-TOLUIDINE - who.int · The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International

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

Concise International Chemical Assessment Document 7

o-TOLUIDINE

First draft prepared byDr N. Gregg, Health & Safety Executive, Liverpool, United Kingdom, Dr S. Dobson, Institute of Terrestrial Ecology, Cambridgeshire, United Kingdom, andMr R. Cary, Health & Safety Executive, Liverpool, United Kingdom

Please note that the layout and pagination of this pdf file are not identical to the printedCICAD

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

World Health OrganizationGeneva, 1998

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

The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) wasestablished in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO,the United Nations Industrial Development Organization, and the Organisation for Economic Co-operationand Development (Participating Organizations), following recommendations made by the 1992 UNConference on Environment and Development to strengthen cooperation and increase coordination in thefield of chemical safety. The purpose of the IOMC is to promote coordination of the policies andactivities pursued by the Participating Organizations, jointly or separately, to achieve the soundmanagement of chemicals in relation to human health and the environment.

WHO Library Cataloguing in Publication Data

o-Toluidine.

(Concise international chemical assessment document ; 7)

1.Toluidines – toxicity 2.Toluidines – adverse effects3.Occupational exposure I.International Programme on ChemicalSafety II.Series

ISBN 92 4 153007 3 (NLM Classification: QV 235)ISSN 1020-6167

The World Health Organization welcomes requests for permission to reproduce or translate itspublications, in part or in full. Applications and enquiries should be addressed to the Office ofPublications, World Health Organization, Geneva, Switzerland, which will be glad to provide the latestinformation on any changes made to the text, plans for new editions, and reprints and translations alreadyavailable.

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

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iii

TABLE OF CONTENTS

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

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

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

3. ANALYTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

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

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

6.1 Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.2 Human exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS ANDHUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . 6

8.1 Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68.2 Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68.3 Short-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68.4 Chronic exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68.5 Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88.6 Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88.7 Immunological and neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

9. EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . . 9

11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

11.1 Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

11.1.1 Hazard identification and dose–response assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 11.1.2 Criteria for setting guidance values for o-toluidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 11.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011.2 Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

13.1 Human health hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013.2 Advice to physicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013.3 Health surveillance advice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013.4 Spillage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10


iv

INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

APPENDIX 1 — SOURCE DOCUMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

APPENDIX 2 — CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

APPENDIX 3 — CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

RÉSUMÉ D’ORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

RESUMEN DE ORIENTACIÓN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

o-Toluidine

1

FOREWORD

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

CICADs are concise documents that providesummaries of the relevant scientific informationconcerning the potential effects of chemicals uponhuman health and/or the environment. They are basedon selected national or regional evaluation documents oron existing EHCs. Before acceptance for publication asCICADs by IPCS, these documents have undergoneextensive peer review by internationally selected expertsto ensure their completeness, accuracy in the way inwhich the original data are represented, and the validityof the conclusions drawn.

The primary objective of CICADs is character-ization of hazard and dose–response from exposure to achemical. CICADs are not a summary of all availabledata on a particular chemical; rather, they include onlythat information considered critical for characterizationof the risk posed by the chemical. The critical studiesare, however, presented in sufficient detail to supportthe conclusions drawn. For additional information, thereader should consult the identified source documentsupon which the CICAD has been based.

Risks to human health and the environment willvary considerably depending upon the type and extentof exposure. Responsible authorities are stronglyencouraged to characterize risk on the basis of locallymeasured or predicted exposure scenarios. To assist thereader, examples of exposure estimation and riskcharacterization are provided in CICADs, wheneverpossible. These examples cannot be considered asrepresenting all possible exposure situations, but areprovided as guidance only. The reader is referred toEHC 1701 for advice on the derivation of health-basedguidance values.

While every effort is made to ensure that CICADsrepresent the current status of knowledge, new informa-tion is being developed constantly. Unless otherwise

stated, CICADs are based on a search of the scientificliterature to the date shown in the executive summary. Inthe event that a reader becomes aware of new infor-mation that would change the conclusions drawn in aCICAD, the reader is requested to contact the IPCS toinform it of the new information.

Procedures

The flow chart shows the procedures followed toproduce a CICAD. These procedures are designed totake advantage of the expertise that exists around theworld — expertise that is required to produce the high-quality evaluations of toxicological, exposure, and otherdata that are necessary for assessing risks to humanhealth and/or the environment.

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

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

The CICAD Final Review Board has severalimportant functions:

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

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

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

– to approve CICADs as international assessments.

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

1 International Programme on Chemical Safety (1994)Assessing human health risks of chemicals: derivationof guidance values for health-based exposure limits.Geneva, World Health Organization (EnvironmentalHealth Criteria 170).


2

SELECTION OF HIGH QUALITYNATIONAL/REGIONAL

ASSESSMENT DOCUMENT(S)

CICAD PREPARATION FLOW CHART

FIRST DRAFTPREPARED

PRIMARY REVIEW AT PRODUCER LEVEL(1-2 OTHER DOCUMENT PRODUCERS) 1

PRODUCER

REVIEW BY IPCS CONTACT POINTS

FINAL REVIEW BOARD 3

FINAL DRAFT 4

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

RESPONSIBLE OFFICER

(RO)

SELECTION OF PRIORITY CHEMICAL

1 Revision as necessary.2 Taking into account the comments from reviewers.3 The second draft of documents is submitted to the Final Review Board together with the reviewers’ comments (6-10 CICADs are usually reviewed atthe Final Review Board). In the case of pesticides the role of the Final Review Board is fulfilled by a joint meeting on pesticides.4 Includes any revisions requested by the Final Review Board.

REVIEW OF COMMENTS (PRODUCER/RO ),PREPARATION

OF SECOND DRAFT 2

o-Toluidine

3

a meeting and the need for balanced geographicrepresentation.

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


4

NH2

CH3

1. EXECUTIVE SUMMARY

This CICAD on ortho-toluidine (o-toluidine) wasbased on a review of primarily occupational humanhealth concerns, prepared by the United KingdomHealth & Safety Executive (Gregg et al., 1996) andcovering data identified up to March 1992. Additionalinformation identified during the international peerreview of this CICAD and following consideration by theFinal Review Board has been incorporated asappropriate. Information on the preparation and peerreview of the source document is presented in Appendix1. Information on the peer review of this CICAD ispresented in Appendix 2. This CICAD was approved forpublication at a meeting of the Final Review Board, heldin Brussels, Belgium, on 18–20 November 1996. Participants at the Final Review Board meeting are listedin Appendix 3. The International Chemical Safety Card(ICSC 0341) for o-toluidine, produced by the Inter-national Programme on Chemical Safety (IPCS, 1993), hasalso been reproduced in this document.

o-Toluidine (CAS no. 95-53-4) is a syntheticchemical that is a light yellow liquid at ambient temper-ature. It is used primarily in the manufacture of dye-stuffs, although it is also used in the production ofrubber, chemicals, and pesticides and as a curing agentfor epoxy resin systems.

o-Toluidine is of moderate to low acute toxicityand has the potential to produce minimal skin irritationand mild eye irritation. Information is not available onthe skin or respiratory sensitization potential of o-tolui-dine. The principal signs of toxicity following acute andshort-term exposure to this chemical are methaemo-globinaemia and related effects in the spleen. Theseeffects have been observed in rats administered o-tolui-dine at 225 mg/kg body weight per day for 5 days; a no-observed-adverse-effect level has not been identified.

In several carcinogenicity studies in which o-tolui-dine was administered orally to rats and mice, there wasa significant increase in the incidence of benign andmalignant tumours in various tissues. o-Toluidine isgenerally not mutagenic in standard bacterial mutageni-city tests, but it is clastogenic in mammalian cells invitro. There is uncertainty concerning the genotoxicityof o-toluidine in vivo; however, some positive resultshave been reported. Based upon the wide distribution oftumours observed in o-toluidine-exposed animals, aswell as the clastogenic activity observed in mammalianin vitro assays, o-toluidine may be acting as a genotoxiccarcinogen. Information relevant to assessing the risksof reproductive or developmental effects of o-toluidinewas not identified.

Owing to the lack of relevant data on exposure, itwas not possible to assess risks to human health associ-ated with indirect exposure to o-toluidine present in thegeneral environment. In the occupational environment,there is the potential for significant risks of carcinogenicand genotoxic effects. Useful data on concentrations ofo-toluidine in various environmental media and on itseffects on aquatic and terrestrial organisms were notidentified, and therefore it was not possible to assess therisks of exposure of environmental organisms to o-tolui-dine.

2. IDENTITY AND PHYSICAL/CHEMICALPROPERTIES

o-Toluidine (CAS no. 95-53-4; C7H9N; 1-amino-2-methylbenzene, 2-aminotoluene, o-methylaniline), asynthetic chemical described as having an “aromatic”odour, exists at ambient temperature as a light yellowliquid that rapidly darkens on exposure to air and light. o-Toluidine has a boiling point of 200°C, a melting pointof !16°C, and a vapour pressure of 0.2 kPa at 20°C. o-Toluidine is completely miscible with ethanol anddiethyl ether; its solubility in water is poor. Additionalphysical/chemical properties are presented in theInternational Chemical Safety Card reproduced in thisdocument. The structural formula for o-toluidine is:Although some toxicological studies on o-toluidine haveemployed its hydrochloride salt (o-toluidine hydro-chloride), this is unlikely to significantly alter theobserved health effects of the parent chemical.

3. ANALYTICAL METHODS

Short- and long-term personal monitoring can beundertaken by pumped sampling either through acid-coated filters or through NIOSH-type silica gel tubes(NIOSH, 1987; HSE, 1993). The filters are desorbed witha neutralizing solution and analysed by high-performance liquid chromatography; the tubes aredesorbed with solvent and analysed by gas chroma-tography. Screening measurements may be conductedusing a colorimetric detector tube.

The analytical monitoring of urine for o-toluidineand its metabolites may be a useful means of assessing

o-Toluidine

5

occupational exposure, especially where there is poten-tial for skin absorption. Methods for biological monitor-ing of occupationally exposed individuals have beenreported (Brown et al., 1995; Ward et al., 1996). Thesetechniques employ urine sampling for the determinationof o-toluidine and its N-acetyl metabolites and bloodsampling for the detection of o-toluidine–haemoglobinadducts.

The determination of o-toluidine in water samplesmay involve extraction under acidic and alkali condi-tions, followed by brominated ether extraction andsubsequent analysis using gas chromatography withelectron capture detection (detection limit 0.1–0.6:g/litre). The analysis of o-toluidine in sediment mayinvolve steam distillation under alkali conditions withquantitation by gas chromatography coupled with elec-tron capture detection (detection limit 0.002–0.012 :g/gdry matter).

4. SOURCES OF HUMAN ANDENVIRONMENTAL EXPOSURE

The principal use of o-toluidine worldwide is in themanufacture of dyestuffs, although it is also used in theproduction of rubber, chemicals, and pesticides and as acuring agent for epoxy resin systems. o-Toluidine isalso used as a corrosion inhibitor in paint formulationsand possibly has limited uses in analytical laboratoryprocedures. There are no known domestic or householduses for o-toluidine.

Global production data for o-toluidine were notidentified. In the USA in 1975, more than 900 t of thechemical were produced, and another 1000 t wereimported. Total production of o-toluidine in Great Britainis approximately 6000 t per year, 90% of which isexported. Approximately 610 and 545 t of o-toluidinewere imported into Japan in 1992 and 1993, respectively.

5. ENVIRONMENTAL TRANSPORT,DISTRIBUTION, AND TRANSFORMATION

Using an equilibrium model to assess partitioningbetween environmental media, Yoshida et al. (1983)estimated the distribution of o-toluidine to be 14.5% toair, 83.3% to water, 0.4% to soil, 1.9% to sediment, 2.3 ×10–5 % to biota (fish), and 0.21% to suspended sediment. The half-life for o-toluidine in Rhine River water wasestimated to be about 1 day (Zoeteman et al., 1980).

6. ENVIRONMENTAL LEVELS ANDHUMAN EXPOSURE

6.1 Environmental levels

o-Toluidine was detected in 3/46 samples of RhineRiver water collected at the Germany–Netherlands borderin 1979; the mean and maximum concentrations were 0.03and 1.8 :g/litre, respectively (Wegman & de Korte,1981). o-Toluidine was detected in water collected froma shallow aquifer contaminated by coal tar wastes in theUSA; however, concentrations were not reported(Pereira et al., 1983).

In Japan, 8/68 samples of surface water collected in1976 contained o-toluidine (detection limit 0.1–0.6:g/litre) at levels ranging from 0.14 to 20 :g/litre; 27samples of sediment collected in the same year con-tained o-toluidine (detection limit 0.002–0.012 mg/kg) atconcentrations ranging from 0.002 to 0.013 mg/kg dryweight (J. Sekizawa, personal communication, 1996). o-Toluidine was not detected (detection limit 0.05–150ng/m3) in 72 samples of air collected in Japan in 1985(J. Sekizawa, personal communication, 1996).

6.2 Human exposure

Exposure of the general population to o-toluidinepresent in the environment could not be estimated,owing to the lack of relevant data on levels of thischemical in air, drinking-water, and foodstuffs. Informa-tion on human exposure to o-toluidine is limited tooccupational settings.

In the United Kingdom in 1992, approximately 120individuals were potentially exposed to o-toluidineduring activities involving its manufacture and use;about a quarter of these were maintenance rather thanprocess workers. Eight-hour time-weighted-averageexposures to o-toluidine in seven different industries inthe United Kingdom ranged from 0.007 to 2.7 ppm(0.03–11.8 mg/m3); all but one of these exposures were#0.3 ppm (#1.3 mg/m3). A concentration of 2.7 ppm (11.8


6

mg/m3) o-toluidine was measured at a site involvingcentrifugation at high temperature. If it is assumed that aworker weighing 70 kg breathes 10 m3 of air during atypical working day and that inhaled o-toluidine iscompletely absorbed, exposure to o-toluidine at aconcentration of 1.3 mg/m3 in workplace air can be esti-mated to result in a daily o-toluidine intake of approxi-mately 0.2 mg/kg body weight. Exposure to o-toluidineassociated with some processes conducted at elevatedtemperatures (i.e. exposure to o-toluidine at 11.8 mg/m3)can be estimated to result in a daily o-toluidine intake ofapproximately 1.7 mg/kg body weight. Dermal exposureto o-toluidine may also occur in the occupationalenvironment; however, quantitative data were notidentified.

7. COMPARATIVE KINETICS ANDMETABOLISM IN LABORATORY ANIMALS

AND HUMANS

Biological monitoring to assess human exposure too-toluidine indicates that absorption may occur throughinhalation and dermal contact; however, quantitativeinformation was not identified. o-Toluidine binds tohaemoglobin (Ward et al., 1996). N-acetylatedmetabolites of o-toluidine are eliminated in the urine(Brown et al., 1995).

In laboratory animals, studies on the kinetics andmetabolism of o-toluidine have involved rats exposedorally or via dermal contact. There is extensive absorp-tion (at least 92% of the administered oral dose) of o-toluidine from the gastrointestinal tract (Cheever et al.,1980). Limited dermal absorption was reported in a poor-quality study (Senczuk et al., 1984), although thestructure of o-toluidine suggests that, like other aromaticamines, it is lipid soluble and therefore likely to bereadily absorbed through the skin. Oral and subcuta-neous studies have revealed that o-[14C]toluidine and itsmetabolites are excreted mainly in the urine, with at least90% of the administered radioactivity appearing in theurine within 72 hours after exposure (Son et al., 1977;Cheever et al., 1980). Small amounts of radioactivitywere also detected in the faeces and exhaled carbondioxide. Up to one-third of the o-toluidine administeredwas recovered unchanged in the urine. The metabolismof o-toluidine is characterized principally by ringhydroxylation and N-acetylation, the major metabolitesbeing 4-amino-m-cresol and, to a lesser extent, N-acetyl-4-amino-m-cresol (Son et al., 1977; Cheever et al., 1980). Sulfate conjugates of o-toluidine predominate overglucuronide conjugates. Binding of o-toluidine

metabolites to haemoglobin has also been observed inrats (Birnier & Neumann, 1988).

8. EFFECTS ON LABORATORYMAMMALS AND IN VITRO TEST SYSTEMS

8.1 Single exposure

o-Toluidine is harmful following acute oralexposure (LD50s of 900 and 940 mg/kg body weight inrats) and is of low acute toxicity following dermalexposure (LD50 of 3235 mg/kg body weight in rabbits)(Smyth et al., 1962; Jacobson, 1972). Acute effectsinclude cyanosis, increased methaemoglobin levels, andrelated effects in the spleen. Useful data on effectsassociated with inhalation exposure were not identified.

8.2 Irritation and sensitization

Minimal skin irritation and ill-defined eye irritationhave been observed in o-toluidine-exposed rabbits(Smyth et al., 1962). There is no information available onthe skin or respiratory sensitization potential ofo-toluidine in animals.

8.3 Short-term exposure

A 13% decrease in body weight, a 1.5- to 3.0-foldincrease in spleen weight, increased methaemoglobinlevels, and congestion, haemosiderosis, and haemato-poiesis in the spleen (all likely associated with met-haemoglobinaemia) were observed in rats orallyadministered o-toluidine for 5 days at a dose of 225mg/kg body weight per day (Short et al., 1983); no otherdoses were tested, and a no-effect level was not iden-tified. Relevant toxicity studies involving short-terminhalation or dermal exposure to o-toluidine were notidentified.

8.4 Chronic exposure and carcinogenicity

Increased incidences of benign and malignanttumours have been observed in rats and mice admin-istered o-toluidine hydrochloride in the diet.

In one study, groups of 50 male and 50 female F344rats were given diets containing 3000 or 6000 ppm(mg/kg) o-toluidine hydrochloride for 101–104 weeks(equivalent to intakes of approximately 150 and 300mg/kg body weight per day, based on a body weight of400 g and the consumption of 20 g of food per day) (NCI,1979; Goodman et al., 1984). Controls consisted of 20animals of each sex. In addition to routine clinical

o-Toluidine

7

observations, gross and microscopic examinations wereconducted on all major tissues and organs and on allgross lesions. Exposure to o-toluidine hydrochloridewas associated with a dose-related decrease in bodyweight gain and survival. In the control, low-dose, andhigh-dose groups, the combined incidence of sarcomas,angiosarcomas, and osteosarcomas of the spleen was0/20, 9/49 (p = 0.36), and 12/49 (p = 0.01), respectively, infemales and 0/20, 8/49, and 4/42, respectively, in males. The combined incidence of sarcomas, fibrosarcomas,angiosarcomas, and osteosarcomas in multiple(unspecified) organs was, among females, 0/20, 3/50, and21/49 (p < 0.001) and, among males, 0/20, 15/50 (p =0.003), and 37/49 (p < 0.001), for animals in the control,low-dose, and high-dose groups, respectively. Infemales, the incidence of transitional cell carcinomas ofthe urinary bladder in the control, low-dose, and high-dose groups was 0/20, 9/45 (p = 0.028), and 22/47(p < 0.001), respectively; the incidence of this tumourwas not significantly increased in the male rats. Theincidence of malignant mesothelioma of the serouscovering of the testes (tunica vaginalis) was 0/20, 10/50,and 6/49 in the control, low-dose, and high-dose groups,respectively. Although not observed among controlanimals, splenic fibromas were noted in the exposedanimals; however, the incidence was significantlyincreased only for males in the low-dose group (10/49;p = 0.024). For animals in the control, low-dose, andhigh-dose groups, the incidence of skin fibromas amongmales was 0/20, 28/50 (p < 0.001), and 27/49 (p < 0.001),respectively, and the incidence of mammary glandfibroadenomas among females was 6/20, 20/50, and 35/49(p = 0.002), respectively.

Non-neoplastic effects that were not observed incontrol animals included splenic fibrosis (in 12–27% and6–12% of exposed males and females, respectively),splenic mesothelial hyperplasia (in 12–37% and 24–65%of exposed males and females, respectively), hyperplasiaof the urinary bladder epithelium (in 16–18% and 28–47%of exposed males and females, respectively), and myo-cardial fibrosis (in 17–34% of exposed males). Livernecrosis was noted in 24–35% of exposed males (10% incontrols) and in 2–31% of exposed females (0% incontrols).

In a study in which groups of 30 male F344 ratsreceived 0 or 62 mg o-toluidine hydrochloride in the dieteach day for 72 weeks (approximately 470 and 130 mg/kgbody weight per day at the beginning and end of thestudy, respectively), followed by a 16-week recoveryperiod, exposure to o-toluidine reduced survival (6/30and 18/30 survivors in the exposed and control groups,respectively) (Hecht et al., 1982). Incidences of thefollowing tumours (in the control and exposed groups,respectively) were: bladder epithelial cell tumours, 0/30and 4/30; skin fibromas, 1/30 and 25/30; splenic fibromas,

0/30 and 10/30; mammary tumours, 0/30 and 13/30; andperitoneal tumours, 2/30 and 14/30. Although neither thestatistical significance of these results nor the incidenceof non-neoplastic effects was discussed in this report,the results reveal an increased occurrence of a variety oftumour types in animals administered o-toluidinehydrochloride for 72 weeks.

In another study in which several chemicals wereexamined, groups of 25 male Charles River CD rats weregiven diets containing o-toluidine hydrochloride atconcentrations of 8000 or 16 000 ppm (mg/kg) for3 months (estimated intakes of approximately 800 and1600 mg/kg body weight per day, assuming 200 g for thebody weight of rats consuming 20 g of food per day)(Weisburger et al., 1978). Excessive toxicity, based uponincreased mortality and reductions in body weight,resulted in the concentrations being reduced to 4000 and8000 ppm (mg/kg) (with estimated intakes of 400 and 800mg/kg body weight per day) for a further 15 months,followed by a 6-month observation and recovery period. Only animals that survived 6 months or more werenecropsied. Data on survival or general toxicity were notprovided. Controls included one matched group (n = 16animals) used for this portion of the overall study, aswell as the pooled controls (n = 111) from the entireinvestigation. There was a statistically significantincrease in the incidence (0/16, 18/111, 18/23, and 21/24 inthe matched control, pooled control, low-dose, and high-dose groups, respectively) of subcutaneous fibroma andfibrosarcoma in o-toluidine-exposed animals. Theincidence of bladder transitional cell carcinoma was 0/16,5/111, 3/23, and 4/24 in the matched control, pooledcontrol, low-dose, and high-dose groups, respectively.

Statistically significant increases in hepatocellular

carcinomas and adenomas, as well as haemangiosarco-mas, were observed in a study in which groups of 50male and 50 female B6C3F1 mice were given dietscontaining 1000 or 3000 ppm (mg/kg) o-toluidine hydro-chloride (estimated intakes of 110 and 340 mg/kg bodyweight per day, assuming 30 g for the body weight ofmice consuming 3.4 g of food per day) for 101–104 weeks(NCI, 1979). Twenty animals of each sex served asunexposed controls. In the control, low-dose, and high-dose groups, the incidences of hepatocellular carcinoma(in females), hepatocellular adenoma (in females), andhaemangiosarcoma (in males) were 0/20, 2/49, and 7/50;0/20, 2/49, and 6/50; and 1/19, 1/50, and 10/50,respectively.

Significantly increased incidences of haemangio-sarcomas and haemangiomas were observed in a studyin which groups of 25 male and 25 female CD-1 mice weregiven diets containing o-toluidine hydrochloride atconcentrations of 16 000 or 32 000 ppm (mg/kg) (esti-mated intakes of 1800 and 3600 mg/kg body weight per


8

day, assuming 30 g for the body weight of mice con-suming 3.4 g of food per day) for 3 months (Weisburgeret al., 1978). Excessive toxicity, based upon increasedmortality and reductions in body weight, resulted in theconcentrations being reduced to 8000 and 16 000 ppm(mg/kg) for a further 15 months, followed by a 3-monthobservation and recovery period. Only animals thatsurvived 6 months or more were necropsied. Controlsincluded one matched group used for this portion of theoverall study, as well as the pooled controls from theentire investigation. In the matched control, pooledcontrol, low-dose, and high-dose groups, the incidenceof abdominal haemangiosarcomas and haemangiomaswas 0/14, 5/99, 5/14, and 9/11 (in males) and 0/15, 9/102,5/18, and 9/21 (in females), respectively.

The results from limited (i.e. poorly conductedand/or reported) dermal and parenteral studies con-ducted in various species and from an oral toxicity studyin dogs (Morigami & Nisimura, 1940; Steinhoff, 1981;Hecht et al., 1983) do not contribute meaningfully to theassessment of o-toluidine.

8.5 Genotoxicity and related end-points

Based upon the results of assays conducted inSalmonella typhimurium and Escherichia coli, o-tolui-dine was not considered to be mutagenic in standardbacterial tests (McCann et al., 1975; Ferretti et al., 1977;Garner & Nutman, 1977; Rosenkranz & Poirier, 1979;Simmon, 1979; Zimmer et al., 1980; Baker & Bonin, 1981,1985; Garner et al., 1981; MacDonald, 1981; Martire et al.,1981; Matsushima et al., 1981; Richold & Jones, 1981;Rowland & Severn, 1981; Simmon & Shepherd, 1981;Trueman, 1981; Venitt & Crofton-Sleigh, 1981; Rexroat &Probst, 1985). However, positive results in the Amestest have been observed when norharman was added tothe test system (Nagao et al., 1978; Nagao & Takahashi,1981; Sugimura & Nagao, 1981). Results from severalcytogenetic studies have indicated that o-toluidine isclastogenic in mammalian cells in vitro (Danford, 1985;Gulati et al., 1985; Ishidate & Sofuni, 1985; Priston &Dean, 1985).

The in vivo genotoxicity of o-toluidine has beenadequately tested only in mice. No evidence of clasto-genicity was observed in several high-quality studies (abone marrow cytogenetic assay and three bone marrowmicronucleus tests) in which the chemical was injectedintraperitoneally (Salamone et al., 1981; Tsuchimoto &Matler, 1981; McFee et al., 1989). Although there was noreporting of bone marrow toxicity in these studies, use ofan intraperitoneal injection with elevated dose levelswould suggest that o-toluidine probably reached thetarget tissue (bone marrow). In contrast, in the bestconducted bone marrow sister chromatid exchangeassay, high doses of o-toluidine apparently produced

positive results in mice (McFee et al., 1989). A positiveresult has also been reported for the induction of DNAsingle strand breaks in mice; however, the poor descrip-tion of the study precludes the drawing of definitiveconclusions (Cesarone et al., 1982). Despite some sug-gestions of clastogenicity, the genotoxic potential of o-toluidine in vivo remains uncertain.

8.6 Reproductive and developmentaltoxicity

Relevant information on the reproductive anddevelopmental toxicity of o-toluidine in laboratoryanimals was not identified.

8.7 Immunological and neurologicaleffects

Relevant toxicological studies in which immuno-logical or neurological effects were assessed were notavailable. However, evidence of specific adverseimmunological and neurological effects has not beenreported in general toxicity studies.

9. EFFECTS ON HUMANS

Relevant case reports on adverse health effectsassociated with exposure to o-toluidine were notavailable.

Other than information on potential carcinogeniceffects, there are few useful data available on otherhealth-related effects associated with exposure to o-toluidine.

Exposure to chemicals including o-toluidine in thedyestuffs industry and more recently in the rubberindustry has been reported to be associated with anincreased incidence of bladder cancer. For example,expected and observed cases of bladder cancer wererecorded in a thorough, well conducted retrospectivecohort study at a rubber chemical plant in upstate NewYork (Ward et al., 1991). The cohort consisted of all 1749male and female workers employed at the plant between1973 and 1988. The work-force was relatively young;72% were born after 1 January 1939. It was estimatedthat cohort members were “slightly more likely” than thegeneral population of the USA to be current or formersmokers. These workers were exposed primarily too-toluidine and aniline. In 1988, airborne o-toluidine andaniline levels were <1 ppm (<4.4 mg/m3 for o-toluidine).

o-Toluidine

9

Based upon 13 identified cases of bladder canceramong all 1749 employees, compared with 3.61 casesexpected (estimated from the rate in the population of thestate of New York, excluding New York City), thestandardized incidence ratio (SIR) was 3.6 (90% confi-dence interval [CI] = 2.13–5.73). The SIRs for bladdercancer among workers “definitely exposed” (n = 708),“possibly exposed” (n = 288), and “probably unex-posed” (n = 753) to o-toluidine and aniline were 6.48(90% CI = 3.04–12.2; 7 observed cases), 3.66 (90% CI =1.25–8.37; 4 observed cases), and 1.39 (90% CI =0.25–4.39; 2 observed cases), respectively. The risk ofbladder cancer increased with duration of exposure andtime since first exposure. The SIRs for bladder canceramong the “definitely exposed” workers with <5, 5–9.99,and $10 years of exposure to these chemicals were 0 (0observed cases), 8.8 (90% CI = 0.45–41.7; 1 observedcase), and 27.2 (90% CI = 11.8–53.7; 6 observed cases),respectively. The SIRs for bladder cancer amongworkers with <10, 10–20, and >20 years since their firstemployment in the “definitely exposed” department ofthe plant were 0 (0 observed cases), 2.03 (90% CI =0.10–9.64; 1 observed case), and 16.4 (90% CI =7.13–32.3; 6 observed cases), respectively. It wascalculated that smoking was unlikely to account for theincreased incidence of bladder cancer in this group ofworkers. The mean latency period for the group ofseven “definitely exposed” workers with bladder cancerwas 23 years. Although the carcinogenic potential ofo-toluidine specifically cannot be definitively determinedfrom this study, the findings merit considerable concern.

Other studies of workers employed in the dye-stuffs industry include those by Vigliani & Barsotti(1961), Khlebnikova et al. (1970), Zavon et al. (1973),Conso & Pontal (1982), and Rubino et al. (1982). How-ever, as in the study of rubber chemical workers, it wasnot possible to definitively link the increased incidenceof bladder cancer specifically to o-toluidine because ofconcurrent exposure to other chemicals.

10. EFFECTS ON OTHER ORGANISMS INTHE LABORATORY AND FIELD

Relevant information on the effects of o-toluidineon aquatic or terrestrial organisms was not identified. However, toxicity thresholds for the inhibition of algalgrowth (Microcystis aeruginosa, 0.31 mg/litre; Scene-

desmus quadricauda, 6.3 mg/litre) have been reported.1

11. EFFECTS EVALUATION

11.1 Evaluation of health effects

11.1.1 Hazard identification and dose–responseassessment

Available data are inadequate to allow the poten-tial risks of reproductive or developmental effects onhuman health to be assessed. Carcinogenicity is consid-ered, however, to be the critical effect associated withpotential exposure to o-toluidine. In several experimentalstudies, the oral administration of o-toluidine hydro-chloride increased the incidence of benign and/ormalignant tumours in various tissues in rats (spleensarcomas and fibromas in males and females, mesotheli-omas of the scrotum in males, transitional cell carcino-mas of the urinary bladder in females, skin fibromas andmammary gland fibroadenomas in males and females,respectively). Clear evidence of carcinogenicity has alsobeen observed in oral studies in mice (hepatocellularcarcinomas and adenomas, haemangiosarcomas, andhaemangiomas). Even where the increased tumourincidences were not statistically significant, they wereconsidered to be of biological significance in view of thelow incidences of such tumours in historical controls(Haseman et al., 1990). o-Toluidine is genotoxic in vitro;although the genotoxicity studies conducted in vivo donot allow definite conclusions to be drawn, there is someevidence of genotoxic potential. Carcinogenicity studiesin rats and mice have yielded tumours in both sexes andin multiple organs; therefore, the possibility ofinvolvement of a genotoxic mechanism cannot beeliminated.

Several studies of workers employed in the dye-stuffs and rubber industries found that exposure tochemicals, including o-toluidine, appears to be associ-ated with an increased incidence of bladder cancer. Although it is difficult to draw definite conclusionsregarding the carcinogenic potential of o-toluidine inhumans from these studies of workers exposed tomultiple chemicals, this evidence, together with datafrom experimental carcinogenicity bioassays, raisesconcern about the risk of cancer in exposed humans. Itwould therefore be prudent to consider that o-toluidineis probably carcinogenic in humans, possibly throughinvolvement of a genotoxic mechanism.

11.1.2 Criteria for setting guidance values foro-toluidine

On the basis that the carcinogenicity of o-toluidinemay involve a genotoxic mechanism, it is not possible toreliably identify a threshold at which exposure to o-tolui-dine would not result in some risk to human health.

1 Source: EnviChem Data Bank of EnvironmentalProperties of Chemicals. Helsinki, Finland, FinnishEnvironment Agency, version 1.0, 1995.


10

11.1.3 Sample risk characterization

It is recognized that there are a number of differentapproaches to assessing the risks to human healthposed by genotoxic and carcinogenic substances. Insome jurisdictions, there are models for characterizingpotency, which may be of some benefit in priority-setting schemes.

The example here is from the occupational environ-ment, as the lack of available data precludes thecharacterization of potential cancer risks for the generalpopulation. In the United Kingdom, a MaximumExposure Limit for o-toluidine (which is not a health-based standard) of 0.2 ppm (0.9 mg/m3; 8-hour time-weighted average) has been proposed. The MaximumExposure Limit was based on a level of control that wasdeemed (by tripartite agreement) to be reasonablypracticable under workplace conditions within theUnited Kingdom. In the United Kingdom, there is acontinuing remit to reduce exposure levels as much asreasonably practicable with the technology that iscurrently available.

11.2 Evaluation of environmental effects

The lack of available information precludesadequate assessment of potential risks to environmentalorganisms.

12. PREVIOUS EVALUATIONS BYINTERNATIONAL BODIES

The International Agency for Research on Cancer(IARC, 1987) has classified o-toluidine in Group 2B(possibly carcinogenic to humans), based uponsufficient evidence for carcinogenicity in animals andinadequate evidence for carcinogenicity in humans.

Information on international hazard classificationand labelling is included in the International ChemicalSafety Card reproduced in this document.

13. HUMAN HEALTH PROTECTION ANDEMERGENCY ACTION

Human health hazards, together with preventative

and protective measures and first aid recommendations,are presented in the International Chemical Safety Card(ICSC 0341) reproduced in this document.

13.1 Human health hazards

Following short-term exposure, o-toluidine couldinduce methaemoglobinaemia. After long-term orrepeated exposure, o-toluidine is considered possiblycarcinogenic to humans.

13.2 Advice to physicians

If splashed with o-toluidine, it is crucial to removeall wet or contaminated clothing and wash the entirebody with soap and water. Following such an incident,the degree of methaemoglobinaemia needs to bedetermined hourly until a decrease is well established. Above 30% methaemoglobinaemia, administer oxygenunder continuous observation; above 50% methaemo-globinaemia, further administer intravenously 1000 cc ofa 5% glucose solution containing ascorbic acid; above60% methaemoglobinaemia, further administer intra-venously 10–20 cc of a 1% solution of methylene blue. If there is no response to treatment with methylene blue,then haemodialysis or exchange transfusion is useful.

13.3 Health surveillance advice

For workers exposed to o-toluidine, a healthsurveillance programme should include regular urinarycytology, with more specific procedures in the case ofpositive results.

13.4 Spillage

In the event of spillage, measures should beundertaken to prevent this chemical from reaching drainsand watercourses.

14. CURRENT REGULATIONS,GUIDELINES, AND STANDARDS

Information on national regulations, guidelines,and standards is available from the International Registerof Potentially Toxic Chemicals (IRPTC) legal file.

The reader should be aware that regulatory deci-sions about chemicals taken in a certain country can befully understood only in the framework of the legislationof that country. The regulations and guidelines of allcountries are subject to change and should always beverified with appropriate regulatory authorities beforeapplication.

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

© IPCS 1999

SEE IMPORTANT INFORMATION ON THE BACK.

IPCSInternationalProgramme onChemical Safety

ortho-TOLUIDINE 0341March 1995

CAS No: 95-53-4RTECS No: XU2975000UN No: 1708EC No:

1-Amino-2-methylbenzene2-Aminotolueneo-MethylanilineC7H9N / C6H4CH3NH2

Molecular mass: 107.2

TYPES OFHAZARD/EXPOSURE

ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING

FIRE Combustible. Gives off irritating ortoxic fumes (or gases) in a fire.

NO open flames. NO contact withnitric acid.

Powder, AFFF, foam, carbondioxide.

EXPLOSION Above 85�C explosive vapour/airmixtures may be formed.

Above 85�C use a closed system,ventilation.

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

EXPOSURE AVOID ALL CONTACT! IN ALL CASES CONSULT ADOCTOR!

Inhalation Blue lips or finger nails. Blue skin.Confusion. Dizziness. Headache.Shortness of breath. Weakness.

Ventilation, local exhaust, orbreathing protection.

Fresh air, rest. Artificial respirationif indicated. Refer for medicalattention.

Skin MAY BE ABSORBED! Redness.Blue lips or fingernails. Blue skin(Further see Inhalation).

Protective gloves. Protectiveclothing.

Remove contaminated clothes.Rinse and then wash skin withwater and soap. Refer for medicalattention.

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

Ingestion Blue lips or fingernails. Blue skin.Dizziness. Headache. Labouredbreathing (further see Inhalation).

Do not eat, drink, or smoke duringwork.

Rinse mouth. Induce vomiting(ONLY IN CONSCIOUSPERSONS!). Refer for medicalattention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Collect leaking and spilled liquid in sealablecontainers as far as possible. Absorb remainingliquid in sand or inert absorbent and remove to safeplace (extra personal protection: completeprotective clothing including self-containedbreathing apparatus).

SymbolR:S:UN Hazard Class: 6.1UN Pack Group: II

Do not transport with food andfeedstuffs.

EMERGENCY RESPONSE STORAGE

NFPA Code: H3; F2; R0 Separated from strong oxidants, strong acids, food and feedstuffs. Cool.Dry. Well closed. Ventilation along the floor.

Boiling point: 200�CMelting point: -16�CRelative density (water = 1): 1.01Solubility in water: poorVapour pressure, kPa at 20�C: 0.2Relative vapour density (air = 1): 3.7

Relative density of the vapour/air-mixture at 20�C (air = 1): 1.00Flash point: 85�C c.c. Auto-ignition temperature: 482�CExplosive limits, vol% in air: 1.5-?Octanol/water partition coefficient as log Pow: 1.32

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 1999

0341 ortho-TOLUIDINE

IMPORTANT DATA

Physical State; AppearanceCOLOURLESS TO YELLOW LIQUID, TURNSREDDISH-BROWN ON EXPOSURE TO AIR AND LIGHT.

Chemical DangersThe substance decomposes on heating or on burningproducing toxic fumes including nitrogen oxides. Reacts withstrong oxidants, especially nitric acid.

Occupational Exposure LimitsTLV: 2 ppm; 8.8 mg/m3 (as TWA) A2 (skin) (ACGIH1994-1995).

Routes of ExposureThe substance can be absorbed into the body by inhalationand through the skin, and by ingestion.

Inhalation RiskEvaporation at 20�C is negligible; a harmful concentration ofairborne particles can, however, be reached quickly onspraying.

Effects of Short-term ExposureThe substance irritates the eyes and the skin. The substancemay cause effects on the blood, bladder and kidneys, resultingin tissue lesions, impaired functions and formation ofmethaemoglobin. Exposure to high concentrations may resultin damage to kidneys and bladder. The effects may bedelayed. Medical observation is indicated. See Notes.

Effects of Long-term or Repeated ExposureThe substance may have effects on the blood, resulting in theformation of methaemoglobin (see Notes). This substance ispossibly carcinogenic to humans.

PHYSICAL PROPERTIES

ENVIRONMENTAL DATA

The substance is harmful to aquatic organisms.

NOTES

Depending on the degree of exposure, periodic medical examination is indicated. Specific treatment is necessary in case ofpoisoning with this substance; the appropriate means with instructions must be available. The odour warning when the exposurelimit value is exceeded is insufficient. Also consult ICSC # 0342, meta-Toluidine and 0343, para-Toluidine.

ADDITIONAL INFORMATION

o-Toluidine

13

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APPENDIX 1 — SOURCE DOCUMENT

Gregg N, South D, Brown R, Cocker J (1996)o-Toluidine; Criteria document for anoccupational exposure limit. London, HSE Books(ISBN 0 7176 1057 8)

The authors’ draft version was initially reviewed internallyby a group of approximately 10 Health & Safety Executiveexperts — mainly toxicologists, but also experts in other relevantdisciplines (e.g. epidemiology, occupational hygiene). Thetoxicology section of the amended draft was then reviewed bytoxicologists from the United Kingdom Department of Health. Subsequently, the entire Criteria Document was reviewed by atripartite advisory committee to the United Kingdom Health &Safety Commission, the Working Group for the Assessment ofToxic Chemicals (WATCH). This committee is composed ofexperts in toxicology and occupational health and hygiene fromindustry, trade unions, and academia.

The members of the WATCH committee at the time ofthe peer review were:

Professor J. Bridges (University of Surrey)Dr A. Hay (Trade Unions Congress)Dr L. Levy (Institute of Occupational Hygiene,Birmingham)Dr M. Molyneux (Chemical Industries Association)Mr A. Moses (Chemical Industries Association)Dr R. Owen (Trade Unions Congress)Mr J. Sanderson (independent consultant)Dr M. Sharratt (University of Surrey)Dr A. Smith (independent consultant)

APPENDIX 2 — CICAD PEER REVIEW

The draft CICAD on o-toluidine was sent for review toinstitutions and organizations identified by IPCS after contactwith IPCS national Contact Points and Participating Institutions,as well as to identified experts. Comments were received from:

BASF Aktiengesellschaft, Ludwigshafen, Germany

Bayer AG, Leverkusen, Germany

Department of Health, London, United Kingdom

Department of Public Health, Albert Szent-GyorgyiUniversity Medical School, Szeged, Hungary

Environmental Health Directorate, Health Canada,Ottawa, Canada

International Agency for Research on Cancer, Lyon,France

Ministry of Health and Welfare, International AffairsDivision, Government of Japan, Tokyo, Japan

National Food Agency of Denmark, Institute ofToxicology, Ministry of Health, Soborg, Denmark

National Institute for Working Life, Solna, Sweden

National Institute of Occupational Health, Budapest,Hungary

United States Department of Health and Human Services(National Institute of Environmental Health Sciences)

United States Environmental Protection Agency (Office ofPollution Prevention and Toxics; National Center forEnvironmental Assessment, Office of Research andDevelopment; Office of Drinking Water)


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APPENDIX 3 — CICAD FINAL REVIEW BOARD

Brussels, Belgium, 18–20 November 1996

Members

Dr A. Aitio, Institute of Occupational Health, Helsinki, Finland

Dr K. Bentley, Director, Environment Policy Section,Commonwealth Department of Human Services and Health,Canberra, Australia

Mr R. Cary, Toxicology and Existing Substances RegulationUnit, Health & Safety Executive, Merseyside, United Kingdom

Dr J. de Fouw, National Institute of Public Health andEnvironmental Protection, Bilthoven, The Netherlands

Dr C. DeRosa, Director, Division of Toxicology, Agency for ToxicSubstances and Disease Registry, Atlanta, GA, USA

Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood,Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom

Dr W. Farland, Director, National Center for EnvironmentalAssessment, Office of Research and Development, USEnvironmental Protection Agency, Washington, DC, USA(Chairperson)

Dr T.I. Fortoul, Depto. Biologia Celular y Tisular, NationalUniversity of Mexico and Environmental Health Directorate ofthe Health Ministry, Mexico D.F., Mexico

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

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

Mr J.R. Hickman, Environmental Health Directorate, HealthCanada, Ottawa, Ontario, Canada

Dr T. Lakhanisky, Head, Division of Toxicology, Institute ofHygiene and Epidemiology, Brussels, Belgium (Vice-

Chairperson)

Dr I. Mangelsdorf, Documentation and Assessment of Chemicals,Fraunhofer Institute for Toxicology and Aerosol Sciences,Hanover, Germany

Ms E. Meek, Head, Priority Substances Section, EnvironmentalHealth Directorate, Health Canada, Ottawa, Ontario, Canada

Dr K. Paksy, National Institute of Occupational Health, Budapest,Hungary

Mr D. Renshaw, Department of Health, London, United Kingdom

Dr J. Sekizawa, Division of Chemo-Bio Informatics, NationalInstitute of Hygienic Sciences, Tokyo, Japan

Dr H. Sterzl-Eckert, GSF-Forschungszentrum für Umwelt undGesundheit GmbH, Institut für Toxikologie, Oberschleissheim,Germany

Professor S. Tarkowski, Department of Environmental HealthHazards, The Nofer Institute of Occupational Medicine, Lodz,Poland

Dr M. Wallen, National Chemicals Inspectorate (KEMI), Solna,Sweden

Observers

Professor F.M.C. Carpanini,1 Director, Centre for Ecotoxicologyand Toxicology of Chemicals (ECETOC), Brussels, Belgium

Mr R. Haigh,1 Head of Unit, Health and Safety Directorate,European Commission, Luxembourg

Mr B.U. Hildebrandt, Federal Ministry for the Environment,Nature Conservation and Nuclear Safety, Bonn, Germany

Mr P. Hurst,1 Chemical and Consumer Policy Officer,Conservation Policy Division, World Wide Fund for Nature,Gland, Switzerland

Dr A. Lombard (Representative of CEFIC), ELF-ATOCHEM,Paris, France

Dr P. McCutcheon,1 Environment, Consumer Protection andNuclear Safety, European Commission, Brussels, Belgium

Dr R. Montaigne, Counsellor, Technical Affairs Department,European Chemical Industry Council (CEFIC), Brussels, Belgium

Dr M. Pemberton, ICI Acrylics, Lancashire, United Kingdom

Dr A. Smith, Organisation for Economic Co-operation andDevelopment, Environment Division, Paris, France

Secretariat

Dr M. Baril, International Programme on Chemical Safety, WorldHealth Organization, Geneva, Switzerland

Dr L. Harrison, International Programme on Chemical Safety,World Health Organization, Geneva, Switzerland

Dr M. Mercier, Director, International Programme on ChemicalSafety, World Health Organization, Geneva, Switzerland

Dr P. Toft, Associate Director, International Programme onChemical Safety, World Health Organization, Geneva,Switzerland

1 Invited but unable to attend.

o-Toluidine

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RÉSUMÉ D’ORIENTATION

Ce CICAD (document international succinct surl’évaluation des risques chimiques) relatif à l’ortho-toluidine (o-toluidine) est fondé sur une étude, menéepar le United Kingdom Health & Safety Executive (Gregget al., 1996), des principaux problèmes posés par cettesubstance du point de vue de l’hygiène industrielle,étude qui prenait en compte les données connues enmars 1992. Des informations complémentaires ont étéincorporées à ce CICAD lors de l’examen par les pairs,puis par le Comité d’Évaluation finale. Les informationsrelatives à la préparation du document initial et à sonexamen par les pairs figurent à l’appendice 1. Lesrenseignements concernant l’examen du CICAD par lespairs font l’objet de l’appendice 2. La publication de ceCICAD a été approuvée à une réunion du Comité d’Éval-uation finale qui s’est tenue à Bruxelles (Belgique) du 18au 20 novembre 1996. La liste des participants à cetteréunion figure à l’appendice 3. La fiche d’informationsur la sécurité chimique de l’o-toluidine (ICSC 0341),préparée par le Programme international sur la sécuritéchimique (IPCS, 1993), est également reproduite dans leprésent document.

L’o-toluidine (CAS N/ 95-53-4) est un produitchimique de synthèse qui se présente à la températureambiante sous la forme d’un liquide jaune pâle. Elle estutilisée principalement dans la fabrication de colorants,mais aussi de caoutchouc, de produits chimiques et depesticides. C’est également un agent de polymérisationdes résines époxy.

La toxicité aigue de l’o-toluidine est modérée àfaible. L’o-toluidine est très légèrement irritante pour lapeau et légèrement irritante pour les yeux. On ne pos-sède pas d’information sur le potentiel de sensibilisationcutanée ou respiratoire. Les principaux signes de toxicitéà la suite d’une exposition massive et de courte duréesont une méthémoglobinémie et des effets connexes surla rate. Ces effets ont été observés chez des rats soumisà une dose de 225 mg/kg de poids corporel par jourpendant cinq jours. Il n’a pas été établi de dose sanseffet observé.

Dans plusieurs études de cancérogénicité, au coursdesquelles de l’o-toluidine avait été administrée par voieorale à des rats et à des souris, on a noté une augmenta-tion significative de l’incidence des tumeurs bénignes etmalignes dans divers tissus. L’o-toluidine n’est géné-ralement pas mutagène dans les épreuves classiques demutagénicité bactérienne, mais elle est clastogène dansles cellules mammaliennes in vitro. Sa génotoxicité n’apas été établie avec certitude in vivo, encore que desrésultats positifs aient été signalés. Compte tenu de lalarge distribution des tumeurs observées chez les

animaux exposés, ainsi que de l’activité clastogèneconstatée dans les épreuves in vitro sur des systèmesmammaliens, on peut considérer que l’o-toluidine secomporte comme un cancérogène génotoxique. On nedispose pas de données permettant d’évaluer le risqued’effets indésirables sur la reproduction ou ledéveloppement.

En raison de l’absence de données pertinentesrelatives à l’exposition, il n’a pas été possible d’évaluerles risques que l’exposition indirecte à l’o-toluidineprésente dans l’environnement général pourraient poserpour la santé de l’homme. Dans l’environnementprofessionnel, les risques d’effets cancérogènes etgénotoxiques pourraient être significatifs. Il n’a pas étépossible de recueillir de données utiles sur lesconcentrations d’o-toluidine dans différents milieux etsur ses effets sur les organismes aquatiques et terrestres,de sorte que les risques pour les organismes en questionn’ont pu être évalués.


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RESUMEN DE ORIENTACIÓN

Esta reseña de la evaluación química internacionalde la orto-toluidina (o-toluidina) está basada en unanálisis del Comité Ejecutivo sobre Salud y Seguridaddel Reino Unido acerca de los aspectos de interés de esecompuesto en relación con la salud humana, sobre todola salud ocupacional (Gregg et al., 1996); el análisisabarca los datos obtenidos hasta marzo de 1992. Posteri-ormente se ha incorporado la información adicionalpertinente reunida durante el examen colegiado inter-nacional de la presente reseña, previo examen por elComité de Revisión Final. En el apéndice 1 se informasobre la preparación y el examen colegiado del docu-mento de partida, y en el apéndice 2 sobre el examencolegiado de la presenta reseña. La publicación de éstafue aprobada en una reunión del Comité de RevisiónFinal, celebrada en Bruselas (Bélgica) del 18 al 20 denoviembre de 1996. El apéndice 3 contiene la lista de losparticipantes en esa reunión. Se ha reproducidoasimismo la ficha internacional de seguridad química(ICSC 0341) de la o-toluidina, elaborada por el ProgramaInternacional de Seguridad de las Sustancias Químicas(IPCS, 1993).

La o-toluidina (CAS No.95-53-4) es una sustanciaquímica sintética que a temperatura ambiente es unlíquido amarillo claro. Se utiliza principalmente en laelaboración de pigmentos, aunque también para producircaucho, productos químicos y plaguicidas, y comoagente polimerizante para los sistemas de resinas epoxí-dicas.

La o-toluidina tiene una toxicidad entre moderada ybaja y puede producir una muy ligera irritación cutánea eirritación moderada de los ojos. No se dispone deinformación sobre su potencial de sensibilización de lapiel o de las vías respiratorias. Los principales signos detoxicidad tras la exposición aguda y de corta duración aesa sustancia química son la metahemoglobinemia y losefectos asociados en el bazo. Tales efectos se hanobservado en ratas a las que se había administrado o-toluidina a dosis diarias de 225 mg/kg de peso corporaldurante 5 días; no se ha establecido un nivel sin efectosadversos observados.

En diversos estudios de carcinogenicidad en quese administró o-toluidina por vía oral a ratas y ratones seobservó un aumento significativo de la incidencia detumores benignos y malignos en distintos tejidos. La o-toluidina no suele tener efectos mutagénicos en laspruebas habituales de mutagenicidad bacteriana, pero esclastogénica en células de mamífero in vitro. No seconoce con certeza la genotoxicidad de la o-toluidina invivo, pero se ha informado de algunos resultados positi-vos. Teniendo en cuenta la amplia distribución de los

tumores que aparecen en los animales expuestos a esasustancia, así como la actividad clastogénica detectadaen ensayos in vitro con células de mamífero, es probableque la o-toluidina actúe como carcinógeno genotóxico. No se hallaron datos de interés para evaluar el riesgo deefectos para la reproducción o el desarrollo.

Debido a la falta de datos pertinentes sobre laexposición, no se han podido evaluar los riesgos para lasalud humana asociados a la exposición indirecta a la o-toluidina presente en el medio ambiente general. En elentorno ocupacional, es posible que haya riesgos signi-ficativos de efectos carcinogénicos y genotóxicos. Nose han hallado datos útiles sobre las concentraciones deo-toluidina en diversos ambientes y sobre sus efectos enorganismos acuáticos y terrestres, por lo que no ha sidoposible evaluar los riesgos de la exposición al compu-esto entre los organismos presentes en el medio.