of lung cancer in thehighest quintile of cumulative exposure (relative risk =1.5; 95% CI = 0.9–2.4), but no exposure–response trend.The exposure categories were as follows:

0.01–0.13 ppm-years: 121 430 person-years0.14–0.57 ppm-years: 69 122 person-years0.58–1.50 ppm-years: 49 800 person-years1.51–8.00 ppm-years: 63 483 person-years

>8.00 ppm-years: 44 807 person-years

It should be noted that the power to detect moder-ate excesses was small for some sites (stomach, brain,breast, prostate, lymphatic/haematopoietic) because ofsmall numbers of expected deaths.

Wood et al. (1998) reported a historical cohortmortality and cancer incidence study in 2559 workerswho had been occupationally exposed to acrylonitrile.There was a total of 75 009 person-years of mortalityobservation among the study subjects. There were nosignificantly elevated SMRs for specific cancer sites.This study was carried out in a company with good-quality information on work practices and industrialhygiene, complete work records, and good follow-up formortality and cancer incidence. The latter is a uniqueadvantage of this data set. The data appear to have beenwell collected and analysed. Limitations include the lackof data on workers’ race and smoking habits. Basedupon a comparison with US rates, there was a 40% all-cause deficit and 34% cancer deficit seen in theWaynesboro cohort, which suggests a lack of reportingof cause of death. While this is a reasonably large study,power to detect dose–response relationships is stilllimited. While considerable effort was made to gatherexposure data, there was no monitoring of acrylonitrilebefore 1975, and data for early years were inferred. Anadditional strength of this study is the number ofperson-years at the high level of exposure.

10. EFFECTS ON OTHER ORGANISMS INTHE LABORATORY AND FIELD

The toxicity of acrylonitrile has been examined in awide range of aquatic organisms, while the data set onthe toxicity of acrylonitrile to terrestrial organisms ismore limited.

10.1 Aquatic organisms

The data set for acrylonitrile includes a wide rangeof information on short- and long-term toxicity in34 species of fish, amphibians, aquatic invertebrates, andalgae, although none complies totally with the require-


22

ments of OECD or similar test guideline protocols, andvolatility was often not adequately addressed (Environ-ment Canada, 1998). Below, a brief summary of the keystudies carried out in general compliance with currentOECD testing protocols and/or where concentrationswere measured or could be adequately adjusted ispresented. Primary studies selected include those whereconcentrations have been measured in static or static-renewal tests or flow-through tests with five turnoversper day (Henderson et al., 1961; Bailey et al., 1985; V.Nabholz, personal communication, 1998).

T.D. Sabourin (personal communication, 1987)determined the ratio of flow-through to static concentra-tions at the 96-h period to be 0.23. Therefore, studieswith 96-h end-points can be adjusted by multiplying thereported concentration by 0.23, although the evidenceprovided by these studies is considered secondary.Tests done under static conditions or those withnominal concentrations only at a time period differentfrom 96 h are considered as supporting evidence only.

Of the freshwater studies, there are five studies onfive fish species and one study with an amphibian thatare considered to provide primary data (Henderson et al.,1961; Sloof, 1979; Analytical BioChemistry Laboratories,1980a; Bailey et al., 1985; Zhang et al., 1996). In additionto these, there is secondary evidence (adjustedconcentrations) from studies with six fish, seven inver-tebrate, and one plant species. In these studies, a varietyof end-points was examined, including survival, growth,respiration, and mobility at exposure durations rangingfrom 24 to 840 h (1–35 days). The remainder of thestudies (i.e., where there was no replication of doses orother limitations such as lack of aeration) were consid-ered as supporting evidence only.

The 96-h LC50s for freshwater fish range from 10 to20 mg/litre (nominal) (Henderson et al., 1961; AnalyticalBioChemistry Laboratories, 1980b; Zhang et al., 1996).Reported 48-h LC50s range between 14.3 and33.5 mg/litre. At 840 h, the LC50 for fathead minnow(Pimephales promelas) was 0.89 mg/litre (AnalyticalBioChemistry Laboratories, 1980a).

Based on the primary evidence, the most sensitiveaquatic end-point was that for long-term exposure of thefrog Bufo bufo gargarizans in its early life stage (Zhanget al., 1996). Three-day-old tadpoles were exposed for 28days in a flow-through system with four turnovers perday. The most sensitive end-point was foreleg growth,where the lower and upper chronic limits around the 28-day EC50 were 0.4 mg/litre and 0.8 mg/litre, respectively.The 96-h and 48-h EC50s for immobility were11.59 mg/litre and 14.22 mg/litre, respectively.

The effect of acrylonitrile on the growth (lengthand wet weight) and mortality of the early life stage (<18-h-old eggs) of the fathead minnow (AnalyticalBioChemistry Laboratories, 1980a) in a flow-throughsystem with more than 5.5 turnovers per day has beenexamined. Mean measured concentrations were 98% ofnominal. The most sensitive end-point in the study wasthe 840-h (35-day) lowest-observed-effect concentration(LOEC) for weight (20% reduction in wet weight) at 0.44mg/litre; the corresponding no-observed-effectconcentration (NOEC) was 0.34 mg/litre. For mortality,the 840-h NOEC (LC15) was 0.44 mg/litre, and the LOEC(LC46) was 0.86 mg/litre.

Henderson et al. (1961) reported mortality offathead minnow exposed to acrylonitrile in a flow-through system in which solutions were renewed every100 min. Test durations were 24, 48, 72, and 96 h and 5,10, 15, 20, 25, and 30 days (720 h). Effects ranged fromthe 24-h LC50 of 33.5 mg/litre through decreasingconcentrations to the most sensitive end-point in thestudy, the 720-h LC50 at 2.6 mg/litre.

Sloof (1979) reported the impact of acrylonitrile asincreased respiration in rainbow trout (Oncorhynchusmykiss) within 24 h of exposure to 5 mg/litre in a flow-through system with continuous injection.

Bailey et al. (1985) examined the effect of acrylo-nitrile on the mortality of bluegill (Lepomis macrochirus)in a flow-through system with measured concentrations.The 96-h LC50 was 9.3 mg/litre.

In addition to primary studies with adequate flow-through or measured concentrations, 96-h LC50s in sixspecies of fish in studies conducted with static/static-renewal nominal concentrations can be adjusted by thefactor 0.23 (T.D. Sabourin, personal communication,1987; V. Nabholz, personal communication, 1998). Basedon this method, the adjusted 96-h LC50s ranged from 1.18to 5.4 mg/litre. The lowest 96-h LC50 of 1.18 mg/litre wasthat for grass carp (Ctenopharyngodon idella) (Zhanget al., 1996).

It is noted that for vertebrate species, the lowestreported effect concentrations were from primary studies.That is, overall, the most sensitive end-point for aquaticvertebrates was the lower chronic limit around the EC50

of 0.4 mg/litre in the frog Bufo bufo gargarizans,determined by Zhang et al. (1996) in a flow-throughsystem with measured concentrations.

Ninety-six-hour tests in 7 of 14 invertebrate and 1of 1 freshwater plant species can be adjusted to providesecondary evidence. Based on the secondary informa-tion, which must be interpreted with caution, it appearsthat, overall, invertebrates are more sensitive to acrylo-

Acrylonitrile

23

nitrile than vertebrates, although this was not discussedfurther by the authors. Effects in invertebrates rangefrom the 96-h LC80 of 0.16 mg/litre (adjusted concentra-tion 0.04 mg/litre) in the pond snail (Lymnaea stagnalis)(Erben & Beader, 1983) to the 96-h immobility EC50 at17.94 mg/litre (adjusted concentration 4.1 mg/litre) in thecommon stream snail (Lymnaea plicatula) (Zhang et al.,1996).

In the one study on freshwater aquatic plants, theeffect of a 96-h exposure to acrylonitrile on growth wasexamined in duckweed (Lemna minor) (Zhang et al.,1996). Solutions were renewed every 24 h, with five testconcentrations, 10 fronds per concentration, and fourreplicates. The 96-h growth inhibition EC50 was6.25 mg/litre (adjusted EC50 is 1.44 mg/litre).

10.2 Terrestrial organisms

Data on the toxicity of acrylonitrile to terrestrialvertebrate wildlife or avian species were not identified;those from mammalian toxicity studies are reviewed insection 8. Studies reviewed below are limited to those oninsect species exposed to acrylonitrile in air.

In nine studies conducted on 13 insect species —including pulse beetle (Callosobruchus chinensis), riceweevil (Sitophilus oryzae), lesser grain borer (Rhyzo-pertha dominica), granary weevil (Sitophilusgranarius), saw-toothed grain beetle (Oryzaephilussurinamensis), red flour beetle (Tribolium castaneum),confused flour beetle (Tribolium confusum),Mediterranean fruit fly (Ceratitis capitata), Oriental fruitfly (Bactrocera (formerly Dacus) dorsalis), and honeybee (Apis mellifera) — short- and long-term exposure viafumigation with acrylonitrile affected survival,reproduction, and enzyme activity (Environment Canada,1998). LC50s in insects ranged from 0.107 to 36.7 mg/litreair (1.07 × 105–3.67 × 107 µg/m3). In 14 of 17 studies on 11species, the 24-h LC50 was #5 mg/litre air (#5 × 106

µg/m3).

The effect on growth, survival, or reproduction ininsects exposed to acrylonitrile via the atmosphereobserved at lowest concentration was that followingfumigation on the 1-day-old eggs of the pulse beetle(Callosobruchus chinensis) (Adu & Muthu, 1985). TheLC50 for eggs exposed to a constant concentration of thefumigant for 24 h and examined for survival up to30 days post-fumigation was 0.107 mg/litre air (1.07 × 105

µg/m3) (95% CI = 0.094–0.122 mg/litre air) (Adu & Muthu,1985).

Rajendran & Muthu (1981a) reported that foradults and pupae of rice weevil (Sitophilus oryzae L.)exposed to the LC50 of 0.40 mg/litre air (4.0 × 105 µg/m3)

for 8 h, there was a 50% decrease in the number ofprogeny.

Of the knockdown times reported for insects, themost sensitive organisms were rice weevil (Sitophilusoryzae L.) adults, for which exposure to 1–1.5 mg/litre air(1–1.5 × 106 µg/m3) for 4 h resulted in 100% mortality(Rajendran & Muthu, 1977).

Of phosphorylase, trehalase, and acetylcholines-terase enzymes involved in carbohydrate and energymetabolism, phosphorylase was the most susceptible.There was no detectable activity (100% decrease) of thisenzyme at a concentration of 1.05 mg/litre air (1.05 × 106

µg/m3) in adult red flour beetle (Tribolium castaneum),which survived exposure to the LC50 of 0.79 mg/litre (7.9× 105 µg/m3) (Rajendran & Muthu, 1981b).

10.3 Microorganisms

There is considerable evidence of the effectivenessof acclimated soil or sludge microorganisms in degradingacrylonitrile in industrial wastewater treatment systems(e.g., Biox reactors). Wyatt & Knowles (1995a,b)demonstrated that complex mixtures of microorganismsunder different dilution rates and a combination of batchand continuous culture can mineralize (degrade)acrylonitrile, acrylamide, acetic acid, cyanopyridine, andsuccinonitrile, as well as more recalcitrant compounds(e.g., maleimide, fumaronitrile, and acrolein), to carbondioxide, ammonia, and biomass.

Generally, concentrations of acrylonitrile up to5000 mg/litre are not toxic to bacteria, since they arereadily degraded by Corynebacterium boffmanii andArthrobacter flavescens (Wenzhong et al., 1991), Arthro-bacter sp. (Narayanasamy et al., 1990), Acinobacter sp.(Finnegan et al., 1991), and an assemblage of acclimatedanaerobic microorganisms (Mills & Stack, 1955).Nocardia rhodochrous can degrade acrylonitrile in amore limited manner, based on its use as a nitrogenrather than carbon source (DiGeronimo & Antoine, 1976).

Kincannon et al. (1983) reported almost completebiodegradation, with 99.9% and 99.1% removal ofacrylonitrile after 8 h in batch reactors and 2 days incomplete mixture activated sludge, respectively. Initialconcentrations of acrylonitrile were 110 and 152 mg/litre,respectively; effluent concentrations post-treatmentwere 1.0 mg/litre after 8 h and <0.05 mg/litre after 2 days,respectively. In the batch reactor, biodegradationaccounted for 75% and stripping accounted for 25% ofremoval of acrylonitrile. In the activated sludge system,biodegradation was responsible for 100% of the removal.

Tabak et al. (1980) reported 100% biodegradationwithin 7 days in a static screening flask test method


24

when microbial inoculum from a sewage treatment plantwas mixed with 5 and 10 mg acrylonitrile/litre.

11. EFFECTS EVALUATION

11.1 Evaluation of health effects

11.1.1 Hazard identification

11.1.1.1 Effects in humans

In case reports of acute intoxication, effects on thecentral nervous system characteristic of cyanide poison-ing and effects on the liver, manifested as increasedenzyme levels in the blood, have been observed. Therehave also been reports that acrylonitrile is a skin irritantand sensitizer, the latter based on patch testing ofworkers (Balda, 1975; Bakker et al., 1991; Chu & Sun,2001).

In the few studies in which non-neoplastic effectsof acrylonitrile have been systematically investigated,only acute irritation has been reported consistently.

Although the database is relatively extensive,there is no consistent, convincing evidence of anassociation between exposure to acrylonitrile and cancerof a particular site that fulfils traditional criteria forcausality in epidemiological studies.

11.1.1.2 Effects in experimental animals

The acute toxicity of acrylonitrile is relatively high.Signs of acute toxicity include respiratory tract irritationand two phases of neurotoxicity, the first resemblingcholinergic overstimulation and the second being centralnervous system dysfunction, resembling cyanidepoisoning. Superficial necrosis of the liver andhaemorrhagic gastritis of the forestomach have also beenobserved following single exposure.

Data on the non-neoplastic effects of acrylonitrilefollowing repeated exposure are restricted to primarilyearly, limited studies, most often unpublished carcino-genesis bioassays, a few more recent investigations ofspecialized end-points, or more recent studies for whichfull accounts are not yet available.

In available short-term inhalation studies withsingle dose levels and a limited range of examined end-points, effects on biochemical parameters, clinical signs,and body weight were observed following exposure ofrats, although there were no histopathological effects onprincipal organs.

In short-term studies by the oral route, biochemicaleffects on the liver and hyperplasia of the gastricmucosa have been observed, with effects on the gastricmucosa occurring at lowest doses in all studies in whichthey were examined. Effects on the adrenal cortexobserved in short-term repeated-dose toxicity studiesfrom one laboratory have not generally been noted inlonger-term investigations in animals exposed to higherconcentrations. In a preliminary report of a recentsubchronic study in mice, decreases in survival andbody weight and haematological effects were noted,although data presented therein were inadequate forcharacterization of dose–response.

In early carcinogenesis bioassays in rats for whichfew published accounts are available, non-neoplasticeffects included reductions in body weight gain, haema-tological effects, increases in liver and kidney weights,and, at higher doses, increased mortality. Followinginhalation, inflammatory changes in the nasal turbinateswere also observed.

There is considerable evidence of the carcinogen-icity of acrylonitrile, based on the results of primarilyearly unpublished investigations, which have beenrestricted to one species (rats).1 In the most sensitivebioassays, a range of tumours (both benign and malig-nant) has been consistently observed following bothingestion and inhalation, including those of the centralnervous system (brain and/or spinal cord), ear canal,gastrointestinal tract, and mammary glands. In almost alladequate bioassays, there have been reported increasesin astrocytomas of the brain and spinal cord, which arerarely observed spontaneously in experimental animals;these have occurred at highest incidence consistentlyacross studies. Increases have been statistically signifi-cant, and there have been clear dose–response trends.Tumours have sometimes been reported at non-toxicdoses or concentrations and at periods as early as 7–12 months following onset of exposure. Tumours havealso been observed in exposed offspring of a multi-generation reproductive study at 45 weeks.

In numerous studies on the genotoxicity of acrylo-nitrile involving examination of a broad spectrum of end-points both in vitro, with and without metabolic activa-tion, and in vivo in mice and rats, the pattern of resultshas been quite mixed, including in in vitro assays wherethere were adequate precautions to control volatilization.Although the results of many of these studies werenegative, there was also a substantial number of positiveresults for a variety of end-points that cannot be dis-counted. Limitations of the in vivo investigations also

1 A carcinogenesis study in mice exposed to acrylonitrile bygavage is under way (NTP, 1998).

Acrylonitrile

25

preclude their meaningful contribution to the weight ofevidence of genotoxic potential.

Results of the few identified investigations inwhich the relative potency of acrylonitrile was comparedwith that of 2-cyanoethylene oxide are consistent withthe oxidative pathway of metabolism being critical ingenotoxicity. The role of mutagenesis and the primarymutagenic lesion induced by acrylonitrile in acrylonitrile-induced carcinogenesis are uncertain. Acrylonitrile–DNA adducts can be induced in vitro and in the liver invivo, although at levels considerably less than thoseassociated with, for example, ethylene oxide. However,when measures were taken to eliminate contamination ofsamples by adducted protein and unbound acrylonitrile,acrylonitrile–DNA adducts were not detected in thebrain, the primary target for acrylonitrile-inducedcarcinogenesis. This is in contrast to observations forethylene oxide, which is also associated with gliomas ofthe brain. If the methods used to achieve greater DNApurity did not cause the loss of adducts or inhibit therecovery of adducted DNA, this suggests thatacrylonitrile-induced DNA damage and mutagenicitymay occur by a mechanism other than the formation ofacrylonitrile–DNA adducts. Alternatively, they may beassociated with an uninvestigated adduct (e.g., cyano-hydroxyethyl adducts).

Investigations of the potential role of free radicalsand oxidative stress in the carcinogenesis of acrylonitrileare under way, with results of most being presentedincompletely at this time. Exposure to acrylonitrile hasbeen associated with the accumulation of 8-oxodeoxy-guanine in the DNA isolated from brain tissue, presum-ably via the action of reactive oxygen species generatedduring acrylonitrile metabolism. Data on dose–responsein this regard are limited to animals exposed for 21 days.Moreover, the predicted greater sensitivity of Sprague-Dawley versus Fischer rats to induction of tumours ofthe brain/spinal cord on the basis of results of shorter-term studies in which 8-oxodeoxyguanine levels in brainhave been determined is not borne out bycarcinogenesis bioassays. The origin of this oxidativedamage is also unclear.

Also, several aspects of tumour development arecharacteristic of those induced by compounds thatinteract directly with DNA. Tumours are systemic andoccur at multiple sites in both sexes following bothinhalation and ingestion, sometimes at non-toxic dosesor concentrations and at periods as early as 7–12 monthsfollowing onset of exposure. The ratio of benign tomalignant tumours is small.

In summary, the mechanism of carcinogenesis ofacrylonitrile is unknown. However, on the basis ofavailable data, tumours are likely induced by a mode

involving direct interaction with DNA. There is limitedevidence for weak genotoxic potential, insufficient dataon acrylonitrile–DNA adducts in the brain, althoughsuch adducts can be induced in the liver in vivo, andsome indication in ongoing studies that oxidativedamage, the origin of which is unclear, may play a role.Available data in support of this latter hypothesis as aplausible pathway for induction of acrylonitrile-associated tumours are inadequate. There is nohypothesized sequence of events for which there aredata to serve as a basis for assessment of the weight ofevidence against traditional criteria of causality such asconsistency, strength, specificity, dose–response,temporal patterns, biological plausibility, and coherence.

Effects on the reproductive system in experimentalanimals (mice) exposed to acrylonitrile are limited todegenerative changes in the seminiferous tubules andassociated decreases in sperm counts in a specializedinvestigation with exposure by gavage, decreases insperm motility in an unpublished 13-week investigationwith exposure by gavage, for which histopathologicalresults are not yet available, and decreased spermcounts, motility, and histopathological changes in anincompletely reported study. In a three-generation studyin rats exposed via drinking-water, adverse effects onpup survival and viability and lactation indices wereattributed to maternal toxicity.

Biologically significant effects in offspring havenot been observed at doses that were not toxic to themothers in developmental studies in rats exposed toacrylonitrile by both inhalation and ingestion. Thesestudies included a recent well conducted investigationwith good characterization of dose–response.

In the few identified investigations of the immuno-logical effects of acrylonitrile, effects on the lung follow-ing inhalation and on the gastrointestinal tract followingingestion have been observed at concentrations anddoses at which histopathological effects have also beenobserved in other investigations.

In recent studies by inhalation (24 weeks) andingestion (12 weeks), clinical signs typical of acuteacetylcholine-like toxicity and partially reversible reduc-tion in motor and sensory conduction were observed(Gagnaire et al., 1998).

11.1.2 Dose–response analyses

11.1.2.1 Effects in humans

In a cross-sectional investigation of workersexposed in acrylic fibre factories to approximately 1 ppm(2.2 mg/m3) acrylonitrile, there was no consistent evi-dence of adverse effects based on examination of a wide


26

range of clinical parameters, including liver functiontests (Muto et al., 1992). Available data in humans areinadequate to serve as a basis for characterization of theconcentrations at which acute irritation occurs.

There has been no consistent evidence of anassociation between exposure to acrylonitrile and cancerof any specific site in recent studies of four cohorts.However, a non-significant excess of lung cancer wasnoted in the most highly exposed quintile in the statis-tically most powerful investigation. A large deficit incancer in one cohort in comparison with national ratesalso suggests an underreporting of cause of death.

It has been suggested that the results of the epide-miological studies contrast quantitatively with those ofbioassays in animals. However, meaningful direct com-parison of these two types of data is precluded primarilyby inadequate data on mode of induction as a basis tocharacterize possible relevant sites of cancer in humans(i.e., site concordance between animals and humans), therelative paucity of data on exposure of workers in therelevant investigations, and the wide range of theconfidence limits on the SMRs for cancers of possibleinterest in the epidemiological studies. (For example, theupper 95% confidence limit on the SMRs for brain cancerin the only recent cohort study in which it was reported[Swaen et al., 1998] was 378, indicating that an almost400% excess could not be excluded; the lower 95%confidence limit was 64.)

While there has been consistent evidence of a lackof association between exposure to acrylonitrile andcancer of a particular site in recent, well conductedepidemiological studies, the power of the investigationsis insufficient to rule out increases in particularly raretumours, such as those of the brain. Indeed, the powerto detect moderate excesses for some sites (stomach,brain, breast, prostate, lymphatic/haematopoietic) wasquite small because of small numbers of expected deaths.

11.1.2.2 Effects in experimental animals

11.1.2.2.1 Non-neoplastic effects

1) Inhalation

In the more informative of available short-terminhalation studies, all of which were restricted to singledose levels and examination of a limited range of end-points (Gut et al., 1984, 1985), clinical signs anddecreases in body and organ weights but no histopatho-logical effects were observed in rats exposed for 5 daysto 130 ppm (280 mg/m3) acrylonitrile.

With the exception of inflammatory changes in thenasal turbinates (Quast et al., 1980b), non-neoplasticeffects observed in the few conducted long-term

inhalation exposure studies were limited primarily to pre-cancerous hyperplastic changes in the central nervoussystem (Maltoni et al., 1977, 1987, 1988; Quast et al.,1980b). Inflammatory changes in the nasal turbinateswere observed at 80 ppm (176 mg/m3). The NOEL forchanges in nasal turbinates is 20 ppm (44 mg/m3); it islikely that secondary renal effects would be present atthis concentration. At high dose levels, survival wasalso decreased, prior to the appearance of the firsttumour (Quast et al., 1980b).

In two developmental studies in rats exposed byinhalation, developmental effects (fetotoxic andteratogenic) have not been observed at concentrationsthat were not toxic to the mothers (Murray et al., 1978;Saillenfait et al., 1993). In the investigation in whichconcentration–response was best characterized (fourexposure concentrations and controls with 2-foldspacing), the LOEL for maternal toxicity and forfetotoxicity was 25 ppm (55 mg/m3); the NOEL was12 ppm (26.4 mg/m3) (Saillenfait et al., 1993).

In recent studies in rats exposed by inhalation to25 ppm (55 mg/m3) and above for 24 weeks, there werepartially reversible time- and concentration-dependentmarginal reductions in motor and sensory conduction(Gagnaire et al., 1998).

2) Ingestion

In investigations in rats by Szabo et al. (1984),effects on non-protein sulfhydryl in gastric mucosa havebeen reported at levels as low as 2 mg/kg body weightper day (drinking-water, 60 days). Effects on hepaticglutathione were also observed by these authors atsimilar doses administered by gavage but not indrinking-water (2.8 mg/kg body weight per day, 21 days),although Silver et al. (1982) noted only slightbiochemical effects but no histopathological effects inthe liver at doses up to 70 mg/kg body weight per day(drinking-water, 21 days). Significant increases inproliferation in the forestomach but no changes in theliver or glandular stomach have been observed at11.7 mg/kg body weight per day (Ghanayem et al., 1995,1997).

Similar to observations in the inhalation studies,non-neoplastic effects observed in the long-term studiesin rats exposed by ingestion were limited primarily to pre-cancerous hyperplastic changes in target organs such asthe non-glandular stomach (Quast et al., 1980a). Otherobserved effects were limited primarily to increasedorgan weights, which were not observed consistentlywithin or across the studies.

Consistent effects on the reproductive organs ofmale or female animals have not been observed in

Acrylonitrile

27

repeated-dose toxicity and carcinogenicity studiesconducted to date. In a specialized investigation in CD-1mice, however, degenerative changes in the seminiferoustubules and associated decreases in sperm counts wereobserved at 10 mg/kg body weight per day (NOEL =1 mg/kg body weight per day) (Tandon et al., 1988).Although epididymal sperm motility was reduced in a 13-week study with B6C3F1 mice, there was no dose–response and no effect upon sperm density at doses upto 12 mg/kg body weight per day, althoughhistopathological results are not yet available (SouthernResearch Institute, 1996). In a three-generation study inrats exposed via drinking-water (14 and 70 mg/kg bodyweight per day), adverse effects on pup survival andviability and lactation indices were attributed to maternaltoxicity (Litton Bionetics Inc., 1980).

In two studies by the oral route, developmental(including both fetotoxic and teratogenic) effects havenot been observed at doses that were not also toxic tothe mothers (lowest reported effect level in the motherswas 14 mg/kg body weight per day) (Murray et al., 1978;Litton Bionetics Inc., 1980). Reversible biochemicaleffects on the brain but not functional neurologicaleffects were observed in offspring of rats exposed to5 mg/kg body weight per day (a dose that did not affectbody weight of the dams); dose–response was notinvestigated in this study (Mehrotra et al., 1988).

Clinical signs resembling those associated withacute acetylcholine toxicity were observed in a recentlycompleted study in rats exposed by gavage to 12.5mg/kg body weight per day and above for 12 weeks(Gagnaire et al., 1998).

11.1.2.2.2 Cancer

Cancer is considered the critical end-point forquantification of dose–response for risk characterizationfor acrylonitrile. This is based on the observation oftumours at non-toxic doses or concentrations in long-term studies at levels less than those that have inducedeffects in (limited) repeated-dose toxicity studies andidentified investigations of neurological, reproductive,and developmental effects. Moreover, there is evidencefor weak genotoxic potential, and data are insufficient tosupport a plausible mode of action for acrylonitrile-induced carcinogenesis other than through directinteraction with DNA.

There is no reason to believe that carcinogenesisis unique to the rat, although there may be quantitativedifferences between experimental animals and humans,based on metabolic studies. Indeed, physiologicallybased pharmacokinetic modelling predicts that concen-trations of cyanoethylene oxide in the brains of humanswould be considerably greater than those in rats

exposed to similar concentrations of acrylonitrile(Kedderis et al., 1996), although increases in brain cancerhave not been observed in epidemiological studies withlimited power to detect excesses of this rare tumour.

In carcinogenesis assays conducted in variousstrains of rats exposed via inhalation or ingestion (mostof which are early unpublished studies), the incidencesof astrocytomas of the central nervous system, Zymbalgland tumours, and tumours of the non-glandular fore-stomach have increased most consistently followingexposure to acrylonitrile. Increases in the incidence oftumours of the tongue, mammary gland, and intestinehave been observed less consistently, and those of theskin and liver in a single study.

Of the tumours increased in incidence most consis-tently, astrocytomas occurred at highest incidence con-sistently across studies; the other two tumours observedmost often were confined to organs not present inhumans (i.e., Zymbal gland, forestomach), for whichincidence was less. The only possible exception instudies by most relevant media of administration was theincidence of tumours of the non-glandular stomach inthe drinking-water assay of Quast et al. (1980a).However, it was not possible to confirm the incidenceson which these calculations were based uponexamination of data in the original study report due todiscrepancies within the critical table (i.e., the number ofanimals in which tumours were reported in the fivecategories for the non-glandular stomach, combined,was greater than the total number of animals examined);there was also a discrepancy between the content of thistable (Table 22) and data presented in the Appendix(Table A-21). Moreover, the tumours that occurred athighest incidence are not consistent with the results ofother studies, and they have therefore not been furtheraddressed here.

Quantitative estimates presented herein are limitedto the tumours that occurred at highest incidence (i.e.,astrocytomas of the central nervous system) inbioassays for which media of intake are most relevant toexposure in the general environment — i.e., inhalationand drinking-water. Of the few inhalation bioassaysidentified, the study by Quast et al. (1980b) is consideredmost suitable for quantification of cancer potency,although it is limited by the fact that there were only twodose levels and controls. Group sizes were large (n = 100per sex per group), however, and animals were exposedfor 2 years. In other identified inhalation bioassays,group sizes were small and/or exposure periods short(Maltoni et al., 1977, 1987, 1988).

Among the bioassays in which acrylonitrile wasadministered in drinking-water (Bio/Dynamics Inc.,


28

1980a,b; Quast et al., 1980a; Gallagher et al., 1988),1

characterization of dose–response was best inBio/Dynamics Inc. (1980b). In this investigation, therewere five doses and controls with good dose spacingand optimum characterization of dose–response,including lower, non-toxic doses. Group sizes were large(n = 100). Group sizes were smaller in other bioassays(Gallagher et al., 1988), or dose spacing was poor(Bio/Dynamics Inc., 1980a). Although group sizes weresmaller and doses higher, tumorigenic doses (TD05s, thedose that causes a 5% increase in tumour incidence overbackground) based on the investigation of Quast et al.(1980a) are also included, since incidence was increasedat more doses (three rather than two in Bio/DynamicsInc., 1980b).

The tumour incidences and resulting TD05s/TC05sfor benign and malignant tumours (combined) of thecentral nervous system (astrocytomas) for the Quast etal. (1980b) inhalation study and the Bio/Dynamics Inc.(1980b) and Quast et al. (1980a) drinking-water bioassaysmodelled using the multistage model (GLOBAL 82) arepresented in Tables 2, 3, and 4. Degrees of freedom,parameter estimates, and nature of any adjustments formortality or period of exposure are also presentedtherein. Benign and malignant tumours have beencombined owing to the observed clear progression,although, as indicated in the tables, numbers of benignlesions included in the incidences on which thesecalculations were based are small; exclusion of thebenign tumours would result in only slightly highervalues of the TD05s/TC05s. In all cases, incidences havebeen adjusted to exclude animals dying before 6 months(i.e., prior to observation of the first tumours). Forcomparison, TC05s developed on the basis of incidencesreported by TERA (1997) for male rats for the Quast et al.(1980b) inhalation bioassay adjusted to exclude animalsdying before approximately 10 months are also included.

With respect to appropriate scaling of the TD05s/TC05s, those for inhalation have been adjusted to reflectdifferences in inhalation volumes and body weightsbetween humans and exposed animals. The TC05s weremultiplied by:

[(0.11 m3/day)/(0.35 kg body weight)] × [(70 kg body weight)/(23 m3/day)]

where 0.11 m3/day is the breathing rate of a rat, 0.35 kgbody weight is the body weight of a rat, 23 m3/day is thebreathing rate of a human, and 70 kg body weight is the

body weight of a human. The estimates of carcinogenicpotency for ingestion were not scaled on the basis ofbody surface area, as the carcinogenicity of acrylonitrileappears to be due to a metabolite rather than to theparent compound.

Tumorigenic potencies developed in this mannerfor ingestion and inhalation are similar.

11.1.3 Sample risk characterization

Although limited, available data are consistentwith air being the principal medium of exposure of thegeneral population to acrylonitrile; intake from othermedia is likely to be negligible in comparison. Moreover,with the exception of air in the vicinity of industrial pointsources, acrylonitrile has seldom been detected in sam-ples of ambient air, indoor air, or drinking-water. This isconsistent with lack of identification of non-pointsources. On this basis, the focus of the sample healthrisk characterization is populations exposed through airin the vicinity of industrial point sources. Moreover, thevast majority of acrylonitrile (>97%) is released to air.However, should there be specific cases where ingestionmay represent a significant source of exposure (e.g.,during spills), the tumorigenic doses presented in Tables3 and 4 may be informative in making judgements aboutrisk as a basis for management.

1 For reasons mentioned in section 8.5.1, including limitationsof histopathological analysis, data on tumour incidence inBigner et al. (1986) are considered inadequate for quantificationof dose–response.

Acrylonitrile

29

Table 5: The margins between carcinogenic potency and limited available data on predicted and measured concentrations of acrylonitrile

Concentration of acrylonitrile(Reference)

Potency(Table 2)

Marginbetweenpotency andconcentration

Category ofequivalent low-dose riskestimates

Vicinity of sources

9.3 µg/m3, concentration predicted by dispersion modelling, 11 m from stack at industrial site in Ontario

TC05 = 6000 µg/m3

95% LCL a = 4500 µg/m3

650480

(>10–5)(>10–5)


TC05 = 6000 µg/m3

95% LCL = 4500 µg/m3

21001550

(>10–5)(>10–5)


TC05 = 6000 µg/m3

95% LCL = 4500 µg/m3

10 0007500

(10–7 to 10–5)(10–7 to 10–5)

0.1 µg/m3, concentration predicted by dispersion modelling,3508 m from stack at industrial site in Ontario

TC05 = 6000 µg/m3

95% LCL = 4500 µg/m3

60 00045 000

(10–7 to 10–5)(10–7 to 10–5)

<52.9 µg/m3, sampling at the site of nitrile-butadiene rubberproduction in Sarnia in 1997, 5 m from company fence line,2 m above ground, downwind (B. Sparks, personalcommunication, 1997; M. Wright, personal communication,1998)

TC05 = 6000 µg/m3

95% LCL = 4500 µg/m3

11085

(>10–5)(>10–5)

0.12 µg/m3, lowest concentration measured in ambient airsampled for 6 days near a chemical manufacturing plant inCobourg, Ontario (Ortech Corporation, 1994)

TC05 = 6000 µg/m3

95% LCL = 4500 µg/m3

50 00038 000

(10–7 to 10–5)(10–7 to 10–5)

0.28 µg/m3, highest concentration measured in ambient airsampled for 6 days near a chemical manufacturing plant inCobourg, Ontario (Ortech Corporation, 1994)

TC05 = 6000 µg/m3

95% LCL = 4500 µg/m3

21 00016 000

(10–7 to 10–5)(10–7 to 10–5)

<251 µg/m3, lowest concentration measured at stack ofchemical manufacturing plant in Cobourg, Ontario, in 1993(Ortech Corporation, 1994)b

TC05 = 6000 µg/m3

95% LCL = 4500 µg/m3

2418

(>10–5)(>10–5)

Ambient air

1.9 µg/m3, maximum (and only detectable) concentrationmeasured in 11 samples at six urban stations in Ontario in1990 (OMOE, 1992a,b)c

TC05 = 6000 µg/m3

95% LCL = 4500 µg/m3

32002400

(>10–5)(>10–5)

<0.64 µg/m3, seven samples in industrialized area of Windsor,Ontario, in 1991 (Ng & Karellas, 1994)

TC05 = 6000 µg/m3

95% LCL = 4500 µg/m3

94007000

(10–7 to 10–5)(10–7 to 10–5)

a 95% LCL = lower 95% confidence limit.b Based on the concentration of 100 763 µg/m3 measured at the stack, risk category is high.c Compound not detected in majority of samples. The detection limit was 0.0003 µg/m3. Risk category for most samples is low.

For compounds such as acrylonitrile, where dataare insufficient to support a consensus view on a plaus-ible mode of action for induction of tumours by otherthan direct interaction with genetic material, estimates ofexposure are compared with quantitative estimates ofcancer potency to characterize risk. The lowest TC05

(human equivalent value) was 2.7 ppm (6.0 mg/m3) for thecombined incidence of benign and malignant tumours ofthe brain and/or spinal cord in female rats exposed byinhalation; the lower 95% confidence limit was 2.0 ppm(4.5 mg/m3) (Quast et al., 1980b; Table 2). This equates toa unit risk of 8.3 × 10–3 per mg/m3. The margins betweencarcinogenic potency and limited available data onpredicted and measured concentrations of acrylonitrileprimarily in the vicinity of point sources in the samplecountry (i.e., Canada) are presented in Table 5. On thisbasis, risks in the vicinity of industrial point are >10–5. It

should be noted, however, that populations residing inthe vicinity of sources would likely be exposed to lowerconcentrations, in view of the proximity of many of thesepredicted and measured values to the stacks, andmonitoring in residential areas in the vicinity of pointsources is desirable.

Of the reported values for occupational exposureto acrylonitrile (section 6.3), the highest average level ofexposure was 5.8 ppm (12.8 mg/m3) for loaders in a USacrylonitrile production plant (IARC, 1999). This con-centration is approximately 2 times more than the lowestTC05 (human equivalent value) of 2.7 ppm (6.0 mg/m3)derived above for a continuous (24 h/day, 7 days/week),lifelong exposure.


30

11.1.4 Uncertainties and degree of confidence inhuman health risk characterization

The degree of confidence in the database on tox-icity of acrylonitrile is moderate. The carcinogenicity ofacrylonitrile in humans has been investigated in wellconducted recent studies of four relatively large cohortsof occupationally exposed workers. While this epidemio-logical database is extensive in comparison with thatavailable for many other compounds, the power of thestudies was insufficient to detect moderate excesses forsome sites. Available data are also insufficient toprovide meaningful direct comparison with the results ofquantitative dose–response analyses based onbioassays in animals due to inadequate information withwhich to characterize possible relevant sites of cancer inhumans (i.e., site concordance between animals andhumans) and the relative paucity of data on exposure ofworkers in the relevant investigations.

The database on non-cancer toxicity in laboratoryanimals is limited, being restricted to primarily earlyunpublished carcinogenesis bioassays in which fewnon-cancer end-points were examined, a few more recentinvestigations of specialized end-points such as neuro-toxicity, or more recent repeated-dose toxicity studies forwhich full accounts are not yet available. Although thereare a relatively large number of bioassays, the databaseon carcinogenicity of acrylonitrile is limited primarily toearly unpublished investigations in one species; abioassay in mice, however, is currently under way.

Based on information acquired to date on thekinetics and metabolism of acrylonitrile, a physiolog-ically based pharmacokinetic model, once completed,holds promise as a more suitable basis for scaling ofTD05s/TC05s than the default assumption about relativeinhalation volumes and body weights.

Tumorigenic potencies for inhalation based on thecombined incidence of benign and malignant tumours ofthe brain and/or spinal cord in female rats were 1.4 timesless than for these tumours in males in the same study(TC05 of 6.0 versus 8.9 mg/m3). These values were also upto 2-fold less than those for tumours at other sites inboth sexes in the critical study (i.e., Quast et al., 1980b).The lower 95% confidence limit on the TC05 for thecombined incidence of benign and malignant tumours ofthe brain and/or spinal cord in female rats was 4.5 mg/m3,compared with the maximum likelihood estimate of 6.0mg/m3.

11.2 Evaluation of environmental effects

11.2.1 Assessment end-points

Acrylonitrile enters the Canadian environmentfrom anthropogenic sources, primarily from industrial on-

site releases. Almost all releases in the environment areto air, with small amounts released to water.

Based on its physical/chemical properties, acrylo-nitrile undergoes various degradation processes in air,with very small amounts transferring to water. Whenreleased into water, it is expected to remain primarily inwater, where it undergoes biodegradation after anacclimation period. Acrylonitrile does not bioaccumulatein organisms.

Based on the sources and fate of acrylonitrile inthe environment, biota are expected to be exposed toacrylonitrile primarily in air and to a much lesser extent inwater. Little exposure to soil or benthic organisms isexpected. Therefore, the focus of the environmental riskcharacterization will be on terrestrial and aquatic organ-isms exposed directly to ambient acrylonitrile in air andwater.

11.2.1.1 Aquatic end-points

Data on aquatic toxicity are available for a varietyof plants, invertebrates, fish, and amphibians. Identifiedsensitive end-points include growth inhibition in aquaticplants (Zhang et al., 1996), mortality in pond snails(Erben & Beader, 1983), mortality and reduced growth infish (Henderson et al., 1961; Analytical BioChemistryLaboratories, 1980a), and reduction in growth of frogs(Zhang et al., 1996).

11.2.1.2 Terrestrial end-points

Data on terrestrial toxicity are available for inverte-brates (particularly grain insect pests) as well as frommammalian toxicology. Identified sensitive end-pointsvia fumigation or inhalation routes of exposure includemortality of insect eggs (Adu & Muthu, 1985), decreasednumber of insect offspring (Rajendran & Muthu, 1981a),maternal and fetal toxicity in rats (Saillenfait et al., 1993),and histopathological changes in the nasal turbinates inrats (Quast et al., 1980b).

11.2.2 Sample environmental riskcharacterization

First-tier (i.e., “hyperconservative”) analyses arepresented below; since resulting quotients were lessthan one, higher-tier analyses were not conducted.

11.2.2.1 Aquatic organisms

Environmental exposure to acrylonitrile is expectedto be greatest near point sources. In general, releases towater (all fresh water in the sample country) are low(0.529 tonnes, or 2.7% of all releases). Recentlydetermined levels in effluent are very low, below the

Acrylonitrile

31

detection limit of 0.0042 mg/litre. Therefore, the value0.0042 mg/litre will be used as the estimated exposurevalue (EEV) in the hyperconservative analysis foraquatic organisms.

For exposure of aquatic biota to acrylonitrile inwater, the critical toxicity value (CTV) is 0.4 mg/litre,based on the lower chronic level around the EC50 offoreleg development after a 28-day exposure in the frogBufo bufo gargarizans (Zhang et al., 1996). This was thelowest value identified from the primary and secondarydata composed of acute and chronic toxicity studiesconducted on 16 species of aquatic invertebrates, plants,fish, and amphibians.

For a hyperconservative analysis, the estimatedno-effects value (ENEV) is derived by dividing this CTVby an application factor of 10. This factor accounts forextrapolation from field to laboratory conditions andinterspecies and intraspecies variations in sensitivity.The resulting ENEV is 0.04 mg/litre.

The hyperconservative quotient is calculated bydividing the EEV of 0.0042 mg/litre by the ENEV asfollows:

Quotient = EEV ENEV

= 0.0042 mg/litre0.04 mg/litre

= 0.1

Since the hyperconservative quotient is less than1, it is unlikely that acrylonitrile causes adverse effectson populations of aquatic organisms in the country onwhich the sample environmental risk characterization isbased (i.e., Canada).

11.2.2.2 Terrestrial organisms

Environmental exposure to acrylonitrile in air isexpected to be greatest near industrial point sources.Levels of acrylonitrile in ambient air in Canada aregenerally below detection. The highest concentration ofacrylonitrile in outdoor air in a half-hour period inCanada is predicted to be 9.3 µg/m3 (H. Michelin, per-sonal communication, 1999) at an 11-m distance from anindustrial stack.

For the exposure of terrestrial organisms to acrylo-nitrile in air, the CTV is the LOEL of 55 mg/m3, causingdecreased maternal weight and fetal toxicity in ratsexposed for 9 days during gestation (Saillenfait et al.,1993). This LOEL was the most sensitive effect identifiedfrom a data set composed of acute and chronic toxicitystudies conducted on 14 species of insects and

mammals. Saillenfait et al. (1993) reported that none ofthese effects were observed at 26.4 mg/m3. For thehyperconservative analysis, the ENEV is derived bydividing the CTV by a factor of 100. This factor accountsfor the extrapolation from laboratory to field conditions,conversion of the LOEL to a long-term no-effects value,interspecies and intraspecies variations in sensitivity,and the moderate data set. As a result, the ENEV is 0.55mg/m3 (550 µg/m3).

The hyperconservative quotient is calculated bydividing the EEV of 9.3 µg/m3 by the ENEV as follows:

Quotient = EEV ENEV

= 9.3 µg/m3 550 µg/m3

= 0.02

Since the hyperconservative quotient is less than1, it is unlikely that acrylonitrile causes adverse effectson populations of terrestrial organisms in the country onwhich the sample environmental risk characterization isbased (i.e., Canada).

11.2.2.3 Discussion of uncertainty

Regarding effects of acrylonitrile on terrestrial andaquatic organisms, uncertainty inevitably surrounds theextrapolation from available toxicity data to potentialecosystem effects. Somewhat surprisingly, the data setlacks information on the toxicity of acrylonitrile in air toplant species. Studies of acrylonitrile in air have focusedon the effects via inhalation and fumigation on labora-tory mammals (particularly rats) and pest insect species.There has been considerable examination of a wide rangeof effects in rats. It is not known to what extent thephysiological effects observed in the rat are representa-tive of long-term ecological effects. Regarding effects ofacrylonitrile on aquatic organisms, the data set includesstudies on organisms from a variety of ecological nichesand taxa for both the short and long term.

12. PREVIOUS EVALUATIONS BYINTERNATIONAL BODIES

IARC (1999) classified acrylonitrile in Group 2B(“possibly carcinogenic to humans”), based on inade-quate evidence in humans but adequate evidence inexperimental animals.


32

In the WHO Air Quality Guidelines for Europe, itwas concluded that owing to its carcinogenicity inanimals and limited evidence of carcinogenicity inhumans (at that time), acrylonitrile was considered as if itwere a human carcinogen, and a unit risk value of 2 ×10–5 per µg/m3 was calculated on the basis of an earlyepidemiological study and an inhalation study in rats(WHO, 1987).

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Solomon JJ, Segal A (1989) DNA adducts of propylene oxideand acrylonitrile epoxide: hydrolytic deamination of 3-alkyl-dCydto 3-alkyl-dUrd. Environmental health perspectives, 81:19–22.

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Acrylonitrile

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42

APPENDIX 1 — SOURCE DOCUMENT

Environment Canada & Health Canada (2000)

Copies of the Canadian Environmental Protection ActPriority Substances List assessment report (Environment Canada& Health Canada, 2000) and unpublished supportingdocumentation for acrylonitrile may be obtained from:

Commercial Chemicals Evaluation BranchEnvironment Canada14th floor, Place Vincent Massey351 St. Joseph Blvd.Hull, QuebecCanada K1A 0H3

or

Environmental Health Centre Health CanadaAddress Locator: 0801ATunney’s PastureOttawa, Ontario Canada K1A 0L2

Initial drafts of the supporting documentation and assess-ment report for acrylonitrile were prepared by staff of HealthCanada and Environment Canada. The health-related sectionsof the supporting documentation and the assessment report werebased in part upon a review of the epidemiological data,prepared under contract by J. Siemiatycki of the Institut Armand-Frappier.

H. Hirtle contributed additional information in thepreparation of the draft CICAD.

Environmental sections of the assessment report werereviewed externally by W. Broadworth (G.E. Plastics Canada), N.Karellas (Ontario Ministry of the Environment), R. Keefe(Imperial Oil), A. Kerr (Bayer-Rubber Division), J. Murray (ANGroup, Inc.), V. Nabholz (US Environmental Protection Agency),J. Pellerin (Université du Québec à Rimouski), J. Soule (DuPontCanada), and A. Tomlin (Agriculture and Agri-Food Canada).

In order to address primarily adequacy of coverage,sections of the supporting documentation pertaining to humanhealth were reviewed externally by J.J. Collins, Solutia Inc., St.Louis, MO; B. Ghanayem, National Institute of EnvironmentalHealth Sciences, Research Triangle Park, NC; G.L. Kedderis,Chemical Industry Institute of Toxicology, Research TrianglePark, NC; N. Krivanek, E.I. du Pont de Nemours & Co., Newark,DE; D. Strother, BP Chemicals Inc., Cleveland, OH; and J.Whysner, American Health Foundation, Valhalla, NY.

Accuracy of reporting, adequacy of coverage, and defensibilityof conclusions with respect to hazard characterization anddose–response analyses were considered in written review bystaff of the Information Department of BIBRA International andat a panel meeting of the following members, convened byToxicology Excellence for Risk Assessment (TERA) on 17November 1998, in Cincinnati, OH:

M.J. Aardema, The Procter & Gamble Co.M.L. Dourson, TERAS. Felter, The Procter & Gamble Co.M.A. Friedman, Private ConsultantM.L. Gargas, ChemRisk Division, McLaren/HartR.G. Tardiff, The Sapphire Group, Inc.V.T. Vu, US Environmental Protection AgencyV. Walker, New York State Department of Health

Acrylonitrile

43

APPENDIX 2 — CICAD PEER REVIEW

The draft CICAD on acrylonitrile was sent for review toinstitutions and organizations identified by IPCS after contactwith IPCS national contact points and Participating Institutions,as well as to identified experts. Comments were received from:

A. Aitio, International Programme on Chemical Safety,World Health Organization, Switzerland

M. Baril, International Programme on Chemical Safety/Institut de Recherche en Santé et en Sécurité du Travaildu Québec, Canada

D.L. Bayliss, National Center for EnvironmentalAssessment, US Environmental Protection Agency, USA

R. Benson, Drinking Water Program, US EnvironmentalProtection Agency, USA

R. Cary, Health and Safety Executive, United Kingdom

R. Chhabra, National Institute of Environmental HealthSciences, National Institutes of Health, USA

H.B.S. Conacher, Bureau of Chemical Safety, HealthCanada, Canada

C. Elliott-Minty, Health and Safety Executive, UnitedKingdom

H. Gibb, National Center for Environmental Assessment,US Environmental Protection Agency, USA

R. Hertel, Federal Institute for Health Protection ofConsumers and Veterinary Medicine, Germany

C. Hiremath, National Center for Environmental Assessment,US Environmental Protection Agency, USA

S. Kristensen, National Industrial Chemicals Notification andAssessment Scheme, Australia

J.F. Murray, AN Group, Inc., USA

H. Nagy, National Institute of Occupational Safety andHealth, USA

S. Tarkowski, Nofer Institute for Occupational Medicine,Poland

W.F. ten Berge, DSM Corporate Safety and Environment,The Netherlands

K. Ziegler-Skylakakis, Commission of the EuropeanCommunities/European Union

APPENDIX 3 — CICAD FINAL REVIEWBOARD

Geneva, Switzerland, 8–12 January 2001

Members

Dr A.E. Ahmed, Molecular Toxicology Laboratory, Departmentof Pathology, University of Texas Medical Branch, Galveston,TX, USA

Mr R. Cary, Health and Safety Executive, Merseyside, UnitedKingdom (Chairperson)

Dr R.S. Chhabra, General Toxicology Group, National Instituteof Environmental Health Sciences, National Institutes of Health,Research Triangle Park, NC, USA

Dr S. Czerczak, Department of Scientific Information, NoferInstitute of Occupational Medicine, Lodz, Poland

Dr S. Dobson, Centre for Ecology and Hydrology,Cambridgeshire, United Kingdom

Dr O.M. Faroon, Division of Toxicology, Agency for ToxicSubstances and Disease Registry, Atlanta, GA, USA

Dr H. Gibb, National Center for Environmental Assessment, USEnvironmental Protection Agency, Washington, DC, USA

Dr R.F. Hertel, Federal Institute for Health Protection ofConsumers and Veterinary Medicine, Berlin, Germany

Dr A. Hirose, Division of Risk Assessment, National Institute ofHealth Sciences, Tokyo, Japan

Dr P.D. Howe, Centre for Ecology and Hydrology,Cambridgeshire, United Kingdom (Rapporteur)

Dr D. Lison, Industrial Toxicology and Occupational MedicineUnit, Université Catholique de Louvain, Brussels, Belgium

Dr R. Liteplo, Existing Substances Division, Bureau of ChemicalHazards, Health Canada, Ottawa, Ontario, Canada

Dr I. Mangelsdorf, Chemical Risk Assessment, FraunhoferInstitute of Toxicology and Aerosol Research, Hanover, Germany

Ms M.E. Meek, Existing Substances Division, Safe EnvironmentsProgram, Health Canada, Ottawa, Ontario, Canada (Vice-Chairperson)

Dr S. Osterman-Golkar, Department of Molecular GenomeResearch, Stockholm University, Stockholm, Sweden

Dr J. Sekizawa, Division of Chem-Bio Informatics, NationalInstitute of Health Sciences, Tokyo, Japan

Dr S. Soliman, Department of Pesticide Chemistry, Faculty ofAgriculture, Alexandria University, El-Shatby, Alexandria, Egypt

Dr M. Sweeney, Education and Information Division, NationalInstitute for Occupational Safety and Health, Cincinnati, OH,USA

Professor M. van den Berg, Environmental Sciences andToxicology, Institute for Risk Assessment Sciences, University ofUtrecht, Utrecht, The Netherlands


44

Observers

Dr W.F. ten Berge, DSM Corporate Safety and Environment,Heerlen, The Netherlands

Dr K. Ziegler-Skylakakis, Commission of the EuropeanCommunities, Luxembourg

Secretariat

Dr A. Aitio, International Programme on Chemical Safety, WorldHealth Organization, Geneva, Switzerland

Dr Y. Hayashi, International Programme on Chemical Safety,World Health Organization, Geneva, Switzerland

Dr P.G. Jenkins, International Programme on Chemical Safety,World Health Organization, Geneva, Switzerland

Dr M. Younes, International Programme on Chemical Safety,World Health Organization, Geneva, Switzerland

Prepared in the context of cooperation between the InternationalProgramme on Chemical Safety and the European Commission

© IPCS 2000

SEE IMPORTANT INFORMATION ON THE BACK.

IPCSInternationalProgramme onChemical Safety

ACRYLONITRILE 0092March 2001

CAS No: 107-13-1RTECS No: AT5250000UN No: 1093EC No: 608-003-00-4

Cyanoethylene2-PropenenitrileVinyl cyanideC3H3N / CH2=CH-CNMolecular mass: 53.1

TYPES OFHAZARD/EXPOSURE

ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING

FIRE Highly flammable. Gives offirritating or toxic fumes (or gases)in a fire.

NO open flames, NO sparks, andNO smoking. NO contact with strongbases and strong acids.

Powder, alcohol-resistant foam,water spray, carbon dioxide.

EXPLOSION Vapour/air mixtures are explosive.Risk of fire and explosion oncontact with strong base(s) andstrong acid(s).

Closed system, ventilation,explosion-proof electrical equipmentand lighting. Use non-sparkinghandtools.

In case of fire: keep drums, etc.,cool by spraying with water.

EXPOSURE AVOID ALL CONTACT! IN ALL CASES CONSULT ADOCTOR!

Inhalation Dizziness. Headache. Nausea.Shortness of breath. Vomiting.Weakness. Convulsions. Chesttightness.

Closed system and ventilation. Fresh air, rest. Refer for medicalattention. See Notes.

Skin MAY BE ABSORBED! Redness.Pain. Blisters. (Further seeInhalation).

Protective gloves. Protectiveclothing.

First rinse with plenty of water, thenremove contaminated clothes andrinse again. Refer for medicalattention.

Eyes Redness. Pain. Safety goggles, or eye protection incombination with breathingprotection.

First rinse with plenty of water forseveral minutes (remove contactlenses if easily possible), then taketo a doctor.

Ingestion Abdominal pain. Vomiting. (Furthersee Inhalation).

Do not eat, drink, or smoke duringwork. Wash hands before eating.

Rinse mouth. Give a slurry ofactivated charcoal in water to drink.Induce vomiting (ONLY INCONSCIOUS PERSONS!). Referfor medical attention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Evacuate danger area! Consult an expert!Ventilation. Collect leaking liquid in coveredcontainers. Absorb remaining liquid in sand or inertabsorbent and remove to safe place. Do NOT washaway into sewer. Do NOT let this chemical enter theenvironment. Chemical protection suit includingself-contained breathing apparatus.

F SymbolT SymbolN SymbolR:45-11-23/24/25-37/38-41-43-51/53S: 9-16-53-45-61Note: D and EUN Hazard Class: 3UN Subsidiary Risks: 6.1UN Pack Group: I

Unbreakable packaging; putbreakable packaging into closedunbreakable container. Do nottransport with food and feedstuffs.

EMERGENCY RESPONSE STORAGE

Transport Emergency Card: TEC (R)-61NFPA Code: H 4; F 3; R 2

Fireproof. Separated from strong oxidants, strong bases, food andfeedstuffs. Cool. Keep in the dark. Ventilation along the floor. Store only ifstabilized.

Boiling point: 77°CMelting point: -84°CRelative density (water = 1): 0.8Solubility in water, g/100 ml at 20°C: 7Vapour pressure, kPa at 20°C: 11.0

Relative vapour density (air = 1): 1.8Relative density of the vapour/air-mixture at 20°C (air = 1): 1.05Flash point: -1°C c.c. Auto-ignition temperature: 481°CExplosive limits, vol% in air: 3.0-17.0Octanol/water partition coefficient as log Pow: 0.25

LEGAL NOTICE Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible for the use which might be made of this information

©IPCS 2000

0092 ACRYLONITRILE

IMPORTANT DATA

Physical State; AppearanceCOLOURLESS OR PALE YELLOW LIQUID, WITH PUNGENTODOUR.

Physical dangersThe vapour is heavier than air and may travel along the ground;distant ignition possible.

Chemical dangersThe substance polymerizes due to heating or under theinfluence of light and bases, causing fire and explosion hazard.The substance decomposes on heating producing toxic fumesincluding hydrogen cyanide, nitrogen oxides. Reacts violentlywith strong acids, and strong oxidants. Attacks plastics andrubber.

Occupational exposure limitsTLV: (as TWA) 2 ppm; skin A3 (ACGIH 2000).

Routes of exposureThe substance can be absorbed into the body by inhalation ofits vapour, through the skin and by ingestion.

Inhalation riskA harmful contamination of the air can be reached very quicklyon evaporation of this substance at 20°C.

Effects of short-term exposureThe substance and the vapour is irritating to the eyes, the skinand the respiratory tract. The substance may cause effects onthe central nervous system. Exposure far above the OEL mayresult in death. The effects may be delayed. See Notes.Medical observation is indicated.

Effects of long-term or repeated exposureRepeated or prolonged contact may cause skin sensitization.The substance may have effects on the central nervous systemand liver. This substance is possibly carcinogenic to humans.

PHYSICAL PROPERTIES

ENVIRONMENTAL DATA

The substance is harmful to aquatic organisms.

NOTES

Depending on the degree of exposure, periodic medical examination is suggested. Exposure to the substance will result in cyanideformation. Also consult ICSC of a cyanide salt, such as 0671. Specific treatment is necessary in case of poisoning with thissubstance; the appropriate means with instructions must be available. The odour warning when the exposure limit value isexceeded is insufficient. Rinse contaminated clothes (fire hazard) with plenty of water.

ADDITIONAL INFORMATION

Acrylonitrile

47

RÉSUMÉ D’ORIENTATION

Ce CICAD relatif à l’acrylonitrile a été préparéconjointement par la Direction de l’Hygiène du Milieu deSanté Canada et la Direction de l’Evaluation des produitschimiques commerciaux d’Environnement Canada à partird’une documentation rédigée simultanément dans lecadre du programme sur les substances prioritairesprévu par la Loi canadienne sur la protection del’environnement (LCPE). Les études sur les substancesprioritaires prescrites par la LCPE ont pour objectifd’évaluer les effets potentiels sur la santé humaine d’uneexposition indirecte à celles de ces substances qui sontprésentes dans l’environnement ainsi que leurs effetssur l’environnement lui-même. La présente mise au pointprend en compte les données publiées jusqu’en avril19981 en ce qui concerne les effets sanitaires et jusqu’àfin mai 1998 en ce qui concerne les effets surl’environnement. D’autres mises au point ont étéégalement consultées, à savoir celles de l’EnvironmentalProtection Agency des Etats-Unis (1980, 1985), de l’IPCS(1983), de l’ATSDR (1990), du CIRC (1999) et de laCommunauté européenne (2000). Des renseignementssur la nature de l’examen par des pairs et la disponibilitédu document de base (Environnement Canada & SantéCanada, 2000) sont donnés à l’appendice 1. Lesinformations concernant l’examen par des pairs duprésent CICAD figurent à l’appendice 2. Ce CICAD a étéapprouvé en tant qu’évaluation internationale lors d’uneréunion du Comité d’évaluation finale qui s’est tenue àGenève (Suisse), du 8 au 12 janvier 2001. La liste desparticipants à cette réunion se trouve à l’appendice 3. Lacarte internationale sur la sécurité chimique de l’acrylo-nitrile (ICSC 0092), préparée par le Programme inter-national sur la sécurité chimique (IPCS, 1993), estégalement reproduite dans le présent document.

L’acrylonitrile (No CAS 107-13-1) se présente, à latempérature ambiante, sous la forme d’un liquide volatil,inflammable et soluble dans l’eau. Au Canada, cecomposé est utilisé en majeure partie comme produit dedépart ou adjuvant chimique dans la fabrication desélastomères nitrile-butadiène et des copolymères acrylo-

nitrile-butadiène-styrène et acrylonitrile-styrène. Onestime que la capacité de production mondiale étaitd’environ 4 millions de tonnes en 1993. Les principaleszones de production sont l’Union européenne (>1,25 mil-lions de tonnes par an), les Etats-Unis (environ 1,5millions de tonnes par an) et le Japon (environ 0,6millions de tonnes par an).

Ce sont principalement les unités de production oud’autres industries chimiques ou plasturgiques qui sontsusceptibles d’en libérer dans l’environnement (plus de95 % dans le pays témoin). On ne lui connaît pas desources naturelles. L’acrylonitrile est largement répandudans les compartiments de l’environnement où il estdéversé (c’est-à-dire l’air ou l’eau), son mouvement versle sol, les sédiments et les biotes étant limité. Il estprincipalement éliminé par réaction chimique et advec-tion. Les enquêtes limitées effectuées dans le payschoisi pour la caractérisation du risque dans l’environne-ment général (le Canada) n’ont permis de trouver del’acrylonitrile qu’à proximité d’installations industrielles.

L’exposition professionnelle à l’acrylonitrile estliée à sa production et à son utilisation pour la fabrica-tion d’autres produits. C’est d’ailleurs dans ce derniercas que le risque est le plus important en raison desdifficultés de confinement. Selon des données récentesrelatives aux pays de l’Union européenne, l’expositionmoyenne pondérée par rapport au temps est #0,45 ppm(1 mg/m3) au cours de la production et #1,01 ppm(2,2 mg/m3) pour diverses utilisations en bout de chaîne.

L’acrylonitrile est rapidement absorbé par toutesles voies d’exposition et il se répartit dans l’ensembledes tissus examinés. Il n’y a guère de possibilité d’accu-mulation dans un organe quelconque, le composé étantexcrété, principalement sous forme de métabolites, dansles 24 à 48 h suivant l’administration. Selon les donnéesdisponibles, la principale voie métabolique de détoxi-cation est une conjugaison avec le glutathion, l’oxy-dation en oxyde de 2-cyanoéthylène étant considéréecomme une voie d’activation.

Les données fournies par l’expérimentation animaleindiquent que l’acrylonitrile est fortement irritant pour lapeau, les yeux et les voies respiratoires. Il peutprovoquer une dermatite allergique de contact, mais onne possède pas suffisamment de données pour évaluerson pouvoir sensibilisateur. A l’exception des effetstoxiques sur le développement (effets foetoxiques ettératogènes), qui ne s’observent d’ailleurs pas aux dosesnon toxiques pour la mère, les données disponibles con-cernant les autres effets non néoplasiques révélés parl’expérimentation animale ne sont pas suffisantes pourpermettre de caractériser la relation dose-réponse. Lorsdes quelques études au cours desquelles on a systéma-tiquement recherché la présence d’effets non néo-

1 Les nouvelles données notées par les auteurs et obtenues parun dépouillement de la littérature effectué avant la réunion duComité d’évaluation finale ont été examinées compte tenu deleur influence probable sur les conclusions essentielles de laprésente évaluation, le but étant avant tout d’établir si leurprise en compte serait prioritaire lors d’une prochaine mise àjour. Les auteurs ayant estimé qu’elles apportaient deséléments d’information supplémentaires, on a ajouté desdonnées plus récentes encore que non essentielles pour lacaractérisation des dangers ou l’analyse des relations dose-réponse.


48

plasiques, seuls des cas d’irritation cutanée aiguë ontété régulièrement observés.

Compte tenu des résultats obtenus sur l’animal,c’est le cancer qui constitue le point d’aboutissementtoxicologique majeur de l’action de l’acrylonitrile chezl’Homme. Aprés inhalation ou ingestion, on observechez le rat toute une variété de tumeurs touchantnotamment le système nerveux central (encéphale etmoelle épinière), le conduit auditif, les voies digestives etles glandes mammaires. La plupart des tests biologiquescorrectement effectués révèlent une augmentation desastrocytomes cérébraux et médullaires, néoplasmes quise produisent rarement de façon spontanée; ces tumeurss’observent régulièrement avec une incidence très élevéedans toutes les études. L’augmentation constatée eststatistiquement significative et il existe une nette relationdose-réponse. On a quelquefois observé des tumeurs àdes doses ou concentrations non toxiques et dès les 7 à12 mois suivant le début de l’exposition. On en aégalement observé au bout de 45 semaines dans laprogéniture exposée lors d’une étude toxicologique surla reproduction portant sur plusieurs générations.

Toutes les études épidémiologiques disponiblesn’ont pas mis systématiquement en évidence une aug-mentation des cancers. Cependant il est impossible deprocéder à une comparaison quantitative valable entreces résultats et ceux de l’expérimentation animale, car onne possède pas suffisamment d’informations sur le moded’induction des tumeurs cérébrales, les données surl’exposition des travailleurs lors des enquêtes en ques-tion sont relativement maigres et les limites de confiancedes SMR (taux comparatifs de mortalité) qui ressortentdes études épidémiologiques pour des cancers pouvantêtre pris en considération présentent une fortedispersion.

Si, en ce qui concerne la génotoxicité, les nom-breuses études portant sur l’examen d’effets très variéstant in vitro, avec ou sans activation métabolique, qu’ invivo chez la souris et le rat, donnent des résultats mitigéspour l’acrylonitrile, son métabolite, l’oxyde de 2-cyano-éthylène, est par contre clairement mutagène. Même siles résultats disponibles ne fournissent pas de preuvedirecte, on peut raisonnablement penser que l’actioncancérogène de l’acrylonitrile est due à une interactionavec le matériel génétique. En ce qui concerne les autresmodes d’induction tumorale possibles, les données sontinsuffisantes. L’acrylonitrile et son époxyde peuventréagir avec les macromolécules.

On estime que le cancer constitue l’effet toxiqueessentiel à prendre en considération pour la quantifi-cation de la relation dose-réponse en vue de lacaractérisation du risque. La concentration tumorigène laplus faible (la CT05, c’est-à-dire la concentration qui

provoque une augmentation de 5 % de l’incidencetumorale par rapport à l’incidence normale) (valeuréquivalente pour l’Homme) a été trouvée égale à 2,7 ppm(6,0 mg/m3) pour l’incidence combinée des tumeurscérébrales ou médullaires bénignes ou malignes chez lerat et la souris exposés par la voie respiratoire. Celacorrespond à un risque unitaire de 8,3 × 10–3 par mg/m3.

Bien que limitées, les données montrent que c’estprincipalement par l’air que la population générale estexposée à l’acrylonitrile; l’absorption à partir d’autresmilieux est négligeable en comparaison. La caractéri-sation du risque pour l’Homme est centrée sur lespopulations vivant à proximité de sources industriellesd’acrylonitrile. Compte tenu de la marge qui existe, dansla caractérisation du risque type, entre les données con-cernant le pouvoir cancérogène du composé et celles,limitées, dont on dispose au sujet des concentrationscalculées et mesurées, notamment au voisinage dessources d’émission ponctuelles, on estime que le risquesur ces sites est >10–5.

S’agissant de la caractérisation du risque environ-nemental type, la concentration dans les eaux résiduairesindustrielles après traitement est inférieure à la valeurestimative à effet nul (ENEV) pour l’organisme aquatiquele plus sensible et la concentration maximale calculée (àproximité d’une usine chimique) est inférieure à l’ENEVpour l’organisme terrestre le plus sensible.

Acrylonitrile

49

RESUMEN DE ORIENTACIÓN

Este CICAD sobre el acrilonitrilo, preparadoconjuntamente por la Dirección de Higiene del Medio delMinisterio de Sanidad del Canadá y la División deEvaluación de Productos Químicos Comerciales delMinisterio de Medio Ambiente del Canadá, se basa en ladocumentación preparada al mismo tiempo como partedel Programa de Sustancias Prioritarias en el marco de laLey Canadiense de Protección del Medio Ambiente(CEPA). Las evaluaciones de sustancias prioritariasprevistas en la CEPA tienen por objeto valorar losefectos potenciales para la salud humana de la exposi-ción indirecta en el medio ambiente general, así como losefectos ecológicos. En estos exámenes se incluyen losdatos identificados hasta el 31 de mayo de 1998 (efectosen el medio ambiente) y abril de 19981 (efectos en lasalud humana). Se consultaron también los exámenessiguientes: US EPA (1980, 1985), IPCS (1983), ATSDR(1990), CIIC (1999) y CE (2000). La información relativa alcarácter del examen colegiado y la disponibilidad deldocumento original (Ministerio de Medio Ambiente delCanadá & Ministerio de Sanidad del Canadá, 2000) figuraen el apéndice 1. La información sobre el examencolegiado de este CICAD aparece en el apéndice 2. EsteCICAD se aprobó como evaluación internacional en unareunión de la Junta de Evaluación Final celebrada enGinebra (Suiza) del 8 al 12 de enero de 2001. La lista departicipantes en esta reunión figura en el apéndice 3. Laficha internacional de seguridad química (ICSC 0092)para el acrilonitrilo, preparada por el ProgramaInternacional de Seguridad de las Sustancias Químicas(IPCS, 1993), también se reproduce en este documento.

El acrilonitrilo (CAS Nº 107-13-1) es un líquidovolátil, inflamable, soluble en agua a temperaturaambiente. La inmensa mayoría del acrilonitrilo se utilizaen el Canadá como materia prima o coadyuvante químicoen la producción de caucho de nitrilo-butadieno y enpolímeros de acrilonitrilo-butadieno-estireno y estireno-acrilonitrilo. La capacidad mundial estimada en 1993 erade unos 4 millones de toneladas. Las principales zonasde producción son la Unión Europea (>1,25 millones de

toneladas al año), los Estados Unidos (alrededor de1,5 millones de toneladas al año) y el Japón (unos 0,6 mil-lones de toneladas al año).

El acrilonitrilo se libera en el medio ambientefundamentalmente a partir de la producción química y lasindustrias de productos químicos y plásticos (>95% enel país de muestra). No hay fuentes naturales conocidas.El acrilonitrilo se distribuye sobre todo en loscompartimentos del medio ambiente en los cuales selibera (es decir, aire o agua), siendo el desplazamientohacia el suelo, los sedimentos o la biota limitado; losprincipales mecanismos de eliminación son la reacción yla advección. En estudios limitados en el país en el cualse basa la caracterización del riesgo de muestra (es decir,el Canadá), se ha detectado acrilonitrilo en el medioambiente general sólo en las cercanías de fuentesindustriales.

La exposición al acrilonitrilo en el lugar de trabajose produce durante su producción y utilización en lafabricación de otros productos; el mayor potencial se daen el segundo caso, donde el compuesto puede no serfácil de contener. Según datos recientes para los paísesde la Unión Europea, la exposición media ponderada porel tiempo es #0,45 ppm (1 mg/m3) durante la produccióny #1,01 ppm (2,2 mg/m3) en diversos usos finales.

El acrilonitrilo se absorbe con rapidez por todas lasvías de exposición y se distribuye en todos los tejidosexaminados. Es poco probable que se acumule de manerasignificativa en un órgano determinado, excretándose lamayor parte del compuesto en la orina, principalmentecomo metabolitos, en las primeras 24-48 horas despuésde la administración. Los datos disponibles coinciden enindicar que la conjugación con el glutatión es la principalvía de desintoxicación, mientras que la oxidación a óxidode 2-cianoetileno se considera una vía de activación.

Los datos disponibles de estudios en animalesindican que el acrilonitrilo es un irritante cutáneo,respiratorio y ocular grave. Puede provocar dermatitisalérgica por contacto, pero no se dispone de datosadecuados para evaluar su capacidad de sensibilización.Con la excepción de la toxicidad en el desarrollo, para lacual no se han observado efectos (fetotóxicos y terato-génicos) a concentraciones que no eran tóxicas para lasmadres, los datos disponibles sobre otros efectos noneoplásicos en animales de experimentación no sonsuficientes para caracterizar la exposición-respuesta. Enun pequeño número de estudios en poblacioneshumanas en los que se han investigado de manerasistemática los efectos no neoplásicos del acrilonitrilo,sólo se ha notificado la presencia continuada deirritación cutánea aguda.

1 Se ha incluido nueva información destacada por losexaminadores y obtenida en una búsqueda bibliográficarealizada antes de la reunión de la Junta de Evaluación Finalpara señalar sus probables repercusiones en las conclusionesesenciales de esta evaluación principalmente con objeto deestablecer la prioridad para su examen en una actualización.Se ha añadido información más reciente, no esencial para lacaracterización del peligro o el análisis de la exposición-respuesta, que a juicio de los examinadores aumentaba suvalor informativo.


50

De los estudios en animales cabe deducir que elcáncer es el efecto final crítico del acrilonitrilo para lasalud humana. Se ha observado de manera constanteuna serie de tumores en ratas - en particular del sistemanervioso central (cerebro y/o médula espinal), elconducto auditivo, el tracto gastrointestinal y lasglándulas mamarias - tras la ingestión o la inhalación. Encasi todas las biovaloraciones adecuadas se hanotificado un mayor número de astrocitomas del cerebroy la médula espinal, que raramente se observan de formaespontánea, correspondiendo siempre a éstos laincidencia más alta en todos los estudios. El aumento hasido estadísticamente significativo y se han observadotendencias claras de dosis-respuesta. Se han notificadoa veces tumores con dosis o concentraciones no tóxicasy ya a los 7-12 meses del comienzo de la exposición. Sehan detectado asimismo tumores en crías expuestas enun estudio de reproducción multigeneracional a las45 semanas.

En los estudios epidemiológicos disponibles no seha observado de manera constante un aumento de laaparición de cáncer. Sin embargo, no se puede realizaruna comparación cuantitativa válida de los resultados deestas investigaciones con los obtenidos en estudios enanimales, debido a la falta de datos adecuados sobre elmecanismo de inducción de tumores cerebrales, larelativa escasez de datos sobre la exposición de lostrabajadores en las investigaciones pertinentes y elamplio intervalo de los límites de confianza para lasrazones normalizadas de mortalidad en los casos decáncer de posible interés en los estudios epidemiológi-cos.

En numerosos estudios sobre la genotoxicidad delacrilonitrilo con un examen de un amplio espectro deefectos finales, tanto in vitro, con activación metabólicay sin ella, como in vivo, en ratones y ratas, losresultados han sido bastante variables, mientras que sumetabolito, el óxido de cianoetileno, es mutagénico.Aunque no hay pruebas directas, según los datosdisponibles, es razonable suponer que la inducción detumores por el acrilonitrilo está relacionada con lainteracción directa con material genético. El valorprobatorio para otros posibles mecanismos de inducciónde tumores es insuficiente. El acrilonitrilo o su epóxidopueden reaccionar con macromoléculas.

El cáncer se considera el efecto final crítico para lacuantificación de la exposición-respuesta en la caracter-ización del riesgo del acrilonitrilo. La concentracióninductora de tumores más baja (CT05, concentración queproduce un aumento del 5% en la incidencia de tumoressobre el nivel basal) (valor equivalente humano) fue de2,7 ppm (6,0 mg/m3) para la incidencia combinada detumores benignos y malignos del cerebro y/o la médula

espinal en ratas expuestas por inhalación. Esto equivalea un riesgo unitario de 8,3 × 10–3 por mg/m3.

Aunque limitados, los datos disponibles son com-patibles con el hecho de que el aire es el principal mediode exposición de la población general al acrilonitrilo; laingesta a partir de otros medios probablemente es insig-nificante en comparación. El objetivo principal de lacaracterización del riesgo para la salud humana es lapoblación expuesta mediante el aire en las proximidadesde fuentes industriales. Basándose en los márgenesentre la potencia carcinogénica y los limitados datosdisponibles sobre las concentraciones de acrilonitriloprevistas y medidas principalmente en las cercanías defuentes puntuales en la caracterización del riesgo demuestra, los riesgos en estos lugares son >10–5.

En la caracterización del riesgo de muestra para elmedio ambiente, los niveles en las aguas residualestratadas son inferiores al valor sin efectos estimados(ENEV) para el organismo acuático más sensible y losniveles máximos pronosticados (cerca de una fábrica deelaboración de la industria química) son inferiores alENEV para el organismo terrestre más sensible.

THE CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT SERIES

Azodicarbonamide (No. 16, 1999)Barium and barium compounds (No. 33, 2001)Benzoic acid and sodium benzoate (No. 26, 2000)Benzyl butyl phthalate (No. 17, 1999)Beryllium and beryllium compounds (No. 32, 2001)Biphenyl (No. 6, 1999)1,3-Butadiene: Human health aspects (No. 30, 2001)2-Butoxyethanol (No. 10, 1998)Chloral hydrate (No. 25, 2000)Chlorinated naphthalenes (No. 34, 2001)Chlorine dioxide (No. 37, 2001)Crystalline silica, Quartz (No. 24, 2000)Cumene (No. 18, 1999)1,2-Diaminoethane (No. 15, 1999)3,3'-Dichlorobenzidine (No. 2, 1998)1,2-Dichloroethane (No. 1, 1998)2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) (No. 23, 2000)N,N-Dimethylformamide (No. 31, 2001)Diphenylmethane diisocyanate (MDI) (No. 27, 2000)Ethylenediamine (No. 15, 1999)Ethylene glycol: environmental aspects (No. 22, 2000)2-Furaldehyde (No. 21, 2000)HCFC-123 (No. 23, 2000)Limonene (No. 5, 1998)Manganese and its compounds (No. 12, 1999)Methyl and ethyl cyanoacrylates (No. 36, 2001)Methyl chloride (No. 28, 2000)Methyl methacrylate (No. 4, 1998)N-Methyl-2-pyrrolidone (No. 35, 2001)Mononitrophenols (No. 20, 2000)N-Nitrosodimethylamine (No. 38, 2001)Phenylhydrazine (No. 19, 2000)N-Phenyl-1-naphthylamine (No. 9, 1998)1,1,2,2-Tetrachloroethane (No. 3, 1998)1,1,1,2-Tetrafluoroethane (No. 11, 1998)o-Toluidine (No. 7, 1998)Tributyltin oxide (No. 14, 1999)Triglycidyl isocyanurate (No. 8, 1998)Triphenyltin compounds (No. 13, 1999)Vanadium pentoxide and other inorganic vanadium compounds (No. 29, 2001)

To order further copies of monographs in this series, please contact Marketing and Dissemination,World Health Organization, 1211 Geneva 27, Switzerland(Fax No.: 41-22-7914857; E-mail: [email protected])