This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, 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 to those of the printed copy

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

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

World Health Organization Geneva, 2002 The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of 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 the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals. The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established 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 and Research, and the Organisation for Economic Co-operation and Development (Participating Organiza- tions), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC 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 the environment.

WHO Library Cataloguing-in-Publication Data

Acrylonitrile.

(Concise international chemical assessment document ; 39)

1.Acrylonitrile - toxicity 2.Risk assessment 3.Environmental exposure 4.Occupational exposure I.International Programme on Chemical Safety II.Series

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

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Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10 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 ...... 6 4.2 Anthropogenic sources ...... 6 4.3 Production and use ...... 7

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

5.1 Air ...... 7 5.2 Water ...... 7 5.3 Soil and sediment ...... 7 5.4 Biota ...... 8 5.5 Environmental partitioning ...... 8

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

6.1 Environmental levels ...... 9 6.1.1 Ambient air ...... 9 6.1.2 Indoor air ...... 9 6.1.3 Surface water and groundwater ...... 9 6.1.4 Drinking-water ...... 10 6.1.5 Soil and sediment ...... 10 6.1.6 Food ...... 10 6.1.7 Multimedia study ...... 10 6.2 Human exposure: environmental ...... 10 6.3 Human exposure: occupational ...... 11

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

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

8.1 Single exposure ...... 14 8.2 Irritation and sensitization ...... 14 8.2.1 Skin irritancy ...... 14 8.2.2 Eye irritancy ...... 14 8.2.3 Respiratory tract irritancy ...... 14 8.2.4 Sensitization ...... 14 8.3 Short-term exposure ...... 14 8.4 Medium-term exposure ...... 15 8.5 Long-term exposure and carcinogenicity ...... 15 8.5.1 Inhalation ...... 15 8.5.2 Drinking-water ...... 16

iii Concise International Chemical Assessment Document 39

8.5.3 Gavage ...... 20 8.6 Genotoxicity and related end-points ...... 20 8.6.1 In vitro studies ...... 20 8.6.2 In vivo studies ...... 21 8.7 Reproductive toxicity ...... 21 8.8 Neurological effects and effects on the immune system ...... 22 8.9 Mode of action ...... 22 8.9.1 Cancer ...... 22 8.9.2 Neurotoxicity ...... 23

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

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

10.1 Aquatic organisms ...... 25 10.2 Terrestrial organisms ...... 26 10.3 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 ...... 27 11.1.1.2 Effects in experimental animals ...... 27 11.1.2 Dose–response analyses ...... 29 11.1.2.1 Effects in humans ...... 29 11.1.2.2 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 ...... 32 11.2 Evaluation of environmental effects ...... 33 11.2.1 Assessment end-points ...... 33 11.2.1.1 Aquatic end-points ...... 33 11.2.1.2 Terrestrial end-points ...... 33 11.2.2 Sample environmental risk characterization ...... 33 11.2.2.1 Aquatic organisms ...... 33 11.2.2.2 Terrestrial organisms ...... 34 11.2.2.3 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

iv Acrylonitrile

FOREWORD 1701 for advice on the derivation of health-based guidance values. Concise International Chemical Assessment While every effort is made to ensure that CICADs Documents (CICADs) are the latest in a family of publications from the International Programme on represent the current status of knowledge, new informa- Chemical Safety (IPCS) — a cooperative programme of tion is being developed constantly. Unless otherwise the World Health Organization (WHO), the International stated, CICADs are based on a search of the scientific Labour Organization (ILO), and the United Nations literature to the date shown in the executive summary. In Environment Programme (UNEP). CICADs join the the event that a reader becomes aware of new informa- Environmental Health Criteria documents (EHCs) as tion that would change the conclusions drawn in a authoritative documents on the risk assessment of CICAD, the reader is requested to contact IPCS to inform chemicals. it of the new information.

Procedures International Chemical Safety Cards on the relevant chemical(s) are attached at the end of the CICAD, to provide the reader with concise information The flow chart on page 2 shows the procedures on the protection of human health and on emergency followed to produce a CICAD. These procedures are action. They are produced in a separate peer-reviewed designed to take advantage of the expertise that exists procedure at IPCS. They may be complemented by around the world — expertise that is required to produce information from IPCS Poison Information Monographs the high-quality evaluations of toxicological, exposure, (PIM), similarly produced separately from the CICAD and other data that are necessary for assessing risks to process. human health and/or the environment. The IPCS Risk Assessment Steering Group advises the Co-ordinator, CICADs are concise documents that provide sum- IPCS, on the selection of chemicals for an IPCS risk maries of the relevant scientific information concerning assessment, the appropriate form of the document (i.e., the potential effects of chemicals upon human health EHC or CICAD), and which institution bears the and/or the environment. They are based on selected responsibility of the document production, as well as on national or regional evaluation documents or on existing the type and extent of the international peer review. EHCs. Before acceptance for publication as CICADs by The first draft is based on an existing national, IPCS, these documents undergo extensive peer review by internationally selected experts to ensure their regional, or international review. Authors of the first completeness, accuracy in the way in which the original draft are usually, but not necessarily, from the institution data are represented, and the validity of the conclusions that developed the original review. A standard outline drawn. has been developed to encourage consistency in form. The first draft undergoes primary review by IPCS and The primary objective of CICADs is characteri- one or more experienced authors of criteria documents to zation of hazard and dose–response from exposure to a ensure that it meets the specified criteria for CICADs. chemical. CICADs are not a summary of all available data on a particular chemical; rather, they include only that The draft is then sent to an international peer information considered critical for characterization of the review by scientists known for their particular expertise risk posed by the chemical. The critical studies are, and by scientists selected from an international roster however, presented in sufficient detail to support the compiled by IPCS through recommendations from IPCS conclusions drawn. For additional information, the national Contact Points and from IPCS Participating reader should consult the identified source documents Institutions. Adequate time is allowed for the selected upon which the CICAD has been based. experts to undertake a thorough review. Authors are required to take reviewers’ comments into account and Risks to human health and the environment will revise their draft, if necessary. The resulting second draft vary considerably depending upon the type and extent is submitted to a Final Review Board together with the of exposure. Responsible authorities are strongly reviewers’ comments. encouraged to characterize risk on the basis of locally measured or predicted exposure scenarios. To assist the reader, examples of exposure estimation and risk 1 characterization are provided in CICADs, whenever International Programme on Chemical Safety (1994) possible. These examples cannot be considered as Assessing human health risks of chemicals: derivation of representing all possible exposure situations, but are guidance values for health-based exposure limits. Geneva, provided as guidance only. The reader is referred to EHC World Health Organization (Environmental Health Criteria 170).

1 Concise International Chemical Assessment Document 39

CICAD PREPARATION FLOW CHART

SELECTION OF PRIORITY CHEMICAL

SELECTION OF HIGH QUALITY NATIONAL/REGIONAL ASSESSMENT DOCUMENT(S)

FIRST DRAFT PREPARED

PRIMARY REVIEW BY IPCS (REVISIONS AS NECESSARY)

REVIEW BY IPCS CONTACT POINTS/ SPECIALIZED EXPERTS

REVIEW OF COMMENTS (PRODUCER/RESPONSIBLE OFFICER), PREPARATION OF SECOND DRAFT 1

FINAL REVIEW BOARD 2

FINAL DRAFT 3

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

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.

2 Acrylonitrile

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

The CICAD Final Review Board has several important functions:

– to ensure that each CICAD has been subjected to an appropriate and thorough peer review; – to verify that the peer reviewers’ comments have been addressed appropriately; – to provide guidance to those responsible for the preparation of CICADs on how to resolve any remaining issues if, in the opinion of the Board, the author has not adequately addressed all comments of the reviewers; and – to approve CICADs as international assessments.

Board members serve in their personal capacity, not as representatives of any organization, government, or industry. They are selected because of their expertise in human and environmental toxicology or because of their experience in the regulation of chemicals. Boards are chosen according to the range of expertise required for a meeting and the need for balanced geographic representation.

Board members, authors, reviewers, consultants, and advisers who participate in the preparation of a CICAD are required to declare any real or potential conflict of interest in relation to the subjects under discussion at any stage of the process. Representatives of nongovernmental organizations may be invited to observe the proceedings of the Final Review Board. Observers may participate in Board discussions only at the invitation of the Chairperson, and they may not participate in the final decision-making process.

3 Concise International Chemical Assessment Document 39

1. EXECUTIVE SUMMARY Acrylonitrile is distributed largely to the environmental compartments to which it is principally released (i.e., air or water), with movement to soil, sediment, or biota This CICAD on acrylonitrile was prepared jointly being limited; reaction and advection are the major by the Environmental Health Directorate of Health removal mechanisms. In limited surveys in the country Canada and the Commercial Chemicals Evaluation on which the sample risk characterization is based (i.e., Branch of Environment Canada based on documentation Canada), acrylonitrile has been detected in the general prepared concurrently as part of the Priority Substances environment only in the vicinity of industrial sources. Program under the Canadian Environmental Protection Act (CEPA). The objective of assessments on Priority Occupational exposure to acrylonitrile occurs Substances under CEPA is to assess potential effects of during production and its use in the manufacture of indirect exposure in the general environment on human other products; potential for exposure is greater in the health as well as environmental effects. Data identified latter case, where the compound may not be as easily as of the end of 31 May 1998 (environmental effects) and contained. Based on recent data for countries in the April 19981 (human health effects) were considered in European Union, time-weighted-average (TWA) expo- this review. Other reviews that were also consulted sures are #0.45 ppm (#1 mg/m3) during production and include US EPA (1980, 1985), IPCS (1983), ATSDR (1990), #1.01 ppm (#2.2 mg/m3) in various end uses. IARC (1999), and EC (2000). Information on the nature of the peer review and availability of the source document Acrylonitrile is rapidly absorbed via all routes of (Environment Canada & Health Canada, 2000) is exposure and distributed throughout examined tissues. presented in Appendix 1. Information on the peer review There is little potential for significant accumulation in of this CICAD is presented in Appendix 2. This CICAD any organ, with most of the compound being excreted was approved as an international assessment at a primarily as metabolites in the urine within the first 24–48 meeting of the Final Review Board, held in Geneva, h following administration. Available data are consistent Switzerland, on 8–12 January 2001. Participants at the with conjugation to glutathione being the major detoxifi- Final Review Board meeting are listed in Appendix 3. The cation pathway, while oxidation to 2-cyanoethylene International Chemical Safety Card on acrylonitrile (ICSC oxide is considered an activation pathway. 0092), produced by the International Programme on Chemical Safety (IPCS, 1993), has also been reproduced Available data from studies in animals indicate that in this document. acrylonitrile is a skin, respiratory, and severe eye irritant. Acrylonitrile may cause allergic contact dermatitis, but Acrylonitrile (CAS No. 107-13-1) is a volatile, the available data are inadequate to assess its sensitiza- flammable, water-soluble liquid at room temperature. The tion potency. With the exception of developmental tox- large majority of acrylonitrile in Canada is used as a icity, for which effects (fetotoxic and teratogenic) have feedstock or chemical aid in the production of nitrile- not been observed at concentrations that were not toxic butadiene rubber and in acrylonitrile-butadiene-styrene to the mothers, available data on other non-neoplastic and styrene-acrylonitrile polymers. Estimated world effects in experimental animals are inadequate to charac- capacity in 1993 was about 4 million tonnes. Major areas terize exposure–response. In the few studies in human of production are the European Union (>1.25 million populations in which non-neoplastic effects of acrylo- tonnes per year), the USA (approximately 1.5 million nitrile have been systematically investigated, only acute tonnes per year), and Japan (approximately 0.6 million dermal irritation has been reported consistently. tonnes per year). Based on studies in animals, cancer is the critical Acrylonitrile is released into the environment pri- end-point for effects of acrylonitrile on human health. A marily from chemical production and the chemical and range of tumours in rats — including those of the central plastic products industries (>95% in the sample nervous system (brain and/or spinal cord), ear canal, country). There are no known natural sources. gastrointestinal tract, and mammary glands — has been consistently observed following both ingestion and inhalation. In almost all adequate bioassays, there have 1 New information flagged by the reviewers or obtained in a been reported increases in astrocytomas of the brain and literature search conducted prior to the Final Review Board spinal cord, which are rarely observed spontaneously; meeting has been scoped to indicate its likely impact on the these have occurred at highest incidence consistently essential conclusions of this assessment, primarily to establish across studies. Increases have been statistically signifi- priority for its consideration in an update. More recent cant, and there have been clear dose–response trends. information not critical to the hazard characterization or Tumours have sometimes been reported at non-toxic exposure–response analysis, considered by reviewers to add to doses or concentrations and at periods as early as informational content, has been added. 7–12 months following onset of exposure. Tumours have

4 Acrylonitrile also been observed in exposed offspring of a multigener- 2. IDENTITY AND PHYSICAL/CHEMICAL ation reproductive study at 45 weeks. PROPERTIES

Increases in cancer incidence have not been con- sistently observed in available epidemiological studies. Acrylonitrile is also known as acrylic acid nitrile, However, the meaningful quantitative comparison of the acrylon, carbacryl, cyanoethylene, fumigrain, propene- results of these investigations with those of studies in nitrile, 2-propenenitrile, propenoic acid nitrile, propylene animals is precluded by inadequate data on mode of nitrile, VCN, ventox, and vinyl cyanide. Its Chemical induction of brain tumours, relative paucity of data on Abstracts Service (CAS) number is 107-13-1, its molecu- exposure of workers in the relevant investigations, and lar formula, C3H3N, and its relative molecular mass, 53.06. the wide range of the confidence limits on the standard- The molecular structure of acrylonitrile is presented in ized mortality ratios for cancers of possible interest in Figure 1. the epidemiological studies. H H In numerous studies on the genotoxicity of acrylo- nitrile involving examination of a broad spectrum of end- C C points both in vitro, with and without metabolic activa- H C N tion, and in vivo in mice and rats, the pattern of results has been quite mixed, while the metabolite, cyanoethyl- Fig. 1: Chemical structure of acrylonitrile. ene oxide, is mutagenic. Although direct evidence is not available, based on available data, it is reasonable to The physical and chemical properties of acrylo- assume that induction of tumours by acrylonitrile nitrile are presented in Table 1. At room temperature, involves direct interaction with genetic material. The acrylonitrile is a volatile, flammable, colourless liquid weight of evidence for other potential modes of induc- with a weakly pungent odour (IPCS, 1983). Acrylonitrile tion of tumours is inadequate. Acrylonitrile or its epoxide has two chemically active sites, at the carbon–carbon can react with macromolecules. double bond and at the nitrile group, where it undergoes a wide variety of reactions. It is a polar molecule because Cancer is considered the critical end-point for of the presence of the cyano (CN) group. It is soluble in quantification of exposure–response for risk characteri- water (75.1 g/litre at 25 °C) and miscible with most zation for acrylonitrile. The lowest tumorigenic concen- organic solvents. The vapours are explosive, with tration (TC , the concentration that causes a 5% 05 cyanide gas being produced. increase in tumour incidence over background) (human equivalent value) was 2.7 ppm (6.0 mg/m3) for the Acrylonitrile may polymerize spontaneously and combined incidence of benign and malignant tumours of violently in the presence of concentrated caustic acid, the brain and/or spinal cord in female rats exposed by on exposure to visible light, or in the presence of inhalation. This equates to a unit risk of 8.3 × 10–3 per concentrated alkali (IPCS, 1983). Hence, it is stored mg/m3. accordingly, often as an acrylonitrile–water formulation that acts as a polymerization inhibitor (Kirk et al., 1983). Although limited, available data are consistent Spontaneous polymerization during storage and with air being the principal medium of exposure of the transport can also be prevented by the addition of an general population to acrylonitrile; intake from other inhibitor, typically hydroquinone methyl ether (NICNAS, media is likely to be negligible in comparison. The focus 2000). of the human health risk characterization is populations exposed through air in the vicinity of industrial sources. Based on the margins between carcinogenic potency and limited available data on predicted and measured 3. ANALYTICAL METHODS concentrations of acrylonitrile primarily in the vicinity of point sources in the sample risk characterization, risks in the vicinity of industrial point sources are >10–5. The most common method for analysis of acrylo- In the sample environmental risk characterization, nitrile is gas chromatography. Method S156 of the US National Institute for Occupational Safety and Health levels in treated industrial wastewaters are less than the (NIOSH, 1978, 1994) specifies sampling with activated estimated no-effects value (ENEV) for the most sensitive charcoal sorption tubes, rinsing with methanol, and aquatic organism, and predicted maximum levels (near a subsequent analysis by gas chromatography with a chemical industry processing plant) are less than the nitrogen–phosphorus detector. The working range of ENEV for the most sensitive terrestrial organism. this method is 0.5–31 ppm (1–68 mg/m3) for a 15-litre sample. The estimated limit of detection is 0.02 ppm

5 Concise International Chemical Assessment Document 39

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 75.1 Martin, 1961; Spencer, 1981; Langvardt, 1985; Howard, 1989; (g/litre) DMER & AEL, 1996

Solubility Miscible with most American Cyanamid Co., 1959 organic solvents

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 11 (8.92–11.14) Mabey et al., 1982; Howard, 1989; Mackay et al., 1995 (Pa@m 3/mol) Log organic carbon/water 1.06 (!0.09 to 1.1) Koch & Nagel, 1988; Walton et al., 1992

partition coefficient (log Koc) Log octanol/water partition 0.25 (!0.92 to 1.2) Collander, 1951; Pratesi et al., 1979; Veith et al., 1980; Tonogai et

coefficient (log Kow) al., 1982; Tanii & Hashimoto, 1984; Sangster, 1989; DMER & AEL, 1996

Log bioconcentration factor 0.48–1.68 Barrows et al., 1980; Lech et al., 1995 (log BCF) in fish

Half-life (t ½) air (h) 55 or 96 (4–189) Callahan et al., 1979; Cupitt, 1980; Atkinson, 1985; DMER & AEL, 96 (13–198) 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); 1 ppm 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 Health limit of detection is about 0.1–1 pmol/g globin (Tavares Administration specifies a similar method of sampling et al., 1996; Licea Perez et al., 1999). with charcoal tubes, desorption with acetone, and subsequent analysis with gas chromatography using a nitrogen–phosphorus detector. The detection limit for this method is 0.01 ppm (0.026 mg/m3) (OSHA, 1982, 4. SOURCES OF HUMAN AND 1990). Health and Safety Executive (1993, 2000) specifies ENVIRONMENTAL EXPOSURE additional methods using porous polymer adsorption tubes and thermal desorption with gas chromatographic analysis. Data on sources and emissions primarily from the source country of the national assessment on which the A method has been developed for monitoring of CICAD is based (i.e., Canada) are presented here as an exposure to acrylonitrile by determination of the adduct, example. Sources and patterns of emissions in other N-(2-cyanoethyl)valine, formed in the reaction of countries are expected to be similar, although quantita- acrylonitrile with the N-terminal group of haemoglobin tive values may vary. (Bergmark et al., 1993; Osterman-Golkar et al., 1994; Tavares et al., 1996). The method is based on a modified 4.1 Natural sources Edman procedure and detection with selected ion monit- oring by gas chromatography–mass spectrometry. The Acrylonitrile is not known to occur naturally, and there are no known reactions that could lead to in situ

6 Acrylonitrile formation of this substance in the atmosphere (Grosjean, 5. ENVIRONMENTAL TRANSPORT, 1990a). DISTRIBUTION, AND TRANSFORMATION

4.2 Anthropogenic sources 5.1 Air The total release of acrylonitrile in Canada in 1996 was 19.1 tonnes (97.3% to air and 2.7% to water) Acrylonitrile emitted to air reacts primarily with (Environment Canada, 1997). The major source of photochemically generated hydroxyl radicals (@OH) in releases was the organic chemicals industry (97.4%) the troposphere (Atkinson et al., 1982; Edney et al., 1982; (namely, the chemicals and chemical products industries Munshi et al., 1989; US DHHS, 1990; Bunce, 1996). The and the plastic products industries), while municipal atmospheric half-life, based on hydroxyl radical reaction wastewater treatment facilities accounted for 2.6% of rate constants, is calculated to be between 4 and 189 h releases. Although accounting for at most 1% of the (Callahan et al., 1979; Cupitt, 1980; Edney et al., 1982; releases to air from chemical industries in Canada, Howard, 1989; Grosjean, 1990b; Kelly et al., 1994). incineration of sewage sludge represents another poten- Modelling of environmental partitioning (section 5.5) is tial source of acrylonitrile release to air. Use of based on a mean half-life for acrylonitrile in air of 55 h. acrylonitrile polymers as conditioners for wastewater treatment is another potential source, although this is The reaction of acrylonitrile with ozone and nitrate also considered to be minor in relation to industrial is slow, because of the absence of chlorine and bromine sources in Canada. atoms in the molecule, and is not likely to constitute a major route of degradation (Bunce, 1996). There is also potential for long-range transport of acrylonitrile (up to 2000 km from its source) based on its The reaction of hydroxyl radicals with acrylonitrile half-life in air of between 55 and 96 h (see Table 1). yields formaldehyde and, to a lesser extent, formic acid, formyl cyanide, carbon monoxide, and hydrogen cyanide Acrylonitrile has also been used in some countries (Edney et al., 1982; Spicer et al., 1985; Munshi et al., as a pesticide. Its registration as a fumigant for stored 1989; Grosjean, 1990a). grain in Canada ceased in 1976 (J. Ballantine, personal communication, 1997). 5.2 Water

Environmental tobacco smoke is a potentially Acrylonitrile in water can be biodegraded by accli- important source of acrylonitrile indoors (Miller et al., matized microorganisms or volatilized (Going et al., 1979). 1998). In water, half-lives of 30–552 h are estimated based on aqueous aerobic biodegradation (Ludzack et al., 1961; 4.3 Production and use Going et al., 1979; Howard et al., 1991). Modelling of environmental partitioning (section 5.5) is based on a World production of acrylonitrile exceeded 3.2 mil- mean half-life for acrylonitrile in water of 170 h (7 days). lion tonnes in 1988, with later production increasing The half-life based on volatilization is 1–6 days (Howard slowly (IARC, 1999). The estimated world capacity in et al., 1991). The hydrolysis of acrylonitrile is slow, with 1991 was 4.2 million tonnes, while world demand in 1993 half-lives under acidic and basic conditions of 13 and was 3.846 million tonnes (PCI, 1994). Major areas of 188 years, respectively (Ellington et al., 1987). production are the European Union (>1.25 million tonnes per year), the USA (approximately 1.5 million tonnes per Acrylonitrile has an initial inhibitory effect on year), and Japan (approximately 0.6 million tonnes per activated sludge systems and other microbial year). The large majority of acrylonitrile is used as a populations and does not meet the criteria of feedstock or chemical aid in the production of nitrile- Organisation for Economic Co-operation and butadiene rubber (68% of 1994 imports in the sample Development (OECD) Test Method 301C for ready country) and in acrylonitrile-butadiene-styrene and biodegradability (Chemicals Inspection and Testing styrene-acrylonitrile polymers (30% of 1994 imports in Institute of Japan, 1992; AN Group, 1996; BASF AG, the sample country). 1996). However, acrylonitrile will be extensively degraded (95–100%) following a short acclimation period if emitted to wastewater treatment plants (Tabak et al., 1980; Kincannon et al., 1983; Stover & Kincannon, 1983; Freeman & Schroy, 1984; Watson, 1993).

7 Concise International Chemical Assessment Document 39

5.3 Soil and sediment were as follows: molecular mass, 53.06 g/mol; water

solubility, 75.5 g/litre; vapour pressure, 11.0 kPa; log Kow, Acrylonitrile is biodegraded in a variety of surface 0.25; Henry’s law constant, 11 Pa@m3/mol; half-life in air, soils (Donberg et al., 1992) and by isolated strains of soil 55 h; half-life in water, 170 h; half-life in soil, 170 h; half- bacteria and fungi (Wenzhong et al., 1991). Concentra- life in sediments, 550 h. Modelling was based on an tions of acrylonitrile up to 100 mg/kg were degraded in assumed default emission rate of 1000 kg/h into a region under 2 days (Donberg et al., 1992). Similar breakdown of 100 000 km2, which includes a surface water area (20 m by microbial populations present in sediment is likely deep) of 10 000 km2. The height of the atmosphere was (DMER & AEL, 1996; EC, 2000). Results of experimental set at 1000 m. Sediments and soils were assumed to have studies (Zhang et al., 1990) or soil sorption coefficients an organic carbon content of 4% and 2% and a depth of calculated by quantitative structure–activity 1 cm and 10 cm, respectively. The estimated percent relationships (Koch & Nagel, 1988; Walton et al., 1992) distribution predicted by this model is not affected by or based on water solubility (Kenaga, 1980) indicate little the assumed emission rate. potential for adsorption of acrylonitrile to soil or sediments. Modelling indicates that when acrylonitrile is continuously discharged into a specific medium, most of A half-life of acrylonitrile in soil of 6–7 days has it (84–97%) can be expected to be present in that medium been reported (Howard et al., 1991; Donberg et al., 1992) (DMER & AEL, 1996). More specifically, Level III (see Table 1). Based on biodegradability and the soil fugacity modelling by DMER & AEL (1996) predicts that: partition coefficient (EC, 1996), the half-life of acrylonitrile in soil was classified in the category of # when released into air, the distribution of mass is 300 days (EC, 2000). Modelling of environmental 92.8% in air, 6.4% in water, 0.8% in soil, and 0.0% partitioning (section 5.5) is based on a mean half-life for in sediment; acrylonitrile in soil of 170 h (7 days). The half-life in the oxic zone of sediment can be assumed to be similar. # when released into water, the distribution of mass is 2.5% in air, 97.3% in water, 0.0% in soil, and 0.1% 5.4 Biota in sediment; and

Bioaccumulation of acrylonitrile is not anticipated, # when released into soil, the distribution of mass is given experimentally derived values of the octanol/water 4.4% in air, 11.9% in water, 83.7% in soil, and 0.0% in sediment. partition coefficient (log Kow) ranging from !0.92 to 1.2 (mean 0.25) (Collander, 1951; Pratesi et al., 1979; Veith et al., 1980; Tonogai et al., 1982; Tanii & Hashimoto, 1984; The major removal mechanisms in air, water, and Sangster, 1989) and a log bioconcentration factor (log soil are reaction within the medium and, to a lesser BCF) of 0 calculated from the water solubility of degree, advection and volatilization. Abiotic and biotic acrylonitrile (EC, 2000). degradation in the various compartments result in low persistence overall and little, if any, bioaccumulation. Log BCF values were 0.48–1.68 in bluegill (Lepomis macrochirus) (Barrows et al., 1980) and rainbow trout Owing to the paucity of data on concentrations of (Oncorhynchus mykiss) (Lech et al., 1995). The acrylonitrile in environmental media, fugacity modelling experimentally derived log BCF of 1.68 reported by with version 4 of the ChemCAN3 model (Mackay et al., Barrows et al. (1980) in whole-body tissue of bluegill may 1995) was also conducted with the conservative assump- be an overestimate, due to uptake of 14C-labelled tion that all known releases in 1996 (Environment degradation products in addition to acrylonitrile and to Canada, 1997) in Canada occurred in southern Ontario. cyanoethylation of macromolecules (EC, 2000). Release to air was considered to be approximately 19 tonnes per year, with simultaneous release to water of 0.53 tonnes per year. Since the half-life of acrylonitrile in 5.5 Environmental partitioning air is the major determinant of its fate in the environment, the model was run using the minimum, median, and Fugacity modelling was conducted to characterize maximum half-life values (4, 55, and 189 h) under summer, key reaction, intercompartment, and advection (move- winter, and year-round conditions. Modelling predicted ment out of a compartment) pathways for acrylonitrile distribution primarily to air (41.9–78.1%) and water and its overall distribution in the environment. A steady- (21.6–57.9%). state, non-equilibrium model (Level III fugacity model) was run using the methods developed by Mackay (1991) and Mackay & Paterson (1991). Assumptions, input parameters, and results are presented in DMER & AEL (1996) and summarized here. Values for input parameters

8 Acrylonitrile

6. ENVIRONMENTAL LEVELS AND Levels of acrylonitrile were <0.64 µg/m3 in all seven HUMAN EXPOSURE samples of ambient air taken in the industrialized area of Windsor, Ontario, in August 1991 (Ng & Karellas, 1994).

Data on concentrations in the environment primar- Ambient air samples were collected from down- ily from the source country of the national assessment town (n = 16) and residential (n = 7) areas of Metropol- on which the CICAD is based (i.e., Canada) are itan Toronto, Ontario, during a personal exposure pilot presented here as a basis for the sample risk survey. The air samples were obtained at 1.5 m above characterization. Patterns of exposure in other countries ground for 12 consecutive hours. Acrylonitrile was not 3 are expected to be similar, although quantitative values detected (detection limit 0.9 µg/m ) in any sample may vary. Detection of acrylonitrile in the general analysed (Bell et al., 1991). environment is restricted primarily to the vicinity of industrial sources. Air samples were collected within the inhalation zone by a personal unit for 1–2 h while the participants were commuting to and from work (n = 19) and while 6.1 Environmental levels they were spending the noon-hour period (n = 8) in downtown Toronto, Ontario, from June to August 1990. Ambient air 6.1.1 Acrylonitrile was not detected (detection limit 0.9 µg/m3) in any sample analysed. Acrylonitrile was also not Maximum predicted rates of emission of acrylo- detected (detection limit 0.9 µg/m3) in four special com- nitrile during any half-hour period were 0.003, 0.018, and posite samples collected during the same study; the first 0.028 g/s for stacks 14, 17, and 11 m high, respectively, two samples were collected while the participants were near the site of the largest user in Canada (a Sarnia, attending meetings, the third was collected while the Ontario, plant), based on dispersion modelling participants were at a barbecue, and the fourth was an conducted in 1998 (H. Michelin, personal communica- overall composite sample of the afternoon and morning tion, 1999). Predicted concentrations at 11, 25, 41, and commutes and the overnight residential indoor air (Bell 1432 m from the stacks under the assumption that et al., 1991). inversion occurs just above stack height and the plume is therefore forced to the ground were 6.6, 2.2, 0.4, and 6.1.2 Indoor air 0.1 µg/m3. Predicted concentrations at 11, 35, 41, and 3508 m under the assumption of close to stable or neutral Environmental tobacco smoke appears to be a atmospheric conditions were 9.3, 2.9, 0.6, and 0.1 µg/m3. source of acrylonitrile in indoor air (California Air Accuracy testing indicates that the model may overpre- Resources Board, 1994). dict actual values by as much as 2 orders of magnitude. Acrylonitrile was not detected in samples collected In six samples taken on 2 different days in the vic- overnight (duration up to 16 h) from June to August inity of a nitrile-butadiene rubber production plant in 1990 in four different residences near Toronto, Ontario Sarnia, Ontario, 5 m outside the company fence line, (detection limit 0.9 µg/m3) (Bell et al., 1991). 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, 6.1.3 Surface water and groundwater personal communication, 1998). Acrylonitrile has been detected only in water Levels of acrylonitrile in ambient air sampled for associated with industrial effluent; it has not been 6 days near a chemical manufacturing plant in Cobourg, detected in ambient surface water in Canada (detection Ontario, ranged from 0.12 to 0.28 µg/m3. Measurements limit 4.2 µg/litre). from stacks of the facility in 1993 ranged from <251 to 100 763 µg/m3 (Ortech Corporation, 1994). The concen- Of the effluents sampled from five companies tration at point of impingement estimated on the basis of using acrylonitrile and discharging to the environment dispersion modelling of these data was 1.62 µg/m3. in 1989–1990 in Ontario, the compound was detected in 12 of 256 samples (OMOE, 1993). Daily concentrations At six urban stations in Ontario in 1990, concentra- ranged from 0.7 to 3941 µg/litre; annual site averages tions of acrylonitrile in 10 of 11 samples were below the ranged from 2.7 to 320 µg/litre. Intake water at the 26 detection limit of 0.0003 µg/m3. In this study, the maxi- organic chemical manufacturing plants sampled over mum and only detectable concentration of acrylonitrile the same period did not contain detectable amounts of was 1.9 µg/m3 in one sample (OMOE, 1992a). acrylonitrile (207 samples; detection limit 4.2 µg/litre) (OMOE, 1992b). Biological treatment reactors have recently been introduced for two of the five companies

9 Concise International Chemical Assessment Document 39

with remaining commercial activity involving acrylo- concentrations of acrylonitrile in five types of food nitrile, and levels from both sites are below 4.2 µg/litre packaged in acrylonitrile-based plastic containers, (Y. Hamdy, personal communication, 1998). purchased from several stores in Ottawa, Ontario. Average concentrations of acrylonitrile (measured in In a large study of Canadian municipal water three duplicate samples of each food type by gas supplies in 1982–1983, acrylonitrile was not detected in chromatography with a nitrogen–phosphorus-selective any of the 42 raw (and 42 treated) water samples from detector) ranged from 8.4 to 38.1 ng/g. nine municipalities on the Great Lakes (detection limit 5 µg/litre) (Otson, 1987). Acrylonitrile was not detected A survey of food packed in acrylonitrile-based (detection limit 2.1 µg/litre) in groundwater samples plastics containing up to 2.6 mg acrylonitrile/kg was downgradient of a wastewater treatment pond at an conducted in Ottawa, Ontario. The samples represented Ontario chemical industry site (Environment Canada, five food companies and a variety of luncheon meats, 1997). including mock chicken, ham, salami, pizza loaf, and several types of bologna. Acrylonitrile was not identified 6.1.4 Drinking-water (detection limit 2 ng/g). Analyses were by gas chroma- tography, with nitrogen–phosphorus-selective detection Acrylonitrile was monitored in municipal water (Page & Charbonneau, 1985). supplies at 150 locations in Newfoundland, Nova Scotia, New Brunswick, and Prince Edward Island over the 6.1.7 Multimedia study period 1985–1988. It was detected at a trace concentra- tion (0.7 µg/litre) in only one sample of treated water in In a multimedia study carried out for Health Nova Scotia in June 1988 (detection limit 0.5–1.0 µg/litre) Canada (Conor Pacific Environmental & Maxxam Ltd., (Environment Canada, 1989a,b,c,d). 1998), exposure to several volatile organic chemicals, including acrylonitrile, was measured for 50 participants Acrylonitrile was not identified in treated (or raw) across Canada. Thirty-five participants were randomly water at facilities near the Great Lakes in 1982–1983 (n = selected from the Greater Toronto Area in Ontario, six 42; detection limit 5 µg/litre during the initial sampling participants from Liverpool, Nova Scotia, and nine from and <1 µg/litre during later sampling after the technique Edmonton, Alberta. For each participant, samples of was modified) over three sampling periods (Otson, 1987). drinking-water, beverages, and indoor, outdoor, and per- Analyses were by gas chromatography–mass sonal air were collected over a 24-h period. Acrylonitrile spectrometry. was not detected in air (detection limit 1.36 µg/m3), water (detection limit 0.7 ng/ml), beverages (detection limit 1.8 6.1.5 Soil and sediment ng/ml), or food (detection limit 0.5 ng/g).

Significant concentrations of acrylonitrile are not 6.2 Human exposure: environmental expected in soil or sediment based on the release patterns and the environmental partitioning, behaviour, Point estimates of average daily intake (per kilo- and fate of the substance (section 5.3). gram body weight) were developed for the sample country (i.e., Canada), based on the few monitoring data Significant levels of acrylonitrile have not been available and reference values for body weight, inhala- detected in Canadian soils. Levels in 18 soil samples at tion volume, and amounts of food and drinking-water an Alberta chemical blending plant were below the consumed daily by six age groups (Environment Canada detection limit of 0.4 ng/g (G. Dinwoodie, personal & Health Canada, 2000). Similar estimates were communication, 1993). Significant quantities of developed based on the results of the ChemCAN3 acrylonitrile in soil at a LaSalle, Quebec, chemical fugacity modelling (Environment Canada & Health industrial site have not been identified since regular Canada, 2000). In view of the limitations of the data on monitoring began at the site in 1992 (Environment which these estimates are based, however (i.e., lack of Canada, 1997). detection of acrylonitrile in most media in which it was monitored or fugacity modelling), these estimates are Data on levels of acrylonitrile in sediment have not primarily useful as a basis for identification of principal been identified. routes and media of exposure.

6.1.6 Food Although it is uncertain, based on this limited information, air (ambient and indoor) is likely the Acrylonitrile may potentially be introduced into principal medium of exposure. Intakes from food and foodstuffs from acrylonitrile-based polymers used in drinking-water are likely to be negligible in comparison. food packaging. Page & Charbonneau (1983) measured This is consistent with the physical/chemical properties

10 Acrylonitrile

of acrylonitrile, which has moderate vapour pressure and styrene polymers is carried out in a partially closed a low log Kow, and the results of fugacity modelling system, with local exhaust ventilation and emission (EC, (section 5.5). On the basis of the estimates derived 2000). above, intake from ambient and indoor air ranges from 96% to 100% of total intake. Recent information on the occupational exposure scenario for Australia (NICNAS, 2000) correlates well Exposures from ambient air may be substantially with the above data. Australia imports approximately higher for populations in the vicinity of point sources. 2000 tonnes of acrylonitrile per year, 70% of which is Data presented above (see section 6.1.1) on concentra- used for the manufacture of styrene-acrylonitrile poly- tions in the vicinity of point sources indicate that popu- mer, which is further compounded into plastic resins. lations in the area might be exposed to levels of acrylo- The remainder is used in the manufacture of latex poly- nitrile in the range of tenths of µg/m3 (Ng & Karellas, mers (polymers dispersed in water) for adhesive and 1994; Ortech Corporation, 1994). Additional data from the coating applications. Of 187 breathing-zone air samples USA indicate that levels vary considerably in the collected in 1991–1999 during normal operations, vicinity of various point sources (Health Canada, 2000). 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 as Limitations of the data preclude development of 8-h TWAs. Personal exposure levels were slightly higher meaningful probabilistic estimates of exposure to acrylo- in latex than in styrene-acrylonitrile polymer and plastic nitrile in the general population. resin manufacturing plants.

6.3 Human exposure: occupational Surveys of full-shift personal exposures in four US acrylonitrile production plants have also been reported Exposure to acrylonitrile may occur during its (Zey et al., 1989, 1990a,b; Zey & McCammon, 1990). production and its use in the manufacture of other Mean 8-h TWA personal exposures for monomer 3 products; potential for exposure is greatest in factories production operators were 1.1 ppm (2.4 mg/m ) or less where acrylonitrile is used to make other products, where from about 1978 to 1986, with some individual TWA 3 it may not be as easily contained (Sax, 1989). IARC (1999) levels up to 37 ppm (82 mg/m ). In three of these plants, indicates that approximately 35 000 workers in Europe levels for maintenance employees averaged below 3 and as many as 80 000 workers in the USA are 0.3 ppm (0.7 mg/m ), but in one plant, the average TWA 3 potentially exposed to acrylonitrile. These individuals exposure for these workers was 1 ppm (2.2 mg/m ). include acrylic resin makers, synthetic organic chemists, Average 8-h TWA exposures for loaders of acrylonitrile pesticide workers, and rubber, synthetic fibre, and textile into tank trucks, rail cars, or barges varied from 0.5 to 5.8 3 makers. The primary routes of potential exposure in the ppm (1.1 to 12.8 mg/m ). For some of the higher values occupational environment are inhalation and dermal. for production and maintenance workers and loaders in these plants, respirator use was noted. Although there Based on data collected in 1995 for countries in the were several changes introduced to reduce exposure European Union (EC, 2000), 8-h time-weighted-average levels, no trends over the years were noted. (TWA) exposures for production and various end uses were as follows: production, #0.45 ppm (1 mg/m3); fibre, In three US fibre plants for which data for full-shift #1.01 ppm (#2.2 mg/m3); latex, #0.10 ppm (#0.22 mg/m3); personal samples were available between the years 1977 acrylonitrile-butadiene-styrene polymer, #0.40 ppm and 1986, the average 8-h TWA exposures were between 3 (#0.88 mg/m3); and acrylamide, #0.20 ppm (#0.44 mg/m3). 0.3 and 1.5 ppm (0.7 and 3.3 mg/m ), based on nearly 3000 individual samples. The dope (viscous pre-fibre For six European producers of acrylonitrile, solution) and spinning operators had exposures averag- 3 average personal monitoring levels at the workplace ing 0.4–0.9 ppm (0.9–2.0 mg/m ). The lower exposure varied from <0.12 to 0.49 ppm (<0.26 to 1.1 mg/m3); the occurred in the plant that dried the polymer before the maximum recorded level was 5.5 ppm (12.1 mg/m3). For spinning operation, resulting in a lower monomer production of acrylonitrile fibres, the average personal content in the polymer. The other plant had a monitoring levels were from <0.26 to 0.43 ppm (<0.57 to continuous wet operation without the drying stage. 0.95 mg/m3), with a maximum value of 3.6 ppm Exposure of maintenance workers averaged 0.2 ppm (0.4 3 (7.9 mg/m3). For production of acrylonitrile-butadiene- mg/m ). Tank farm operators, who are also likely to styrene polymers, the average levels for personal unload acrylonitrile monomer from trucks, rail cars, or monitoring were 0.08–0.3 ppm (0.18–0.66 mg/m3), with a barges, had homogeneous exposure levels (0.5 ppm [1.1 3 maximum recorded value of 8.6 ppm (19.0 mg/m3). The mg/m ]) across plants (IARC, 1999). higher levels in use were consistent with production of acrylonitrile being initially in a closed system, while Haemoglobin adduct measurement is an extremely manufacture of, for example, acrylonitrile-butadiene- sensitive method for monitoring exposure to acrylo-

11 Concise International Chemical Assessment Document 39

nitrile. The level of N-(2-cyanoethyl)valine reflects Available data1 are consistent with conjugation with exposure during a 4-month period (i.e., the life span of glutathione being the major detoxification pathway of the erythrocytes) prior to blood sampling. Licea Perez et acrylonitrile, while the oxidation of acrylonitrile to 2- al. (1999) reported levels of 0.76 ± 0.36 pmol/g globin in cyanoethylene oxide can be viewed as an activation 18 non-smokers (who claimed that they were not pathway, producing a greater proportion of the total exposed to environmental tobacco smoke). Adduct metabolites in mice than in rats. Available data also levels in smokers range from 8 to a few hundred pmol/g indicate that there are route-specific variations in globin and are related to cigarette consumption. Adduct metabolism (Lambotte-Vandepaer et al., 1985; Tardif et levels in 10 smoking mothers (92.5–373 pmol/g globin) al., 1987). Based on studies in which 2-cyanoethylene and their newborns (34.6–211 pmol/g globin) were oxide has been administered, there is no indication of strongly correlated and demonstrated that transplacental preferential uptake or retention in specific organs, transfer of acrylonitrile occurs (Tavares et al., 1996). including the brain (Kedderis et al., 1993b). Adduct levels ranging from 20 to 66 000 pmol/g have been observed in occupationally exposed workers Liver microsomes from rats, mice, and humans (Bergmark et al., 1993; Tavares et al., 1996; Thier et al., produced 2-cyanoethylene oxide at a greater rate than 1999). Polymorphism with respect to the glutathione lung or brain microsomes, indicating that the liver is the transferases GSTTI and GSTMI had little effect on major site of formation in vivo of 2-cyanoethylene oxide adduct levels (Thier et al., 1999; Fennell et al., 2000). (Roberts et al., 1989; Kedderis & Batra, 1991). Studies in subcellular hepatic fractions indicate that there is an active epoxide hydrolase pathway for 2-cyanoethylene oxide in humans, which is inactive, although inducible, in 7. COMPARATIVE KINETICS AND rodents (Kedderis & Batra, 1993). Studies with inhibitory METABOLISM IN LABORATORY ANIMALS antibodies in human hepatic microsomes indicate that AND HUMANS the 2E1 isoform of cytochrome P-450 is primarily involved in epoxidation of acrylonitrile (Guengerich et al., 1991; Kedderis et al., 1993c). Based on studies conducted primarily in laboratory A physiologically based pharmacokinetic model animals, acrylonitrile is rapidly absorbed by all routes of administration and distributed throughout examined has been developed and verified for the rat (Gargas et al., tissues. In inhalation studies with volunteers, 50% of 1995; Kedderis et al., 1996), and work is under way to acrylonitrile was absorbed (Jakubowski et al., 1987). scale it to humans. In a recent, although incompletely However, there appears to be little potential for signifi- reported, study, Kedderis (1997) estimated in vivo cant accumulation in any organ, with most of the com- activity of epoxide hydrolase in humans based on the pound being excreted primarily as metabolites in urine in ratio of epoxide hydrolase to P-450 activity in subcellular the first 24–48 h following administration (Kedderis et al., hepatic fractions multiplied by the P-450 activity in vivo. 1993a; Burka et al., 1994). Human blood to air coefficients for acrylonitrile and 2- cyanoethylene oxide have also been recently Acrylonitrile is metabolized primarily by two path- determined, although incompletely reported at present ways: conjugation with glutathione to form N-acetyl-S- (Kedderis & Held, 1998). Research is in progress to (2-cyanoethyl)cysteine and oxidation by cytochrome P- determine partition coefficients for other human tissues. 450 to form remaining urinary metabolites (Langvardt et al., 1980; Geiger et al., 1983; Fennell et al., 1991; Kedderis et al., 1993a) (Figure 2). Oxidative metabolism of acrylonitrile leads to the formation of 2-cyanoethylene oxide, which is either conjugated with glutathione (Fennell & Sumner, 1994; Kedderis et al., 1995) to form a series of metabolites including cyanide and thiocyanate or directly hydrolysed by epoxide hydrolase (Borak, 1992; Kim et al., 1993). Recent data indicate that cytochrome P4502E1 is the sole P-450 catalysing the oxidation of acrylonitrile (Sumner et al., 1999).

1 Including results of short-term toxicity studies in which the oxidative pathway has been induced prior to administration with acrylonitrile or antioxidants have been administered concomitantly with acrylonitrile.

12 Figure 2 Metabolic pathway of acrylonitrile (IARC, 1999)

COOH

H2C CH CN GS CH2CH2CN HCCH2 S CH2CH2CN HOOCCH2 S CH2CH2CN Glutathione Acrylonitrile S-transferase HN COCH3 S-(2-Cyanoethyl)thioacetic acid _ _ N-Acetyl-S-(2-cyanoethyl)cysteine CN SCN Cytochrome P450 COOH GS CH2CHOH HCCH2 S CH2CH2OH O Glutathione S-transferase CN HN COCH3 H2C CH CN N-Acetyl-S-(2-hydroxyethyl)cysteine 2-Cyanoethylene oxide GS CHCH2OH COOH [CO CH2 CN] CN HCCH2 S CH2COOH HOOC CH2 CN HN COCH3 Cyanoacetic acid N-Acetyl-S-(2-carboxymethyl)cysteine COOH CN

HOCH2 CH2 CN HCCH2 S CHCH2OH HOOCCH2 S CH2COOH 2-Cyanoethanol HN COCH3 N-Acetyl-S-(1-cyano-2-hydroxyethyl)cysteine Thiodiglycolic acid 8. EFFECTS ON LABORATORY rabbit was washed with tap water for 1 min. Acrylonitrile MAMMALS AND IN VITRO TEST SYSTEMS produced moderate corneal opacity, moderate iritis, and severe conjunctival irritation in the unwashed treated eye. In the washed eye, there was slight temporary 8.1 Single exposure corneal opacity, transient, moderate iritic congestion, and moderate conjunctival irritation. These effects were The acute toxicity of acrylonitrile is relatively high, not completely reversible in the unwashed eye; by wash- ing the eye, the effects were considerably lessened, as with 4-h LC50s ranging from 140 to 410 ppm (300 to 3 was the duration of these ocular effects. 900 mg/m ) (Knobloch et al., 1971, 1972) and oral LD50s ranging from 25 to 186 mg/kg body weight (Maltoni et Respiratory tract irritancy al., 1987). Dermal LD50 values for various species were in 8.2.3 the range of 148–693 mg/kg body weight, with the rat being most sensitive (BUA, 1995). Signs of acute toxicity While not examined directly, in repeated-dose include respiratory tract irritation and central nervous toxicity studies, there has been evidence of irritant system dysfunction, resembling cyanide poisoning. effects on the upper respiratory tract, including nasal Superficial necrosis of the liver and haemorrhagic discharge in rats acutely exposed (Food and Drug gastritis of the forestomach have also been observed Research Laboratories, 1985) and rhinitis and hyper- following acute exposure (Silver et al., 1982). plastic changes in the nasal mucosa following chronic exposure (Quast et al., 1980b). Acrylonitrile-induced neurotoxicity following acute exposure via inhalation or ingestion has been described 8.2.4 Sensitization as a two-phase phenomenon. The first phase, which occurs shortly after exposure and is consistent with In a guinea-pig maximization test, animals chal- cholinergic overstimulation, has been likened to toxicity lenged with 0.5% and 1.0% acrylonitrile had a 95% caused by acetylcholinesterase inhibition. positive sensitization rate. Exposure to 0.2% on chal- Cholinomimetic signs in rats exposed to acrylonitrile lenge caused an 80% sensitization rate (Koopmans & have included vasodilation, salivation, lacrimation, Daamen, 1989). diarrhoea, and gastric secretion. These effects are maximal within 1 h of dosing. The second phase of 8.3 Short-term exposure toxicity is delayed by 4 h or more and includes signs of central nervous system disturbance, such as trembling, Available short-term inhalation studies are ataxia, convulsions, and respiratory failure (TERA, 1997). restricted to a few investigations involving administra- tion of single dose levels and, for one, examination of 8.2 Irritation and sensitization clinical signs only. Exposure–response has not, there- fore, been well characterized. There were effects on Available data indicate that acrylonitrile is a skin, biochemical parameters, clinical signs, and body weight, respiratory, and severe eye irritant. It induces skin although no histopathological effects on principal sensitization in guinea-pigs, but available data are organs, following exposure of rats to 130 ppm inadequate to assess its sensitization potency. (280 mg/m3) acrylonitrile (Gut et al., 1984, 1985).

8.2.1 Skin irritancy In short-term studies by the oral route, effects on the liver, adrenal, and gastric mucosa have been Identified data on irritancy to the skin are restricted observed, with effects on the gastric mucosa occurring to three studies in which acrylonitrile was applied to the at lowest doses in all studies in which they were shaved skin of rabbits (McOmie, 1949; Zeller et al., 1969; examined. Effects on the adrenal cortex observed in Vernon et al., 1990). In early periods following short-term repeated-dose toxicity studies from one administration (e.g., 15 min), slight local vasodilation and laboratory have not been noted in longer-term oedema were observed; at longer periods (20 h), effects investigations in animals exposed to higher were more severe, with necrosis reported. concentrations. In investigations by Szabo et al. (1984), effects on the non-protein sulfhydryl content in gastric mucosa and hyperplasia in the adrenal cortex have been 8.2.2 Eye irritancy reported at levels as low as 2 mg/kg body weight per day administered by drinking-water and gavage, Identified investigations of eye irritancy are respectively, for 60 days. Effects on hepatic glutathione restricted to principally early unpublished studies were also observed by these authors at similar doses (McOmie, 1949; BASF, 1963; Zeller et al., 1969; DuPont, administered by gavage but not in drinking-water (2.8 1975). Results of these investigations were consistent mg/kg body weight per day for 21 days), although Silver with those reported in the most recent study conducted et al. (1982) noted only slight biochemical effects but no by DuPont (1975), in which 0.1 ml of undiluted acrylo- histopathological effects in the liver at doses up to 70 nitrile was placed in the right conjunctival sac of each of mg/kg body weight per day (drinking-water, 21 days). two albino rabbits. After 20 s, the treated eye of one

13 Concise International Chemical Assessment Document 39

Significant increases in proliferation in the forestomach treatment were present in the nasal turbinates and the but no changes in the liver or glandular stomach have central nervous system of both males and females. In the been observed at 11.7 mg/kg body weight (Ghanayem et brain, the changes were characterized by focal gliosis al., 1995, 1997). and perivascular cuffing at the highest concentration. The inflammatory changes in the nasal turbinates were Gastric lesions in the rat have been accompanied considered to be due to acrylonitrile irritation. These by a decrease of gastric reduced glutathione concentra- effects were not observed at 20 ppm (44 mg/m3), and this tion. It has been suggested that depletion and/or dose is considered as a no-observed-effect level (NOEL) inactivation of critical endogenous sulfhydryl groups for inflammatory changes in the nasal turbinates. There cause configurational changes of cholinergic receptors was an early onset of chronic renal disease in the group and increase agonist binding affinity, which may lead to exposed to 20 ppm (44 mg/m3) based upon histopatho- gastric mucosal erosion (Ghanayem et al., 1985; logical examination. The renal effect was not apparent at Ghanayem & Ahmed, 1986). the high dose because of early mortality. The chronic renal disease, which is commonly observed in older rats Effects of pretreatment with inducers of the mixed- of this strain, was considered a secondary effect caused function oxidase system or antioxidants on toxicity in by increased water intake, although there was no pair- short-term studies have been consistent with metabolism fed control study, and clinical analyses were inadequate to the epoxide 2-cyanoethylene oxide being the puta- to confirm the cause. In males, mortality at 80 ppm tively toxic metabolic pathway (Szabo et al., 1983). (176 mg/m3) was consistently and significantly increased from days 211–240 to the end of the experiment. Similar 8.4 Medium-term exposure findings were noted for females beginning at days 361– 390. Results of identified subchronic toxicity studies are limited to an early 13-week inhalation study in rats In both sexes, there was an increase in the com- and dogs that has not been validated (IBT, 1976) and a bined incidence of malignant and benign tumours of the preliminary brief report of the results of a 13-week brain and spinal cord (Table 2) and benign and malignant National Toxicology Program (NTP) gavage study in tumours of the Zymbal gland at the high dose. In males, mice.1 Lack of validation and inadequate detail limit the the combined incidence of benign and malignant utility of these studies for hazard evaluation or tumours of the small intestine and the tongue was characterization of dose–response. increased at the high dose. The incidence of adenocarci- noma of the mammary gland was increased at the high 8.5 Long-term exposure and dose in females (Quast et al., 1980b). carcinogenicity Although Maltoni et al. (1977) reported an Data on effects of long-term exposure to acrylo- increased incidence of tumours in the mammary gland, nitrile are currently restricted to those conducted in rats, forestomach, and skin in Sprague-Dawley rats exposed 3 although an NTP bioassay in mice is under way (NTP, to up to 40 ppm (88 mg/m ) for 52 weeks, low concen- 1998). In the descriptions of the following studies, trations of acrylonitrile, short exposure time, and small tumour types are reported as described by the authors. group size (n = 30) limit the sensitivity of the study. In a However, it should be noted that the histopathology of follow-up study (Maltoni et al., 1987, 1988), 54 female the tumours may be unclear (see footnote on page 18 in Sprague-Dawley rat breeders and offspring were admin- 3 section 8.5.2). istered 60 ppm (132 mg/m ) by inhalation for 4–7 h/day, 5 days/week. The breeders and some of the offspring were 8.5.1 Inhalation exposed for 104 weeks, and the remaining offspring were exposed for 15 weeks only. The non-neoplastic Quast et al. (1980b) conducted a bioassay in which treatment-related changes included slight, but Sprague-Dawley (Spartan substrain) rats (100 per sex per significant, increases in the incidence of encephalic glial group) were exposed by inhalation to average cell hyperplasia and dysplasia in offspring exposed for concentrations of 0, 20, or 80 ppm (0, 44, or 176 mg/m3) 104 weeks. The incidence of various tumours was acrylonitrile 6 h/day, 5 days/week, for 2 years. Non- neoplastic histopathological changes related to the

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 and Human Services, National Toxicology Program.

14 Acrylonitrile

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

Animal data Human equivalent Dose Incidence Parameter estimates values

b 3 d Males: Brain and/or control 0/98 TC05 = 52 mg/m TC05 = spinal cord, benign and 44 mg/m3 (20 ppm) 4/97 (4 astrocytoma) 95% LCL c = 29 mg/m3 8.9 mg/m3 malignant; excluding 176 mg/m3 (80 ppm) 22/98 (15 astrocytoma, 7 benign) Chi-square = 0.73 95% LCL = animals dying or sacri- Degrees of freedom = 5 mg/m3 ficed before 6 months 1 P-value = 1.00

e b 3 d Males: Brain and/or control 0/97 TC05 = 51 mg/m TC05 = spinal cord, benign and 44 mg/m3 (20 ppm) 4/93e 95% LCL = 33 mg/m3 8.7 mg/m3 malignant; excluding 176 mg/m3 (80 ppm) 15/83e Chi-square = 0.00 95% LCL = animals dying or sacri- Degrees of freedom = 5.6 mg/m3 ficed before 10 months 1 (TERA, 1997) P-value = 1.00

b 3 d Females: Brain and/or control 0/99 TC05 = 35 mg/m TC05 = spinal cord, benign and 44 mg/m3 (20 ppm) 8/100 (4 astrocytoma, 4 benign) 95% LCL = 26 mg/m3 6.0 mg/m3 malignant; excluding 176 mg/m3 (80 ppm) 21/99 (17 astrocytoma, 4 benign) Chi-square = 0.65 95% LCL = animals dying or sacri- Degrees of freedom = 4.5 mg/m3 ficed before 6 months 2 P-value = 0.72

e b 3 d Females: Brain and/or control 0/99 TC05 = 35 mg/m TC05 = spinal cord, benign and 44 mg/m3 (20 ppm) 8/99e 95% LCL = 26 mg/m3 5.9 mg/m3 malignant; excluding 176 mg/m3 (80 ppm) 21/99e Chi-square = 0.69 95% LCL = animals dying or sacri- Degrees of freedom = 4.4 mg/m3 ficed before 6 months 2 (TERA, 1997) P-value = 0.71 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 3 3 To scale from rats to humans, the TC05s were multiplied by [(0.11 m /day)/(0.35 kg body weight)] × [(70 kg body weight)/(23 m /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 a human, 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 and cytomas) were observed as early as 7–12 months in females. These included mammary gland tumours in females in the high-dose group; in other dose groups, females, Zymbal gland tumours in males, extrahepatic tumours appeared initially in the 13- to 18-month period. angiosarcoma in both males and females, hepatomas in In both males and females, the combined incidence of males, and encephalic gliomas in both males and females. benign and malignant tumours of the brain and spinal The most pronounced acrylonitrile-related tumour was cord was significantly increased in a dose-related encephalic glioma (in control and exposure groups, manner at all levels of exposure (Table 3). respectively: 2/158 and 11/67 in males; 2/149 and 10/54 in females) in the offspring treated with acrylonitrile for 104 In a study conducted by Bio/Dynamics Inc. weeks. (1980a), Sprague-Dawley rats were administered acrylonitrile at dose levels of 0, 1, or 100 mg/litre in 8.5.2 Drinking-water drinking-water for 19 and 22 months. Non-neoplastic effects included increased weight of kidney and testes. Quast et al. (1980a) administered acrylonitrile in The concentration of 1 mg/litre can be considered as a drinking-water to Sprague-Dawley rats for 2 years at NOEL and 100 mg/litre as a lowest-observed-adverse- dose levels of 0, 35, 100, or 300 mg/litre. There was effect level (LOAEL) for non-neoplastic effects. In high- treatment-related hyperplasia and hyperkeratosis of the dose males, increased incidences of squamous cell squamous epithelium of the forestomach in females at all carcinoma of the stomach and carcinoma of the Zymbal dose levels and in males at 100 and 300 mg/litre. In the gland were observed. In high-dose females, astrocytoma brain of females, there was a significantly increased of the brain and carcinoma of the Zymbal gland were incidence of focal gliosis and perivascular cuffing in the increased. At the high dose, there was an increased 35 and 100 mg/litre groups. Tumours (including astro- cumulative incidence of astrocytoma of the brain, carci-

15 noma of the Zymbal gland, and papilloma/carcinoma of was 0/20, 2/19, and 4/17 (P < 0.05), respectively. The the stomach in both sexes. In females, the incidence of tumour incidence was low, but the exposure and obser- astrocytoma of the spinal cord was significantly vation period (approximately 45 weeks) was also increased at the high dose. The spinal cord tissue of the relatively short. Not all tissues were examined histo- males was not examined. Dose spacing was poor in this pathologically. study. More recently, Bigner et al. (1986) observed neuro- These results are consistent with those of a oncogenic effects in Fischer 344 rats administered 0, 100, second bioassay by Bio/Dynamics Inc. (1980b), in which or 500 mg acrylonitrile/litre in drinking-water (0, 14, and exposure–response was better characterized. Fischer 344 70 mg/kg body weight per day; Health Canada, 1994). rats (200 per sex, control group; 100 per sex per dose Each exposure group consisted of 50 male and 50 female group) were administered acrylonitrile in drinking-water rats. A fourth group of 300 rats (147 males, 153 females) for approximately 2 years. The dose levels were 0, 1, 3, was exposed to 500 mg acrylonitrile/litre. Although the 10, 30, and 100 mg acrylonitrile/litre (0, 0.1, 0.3, 0.8, 2.5, protocol of the study indicated that rats were exposed and 8.4 mg/kg body weight per day for males and 0, 0.1, for their lifetime, results were presented for an 18-month 0.4, 1.3, 3.7, and 10.9 mg/kg body weight per day for observation period. There was a dose-related significant females, as reported by US EPA, 1985). Serial sacrifices reduction in body weight in both males and females at were conducted at 6, 12, and 18 months (20 per sex per 500 mg/litre. In rats exposed for 12–18 months, control group and 10 per sex per treated group). To neurological signs such as decreased activity, paralysis, ensure at least 10 rats per sex per group for head tilt, circling, and seizures were observed in the 100 histopathological evaluation, all females were sacrificed and 500 mg/litre groups. In control, low-exposure, and at 23 months, owing to low survival. The males were two high-exposure groups, the incidence of neurological continued on test until the 26th month. signs was 0/100, 4/100, 16/100, and 29/300, respectively. Based on histopathological examination of 215 animals in The consistently elevated mortality in the highest the 500 mg/litre group, there were 49 primary brain dose groups was primarily a consequence of tumours. tumours, which were difficult to classify.1 Other tumours Other changes observed primarily in the highest expo- frequently observed included Zymbal gland tumours, sure group included consistently lower body weights in forestomach papillomas, and subcutaneous papillomas. females and males and consistent reduction in haemo- No further details, however, were presented. The authors globin, haematocrit, and erythrocyte counts in females reported that the increase in incidence of the primary throughout the study. A decrease in water intake was brain tumour in the highest exposure group was also observed, while food consumption was comparable significant (P-values were not reported, data were poorly for all groups (Bio/Dynamics Inc., 1980b). presented). Other end-points were not examined. The results are inadequate, therefore, for establishing effect An increase in the relative organ weights of the levels for non-neoplastic effects or for characterizing liver and kidney was noted at the highest dose levels; exposure–response for tumours. however, the mean absolute weights for these organs were either comparable to those in the controls or only Gallagher et al. (1988) investigated the carcino- slightly increased. At terminal sacrifice, the absolute genicity of acrylonitrile administered via drinking-water liver and heart weights were elevated in females exposed at 0, 20, 100, or 500 mg/litre (approximately 0, 2.8, 14, and to 30 mg/litre, but body weight was comparable to that in 70 mg/kg body weight per day; Health Canada, 1994) to controls. The LOAEL is considered 100 mg/litre, the male Sprague-Dawley rats (20 per group) for 2 years. lowest-observed-effect level (LOEL), 30 mg/litre, and the There was no survival in the 500 mg/litre exposure group NOEL for non-carcinogenic effects, 10 mg/litre. In both at 2 years. Ingestion of acrylonitrile at males and females, the incidences of astrocytoma of the brain (Table 4) and of carcinoma of the Zymbal gland were significantly increased at the two highest dose levels (Bio/Dynamics Inc., 1980b).

In a multigeneration reproductive study, 0, 100, or 500 mg acrylonitrile/litre (0, 14, or 70 mg/kg body weight per day; Health Canada, 1994) was administered in 1 “The brain tumours were remarkably similar from animal to animal, regardless of their size or anatomical location within drinking-water to breeders (F0) and the offspring of Charles River Sprague-Dawley rats (Litton Bionetics Inc., the brain. They were also similar to, and probably indistin- guishable from, a subset of spontaneously occurring rat-brain 1980). Rats of the F1b generation in the high-exposure group had a significantly increased incidence of tumours that have been generally classified as astrocytomas or astrocytomas and Zymbal gland tumours. For control, anaplastic astrocytomas by light-microscopic evaluation of low-exposure, and high-exposure groups, the incidence H&E-stained slides. Despite this superficial similarity to of astrocytomas was 0/20, 1/19, and 4/17 (P < 0.05), astrocytomas, we have found no hard evidence on which to respectively, and the incidence of Zymbal gland tumours identify any of the neoplastic cells as astrocytic in lineage or relatedness” (Bigner et al., 1986).

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

Animal data

Dose Incidence Parameter estimates Human equivalent values

Males: Brain and/or control 1/79 (1 astrocytoma) TD05 = 0.84 mg/kg body weight per day TD05 = 0.84 mg/kg body weight per day spinal cord, benign and 3.4 mg/kg body weight per day (35 ppm) 12/47 (8 astrocytoma, 4 benign) 95% LCL b = 0.68 mg/kg body weight per 95% LCL = 0.68 mg/kg body weight per malignant; excluding 8.5 mg/kg body weight per day (100 ppm) 23/47 (19 astrocytoma, 4 benign) day day animals dying or sacri- 21.2 mg/kg body weight per day (300 ppm) 31/48 (23 astrocytoma, 8 benign) Chi-square = 3.68 ficed before 6 months Degrees of freedom = 2 P-value = 0.16

c Females: Brain and/or control 1/80 (1 astrocytoma) Parameter estimates excluding high-dose TD05 = 0.56 mg/kg body weight per day spinal cord, benign and 4.4 mg/kg body weight per day (35 ppm) 22/48 (17 astrocytoma, 5 benign) group: 95% LCL = 0.44 mg/kg body weight per c malignant; excluding 10.8 mg/kg body weight per day (100 ppm) 26/48 (22 astrocytoma, 4 benign) TD05 = 0.56 mg/kg body weight per day day animals dying or sacri- 95% LCL = 0.44 mg/kg body weight per day ficed before 6 months [25.0 mg/kg body weight per day (300 ppm)] [31/47 (24 astrocytoma, 7 benign)] Chi-square = 4.77 Degrees of freedom = 1 P-value = 0.08 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

b Males: Nervous system, control 5/182 (3 astrocytoma, 2 benign) TD05 = 1.8 mg/kg body weight per day TD05 = 2.3 mg/kg body weight per day combined incidence, 0.08 mg/kg body weight per day (1 ppm) 2/90 (2 astrocytoma) 95% LCL c = 1.2 mg/kg body weight per 95% LCL = 1.6 mg/kg body weight per astrocytoma and focal gliosis, 0.25 mg/kg body weight per day (3 ppm) 1/89 (1 astrocytoma) day day excluding animals dying or 0.84 mg/kg body weight per day (10 ppm) 2/90 (2 astrocytoma) Chi-square = 3.0 sacrificed before 6 months 2.49 mg/kg body weight per day (30 ppm) 10/89 (10 astrocytoma) Degrees of freedom = 3 8.37 mg/kg body weight per day (100 ppm) 22/90 (21 astrocytoma, 1 benign) P-value = 0.39

Females: Brain and/or spinal control 1/178 (1 astrocytoma) TD05 = 2.0 mg/kg body weight per day TD05 = 2.3 mg/kg body weight per day cord, benign and malignant; 0.10 mg/kg body weight per day (1 ppm) 1/90 (1 astrocytoma) 95% LCL = 1.2 mg/kg body weight per 95% LCL = 1.4 mg/kg body weight per excluding animals dying or 0.40 mg/kg body weight per day (3 ppm) 2/90 (2 astrocytoma) day day sacrificed before 6 months 1.30 mg/kg body weight per day (10 ppm) 5/88 (4 astrocytoma, 1 benign) Chi-square = 1.8 3.70 mg/kg body weight per day (30 ppm) 6/90 (6 astrocytoma) Degrees of freedom = 3 10.90 mg/kg body weight per day (100 26/90 (24 astrocytoma, 2 benign) P-value = 0.62 ppm) a From Bio/Dynamics Inc. (1980b). b 2 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) , 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 the standard lifetime. c 95% LCL = lower 95% confidence limit. concentrations up to and including 100 mg/litre did not (Anderson & Cross, 1985). It was also mutagenic at the increase mortality. There was a significant increase in TK locus in human lymphoblasts with metabolic Zymbal gland tumours at 500 mg/litre (0/18, 0/20, 1/19, activation (Crespi et al., 1985; Recio & Skopek, 1988). and 9/18 [P < 0.005] in control, low-, mid-, and high-dose groups, respectively). No increase in tumours of other Acrylonitrile induced structural chromosomal organs including brain was observed, although four rats aberrations either with or without metabolic activation in developed papillomatous proliferation of the epithelium Chinese hamster ovary cells (Danford, 1985; Gulati et al., of the forestomach in the high-exposure group. 1985; Natarajan et al., 1985) and without metabolic activation in Chinese hamster lung cells (Ishidate & 8.5.3 Gavage Sofuni, 1985). Results for sister chromatid exchanges in Chinese hamster ovary cells and human lymphocytes Groups of 100 male and female Sprague-Dawley both with and without metabolic activation are mixed rats were exposed in a Bio/Dynamics Inc. (1980c) study (Brat & Williams, 1982; Perocco et al., 1982; Gulati et al., to acrylonitrile in water by intubation at 0, 0.1, or 1985; Natarajan et al., 1985; Obe et al., 1985; Chang et al., 10 mg/kg body weight per day for 20 months. The non- 1990). neoplastic effects in the high-dose group included higher mortality (both sexes), decreased body weight Results of in vitro assays for DNA single strand (males), and increased relative liver weight (males). The breaks (Bradley, 1985; Lakhanisky & Hendrickx, 1985; dose of 10 mg/kg body weight per day is a LOAEL, Bjorge et al., 1996) and DNA repair (unscheduled DNA based upon decreased body weight and increased liver synthesis) (Perocco et al., 1982; Glauert et al., 1985; to body weight ratio in males, with 0.1 mg/kg body Martin & Campbell, 1985; Probst & Hill, 1985; Williams et weight being the NOEL. In both sexes at the high dose, al., 1985; Butterworth et al., 1992) were mixed but more there was an increased incidence of astrocytoma of the commonly negative in a range of cell types from rats and brain, squamous cell carcinoma of the Zymbal gland, and humans, with and without activation. Cell transformation papilloma/carcinoma of the stomach. in mouse and hamster embryo cells has also been investigated, with mixed results (Lawrence & McGregor, Maltoni et al. (1977) exposed 40 Sprague-Dawley 1985; Matthews et al., 1985; Sanner & Rivedal, 1985; rats of each sex by gavage to acrylonitrile in olive oil at 0 Abernethy & Boreiko, 1987; Yuan & Wong, 1991). or 5 mg/kg body weight per day, 3 days/week for 52 weeks. In females, the incidence of mammary gland Binding of 2-cyanoethylene oxide to nucleic acids carcinomas was 7/75 and 4/40 in control and exposed has also been reported in in vitro studies at high groups, respectively; the incidence of forestomach concentrations (Hogy & Guengerich, 1986; Solomon & epithelial tumours was 0/75 and 4/40 in control and Segal, 1989; Solomon et al., 1993; Yates et al., 1993, exposed groups, respectively. However, a high spon- 19941). The formation of acrylonitrile–DNA adducts is taneous incidence of mammary gland tumours in this increased substantially in the presence of metabolic strain of rats, the single dose level, and the short activation. Under non-activating conditions involving duration of exposure limit contribution of the study to incubation of calf thymus DNA with either acrylonitrile characterization of exposure–response. or 2-cyanoethylene oxide in vitro, 2-cyanoethylene oxide alkylates DNA much more readily than acrylonitrile Genotoxicity and related end-points 8.6 (Guengerich et al., 1981; Solomon et al., 1984, 1993). Incubation of DNA with 2-cyanoethylene oxide yields 7- 8.6.1 In vitro studies (2-oxoethyl)-guanine (Guengerich et al., 1981; Hogy & Guengerich, 1986; Solomon & Segal, 1989; Solomon et In the Salmonella assay, acrylonitrile has induced al., 1993; Yates et al., 1993, 1994) as well as other reverse mutations in strains TA1535 (Lijinsky & adducts. Compared with studies with rat liver Andrews, 1980), TA1535, and TA100 (Zeiger & Haworth, microsomes, little or no DNA alkylation by acrylonitrile 1985), but only when hamster or rat S9 was present. was observed with rat brain microsomes (Guengerich et Weak positive results were also reported in several al., 1981). DNA alkylation in human liver microsomes was Escherichia coli strains in the absence of metabolic much less than that observed with rat microsomes activation (Venitt et al., 1977). (Guengerich et al., 1981); although there was no glutathione S-transferase activity in cytosol preparations In mammalian cells, acrylonitrile induced hprt from human liver exposed to acrylonitrile, there was mutations in human lymphoblasts without metabolic some activity for 2-cyanoethylene oxide (Guengerich et activation (Crespi et al., 1985), but not in Chinese al., 1981). hamster V79 cells (Lee & Webber, 1985). In several studies, acrylonitrile was positive at the TK locus in mouse lymphoma L5178 TK+/! cells, either with or without rat S9 (Amacher & Turner, 1985; Lee & Webber, 1985; Myhr et al., 1985; Oberly et al., 1985), and in mouse lymphoma P388F cells with metabolic activation 1 Yates et al. (1994) also reported single and double strand breaks in plasmid DNA incubated with 2-cyanoethylene oxide.

17 Concise International Chemical Assessment Document 39

8.6.2 In vivo studies administered acrylonitrile by stomach intubation (Lambotte-Vandepaer et al., 1985). Thiocyanate, hydroxy- Limitations of the few in vivo studies conducted in ethylmercapturic acid, and cyanoethylmercapturic acid which the genotoxicity of acrylonitrile has been investi- were not believed to be responsible for urinary gated preclude definitive conclusions. Data from these mutagenicity. studies are also inadequate for characterization of dose– response for comparison between studies or with the In in vivo studies in F344 rats administered 50 mg cancer bioassays. acrylonitrile/kg body weight intraperitoneally, 7-(2- oxoethyl)-guanine adducts were detected in liver (Hogy Exposure to acrylonitrile in drinking-water resulted & Guengerich, 1986). Incorporation of acrylonitrile into in increased frequency of mutants at the hprt locus in hepatic RNA was observed following intraperitoneal splenic T-cells (Walker & Walker, 1997). Five female F344 administration to rats (Peter et al., 1983). However, no rats were exposed to 0, 33, 100, or 500 mg/litre (0, 8, 21, or DNA adducts were detected in the brain, which is the 76 mg/kg body weight per day; Health Canada, 1994) in primary target for acrylonitrile-induced tumorigenesis, in drinking-water for up to 4 weeks and serially sacrificed this or a subsequent study in which F344 rats received throughout exposure and up to 8 weeks post-exposure. 50 or 100 mg acrylonitrile/kg body weight by At 4 weeks post-exposure, the average observed mutant subcutaneous injection (Prokopczyk et al., 1988). In frequency in splenic T-cells was increased in a dose- contrast, in three studies from one laboratory, exposure related manner (significant at the two highest doses). of SD rats to 46.5 mg [14C]acrylonitrile/kg body weight (50 µCi/kg body weight) resulted in apparent binding of Results of a range of assays for structural chromo- radioactivity to DNA from liver, stomach, brain somal aberrations, micronuclei in bone marrow, and (Farooqui & Ahmed, 1983), lung (Ahmed et al., 1992a), micronuclei in peripheral blood cells have been negative and testicles (Ahmed et al., 1992b). In each tissue, there or inconclusive, although there was no indication in the was a rapid decrease in radioactivity of DNA samples published accounts of three of the four studies that the collected up to 72 h following treatment. compound reached the target site. These include studies in Swiss (Rabello-Gay & Ahmed, 1980), NMRI (Leonard It is not clear why acrylonitrile–DNA binding was et al., 1981), and C57B1/6 (Sharief et al., 1986) mice and a detected in the brain in these studies and not in those by collaborative study following exposure by multiple Hogy & Guengerich (1986) or Prokopczyk et al. (1988). routes in mice and rats (Morita et al., 1997). The DNA isolation protocols and method for correcting for contaminating protein in the DNA sample used by Results of dominant lethal assays were inconclu- Hogy & Guengerich (1986) may have allowed a more sive in mice (Leonard et al., 1981) and negative in rats stringent determination of DNA-bound material. Alter- (Working et al., 1987). natively, the methods used to achieve greater DNA purity might have caused the loss of adducts or In assays for unscheduled DNA synthesis in rats, inhibited the recovery of adducted DNA; more likely, results were positive only for the liver (Hogy & Guen- however, 7-oxoethylguanine and cyanoethyl adducts are gerich, 1986), equivocal in lung, testes, and gastric of little consequence in the induction of tissues (Ahmed et al., 1992a,b; Abdel-Rahman et al., acrylonitrile-induced brain tumours. Indeed, 1994), and, notably, negative in the brain (Hogy & investigation of the role of cyanohydroxyethylguanine Guengerich, 1986). In these studies, however, unsched- and other adducts in the induction of these tumours uled DNA synthesis was measured by liquid scintillation seems warranted. counting to determine [3H]thymidine uptake in the cell population, which does not discriminate between cells 8.7 Reproductive toxicity undergoing repair and those that are replicating. Results for unscheduled DNA synthesis in rat liver and sperma- Consistent effects on the reproductive organs of 3 tocytes were negative when [ H]thymidine uptake in male or female animals have not been observed in individual cells was determined by autoradiography, repeated-dose toxicity and carcinogenicity studies which eliminates replicating cells from the analysis conducted to date. In a specialized investigation in CD-1 (Butterworth et al., 1992). mice exposed by gavage, however, degenerative changes in the seminiferous tubules and associated Urine from acrylonitrile-exposed rats and mice was decreases in sperm counts were observed at 10 mg/kg also mutagenic in Salmonella typhimurium following body weight per day (NOEL = 1 mg/kg body weight per intraperitoneal administration of acrylonitrile to rats and day) (Tandon et al., 1988). Although epididymal sperm mice (Lambotte-Vandepaer et al., 1980, 1981). In both motility was reduced in a 13-week study with B6C3F1 species, mutagenic activity occurred without activation. mice, there was no dose–response and no effect upon Mutagenic activity was also observed in urine of rats sperm density at doses up to 12 mg/kg body weight per

18 Acrylonitrile

day by gavage, although histopathological results were 8.9 Mode of action not reported (Southern Research Institute, 1996). In a three-generation study in rats exposed via drinking- 8.9.1 Cancer water (14 or 70 mg/kg body weight per day), adverse effects on pup survival and viability and lactation Results of the few identified investigations in indices were attributed to maternal toxicity (Litton which the relative potency of acrylonitrile was compared Bionetics Inc., 1980). with that of cyanoethylene oxide are consistent with the oxidative pathway of metabolism being critical in geno- In two studies by inhalation, developmental effects toxicity. In an assay with two strains of S. typhimurium, (fetotoxic and teratogenic) were not observed at concen- cyanoethylene oxide was mutagenic without activation, trations that were not toxic to the mothers (Murray et al., whereas acrylonitrile required activation (Cerna et al., 1978; Saillenfait et al., 1993). In the investigation in which 1981). In one study, cyanoethylene oxide was approxi- concentration–response was best characterized (four mately 15-fold more mutagenic than acrylonitrile at the exposure concentrations and controls with 2-fold TK locus in cultured human lymphoblastoid cells (Recio spacing: 0, 12, 25, 50, and 100 ppm [0, 26.4, 55, 110, and & Skopek, 1988). In vitro, the formation of DNA adducts 3 220 mg/m ]), the LOEL for maternal toxicity and for at high unphysiological concentrations is increased 3 fetotoxicity was 25 ppm (55 mg/m ); the NOEL was substantially in the presence of metabolic activation. 3 12 ppm (26.4 mg/m ) (Saillenfait et al., 1993). Under non-activating conditions, cyanoethylene oxide alkylates DNA much more readily than acrylonitrile Similarly, in two studies by the oral route, develop- (Guengerich et al., 1981; Solomon et al., 1984, 1993). mental effects have not been observed at doses that were not also toxic to the mothers (lowest reported effect Data on the binding of acrylonitrile to DNA are level in the mothers was 14 mg/kg body weight per day) presented in section 8.6. However, available data are (Murray et al., 1978; Litton Bionetics Inc., 1980). inadequate to implicate a particular adduct in the Reversible biochemical effects on the brain but not func- induction of acrylonitrile-induced brain tumours. tional neurological effects were observed in offspring of rats exposed to 5 mg/kg body weight per day (a dose There are some suggestions from in vitro studies that did not impact on body weight of the dams); dose– reported as abstracts that free radicals (@OH, O2@) and response was not investigated in this study (Mehrotra et hydrogen peroxide may be directly implicated in the al., 1988). oxidation of acrylonitrile and DNA damage. Formation of free radicals may be partially related to the release of 8.8 Neurological effects and effects on the cyanide or other mechanisms responsible for cellular and immune system DNA damage (Ahmed et al., 1996; Ahmed & Nouraldeen, 1996; El-zahaby et al., 1996; Mohamadin et al., 1996). In recently published studies in rats exposed by inhalation to 25 ppm (55 mg/m3) acrylonitrile and above In more recent investigations, the results of which for 24 weeks, there were partially reversible time- and have been presented incompletely at this time, Prow et concentration-dependent reductions in motor and al. (1997) reported that acrylonitrile inhibited gap sensory conduction (Gagnaire et al., 1998). junctional intercellular communication in a rat astrocyte cell line in a dose-dependent manner, possibly through In the few identified investigations of the immuno- an oxidative stress mechanism. Similarly, Zhang et al. logical effects of acrylonitrile, effects on the lung (1998) assayed acrylonitrile with Syrian hamster embryo following inhalation (Bhooma et al., 1992) and on the cells, with and without an antioxidant, and concluded gastrointestinal tract following ingestion (Hamada et al., that oxidative stress contributed to morphological 1998) have been observed at concentrations and doses transformation in the cells. Jiang et al. (1998) assayed at which histopathological effects have also been acrylonitrile with a rat astrocyte cell line and reported observed. The effects on the lungs included an increase oxidative damage (indicated by the presence of 8- in the level of procoagulant activity in alveolar hydroxy-2'-deoxyguanosine) at all concentrations tested. macrophages (Bhooma et al., 1992). The effects on the gastrointestinal tract consisted of an increase in the Jiang et al. (1997) exposed male Sprague-Dawley number of IgA-producing cells in the duodenum, rats to 0 or 100 mg acrylonitrile/litre in drinking-water for jejunum, and ileum, an increase in the number of cells in 2 weeks. End-points examined were levels of glutathione S-phase in the duodenum and ileum, and a decrease in and reactive oxygen species in brain and liver, presence the response of splenocytes to mitogens (Hamada et al., of 8-hydroxy-2'-deoxyguanosine (indicative of oxidative 1998). DNA damage) in several tissues, and determination of

activation of NF-KB (a transcription factor strongly associated with oxidative stress). Glutathione in brain

19 Concise International Chemical Assessment Document 39

was decreased. (Whysner et al. [1998a] reported no 8.9.2 Neurotoxicity effects upon concentrations of glutathione in brain of male Sprague-Dawley rats exposed to 3, 30, or 300 mg Neurotoxicity following inhalation by male acrylonitrile/litre in drinking-water for 3 weeks.) Reactive Sprague-Dawley rats of 0, 25, 50, or 100 ppm (0, 55, 110, oxygen species were increased 4-fold in brain. Levels of or 220 mg/m3) acrylonitrile for 6 h/day, 5 days/week, for 8-hydroxy-2'-deoxyguanosine were increased 3-fold in 24 weeks, followed by 8 weeks of recovery, was reported the brain. Activation of NF-KB was also observed in the by Gagnaire et al. (1998). Body weight at the high dose brain. was significantly reduced throughout exposure. Clinical observations at the mid and high doses included wet fur In recently conducted studies, levels of 8-oxo- and hypersalivation during exposure. The authors noted deoxyguanosine in the brain of rats exposed to acrylo- that signs were similar to those associated with acute nitrile in drinking-water in each of the three following acetylcholine-like toxicity. There were time- and protocols have been examined (Whysner et al., 1997, concentration-dependent reductions in motor 1998a): conduction velocity, sensory conduction velocity, and amplitude of sensory action potential in tail nerve, which # In male Sprague-Dawley rats exposed for 21 days were partially reversible after 8 weeks of recovery (LOEL 3 to 0, 3, 30, or 300 mg/litre, there was a significant = 25 ppm [55 mg/m ]). The protocol did not include increase in 8-oxodeoxyguanosine in brain nuclear histological examination. DNA at the two highest doses. In the liver, nuclear DNA 8-oxodeoxyguanosine concentrations were significantly increased at the two highest doses (Whysner et al., 1998a). In a bioassay with 9. EFFECTS ON HUMANS comparable dose levels, the incidence of brain and/or spinal cord tumours was significantly In case reports of acute intoxication, effects on the increased in male Sprague-Dawley rats exposed to central nervous system characteristic of cyanide poison- 35 mg acrylonitrile/litre (3.4 mg/kg body weight per ing and effects on the liver, manifested as increased day) and higher for 2 years (Quast et al., 1980a). enzyme levels in the blood, have been observed. There have also been reports that acrylonitrile is a skin irritant # In male F344 rats exposed for 21 days to 0, 1, 3, 10, and skin sensitizer, the latter based on patch testing of 30, or 100 mg/litre, there were no significant workers (Balda, 1975; Bakker et al., 1991; EC, 2000; Chu & differences between groups for 8-oxodeoxy- Sun, 2001). guanosine in the brain (Whysner et al., 1998a). In the few studies in which non-neoplastic effects # In male Sprague-Dawley rats exposed for up to of acrylonitrile have been systematically investigated, 94 days to 0 or 100 mg/litre, concentrations of 8- only acute dermal irritation has been reported consis- oxodeoxyguanosine in the brain were significantly tently. In a cross-sectional investigation of workers increased after 3, 10, and 94 days of exposure exposed in acrylic fibre factories to approximately 1 ppm 3 (Whysner et al., 1998a). In the 2-year drinking- (2.2 mg/m ), there was no consistent evidence of adverse water bioassay with male Sprague-Dawley rats effects based on examination of a wide range of clinical (Quast et al., 1980a), the incidence of brain and/or parameters, including liver function tests (Muto et al., spinal cord tumours was significantly increased at 1992). However, there was an increase in subjective 100 mg/litre (8.5 mg/kg body weight per day). symptoms of acute dermal irritation, consistent with observations in another cohort of acrylic fibre manufac- The end-point for which changes were turing workers (Kaneko & Omae, 1992). consistently observed in male Sprague-Dawley rats was the induction of oxidative DNA damage, including the In a cross-sectional investigation of a smaller accumulation of 8-oxodeoxyguanosine in the brain. The group of workers producing acrylic textile fibres for authors drew correlations between these results and the which quantitative data on exposure were not reported, incidence of brain/spinal cord tumours that had been there was no evidence of induction of hepatic cyto- reported in carcinogenicity bioassays in which male chrome P-450 or genotoxicity of urine (Borba et al., 1996). Sprague-Dawley rats were exposed to acrylonitrile via drinking-water. Although there was some evidence in primarily early limited studies of excesses of lung cancer (Thiess Increased levels of 8-oxodeoxyguanosine occur et al., 1980), “all tumours” (Zhou & Wang, 1991), and only in the anterior portion of the brain, which contains colorectal cancer (Mastrangelo et al., 1993), such rapidly dividing glial cells (Whysner et al., 1998b). excesses have not been confirmed in well conducted and well reported recent investigations in four relatively large

20 Acrylonitrile

cohorts of workers (Benn & Osborne, 1998; Blair et al., small (non-significant) excess of lung cancer in the 1998; Swaen et al., 1998; Wood et al., 1998). Indeed, there highest quintile of cumulative exposure (relative risk = is no consistent, convincing evidence of an association 1.5; 95% CI = 0.9–2.4), but no exposure–response trend. between exposure to acrylonitrile and cancer of a The exposure categories were as follows: particular site that fulfils, even in part, traditional criteria for causality in epidemiological studies. 0.01–0.13 ppm-years: 121 430 person-years 0.14–0.57 ppm-years: 69 122 person-years Benn & Osborne (1998) reported results of a 0.58–1.50 ppm-years: 49 800 person-years historical cohort study carried out in 2763 workers. Vital 1.51–8.00 ppm-years: 63 483 person-years status was traced from 1978 through 1991, and follow-up >8.00 ppm-years: 44 807 person-years was virtually complete. Only for lung cancer was there any indication of excess risk, and that was in the more It should be noted that the power to detect moder- highly exposed jobs and among the very young; how- ate excesses was small for some sites (stomach, brain, ever, based upon detailed analyses, there was no consis- breast, prostate, lymphatic/haematopoietic) because of tent support for the hypothesis of a causal relationship small numbers of expected deaths. between exposure to acrylonitrile and lung cancer. Limited information on exposure levels, questionable Wood et al. (1998) reported a historical cohort quality of source records of work histories, and use of mortality and cancer incidence study in 2559 workers national rather than local rates for computing standard- who had been occupationally exposed to acrylonitrile. ized mortality ratios (SMRs) compromise the inferences There was a total of 75 009 person-years of mortality that can be drawn. observation among the study subjects. There were no significantly elevated SMRs for specific cancer sites. Swaen et al. (1998) conducted a historical cohort This study was carried out in a company with good- study in 2842 workers occupationally exposed to acrylo- quality information on work practices and industrial nitrile. Extensive industrial hygiene assessments were hygiene, complete work records, and good follow-up for conducted to quantify past exposure to acrylonitrile. The mortality and cancer incidence. The latter is a unique follow-up between 1979 and 1995 was 99.6% complete; in advantage of this data set. The data appear to have been 99.3% of cases, the cause of death could be ascertained. well collected and analysed. Limitations include the lack Selected cause-specific SMRs in the exposed cohort of data on workers’ race and smoking habits. Based were as follows: lung, 109.8 (95% confidence interval [CI] upon a comparison with US rates, there was a 40% all- = 81–146, number of observed cases [Obs] = 47); colon, cause deficit and 34% cancer deficit seen in the 126.0 (95% CI = 58–239, Obs = 9); leukaemia, 266.7 (95% Waynesboro cohort, which suggests a lack of reporting CI = 54–390, Obs = 5); prostate, 83.3 (95% CI = 22–213, of cause of death. While this is a reasonably large study, Obs = 4); bladder, 97.9 (95% CI = 20–286, Obs = 3); brain, power to detect dose–response relationships is still 173.9 (95% CI = 64–378, Obs = 6). Some of these results limited. While considerable effort was made to gather are suggestive of excess risks, but the evidence of exposure data, there was no monitoring of acrylonitrile excess for any specific type of cancer is not strong. The before 1975, and data for early years were inferred. An data appear to have been well collected and analysed, additional strength of this study is the number of and follow-up was good. While this is a reasonably large person-years at the high level of exposure. study, the power to detect dose–response relationships is still limited. Smoking was not considered.

The largest and most statistically powerful of the 10. EFFECTS ON OTHER ORGANISMS IN recent cohort studies was that conducted by Blair et al. THE LABORATORY AND FIELD (1998), which included 25 460 workers from eight plants producing and using acrylonitrile. Estimates of exposure to acrylonitrile were based on information from produc- The toxicity of acrylonitrile has been examined in a tion procedures at the plants, interviews with manage- wide range of aquatic organisms, while the data set on ment and labour, monitoring data from the companies, the toxicity of acrylonitrile to terrestrial organisms is and monitoring conducted by the investigators specifi- more limited. cally for the study. Vital status was successfully deter- mined for 96% of the cohort. There was a total of 545 369 10.1 Aquatic organisms person-years of follow-up, of which one-third was in unexposed workers. This study had the most extensive The data set for acrylonitrile includes a wide range exposure assessment protocol and the most extensive of information on short- and long-term toxicity in data on smoking. The mortality follow-up was complete, 34 species of fish, amphibians, aquatic invertebrates, and and the observation period was lengthy. There was a algae, although none complies totally with the require-

21 Concise International Chemical Assessment Document 39

ments of OECD or similar test guideline protocols, and The effect of acrylonitrile on the growth (length volatility was often not adequately addressed (Environ- and wet weight) and mortality of the early life stage (<18- ment Canada, 1998). Below, a brief summary of the key h-old eggs) of the fathead minnow (Analytical studies carried out in general compliance with current BioChemistry Laboratories, 1980a) in a flow-through OECD testing protocols and/or where concentrations system with more than 5.5 turnovers per day has been were measured or could be adequately adjusted is examined. Mean measured concentrations were 98% of presented. Primary studies selected include those where nominal. The most sensitive end-point in the study was concentrations have been measured in static or static- the 840-h (35-day) lowest-observed-effect concentration renewal tests or flow-through tests with five turnovers (LOEC) for weight (20% reduction in wet weight) at 0.44 per day (Henderson et al., 1961; Bailey et al., 1985; V. mg/litre; the corresponding no-observed-effect Nabholz, personal communication, 1998). concentration (NOEC) was 0.34 mg/litre. For mortality,

the 840-h NOEC (LC15) was 0.44 mg/litre, and the LOEC T.D. Sabourin (personal communication, 1987) (LC46) was 0.86 mg/litre. determined the ratio of flow-through to static concentra- tions at the 96-h period to be 0.23. Therefore, studies Henderson et al. (1961) reported mortality of with 96-h end-points can be adjusted by multiplying the fathead minnow exposed to acrylonitrile in a flow- reported concentration by 0.23, although the evidence through system in which solutions were renewed every provided by these studies is considered secondary. 100 min. Test durations were 24, 48, 72, and 96 h and 5, Tests done under static conditions or those with 10, 15, 20, 25, and 30 days (720 h). Effects ranged from nominal concentrations only at a time period different the 24-h LC50 of 33.5 mg/litre through decreasing from 96 h are considered as supporting evidence only. concentrations to the most sensitive end-point in the

study, the 720-h LC50 at 2.6 mg/litre. Of the freshwater studies, there are five studies on five fish species and one study with an amphibian that Sloof (1979) reported the impact of acrylonitrile as are considered to provide primary data (Henderson et al., increased respiration in rainbow trout (Oncorhynchus 1961; Sloof, 1979; Analytical BioChemistry Laboratories, mykiss) within 24 h of exposure to 5 mg/litre in a flow- 1980a; Bailey et al., 1985; Zhang et al., 1996). In addition through system with continuous injection. to these, there is secondary evidence (adjusted concentrations) from studies with six fish, seven inver- Bailey et al. (1985) examined the effect of acrylo- tebrate, and one plant species. In these studies, a variety nitrile on the mortality of bluegill (Lepomis macrochirus) of end-points was examined, including survival, growth, in a flow-through system with measured concentrations. respiration, and mobility at exposure durations ranging The 96-h LC50 was 9.3 mg/litre. from 24 to 840 h (1–35 days). The remainder of the studies (i.e., where there was no replication of doses or In addition to primary studies with adequate flow- other limitations such as lack of aeration) were consid- through or measured concentrations, 96-h LC50s in six ered as supporting evidence only. species of fish in studies conducted with static/static- renewal nominal concentrations can be adjusted by the

The 96-h LC50s for freshwater fish range from 10 to factor 0.23 (T.D. Sabourin, personal communication, 20 mg/litre (nominal) (Henderson et al., 1961; Analytical 1987; V. Nabholz, personal communication, 1998). Based

BioChemistry Laboratories, 1980b; Zhang et al., 1996). on this method, the adjusted 96-h LC50s ranged from 1.18 Reported 48-h LC50s range between 14.3 and to 5.4 mg/litre. The lowest 96-h LC50 of 1.18 mg/litre was 33.5 mg/litre. At 840 h, the LC50 for fathead minnow that for grass carp (Ctenopharyngodon idella) (Zhang (Pimephales promelas) was 0.89 mg/litre (Analytical et al., 1996). BioChemistry Laboratories, 1980a). It is noted that for vertebrate species, the lowest Based on the primary evidence, the most sensitive reported effect concentrations were from primary studies. aquatic end-point was that for long-term exposure of the That is, overall, the most sensitive end-point for aquatic frog Bufo bufo gargarizans in its early life stage (Zhang vertebrates was the lower chronic limit around the EC50 et al., 1996). Three-day-old tadpoles were exposed for 28 of 0.4 mg/litre in the frog Bufo bufo gargarizans, days in a flow-through system with four turnovers per determined by Zhang et al. (1996) in a flow-through day. The most sensitive end-point was foreleg growth, system with measured concentrations. where the lower and upper chronic limits around the 28- day EC50 were 0.4 mg/litre and 0.8 mg/litre, respectively. Ninety-six-hour tests in 7 of 14 invertebrate and 1 The 96-h and 48-h EC50s for immobility were of 1 freshwater plant species can be adjusted to provide 11.59 mg/litre and 14.22 mg/litre, respectively. secondary evidence. Based on the secondary informa- tion, which must be interpreted with caution, it appears that, overall, invertebrates are more sensitive to acrylo-

22 Acrylonitrile

nitrile than vertebrates, although this was not discussed for 8 h, there was a 50% decrease in the number of further by the authors. Effects in invertebrates range progeny. from the 96-h LC80 of 0.16 mg/litre (adjusted concentra- tion 0.04 mg/litre) in the pond snail (Lymnaea stagnalis) Of the knockdown times reported for insects, the

(Erben & Beader, 1983) to the 96-h immobility EC50 at most sensitive organisms were rice weevil (Sitophilus 17.94 mg/litre (adjusted concentration 4.1 mg/litre) in the oryzae L.) adults, for which exposure to 1–1.5 mg/litre air common stream snail (Lymnaea plicatula) (Zhang et al., (1–1.5 × 106 µg/m3) for 4 h resulted in 100% mortality 1996). (Rajendran & Muthu, 1977).

In the one study on freshwater aquatic plants, the Of phosphorylase, trehalase, and acetylcholines- effect of a 96-h exposure to acrylonitrile on growth was terase enzymes involved in carbohydrate and energy examined in duckweed (Lemna minor) (Zhang et al., metabolism, phosphorylase was the most susceptible. 1996). Solutions were renewed every 24 h, with five test There was no detectable activity (100% decrease) of this concentrations, 10 fronds per concentration, and four enzyme at a concentration of 1.05 mg/litre air (1.05 × 106 3 replicates. The 96-h growth inhibition EC50 was µg/m ) in adult red flour beetle (Tribolium castaneum), 6.25 mg/litre (adjusted EC50 is 1.44 mg/litre). which survived exposure to the LC50 of 0.79 mg/litre (7.9 × 105 µg/m3) (Rajendran & Muthu, 1981b). 10.2 Terrestrial organisms 10.3 Microorganisms Data on the toxicity of acrylonitrile to terrestrial vertebrate wildlife or avian species were not identified; There is considerable evidence of the effectiveness those from mammalian toxicity studies are reviewed in of acclimated soil or sludge microorganisms in degrading section 8. Studies reviewed below are limited to those on acrylonitrile in industrial wastewater treatment systems insect species exposed to acrylonitrile in air. (e.g., Biox reactors). Wyatt & Knowles (1995a,b) demonstrated that complex mixtures of microorganisms In nine studies conducted on 13 insect species — under different dilution rates and a combination of batch including pulse beetle (Callosobruchus chinensis), rice and continuous culture can mineralize (degrade) weevil (Sitophilus oryzae), lesser grain borer (Rhyzo- acrylonitrile, acrylamide, acetic acid, cyanopyridine, and pertha dominica), granary weevil (Sitophilus succinonitrile, as well as more recalcitrant compounds granarius), saw-toothed grain beetle (Oryzaephilus (e.g., maleimide, fumaronitrile, and acrolein), to carbon surinamensis), red flour beetle (Tribolium castaneum), dioxide, ammonia, and biomass. confused flour beetle (Tribolium confusum), Mediterranean fruit fly (Ceratitis capitata), Oriental fruit Generally, concentrations of acrylonitrile up to fly (Bactrocera (formerly Dacus) dorsalis), and honey 5000 mg/litre are not toxic to bacteria, since they are bee (Apis mellifera) — short- and long-term exposure via readily degraded by Corynebacterium boffmanii and fumigation with acrylonitrile affected survival, Arthrobacter flavescens (Wenzhong et al., 1991), Arthro- reproduction, and enzyme activity (Environment Canada, bacter sp. (Narayanasamy et al., 1990), Acinobacter sp.

1998). LC50s in insects ranged from 0.107 to 36.7 mg/litre (Finnegan et al., 1991), and an assemblage of acclimated air (1.07 × 105–3.67 × 107 µg/m3). In 14 of 17 studies on 11 anaerobic microorganisms (Mills & Stack, 1955). 6 species, the 24-h LC50 was #5 mg/litre air (#5 × 10 Nocardia rhodochrous can degrade acrylonitrile in a µg/m3). more limited manner, based on its use as a nitrogen rather than carbon source (DiGeronimo & Antoine, 1976). The effect on growth, survival, or reproduction in insects exposed to acrylonitrile via the atmosphere Kincannon et al. (1983) reported almost complete observed at lowest concentration was that following biodegradation, with 99.9% and 99.1% removal of fumigation on the 1-day-old eggs of the pulse beetle acrylonitrile after 8 h in batch reactors and 2 days in (Callosobruchus chinensis) (Adu & Muthu, 1985). The complete mixture activated sludge, respectively. Initial

LC50 for eggs exposed to a constant concentration of the concentrations of acrylonitrile were 110 and 152 mg/litre, fumigant for 24 h and examined for survival up to respectively; effluent concentrations post-treatment 30 days post-fumigation was 0.107 mg/litre air (1.07 × 105 were 1.0 mg/litre after 8 h and <0.05 mg/litre after 2 days, µg/m3) (95% CI = 0.094–0.122 mg/litre air) (Adu & Muthu, respectively. In the batch reactor, biodegradation 1985). accounted for 75% and stripping accounted for 25% of removal of acrylonitrile. In the activated sludge system, Rajendran & Muthu (1981a) reported that for biodegradation was responsible for 100% of the removal. adults and pupae of rice weevil (Sitophilus oryzae L.) 5 3 exposed to the LC50 of 0.40 mg/litre air (4.0 × 10 µg/m ) Tabak et al. (1980) reported 100% biodegradation within 7 days in a static screening flask test method

23 Concise International Chemical Assessment Document 39

when microbial inoculum from a sewage treatment plant In short-term studies by the oral route, biochemical was mixed with 5 and 10 mg acrylonitrile/litre. effects on the liver and hyperplasia of the gastric mucosa have been observed, with effects on the gastric mucosa occurring at lowest doses in all studies in which they were examined. Effects on the adrenal cortex 11. EFFECTS EVALUATION observed in short-term repeated-dose toxicity studies from one laboratory have not generally been noted in longer-term investigations in animals exposed to higher 11.1 Evaluation of health effects concentrations. In a preliminary report of a recent subchronic study in mice, decreases in survival and 11.1.1 Hazard identification body weight and haematological effects were noted, although data presented therein were inadequate for 11.1.1.1 Effects in humans characterization of dose–response.

In case reports of acute intoxication, effects on the In early carcinogenesis bioassays in rats for which central nervous system characteristic of cyanide poison- few published accounts are available, non-neoplastic ing and effects on the liver, manifested as increased effects included reductions in body weight gain, haema- enzyme levels in the blood, have been observed. There tological effects, increases in liver and kidney weights, have also been reports that acrylonitrile is a skin irritant and, at higher doses, increased mortality. Following and sensitizer, the latter based on patch testing of inhalation, inflammatory changes in the nasal turbinates workers (Balda, 1975; Bakker et al., 1991; Chu & Sun, were also observed. 2001). There is considerable evidence of the carcinogen- In the few studies in which non-neoplastic effects icity of acrylonitrile, based on the results of primarily of acrylonitrile have been systematically investigated, early unpublished investigations, which have been only acute irritation has been reported consistently. restricted to one species (rats).1 In the most sensitive bioassays, a range of tumours (both benign and malig- Although the database is relatively extensive, nant) has been consistently observed following both there is no consistent, convincing evidence of an ingestion and inhalation, including those of the central association between exposure to acrylonitrile and cancer nervous system (brain and/or spinal cord), ear canal, of a particular site that fulfils traditional criteria for gastrointestinal tract, and mammary glands. In almost all causality in epidemiological studies. adequate bioassays, there have been reported increases in astrocytomas of the brain and spinal cord, which are 11.1.1.2 Effects in experimental animals rarely observed spontaneously in experimental animals; these have occurred at highest incidence consistently The acute toxicity of acrylonitrile is relatively high. across studies. Increases have been statistically signifi- Signs of acute toxicity include respiratory tract irritation cant, and there have been clear dose–response trends. and two phases of neurotoxicity, the first resembling Tumours have sometimes been reported at non-toxic cholinergic overstimulation and the second being central doses or concentrations and at periods as early as 7– nervous system dysfunction, resembling cyanide 12 months following onset of exposure. Tumours have poisoning. Superficial necrosis of the liver and also been observed in exposed offspring of a multi- haemorrhagic gastritis of the forestomach have also been generation reproductive study at 45 weeks. observed following single exposure. In numerous studies on the genotoxicity of acrylo- Data on the non-neoplastic effects of acrylonitrile nitrile involving examination of a broad spectrum of end- following repeated exposure are restricted to primarily points both in vitro, with and without metabolic activa- early, limited studies, most often unpublished carcino- tion, and in vivo in mice and rats, the pattern of results genesis bioassays, a few more recent investigations of has been quite mixed, including in in vitro assays where specialized end-points, or more recent studies for which there were adequate precautions to control volatilization. full accounts are not yet available. Although the results of many of these studies were negative, there was also a substantial number of positive In available short-term inhalation studies with results for a variety of end-points that cannot be dis- single dose levels and a limited range of examined end- counted. Limitations of the in vivo investigations also points, effects on biochemical parameters, clinical signs, and body weight were observed following exposure of rats, although there were no histopathological effects on 1 principal organs. A carcinogenesis study in mice exposed to acrylonitrile by gavage is under way (NTP, 1998).

24 Acrylonitrile

preclude their meaningful contribution to the weight of involving direct interaction with DNA. There is limited evidence of genotoxic potential. evidence for weak genotoxic potential, insufficient data on acrylonitrile–DNA adducts in the brain, although Results of the few identified investigations in such adducts can be induced in the liver in vivo, and which the relative potency of acrylonitrile was compared some indication in ongoing studies that oxidative with that of 2-cyanoethylene oxide are consistent with damage, the origin of which is unclear, may play a role. the oxidative pathway of metabolism being critical in Available data in support of this latter hypothesis as a genotoxicity. The role of mutagenesis and the primary plausible pathway for induction of acrylonitrile- mutagenic lesion induced by acrylonitrile in acrylonitrile- associated tumours are inadequate. There is no induced carcinogenesis are uncertain. Acrylonitrile– hypothesized sequence of events for which there are DNA adducts can be induced in vitro and in the liver in data to serve as a basis for assessment of the weight of vivo, although at levels considerably less than those evidence against traditional criteria of causality such as associated with, for example, ethylene oxide. However, consistency, strength, specificity, dose–response, when measures were taken to eliminate contamination of temporal patterns, biological plausibility, and coherence. samples by adducted protein and unbound acrylonitrile, acrylonitrile–DNA adducts were not detected in the Effects on the reproductive system in experimental brain, the primary target for acrylonitrile-induced animals (mice) exposed to acrylonitrile are limited to carcinogenesis. This is in contrast to observations for degenerative changes in the seminiferous tubules and ethylene oxide, which is also associated with gliomas of associated decreases in sperm counts in a specialized the brain. If the methods used to achieve greater DNA investigation with exposure by gavage, decreases in purity did not cause the loss of adducts or inhibit the sperm motility in an unpublished 13-week investigation recovery of adducted DNA, this suggests that with exposure by gavage, for which histopathological acrylonitrile-induced DNA damage and mutagenicity results are not yet available, and decreased sperm may occur by a mechanism other than the formation of counts, motility, and histopathological changes in an acrylonitrile–DNA adducts. Alternatively, they may be incompletely reported study. In a three-generation study associated with an uninvestigated adduct (e.g., cyano- in rats exposed via drinking-water, adverse effects on hydroxyethyl adducts). pup survival and viability and lactation indices were attributed to maternal toxicity. Investigations of the potential role of free radicals and oxidative stress in the carcinogenesis of acrylonitrile Biologically significant effects in offspring have are under way, with results of most being presented not been observed at doses that were not toxic to the incompletely at this time. Exposure to acrylonitrile has mothers in developmental studies in rats exposed to been associated with the accumulation of 8-oxodeoxy- acrylonitrile by both inhalation and ingestion. These guanine in the DNA isolated from brain tissue, presum- studies included a recent well conducted investigation ably via the action of reactive oxygen species generated with good characterization of dose–response. during acrylonitrile metabolism. Data on dose–response in this regard are limited to animals exposed for 21 days. In the few identified investigations of the immuno- Moreover, the predicted greater sensitivity of Sprague- logical effects of acrylonitrile, effects on the lung follow- Dawley versus Fischer rats to induction of tumours of ing inhalation and on the gastrointestinal tract following the brain/spinal cord on the basis of results of shorter- ingestion have been observed at concentrations and term studies in which 8-oxodeoxyguanine levels in brain doses at which histopathological effects have also been have been determined is not borne out by observed in other investigations. carcinogenesis bioassays. The origin of this oxidative damage is also unclear. In recent studies by inhalation (24 weeks) and ingestion (12 weeks), clinical signs typical of acute Also, several aspects of tumour development are acetylcholine-like toxicity and partially reversible reduc- characteristic of those induced by compounds that tion in motor and sensory conduction were observed interact directly with DNA. Tumours are systemic and (Gagnaire et al., 1998). occur at multiple sites in both sexes following both inhalation and ingestion, sometimes at non-toxic doses 11.1.2 Dose–response analyses or concentrations and at periods as early as 7–12 months following onset of exposure. The ratio of benign to 11.1.2.1 Effects in humans malignant tumours is small. In a cross-sectional investigation of workers In summary, the mechanism of carcinogenesis of exposed in acrylic fibre factories to approximately 1 ppm acrylonitrile is unknown. However, on the basis of (2.2 mg/m3) acrylonitrile, there was no consistent evi- available data, tumours are likely induced by a mode dence of adverse effects based on examination of a wide

25 Concise International Chemical Assessment Document 39

range of clinical parameters, including liver function inhalation exposure studies were limited primarily to pre- tests (Muto et al., 1992). Available data in humans are cancerous hyperplastic changes in the central nervous inadequate to serve as a basis for characterization of the system (Maltoni et al., 1977, 1987, 1988; Quast et al., concentrations at which acute irritation occurs. 1980b). Inflammatory changes in the nasal turbinates were observed at 80 ppm (176 mg/m3). The NOEL for There has been no consistent evidence of an changes in nasal turbinates is 20 ppm (44 mg/m3); it is association between exposure to acrylonitrile and cancer likely that secondary renal effects would be present at of any specific site in recent studies of four cohorts. this concentration. At high dose levels, survival was However, a non-significant excess of lung cancer was also decreased, prior to the appearance of the first noted in the most highly exposed quintile in the statis- tumour (Quast et al., 1980b). tically most powerful investigation. A large deficit in cancer in one cohort in comparison with national rates In two developmental studies in rats exposed by also suggests an underreporting of cause of death. inhalation, developmental effects (fetotoxic and teratogenic) have not been observed at concentrations It has been suggested that the results of the epide- that were not toxic to the mothers (Murray et al., 1978; miological studies contrast quantitatively with those of Saillenfait et al., 1993). In the investigation in which bioassays in animals. However, meaningful direct com- concentration–response was best characterized (four parison of these two types of data is precluded primarily exposure concentrations and controls with 2-fold by inadequate data on mode of induction as a basis to spacing), the LOEL for maternal toxicity and for characterize possible relevant sites of cancer in humans fetotoxicity was 25 ppm (55 mg/m3); the NOEL was (i.e., site concordance between animals and humans), the 12 ppm (26.4 mg/m3) (Saillenfait et al., 1993). relative paucity of data on exposure of workers in the relevant investigations, and the wide range of the In recent studies in rats exposed by inhalation to confidence limits on the SMRs for cancers of possible 25 ppm (55 mg/m3) and above for 24 weeks, there were interest in the epidemiological studies. (For example, the partially reversible time- and concentration-dependent upper 95% confidence limit on the SMRs for brain cancer marginal reductions in motor and sensory conduction in the only recent cohort study in which it was reported (Gagnaire et al., 1998). [Swaen et al., 1998] was 378, indicating that an almost 400% excess could not be excluded; the lower 95% 2) Ingestion confidence limit was 64.) In investigations in rats by Szabo et al. (1984), While there has been consistent evidence of a lack effects on non-protein sulfhydryl in gastric mucosa have of association between exposure to acrylonitrile and been reported at levels as low as 2 mg/kg body weight cancer of a particular site in recent, well conducted per day (drinking-water, 60 days). Effects on hepatic epidemiological studies, the power of the investigations glutathione were also observed by these authors at is insufficient to rule out increases in particularly rare similar doses administered by gavage but not in tumours, such as those of the brain. Indeed, the power drinking-water (2.8 mg/kg body weight per day, 21 days), to detect moderate excesses for some sites (stomach, although Silver et al. (1982) noted only slight brain, breast, prostate, lymphatic/haematopoietic) was biochemical effects but no histopathological effects in quite small because of small numbers of expected deaths. the liver at doses up to 70 mg/kg body weight per day (drinking-water, 21 days). Significant increases in 11.1.2.2 Effects in experimental animals proliferation in the forestomach but no changes in the liver or glandular stomach have been observed at 11.1.2.2.1 Non-neoplastic effects 11.7 mg/kg body weight per day (Ghanayem et al., 1995, 1997). 1) Inhalation Similar to observations in the inhalation studies, In the more informative of available short-term non-neoplastic effects observed in the long-term studies inhalation studies, all of which were restricted to single in rats exposed by ingestion were limited primarily to pre- dose levels and examination of a limited range of end- cancerous hyperplastic changes in target organs such as points (Gut et al., 1984, 1985), clinical signs and the non-glandular stomach (Quast et al., 1980a). Other decreases in body and organ weights but no histopatho- observed effects were limited primarily to increased logical effects were observed in rats exposed for 5 days organ weights, which were not observed consistently to 130 ppm (280 mg/m3) acrylonitrile. within or across the studies.

With the exception of inflammatory changes in the Consistent effects on the reproductive organs of nasal turbinates (Quast et al., 1980b), non-neoplastic male or female animals have not been observed in effects observed in the few conducted long-term

26 Acrylonitrile

repeated-dose toxicity and carcinogenicity studies exposed to similar concentrations of acrylonitrile conducted to date. In a specialized investigation in CD-1 (Kedderis et al., 1996), although increases in brain cancer mice, however, degenerative changes in the seminiferous have not been observed in epidemiological studies with tubules and associated decreases in sperm counts were limited power to detect excesses of this rare tumour. observed at 10 mg/kg body weight per day (NOEL = 1 mg/kg body weight per day) (Tandon et al., 1988). In carcinogenesis assays conducted in various Although epididymal sperm motility was reduced in a 13- strains of rats exposed via inhalation or ingestion (most week study with B6C3F1 mice, there was no dose– of which are early unpublished studies), the incidences response and no effect upon sperm density at doses up of astrocytomas of the central nervous system, Zymbal to 12 mg/kg body weight per day, although gland tumours, and tumours of the non-glandular fore- histopathological results are not yet available (Southern stomach have increased most consistently following Research Institute, 1996). In a three-generation study in exposure to acrylonitrile. Increases in the incidence of rats exposed via drinking-water (14 and 70 mg/kg body tumours of the tongue, mammary gland, and intestine weight per day), adverse effects on pup survival and have been observed less consistently, and those of the viability and lactation indices were attributed to maternal skin and liver in a single study. toxicity (Litton Bionetics Inc., 1980). Of the tumours increased in incidence most consis- In two studies by the oral route, developmental tently, astrocytomas occurred at highest incidence con- (including both fetotoxic and teratogenic) effects have sistently across studies; the other two tumours observed not been observed at doses that were not also toxic to most often were confined to organs not present in the mothers (lowest reported effect level in the mothers humans (i.e., Zymbal gland, forestomach), for which was 14 mg/kg body weight per day) (Murray et al., 1978; incidence was less. The only possible exception in Litton Bionetics Inc., 1980). Reversible biochemical studies by most relevant media of administration was the effects on the brain but not functional neurological incidence of tumours of the non-glandular stomach in effects were observed in offspring of rats exposed to the drinking-water assay of Quast et al. (1980a). 5 mg/kg body weight per day (a dose that did not affect However, it was not possible to confirm the incidences body weight of the dams); dose–response was not on which these calculations were based upon investigated in this study (Mehrotra et al., 1988). examination of data in the original study report due to discrepancies within the critical table (i.e., the number of Clinical signs resembling those associated with animals in which tumours were reported in the five acute acetylcholine toxicity were observed in a recently categories for the non-glandular stomach, combined, completed study in rats exposed by gavage to 12.5 was greater than the total number of animals examined); mg/kg body weight per day and above for 12 weeks there was also a discrepancy between the content of this (Gagnaire et al., 1998). table (Table 22) and data presented in the Appendix (Table A-21). Moreover, the tumours that occurred at 11.1.2.2.2 Cancer highest incidence are not consistent with the results of other studies, and they have therefore not been further Cancer is considered the critical end-point for addressed here. quantification of dose–response for risk characterization for acrylonitrile. This is based on the observation of Quantitative estimates presented herein are limited tumours at non-toxic doses or concentrations in long- to the tumours that occurred at highest incidence (i.e., term studies at levels less than those that have induced astrocytomas of the central nervous system) in effects in (limited) repeated-dose toxicity studies and bioassays for which media of intake are most relevant to identified investigations of neurological, reproductive, exposure in the general environment — i.e., inhalation and developmental effects. Moreover, there is evidence and drinking-water. Of the few inhalation bioassays for weak genotoxic potential, and data are insufficient to identified, the study by Quast et al. (1980b) is considered support a plausible mode of action for acrylonitrile- most suitable for quantification of cancer potency, induced carcinogenesis other than through direct although it is limited by the fact that there were only two interaction with DNA. dose levels and controls. Group sizes were large (n = 100 per sex per group), however, and animals were exposed There is no reason to believe that carcinogenesis for 2 years. In other identified inhalation bioassays, is unique to the rat, although there may be quantitative group sizes were small and/or exposure periods short differences between experimental animals and humans, (Maltoni et al., 1977, 1987, 1988). based on metabolic studies. Indeed, physiologically based pharmacokinetic modelling predicts that concen- Among the bioassays in which acrylonitrile was trations of cyanoethylene oxide in the brains of humans administered in drinking-water (Bio/Dynamics Inc., would be considerably greater than those in rats

27 Concise International Chemical Assessment Document 39

1980a,b; Quast et al., 1980a; Gallagher et al., 1988),1 body weight of a human. The estimates of carcinogenic characterization of dose–response was best in potency for ingestion were not scaled on the basis of Bio/Dynamics Inc. (1980b). In this investigation, there body surface area, as the carcinogenicity of acrylonitrile were five doses and controls with good dose spacing appears to be due to a metabolite rather than to the and optimum characterization of dose–response, parent compound. including lower, non-toxic doses. Group sizes were large (n = 100). Group sizes were smaller in other bioassays Tumorigenic potencies developed in this manner (Gallagher et al., 1988), or dose spacing was poor for ingestion and inhalation are similar. (Bio/Dynamics Inc., 1980a). Although group sizes were smaller and doses higher, tumorigenic doses (TD05s, the 11.1.3 Sample risk characterization dose that causes a 5% increase in tumour incidence over background) based on the investigation of Quast et al. Although limited, available data are consistent (1980a) are also included, since incidence was increased with air being the principal medium of exposure of the at more doses (three rather than two in Bio/Dynamics general population to acrylonitrile; intake from other Inc., 1980b). media is likely to be negligible in comparison. Moreover, with the exception of air in the vicinity of industrial point The tumour incidences and resulting TD05s/TC05s sources, acrylonitrile has seldom been detected in sam- for benign and malignant tumours (combined) of the ples of ambient air, indoor air, or drinking-water. This is central nervous system (astrocytomas) for the Quast et consistent with lack of identification of non-point al. (1980b) inhalation study and the Bio/Dynamics Inc. sources. On this basis, the focus of the sample health (1980b) and Quast et al. (1980a) drinking-water bioassays risk characterization is populations exposed through air modelled using the multistage model (GLOBAL 82) are in the vicinity of industrial point sources. Moreover, the presented in Tables 2, 3, and 4. Degrees of freedom, vast majority of acrylonitrile (>97%) is released to air. parameter estimates, and nature of any adjustments for However, should there be specific cases where ingestion mortality or period of exposure are also presented may represent a significant source of exposure (e.g., therein. Benign and malignant tumours have been during spills), the tumorigenic doses presented in Tables combined owing to the observed clear progression, 3 and 4 may be informative in making judgements about although, as indicated in the tables, numbers of benign risk as a basis for management. lesions included in the incidences on which these calculations were based are small; exclusion of the benign tumours would result in only slightly higher values of the TD05s/TC05s. In all cases, incidences have been adjusted to exclude animals dying before 6 months (i.e., prior to observation of the first tumours). For comparison, TC05s developed on the basis of incidences reported by TERA (1997) for male rats for the Quast et al. (1980b) inhalation bioassay adjusted to exclude animals dying before approximately 10 months are also included.

With respect to appropriate scaling of the TD05s/ TC05s, those for inhalation have been adjusted to reflect differences in inhalation volumes and body weights between humans and exposed animals. 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 a human, and 70 kg body weight is the

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

28 Acrylonitrile

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

Margin Category of between equivalent low- Concentration of acrylonitrile Potency potency and dose risk (Reference) (Table 2) concentration estimates Vicinity of sources

3 3 –5 9.3 µg/m , concentration predicted by dispersion modelling, TC05 = 6000 µg/m 650 (>10 ) 11 m from stack at industrial site in Ontario 95% LCL a = 4500 µg/m3 480 (>10–5)

3 3 –5 2.9 µg/m , concentration predicted by dispersion modelling, TC05 = 6000 µg/m 2100 (>10 ) 35 m from stack at industrial site in Ontario 95% LCL = 4500 µg/m3 1550 (>10–5)

3 3 –7 –5 0.6 µg/m , concentration predicted by dispersion modelling, TC05 = 6000 µg/m 10 000 (10 to 10 ) 41 m from stack at industrial site in Ontario 95% LCL = 4500 µg/m3 7500 (10–7 to 10–5)

3 3 –7 –5 0.1 µg/m , concentration predicted by dispersion modelling, TC05 = 6000 µg/m 60 000 (10 to 10 ) 3508 m from stack at industrial site in Ontario 95% LCL = 4500 µg/m3 45 000 (10–7 to 10–5)

3 3 –5 <52.9 µg/m , sampling at the site of nitrile-butadiene rubber TC05 = 6000 µg/m 110 (>10 ) production in Sarnia in 1997, 5 m from company fence line, 95% LCL = 4500 µg/m3 85 (>10–5) 2 m above ground, downwind (B. Sparks, personal communication, 1997; M. Wright, personal communication, 1998)

3 3 –7 –5 0.12 µg/m , lowest concentration measured in ambient air TC05 = 6000 µg/m 50 000 (10 to 10 ) sampled for 6 days near a chemical manufacturing plant in 95% LCL = 4500 µg/m3 38 000 (10–7 to 10–5) Cobourg, Ontario (Ortech Corporation, 1994)

3 3 –7 –5 0.28 µg/m , highest concentration measured in ambient air TC05 = 6000 µg/m 21 000 (10 to 10 ) sampled for 6 days near a chemical manufacturing plant in 95% LCL = 4500 µg/m3 16 000 (10–7 to 10–5) Cobourg, Ontario (Ortech Corporation, 1994)

3 3 –5 <251 µg/m , lowest concentration measured at stack of TC05 = 6000 µg/m 24 (>10 ) chemical manufacturing plant in Cobourg, Ontario, in 1993 95% LCL = 4500 µg/m3 18 (>10–5) (Ortech Corporation, 1994)b

Ambient air

3 3 –5 1.9 µg/m , maximum (and only detectable) concentration TC05 = 6000 µg/m 3200 (>10 ) measured in 11 samples at six urban stations in Ontario in 95% LCL = 4500 µg/m3 2400 (>10–5) 1990 (OMOE, 1992a,b)c

3 3 –7 –5 <0.64 µg/m , seven samples in industrialized area of Windsor, TC05 = 6000 µg/m 9400 (10 to 10 ) Ontario, in 1991 (Ng & Karellas, 1994) 95% LCL = 4500 µg/m3 7000 (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 data should be noted, however, that populations residing in are insufficient to support a consensus view on a plaus- the vicinity of sources would likely be exposed to lower ible mode of action for induction of tumours by other concentrations, in view of the proximity of many of these than direct interaction with genetic material, estimates of predicted and measured values to the stacks, and exposure are compared with quantitative estimates of monitoring in residential areas in the vicinity of point cancer potency to characterize risk. The lowest TC05 sources is desirable. (human equivalent value) was 2.7 ppm (6.0 mg/m3) for the combined incidence of benign and malignant tumours of Of the reported values for occupational exposure the brain and/or spinal cord in female rats exposed by to acrylonitrile (section 6.3), the highest average level of inhalation; the lower 95% confidence limit was 2.0 ppm exposure was 5.8 ppm (12.8 mg/m3) for loaders in a US (4.5 mg/m3) (Quast et al., 1980b; Table 2). This equates to acrylonitrile production plant (IARC, 1999). This con- a unit risk of 8.3 × 10–3 per mg/m3. The margins between centration is approximately 2 times more than the lowest 3 carcinogenic potency and limited available data on TC05 (human equivalent value) of 2.7 ppm (6.0 mg/m ) predicted and measured concentrations of acrylonitrile derived above for a continuous (24 h/day, 7 days/week), primarily in the vicinity of point sources in the sample lifelong exposure. country (i.e., Canada) are presented in Table 5. On this basis, risks in the vicinity of industrial point are >10–5. It

29 Concise International Chemical Assessment Document 39

11.1.4 Uncertainties and degree of confidence in site releases. Almost all releases in the environment are human health risk characterization to air, with small amounts released to water.

The degree of confidence in the database on tox- Based on its physical/chemical properties, acrylo- icity of acrylonitrile is moderate. The carcinogenicity of nitrile undergoes various degradation processes in air, acrylonitrile in humans has been investigated in well with very small amounts transferring to water. When conducted recent studies of four relatively large cohorts released into water, it is expected to remain primarily in of occupationally exposed workers. While this epidemio- water, where it undergoes biodegradation after an logical database is extensive in comparison with that acclimation period. Acrylonitrile does not bioaccumulate available for many other compounds, the power of the in organisms. studies was insufficient to detect moderate excesses for some sites. Available data are also insufficient to Based on the sources and fate of acrylonitrile in provide meaningful direct comparison with the results of the environment, biota are expected to be exposed to quantitative dose–response analyses based on acrylonitrile primarily in air and to a much lesser extent in bioassays in animals due to inadequate information with water. Little exposure to soil or benthic organisms is which to characterize possible relevant sites of cancer in expected. Therefore, the focus of the environmental risk humans (i.e., site concordance between animals and characterization will be on terrestrial and aquatic organ- humans) and the relative paucity of data on exposure of isms exposed directly to ambient acrylonitrile in air and workers in the relevant investigations. water.

The database on non-cancer toxicity in laboratory 11.2.1.1 Aquatic end-points animals is limited, being restricted to primarily early unpublished carcinogenesis bioassays in which few Data on aquatic toxicity are available for a variety non-cancer end-points were examined, a few more recent of plants, invertebrates, fish, and amphibians. Identified investigations of specialized end-points such as neuro- sensitive end-points include growth inhibition in aquatic toxicity, or more recent repeated-dose toxicity studies for plants (Zhang et al., 1996), mortality in pond snails which full accounts are not yet available. Although there (Erben & Beader, 1983), mortality and reduced growth in are a relatively large number of bioassays, the database fish (Henderson et al., 1961; Analytical BioChemistry on carcinogenicity of acrylonitrile is limited primarily to Laboratories, 1980a), and reduction in growth of frogs early unpublished investigations in one species; a (Zhang et al., 1996). bioassay in mice, however, is currently under way. 11.2.1.2 Terrestrial end-points Based on information acquired to date on the kinetics and metabolism of acrylonitrile, a physiolog- Data on terrestrial toxicity are available for inverte- ically based pharmacokinetic model, once completed, brates (particularly grain insect pests) as well as from holds promise as a more suitable basis for scaling of mammalian toxicology. Identified sensitive end-points TD s/TC s than the default assumption about relative 05 05 via fumigation or inhalation routes of exposure include inhalation volumes and body weights. mortality of insect eggs (Adu & Muthu, 1985), decreased number of insect offspring (Rajendran & Muthu, 1981a), Tumorigenic potencies for inhalation based on the maternal and fetal toxicity in rats (Saillenfait et al., 1993), combined incidence of benign and malignant tumours of and histopathological changes in the nasal turbinates in the brain and/or spinal cord in female rats were 1.4 times rats (Quast et al., 1980b). less than for these tumours in males in the same study (TC of 6.0 versus 8.9 mg/m3). These values were also up 05 Sample environmental risk to 2-fold less than those for tumours at other sites in 11.2.2 both sexes in the critical study (i.e., Quast et al., 1980b). characterization

The lower 95% confidence limit on the TC05 for the combined incidence of benign and malignant tumours of First-tier (i.e., “hyperconservative”) analyses are the brain and/or spinal cord in female rats was 4.5 mg/m3, presented below; since resulting quotients were less compared with the maximum likelihood estimate of 6.0 than one, higher-tier analyses were not conducted. mg/m3. 11.2.2.1 Aquatic organisms 11.2 Evaluation of environmental effects Environmental exposure to acrylonitrile is expected 11.2.1 Assessment end-points to be greatest near point sources. In general, releases to water (all fresh water in the sample country) are low Acrylonitrile enters the Canadian environment (0.529 tonnes, or 2.7% of all releases). Recently from anthropogenic sources, primarily from industrial on- determined levels in effluent are very low, below the

30 Acrylonitrile

detection limit of 0.0042 mg/litre. Therefore, the value mammals. Saillenfait et al. (1993) reported that none of 0.0042 mg/litre will be used as the estimated exposure these effects were observed at 26.4 mg/m3. For the value (EEV) in the hyperconservative analysis for hyperconservative analysis, the ENEV is derived by aquatic organisms. dividing the CTV by a factor of 100. This factor accounts for the extrapolation from laboratory to field conditions, For exposure of aquatic biota to acrylonitrile in conversion of the LOEL to a long-term no-effects value, water, the critical toxicity value (CTV) is 0.4 mg/litre, interspecies and intraspecies variations in sensitivity, based on the lower chronic level around the EC50 of and the moderate data set. As a result, the ENEV is 0.55 foreleg development after a 28-day exposure in the frog mg/m3 (550 µg/m3). Bufo bufo gargarizans (Zhang et al., 1996). This was the lowest value identified from the primary and secondary The hyperconservative quotient is calculated by data composed of acute and chronic toxicity studies dividing the EEV of 9.3 µg/m3 by the ENEV as follows: conducted on 16 species of aquatic invertebrates, plants, fish, and amphibians. Quotient = EEV ENEV

For a hyperconservative analysis, the estimated 3 = 9.3 µg/m no-effects value (ENEV) is derived by dividing this CTV 550 µg/m3 by an application factor of 10. This factor accounts for extrapolation from field to laboratory conditions and = 0.02 interspecies and intraspecies variations in sensitivity. The resulting ENEV is 0.04 mg/litre. Since the hyperconservative quotient is less than 1, it is unlikely that acrylonitrile causes adverse effects The hyperconservative quotient is calculated by on populations of terrestrial organisms in the country on dividing the EEV of 0.0042 mg/litre by the ENEV as which the sample environmental risk characterization is follows: based (i.e., Canada).

Quotient = EEV ENEV 11.2.2.3 Discussion of uncertainty

= 0.0042 mg/litre Regarding effects of acrylonitrile on terrestrial and 0.04 mg/litre aquatic organisms, uncertainty inevitably surrounds the extrapolation from available toxicity data to potential = 0.1 ecosystem effects. Somewhat surprisingly, the data set lacks information on the toxicity of acrylonitrile in air to Since the hyperconservative quotient is less than plant species. Studies of acrylonitrile in air have focused 1, it is unlikely that acrylonitrile causes adverse effects on the effects via inhalation and fumigation on labora- on populations of aquatic organisms in the country on tory mammals (particularly rats) and pest insect species. which the sample environmental risk characterization is There has been considerable examination of a wide range based (i.e., Canada). of effects in rats. It is not known to what extent the physiological effects observed in the rat are representa- 11.2.2.2 Terrestrial organisms tive of long-term ecological effects. Regarding effects of acrylonitrile on aquatic organisms, the data set includes Environmental exposure to acrylonitrile in air is studies on organisms from a variety of ecological niches expected to be greatest near industrial point sources. and taxa for both the short and long term. Levels of acrylonitrile in ambient air in Canada are generally below detection. The highest concentration of acrylonitrile in outdoor air in a half-hour period in 3 Canada is predicted to be 9.3 µg/m (H. Michelin, per- 12. PREVIOUS EVALUATIONS BY sonal communication, 1999) at an 11-m distance from an INTERNATIONAL BODIES industrial stack.

For the exposure of terrestrial organisms to acrylo- nitrile in air, the CTV is the LOEL of 55 mg/m3, causing IARC (1999) classified acrylonitrile in Group 2B decreased maternal weight and fetal toxicity in rats (“possibly carcinogenic to humans”), based on inade- exposed for 9 days during gestation (Saillenfait et al., quate evidence in humans but adequate evidence in 1993). This LOEL was the most sensitive effect identified experimental animals. from a data set composed of acute and chronic toxicity studies conducted on 14 species of insects and

31 Concise International Chemical Assessment Document 39

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32 Acrylonitrile

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Zeiger E, Haworth S (1985) Tests with a preincubation modification of the Salmonella/microsome assay.In: Ashby J, de

41 Concise International Chemical Assessment Document 39

APPENDIX 1 — SOURCE DOCUMENT Accuracy of reporting, adequacy of coverage, and defensibility of conclusions with respect to hazard characterization and dose–response analyses were considered in written review by staff of the Information Department of BIBRA International and Environment Canada & Health Canada (2000) at a panel meeting of the following members, convened by Toxicology Excellence for Risk Assessment (TERA) on 17 Copies of the Canadian Environmental Protection Act November 1998, in Cincinnati, OH: Priority Substances List assessment report (Environment Canada & Health Canada, 2000) and unpublished supporting M.J. Aardema, The Procter & Gamble Co. documentation for acrylonitrile may be obtained from: M.L. Dourson, TERA S. Felter, The Procter & Gamble Co. Commercial Chemicals Evaluation Branch M.A. Friedman, Private Consultant Environment Canada M.L. Gargas, ChemRisk Division, McLaren/Hart 14th floor, Place Vincent Massey R.G. Tardiff, The Sapphire Group, Inc. 351 St. Joseph Blvd. V.T. Vu, US Environmental Protection Agency Hull, Quebec V. Walker, New York State Department of Health Canada K1A 0H3 or

Environmental Health Centre Health Canada Address Locator: 0801A Tunney’s Pasture Ottawa, Ontario Canada K1A 0L2

Initial drafts of the supporting documentation and assess- ment report for acrylonitrile were prepared by staff of Health Canada and Environment Canada. The health-related sections of the supporting documentation and the assessment report were based 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 the preparation of the draft CICAD.

Environmental sections of the assessment report were reviewed 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 (AN Group, Inc.), V. Nabholz (US Environmental Protection Agency), J. Pellerin (Université du Québec à Rimouski), J. Soule (DuPont Canada), and A. Tomlin (Agriculture and Agri-Food Canada).

In order to address primarily adequacy of coverage, sections of the supporting documentation pertaining to human health were reviewed externally by J.J. Collins, Solutia Inc., St. Louis, MO; B. Ghanayem, National Institute of Environmental Health Sciences, Research Triangle Park, NC; G.L. Kedderis, Chemical Industry Institute of Toxicology, Research Triangle Park, 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.

42 Acrylonitrile

APPENDIX 2 — CICAD PEER REVIEW APPENDIX 3 — CICAD FINAL REVIEW BOARD

The draft CICAD on acrylonitrile was sent for review to Geneva, Switzerland, 8–12 January 2001 institutions and organizations identified by IPCS after contact with IPCS national contact points and Participating Institutions, as well as to identified experts. Comments were received from: Members A. Aitio, International Programme on Chemical Safety, World Health Organization, Switzerland Dr A.E. Ahmed, Molecular Toxicology Laboratory, Department of Pathology, University of Texas Medical Branch, Galveston, M. Baril, International Programme on Chemical Safety/ TX, USA Institut de Recherche en Santé et en Sécurité du Travail du Québec, Canada Mr R. Cary, Health and Safety Executive, Merseyside, United Kingdom (Chairperson) D.L. Bayliss, National Center for Environmental Assessment, US Environmental Protection Agency, USA Dr R.S. Chhabra, General Toxicology Group, National Institute of Environmental Health Sciences, National Institutes of Health, R. Benson, Drinking Water Program, US Environmental Research Triangle Park, NC, USA Protection Agency, USA Dr S. Czerczak, Department of Scientific Information, Nofer R. Cary, Health and Safety Executive, United Kingdom Institute of Occupational Medicine, Lodz, Poland

R. Chhabra, National Institute of Environmental Health Dr S. Dobson, Centre for Ecology and Hydrology, Sciences, National Institutes of Health, USA Cambridgeshire, United Kingdom

H.B.S. Conacher, Bureau of Chemical Safety, Health Dr O.M. Faroon, Division of Toxicology, Agency for Toxic Canada, Canada Substances and Disease Registry, Atlanta, GA, USA

C. Elliott-Minty, Health and Safety Executive, United Dr H. Gibb, National Center for Environmental Assessment, US Kingdom Environmental Protection Agency, Washington, DC, USA

H. Gibb, National Center for Environmental Assessment, Dr R.F. Hertel, Federal Institute for Health Protection of US Environmental Protection Agency, USA Consumers and Veterinary Medicine, Berlin, Germany

R. Hertel, Federal Institute for Health Protection of Dr A. Hirose, Division of Risk Assessment, National Institute of Consumers and Veterinary Medicine, Germany Health Sciences, Tokyo, Japan

C. Hiremath, National Center for Environmental Assessment, Dr P.D. Howe, Centre for Ecology and Hydrology, US Environmental Protection Agency, USA Cambridgeshire, United Kingdom (Rapporteur)

S. Kristensen, National Industrial Chemicals Notification and Dr D. Lison, Industrial Toxicology and Occupational Medicine Assessment Scheme, Australia Unit, Université Catholique de Louvain, Brussels, Belgium

J.F. Murray, AN Group, Inc., USA Dr R. Liteplo, Existing Substances Division, Bureau of Chemical Hazards, Health Canada, Ottawa, Ontario, Canada H. Nagy, National Institute of Occupational Safety and Health, USA Dr I. Mangelsdorf, Chemical Risk Assessment, Fraunhofer Institute of Toxicology and Aerosol Research, Hanover, Germany S. Tarkowski, Nofer Institute for Occupational Medicine, Poland Ms M.E. Meek, Existing Substances Division, Safe Environments Program, Health Canada, Ottawa, Ontario, Canada (Vice- W.F. ten Berge, DSM Corporate Safety and Environment, Chairperson) The Netherlands Dr S. Osterman-Golkar, Department of Molecular Genome K. Ziegler-Skylakakis, Commission of the European Research, Stockholm University, Stockholm, Sweden Communities/European Union Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute of Health Sciences, Tokyo, Japan

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

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

Professor M. van den Berg, Environmental Sciences and Toxicology, Institute for Risk Assessment Sciences, University of Utrecht, Utrecht, The Netherlands

43 Concise International Chemical Assessment Document 39

Observers

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

Dr K. Ziegler-Skylakakis, Commission of the European Communities, Luxembourg

Secretariat

Dr A. Aitio, International Programme on Chemical Safety, World Health 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

44 ACRYLONITRILE 0092 March 2001 CAS No: 107-13-1 Cyanoethylene RTECS No: AT5250000 2-Propenenitrile UN No: 1093 Vinyl cyanide

EC No: 608-003-00-4 C3H3N / CH2=CH-CN Molecular mass: 53.1

TYPES OF HAZARD/ ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING EXPOSURE

FIRE Highly flammable. Gives off NO open flames, NO sparks, and Powder, alcohol-resistant foam, irritating or toxic fumes (or gases) NO smoking. NO contact with strong water spray, carbon dioxide. in a fire. bases and strong acids.

EXPLOSION Vapour/air mixtures are explosive. Closed system, ventilation, In case of fire: keep drums, etc., Risk of fire and explosion on explosion-proof electrical equipment cool by spraying with water. contact with strong base(s) and and lighting. Use non-sparking strong acid(s). handtools.

EXPOSURE AVOID ALL CONTACT! IN ALL CASES CONSULT A DOCTOR!

Inhalation Dizziness. Headache. Nausea. Closed system and ventilation. Fresh air, rest. Refer for medical Shortness of breath. Vomiting. attention. See Notes. Weakness. Convulsions. Chest tightness.

Skin MAY BE ABSORBED! Redness. Protective gloves. Protective First rinse with plenty of water, then Pain. Blisters. (Further see clothing. remove contaminated clothes and Inhalation). rinse again. Refer for medical attention.

Eyes Redness. Pain. Safety goggles, or eye protection in First rinse with plenty of water for combination with breathing several minutes (remove contact protection. lenses if easily possible), then take to a doctor.

Ingestion Abdominal pain. Vomiting. (Further Do not eat, drink, or smoke during Rinse mouth. Give a slurry of see Inhalation). work. Wash hands before eating. activated charcoal in water to drink. Induce vomiting (ONLY IN CONSCIOUS PERSONS!). Refer for medical attention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Evacuate danger area! Consult an expert! F Symbol Unbreakable packaging; put Ventilation. Collect leaking liquid in covered T Symbol breakable packaging into closed containers. Absorb remaining liquid in sand or inert N Symbol unbreakable container. Do not absorbent and remove to safe place. Do NOT wash R: transport with food and feedstuffs. away into sewer. Do NOT let this chemical enter the 45-11-23/24/25-37/38-41-43-51/53 environment. Chemical protection suit including S: 9-16-53-45-61 self-contained breathing apparatus. Note: D and E UN Hazard Class: 3 UN Subsidiary Risks: 6.1 UN Pack Group: I

EMERGENCY RESPONSE STORAGE

Transport Emergency Card: TEC (R)-61 Fireproof. Separated from strong oxidants, strong bases, food and NFPA Code: H 4; F 3; R 2 feedstuffs. Cool. Keep in the dark. Ventilation along the floor. Store only if stabilized.

Prepared in the context of cooperation between the International IPCS Programme on Chemical Safety and the European Commission International © IPCS 2000 Programme on Chemical Safety SEE IMPORTANT INFORMATION ON THE BACK. 0092 ACRYLONITRILE

IMPORTANT DATA Physical State; Appearance Routes of exposure COLOURLESS OR PALE YELLOW LIQUID, WITH PUNGENT The substance can be absorbed into the body by inhalation of ODOUR. its vapour, through the skin and by ingestion.

Physical dangers Inhalation risk The vapour is heavier than air and may travel along the ground; A harmful contamination of the air can be reached very quickly distant ignition possible. on evaporation of this substance at 20°C.

Chemical dangers Effects of short-term exposure The substance polymerizes due to heating or under the The substance and the vapour is irritating to the eyes, the skin influence of light and bases, causing fire and explosion hazard. and the respiratory tract. The substance may cause effects on The substance decomposes on heating producing toxic fumes the central nervous system. Exposure far above the OEL may including hydrogen cyanide, nitrogen oxides. Reacts violently result in death. The effects may be delayed. See Notes. with strong acids, and strong oxidants. Attacks plastics and Medical observation is indicated. rubber. Effects of long-term or repeated exposure Occupational exposure limits Repeated or prolonged contact may cause skin sensitization. TLV: (as TWA) 2 ppm; skin A3 (ACGIH 2000). The substance may have effects on the central nervous system and liver. This substance is possibly carcinogenic to humans.

PHYSICAL PROPERTIES

Boiling point: 77°C Relative vapour density (air = 1): 1.8 Melting point: -84°C Relative density of the vapour/air-mixture at 20°C (air = 1): 1.05 Relative density (water = 1): 0.8 Flash point: -1°C c.c. Auto-ignition temperature: 481°C Solubility in water, g/100 ml at 20°C: 7 Explosive limits, vol% in air: 3.0-17.0 Vapour pressure, kPa at 20°C: 11.0 Octanol/water partition coefficient as log Pow: 0.25

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 cyanide formation. Also consult ICSC of a cyanide salt, such as 0671. Specific treatment is necessary in case of poisoning with this substance; the appropriate means with instructions must be available. The odour warning when the exposure limit value is exceeded is insufficient. Rinse contaminated clothes (fire hazard) with plenty of water.

ADDITIONAL INFORMATION

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 Acrylonitrile

RÉSUMÉ D’ORIENTATION nitrile-butadiène-styrène et acrylonitrile-styrène. On estime que la capacité de production mondiale était d’environ 4 millions de tonnes en 1993. Les principales Ce CICAD relatif à l’acrylonitrile a été préparé zones de production sont l’Union européenne (>1,25 mil- conjointement par la Direction de l’Hygiène du Milieu de lions de tonnes par an), les Etats-Unis (environ 1,5 Santé Canada et la Direction de l’Evaluation des produits millions de tonnes par an) et le Japon (environ 0,6 chimiques commerciaux d’Environnement Canada à partir millions de tonnes par an). d’une documentation rédigée simultanément dans le cadre du programme sur les substances prioritaires Ce sont principalement les unités de production ou prévu par la Loi canadienne sur la protection de d’autres industries chimiques ou plasturgiques qui sont l’environnement (LCPE). Les études sur les substances susceptibles d’en libérer dans l’environnement (plus de prioritaires prescrites par la LCPE ont pour objectif 95 % dans le pays témoin). On ne lui connaît pas de d’évaluer les effets potentiels sur la santé humaine d’une sources naturelles. L’acrylonitrile est largement répandu exposition indirecte à celles de ces substances qui sont dans les compartiments de l’environnement où il est présentes dans l’environnement ainsi que leurs effets déversé (c’est-à-dire l’air ou l’eau), son mouvement vers sur l’environnement lui-même. La présente mise au point le sol, les sédiments et les biotes étant limité. Il est prend en compte les données publiées jusqu’en avril principalement éliminé par réaction chimique et advec- 19981 en ce qui concerne les effets sanitaires et jusqu’à tion. Les enquêtes limitées effectuées dans le pays fin mai 1998 en ce qui concerne les effets sur choisi pour la caractérisation du risque dans l’environne- l’environnement. D’autres mises au point ont été ment général (le Canada) n’ont permis de trouver de également consultées, à savoir celles de l’Environmental l’acrylonitrile qu’à proximité d’installations industrielles. Protection Agency des Etats-Unis (1980, 1985), de l’IPCS (1983), de l’ATSDR (1990), du CIRC (1999) et de la L’exposition professionnelle à l’acrylonitrile est Communauté européenne (2000). Des renseignements liée à sa production et à son utilisation pour la fabrica- sur la nature de l’examen par des pairs et la disponibilité tion d’autres produits. C’est d’ailleurs dans ce dernier du document de base (Environnement Canada & Santé cas que le risque est le plus important en raison des Canada, 2000) sont donnés à l’appendice 1. Les difficultés de confinement. Selon des données récentes informations concernant l’examen par des pairs du relatives aux pays de l’Union européenne, l’exposition présent CICAD figurent à l’appendice 2. Ce CICAD a été moyenne pondérée par rapport au temps est #0,45 ppm approuvé en tant qu’évaluation internationale lors d’une (1 mg/m3) au cours de la production et #1,01 ppm réunion du Comité d’évaluation finale qui s’est tenue à (2,2 mg/m3) pour diverses utilisations en bout de chaîne. Genève (Suisse), du 8 au 12 janvier 2001. La liste des participants à cette réunion se trouve à l’appendice 3. La L’acrylonitrile est rapidement absorbé par toutes carte internationale sur la sécurité chimique de l’acrylo- les voies d’exposition et il se répartit dans l’ensemble nitrile (ICSC 0092), préparée par le Programme inter- des tissus examinés. Il n’y a guère de possibilité d’accu- national sur la sécurité chimique (IPCS, 1993), est mulation dans un organe quelconque, le composé étant également reproduite dans le présent document. excrété, principalement sous forme de métabolites, dans les 24 à 48 h suivant l’administration. Selon les données L’acrylonitrile (No CAS 107-13-1) se présente, à la disponibles, la principale voie métabolique de détoxi- température ambiante, sous la forme d’un liquide volatil, cation est une conjugaison avec le glutathion, l’oxy- inflammable et soluble dans l’eau. Au Canada, ce dation en oxyde de 2-cyanoéthylène étant considérée composé est utilisé en majeure partie comme produit de comme une voie d’activation. départ ou adjuvant chimique dans la fabrication des élastomères nitrile-butadiène et des copolymères acrylo- Les données fournies par l’expérimentation animale indiquent que l’acrylonitrile est fortement irritant pour la peau, les yeux et les voies respiratoires. Il peut provoquer une dermatite allergique de contact, mais on 1 Les nouvelles données notées par les auteurs et obtenues par ne possède pas suffisamment de données pour évaluer un dépouillement de la littérature effectué avant la réunion du son pouvoir sensibilisateur. A l’exception des effets Comité d’évaluation finale ont été examinées compte tenu de toxiques sur le développement (effets foetoxiques et leur influence probable sur les conclusions essentielles de la tératogènes), qui ne s’observent d’ailleurs pas aux doses présente évaluation, le but étant avant tout d’établir si leur non toxiques pour la mère, les données disponibles con- prise en compte serait prioritaire lors d’une prochaine mise à cernant les autres effets non néoplasiques révélés par jour. Les auteurs ayant estimé qu’elles apportaient des l’expérimentation animale ne sont pas suffisantes pour éléments d’information supplémentaires, on a ajouté des permettre de caractériser la relation dose-réponse. Lors données plus récentes encore que non essentielles pour la des quelques études au cours desquelles on a systéma- caractérisation des dangers ou l’analyse des relations dose- tiquement recherché la présence d’effets non néo- réponse.

47 Concise International Chemical Assessment Document 39

plasiques, seuls des cas d’irritation cutanée aiguë ont provoque une augmentation de 5 % de l’incidence été régulièrement observés. tumorale par rapport à l’incidence normale) (valeur équivalente pour l’Homme) a été trouvée égale à 2,7 ppm Compte tenu des résultats obtenus sur l’animal, (6,0 mg/m3) pour l’incidence combinée des tumeurs c’est le cancer qui constitue le point d’aboutissement cérébrales ou médullaires bénignes ou malignes chez le toxicologique majeur de l’action de l’acrylonitrile chez rat et la souris exposés par la voie respiratoire. Cela l’Homme. Aprés inhalation ou ingestion, on observe correspond à un risque unitaire de 8,3 × 10–3 par mg/m3. chez le rat toute une variété de tumeurs touchant notamment le système nerveux central (encéphale et Bien que limitées, les données montrent que c’est moelle épinière), le conduit auditif, les voies digestives et principalement par l’air que la population générale est les glandes mammaires. La plupart des tests biologiques exposée à l’acrylonitrile; l’absorption à partir d’autres correctement effectués révèlent une augmentation des milieux est négligeable en comparaison. La caractéri- astrocytomes cérébraux et médullaires, néoplasmes qui sation du risque pour l’Homme est centrée sur les se produisent rarement de façon spontanée; ces tumeurs populations vivant à proximité de sources industrielles s’observent régulièrement avec une incidence très élevée d’acrylonitrile. Compte tenu de la marge qui existe, dans dans toutes les études. L’augmentation constatée est la caractérisation du risque type, entre les données con- statistiquement significative et il existe une nette relation cernant le pouvoir cancérogène du composé et celles, dose-réponse. On a quelquefois observé des tumeurs à limitées, dont on dispose au sujet des concentrations des doses ou concentrations non toxiques et dès les 7 à calculées et mesurées, notamment au voisinage des 12 mois suivant le début de l’exposition. On en a sources d’émission ponctuelles, on estime que le risque également observé au bout de 45 semaines dans la sur ces sites est >10–5. progéniture exposée lors d’une étude toxicologique sur la reproduction portant sur plusieurs générations. S’agissant de la caractérisation du risque environ- nemental type, la concentration dans les eaux résiduaires Toutes les études épidémiologiques disponibles industrielles après traitement est inférieure à la valeur n’ont pas mis systématiquement en évidence une aug- estimative à effet nul (ENEV) pour l’organisme aquatique mentation des cancers. Cependant il est impossible de le plus sensible et la concentration maximale calculée (à procéder à une comparaison quantitative valable entre proximité d’une usine chimique) est inférieure à l’ENEV ces résultats et ceux de l’expérimentation animale, car on pour l’organisme terrestre le plus sensible. ne possède pas suffisamment d’informations sur le mode d’induction des tumeurs cérébrales, les données sur l’exposition des travailleurs lors des enquêtes en ques- tion sont relativement maigres et les limites de confiance des SMR (taux comparatifs de mortalité) qui ressortent des études épidémiologiques pour des cancers pouvant être pris en considération présentent une forte dispersion.

Si, en ce qui concerne la génotoxicité, les nom- breuses études portant sur l’examen d’effets très variés tant in vitro, avec ou sans activation métabolique, qu’ in vivo chez la souris et le rat, donnent des résultats mitigés pour l’acrylonitrile, son métabolite, l’oxyde de 2-cyano- éthylène, est par contre clairement mutagène. Même si les résultats disponibles ne fournissent pas de preuve directe, on peut raisonnablement penser que l’action cancérogène de l’acrylonitrile est due à une interaction avec le matériel génétique. En ce qui concerne les autres modes d’induction tumorale possibles, les données sont insuffisantes. L’acrylonitrile et son époxyde peuvent réagir avec les macromolécules.

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

48 Acrylonitrile

RESUMEN DE ORIENTACIÓN toneladas al año), los Estados Unidos (alrededor de 1,5 millones de toneladas al año) y el Japón (unos 0,6 mil- lones de toneladas al año). Este CICAD sobre el acrilonitrilo, preparado conjuntamente por la Dirección de Higiene del Medio del El acrilonitrilo se libera en el medio ambiente Ministerio de Sanidad del Canadá y la División de fundamentalmente a partir de la producción química y las Evaluación de Productos Químicos Comerciales del industrias de productos químicos y plásticos (>95% en Ministerio de Medio Ambiente del Canadá, se basa en la el país de muestra). No hay fuentes naturales conocidas. documentación preparada al mismo tiempo como parte El acrilonitrilo se distribuye sobre todo en los del Programa de Sustancias Prioritarias en el marco de la compartimentos del medio ambiente en los cuales se Ley Canadiense de Protección del Medio Ambiente libera (es decir, aire o agua), siendo el desplazamiento (CEPA). Las evaluaciones de sustancias prioritarias hacia el suelo, los sedimentos o la biota limitado; los previstas en la CEPA tienen por objeto valorar los principales mecanismos de eliminación son la reacción y efectos potenciales para la salud humana de la exposi- la advección. En estudios limitados en el país en el cual ción indirecta en el medio ambiente general, así como los se basa la caracterización del riesgo de muestra (es decir, efectos ecológicos. En estos exámenes se incluyen los el Canadá), se ha detectado acrilonitrilo en el medio datos identificados hasta el 31 de mayo de 1998 (efectos ambiente general sólo en las cercanías de fuentes en el medio ambiente) y abril de 19981 (efectos en la industriales. salud humana). Se consultaron también los exámenes siguientes: US EPA (1980, 1985), IPCS (1983), ATSDR La exposición al acrilonitrilo en el lugar de trabajo (1990), CIIC (1999) y CE (2000). La información relativa al se produce durante su producción y utilización en la carácter del examen colegiado y la disponibilidad del fabricación de otros productos; el mayor potencial se da documento original (Ministerio de Medio Ambiente del en el segundo caso, donde el compuesto puede no ser Canadá & Ministerio de Sanidad del Canadá, 2000) figura fácil de contener. Según datos recientes para los países en el apéndice 1. La información sobre el examen de la Unión Europea, la exposición media ponderada por 3 colegiado de este CICAD aparece en el apéndice 2. Este el tiempo es #0,45 ppm (1 mg/m ) durante la producción 3 CICAD se aprobó como evaluación internacional en una y #1,01 ppm (2,2 mg/m ) en diversos usos finales. reunión de la Junta de Evaluación Final celebrada en Ginebra (Suiza) del 8 al 12 de enero de 2001. La lista de El acrilonitrilo se absorbe con rapidez por todas las participantes en esta reunión figura en el apéndice 3. La vías de exposición y se distribuye en todos los tejidos ficha internacional de seguridad química (ICSC 0092) examinados. Es poco probable que se acumule de manera para el acrilonitrilo, preparada por el Programa significativa en un órgano determinado, excretándose la Internacional de Seguridad de las Sustancias Químicas mayor parte del compuesto en la orina, principalmente (IPCS, 1993), también se reproduce en este documento. como metabolitos, en las primeras 24-48 horas después de la administración. Los datos disponibles coinciden en El acrilonitrilo (CAS Nº 107-13-1) es un líquido indicar que la conjugación con el glutatión es la principal volátil, inflamable, soluble en agua a temperatura vía de desintoxicación, mientras que la oxidación a óxido ambiente. La inmensa mayoría del acrilonitrilo se utiliza de 2-cianoetileno se considera una vía de activación. en el Canadá como materia prima o coadyuvante químico en la producción de caucho de nitrilo-butadieno y en Los datos disponibles de estudios en animales polímeros de acrilonitrilo-butadieno-estireno y estireno- indican que el acrilonitrilo es un irritante cutáneo, acrilonitrilo. La capacidad mundial estimada en 1993 era respiratorio y ocular grave. Puede provocar dermatitis de unos 4 millones de toneladas. Las principales zonas alérgica por contacto, pero no se dispone de datos de producción son la Unión Europea (>1,25 millones de adecuados para evaluar su capacidad de sensibilización. Con la excepción de la toxicidad en el desarrollo, para la cual no se han observado efectos (fetotóxicos y terato- génicos) a concentraciones que no eran tóxicas para las madres, los datos disponibles sobre otros efectos no 1 Se ha incluido nueva información destacada por los neoplásicos en animales de experimentación no son examinadores y obtenida en una búsqueda bibliográfica suficientes para caracterizar la exposición-respuesta. En realizada antes de la reunión de la Junta de Evaluación Final un pequeño número de estudios en poblaciones para señalar sus probables repercusiones en las conclusiones humanas en los que se han investigado de manera esenciales de esta evaluación principalmente con objeto de sistemática los efectos no neoplásicos del acrilonitrilo, establecer la prioridad para su examen en una actualización. sólo se ha notificado la presencia continuada de Se ha añadido información más reciente, no esencial para la irritación cutánea aguda. caracterización del peligro o el análisis de la exposición- respuesta, que a juicio de los examinadores aumentaba su valor informativo.

49 Concise International Chemical Assessment Document 39

De los estudios en animales cabe deducir que el espinal en ratas expuestas por inhalación. Esto equivale cáncer es el efecto final crítico del acrilonitrilo para la a un riesgo unitario de 8,3 × 10–3 por mg/m3. salud humana. Se ha observado de manera constante una serie de tumores en ratas - en particular del sistema Aunque limitados, los datos disponibles son com- nervioso central (cerebro y/o médula espinal), el patibles con el hecho de que el aire es el principal medio conducto auditivo, el tracto gastrointestinal y las de exposición de la población general al acrilonitrilo; la glándulas mamarias - tras la ingestión o la inhalación. En ingesta a partir de otros medios probablemente es insig- casi todas las biovaloraciones adecuadas se ha nificante en comparación. El objetivo principal de la notificado un mayor número de astrocitomas del cerebro caracterización del riesgo para la salud humana es la y la médula espinal, que raramente se observan de forma población expuesta mediante el aire en las proximidades espontánea, correspondiendo siempre a éstos la de fuentes industriales. Basándose en los márgenes incidencia más alta en todos los estudios. El aumento ha entre la potencia carcinogénica y los limitados datos sido estadísticamente significativo y se han observado disponibles sobre las concentraciones de acrilonitrilo tendencias claras de dosis-respuesta. Se han notificado previstas y medidas principalmente en las cercanías de a veces tumores con dosis o concentraciones no tóxicas fuentes puntuales en la caracterización del riesgo de y ya a los 7-12 meses del comienzo de la exposición. Se muestra, los riesgos en estos lugares son >10–5. han detectado asimismo tumores en crías expuestas en un estudio de reproducción multigeneracional a las En la caracterización del riesgo de muestra para el 45 semanas. medio ambiente, los niveles en las aguas residuales tratadas son inferiores al valor sin efectos estimados En los estudios epidemiológicos disponibles no se (ENEV) para el organismo acuático más sensible y los ha observado de manera constante un aumento de la niveles máximos pronosticados (cerca de una fábrica de aparición de cáncer. Sin embargo, no se puede realizar elaboración de la industria química) son inferiores al una comparación cuantitativa válida de los resultados de ENEV para el organismo terrestre más sensible. estas investigaciones con los obtenidos en estudios en animales, debido a la falta de datos adecuados sobre el mecanismo de inducción de tumores cerebrales, la relativa escasez de datos sobre la exposición de los trabajadores en las investigaciones pertinentes y el amplio intervalo de los límites de confianza para las razones normalizadas de mortalidad en los casos de cáncer de posible interés en los estudios epidemiológi- cos.

En numerosos estudios sobre la genotoxicidad del acrilonitrilo con un examen de un amplio espectro de efectos finales, tanto in vitro, con activación metabólica y sin ella, como in vivo, en ratones y ratas, los resultados han sido bastante variables, mientras que su metabolito, el óxido de cianoetileno, es mutagénico. Aunque no hay pruebas directas, según los datos disponibles, es razonable suponer que la inducción de tumores por el acrilonitrilo está relacionada con la interacción directa con material genético. El valor probatorio para otros posibles mecanismos de inducción de tumores es insuficiente. El acrilonitrilo o su epóxido pueden reaccionar con macromoléculas.

El cáncer se considera el efecto final crítico para la cuantificación de la exposición-respuesta en la caracter- ización del riesgo del acrilonitrilo. La concentración inductora de tumores más baja (CT05, concentración que produce un aumento del 5% en la incidencia de tumores sobre el nivel basal) (valor equivalente humano) fue de 2,7 ppm (6,0 mg/m3) para la incidencia combinada de tumores benignos y malignos del cerebro y/o la médula

50 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)

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