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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT NO. 7


    o-TOLUIDINE

    INTER-ORGANIZATION PROGRAMME FOR THE SOUND MANAGEMENT OF CHEMICALS
    A cooperative agreement among UNEP, ILO, FAO, WHO, UNIDO, UNITAR and
    OECD

    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 Organisation, or the World Health Organization.


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


    Published under the joint sponsorship of the United Nations
    Environment Programme, the International Labour Organisation, 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, 1998

         The International Programme on Chemical Safety (IPCS),
    established in 1980, is a joint venture of 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 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, and the Organisation for
    Economic Co-operation and Development (Participating Organizations),
    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

    o-Toluidine.

         (Concise international chemical assessment document ; 7)

         1.Toluidines - toxicity   2.Toluidines - adverse effects
         3.Occupational exposure   I.International Programme on Chemical
         Safety   II.Series

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

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    reproduce or translate its publications, in part or in full. 
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    (c) World Health Organization 1998

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    TABLE OF CONTENTS

         FOREWORD

    1. EXECUTIVE SUMMARY

    2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

    3. ANALYTICAL METHODS

    4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         6.1. Environmental levels
         6.2. Human exposure

    7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
         

    8. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         8.1. Single exposure
         8.2. Irritation and sensitization
         8.3. Short-term exposure
         8.4. Chronic exposure and carcinogenicity
         8.5. Genotoxicity and related end-points
         8.6. Reproductive and developmental toxicity
         8.7. Immunological and neurological effects

    9. EFFECTS ON HUMANS

    10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    11. EFFECTS EVALUATION

         11.1. Evaluation of health effects
              11.1.1. Hazard identification and dose-response assessment
                      
              11.1.2. Criteria for setting guidance values for  o-toluidine
                      
              11.1.3. Sample risk characterization
         11.2. Evaluation of environmental effects

    12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION

         13.1. Human health hazards
         13.2. Advice to physicians
         13.3. Health surveillance advice
         13.4. Spillage

    14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

         INTERNATIONAL CHEMICAL SAFETY CARD

         REFERENCES

         APPENDIX 1 - SOURCE DOCUMENT

         APPENDIX 2 - CICAD PEER REVIEW

         APPENDIX 3 - CICAD FINAL REVIEW BOARD

         RÉSUMÉ D'ORIENTATION

         RESUMEN DE ORIENTACION
    

    FOREWORD

         Concise International Chemical Assessment Documents (CICADs) are
    the latest in a family of publications from the International
    Programme on Chemical Safety (IPCS) - a cooperative programme of the
    World Health Organization (WHO), the International Labour Organisation
    (ILO), and the United Nations Environment Programme (UNEP).  CICADs
    join the Environmental Health Criteria documents (EHCs) as
    authoritative documents on the risk assessment of chemicals.

         CICADs are concise documents that provide summaries of the
    relevant scientific information concerning the potential effects of
    chemicals upon human health and/or the environment.  They are based on
    selected national or regional evaluation documents or on existing
    EHCs.  Before acceptance for publication as CICADs by IPCS, these
    documents have undergone extensive peer review by internationally
    selected experts to ensure their completeness, accuracy in the way in
    which the original data are represented, and the validity of the
    conclusions drawn.

         The primary objective of CICADs is characterization of hazard and
    dose-response from exposure to a chemical.  CICADs are not a summary
    of all available data on a particular chemical; rather, they include
    only that information considered critical for characterization of the
    risk posed by the chemical.  The critical studies are, however,
    presented in sufficient detail to support the conclusions drawn.  For
    additional information, the reader should consult the identified
    source documents upon which the CICAD has been based.

         Risks to human health and the environment will vary considerably
    depending upon the type and extent of exposure.  Responsible
    authorities are strongly encouraged to characterize risk on the basis
    of locally measured or predicted exposure scenarios.  To assist the
    reader, examples of exposure estimation and risk characterization are
    provided in CICADs, whenever possible.  These examples cannot be
    considered as representing all possible exposure situations, but are
    provided as guidance only.  The reader is referred to EHC 1701 for
    advice on the derivation of health-based guidance values.

              

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

         While every effort is made to ensure that CICADs represent the
    current status of knowledge, new information is being developed
    constantly.  Unless otherwise stated, CICADs are based on a search of
    the scientific literature to the date shown in the executive summary. 
    In the event that a reader becomes aware of new information that would
    change the conclusions drawn in a CICAD, the reader is requested to
    contact the IPCS to inform it of the new information.

    Procedures

         The flow chart shows the procedures followed to produce a CICAD. 
    These procedures are designed to take advantage of the expertise that
    exists around the world - expertise that is required to produce the
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    that are necessary for assessing risks to human health and/or the
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         The first draft is based on an existing national, regional, or
    international review.  Authors of the first draft are usually, but not
    necessarily, from the institution that developed the original review. 
    A standard outline has been developed to encourage consistency in
    form.  The first draft undergoes primary review by IPCS and one or
    more experienced authors of criteria documents to ensure that it meets
    the specified criteria for CICADs.

         The second stage involves international peer review by scientists
    known for their particular expertise and by scientists selected from
    an international roster compiled by IPCS through recommendations from
    IPCS national Contact Points and from IPCS Participating Institutions. 
    Adequate time is allowed for the selected experts to undertake a
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    into account and revise their draft, if necessary.  The resulting
    second draft is submitted to a Final Review Board together with the
    reviewers' comments.

         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;
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         of the Board, the author has not adequately addressed all
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    may not participate in the final decision-making process.

    FIGURE 1

    1.  EXECUTIVE SUMMARY

         This CICAD on  ortho-toluidine  (o-toluidine) was based on a
    review of primarily occupational human health concerns, prepared by
    the United Kingdom Health & Safety Executive (Gregg et al., 1996) and
    covering data identified up to March 1992.  Additional information
    identified during the international peer review of this CICAD and
    following consideration by the Final Review Board has been
    incorporated as appropriate.  Information on the preparation and peer
    review of the source document is presented in Appendix 1.  Information
    on the peer review of this CICAD is presented in Appendix 2.  This
    CICAD was approved for publication at a meeting of the Final Review
    Board, held in Brussels, Belgium, on 18-20 November 1996. 
    Participants at the Final Review Board meeting are listed in Appendix
    3.  The International Chemical Safety Card (ICSC 0341) for
     o-toluidine, produced by the International Programme on Chemical
    Safety (IPCS, 1993), has also been reproduced in this document.

          o-Toluidine (CAS no. 95-53-4) is a synthetic chemical that is a
    light yellow liquid at ambient temperature.  It is used primarily in
    the manufacture of dyestuffs, although it is also used in the
    production of rubber, chemicals, and pesticides and as a curing agent
    for epoxy resin systems.

          o-Toluidine is of moderate to low acute toxicity and has the
    potential to produce minimal skin irritation and mild eye irritation. 
    Information is not available on the skin or respiratory sensitization
    potential of  o-toluidine.  The principal signs of toxicity following
    acute and short-term exposure to this chemical are methaemoglobinaemia
    and related effects in the spleen.  These effects have been observed
    in rats administered  o-toluidine 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-toluidine was
    administered orally to rats and mice, there was a significant increase
    in the incidence of benign and malignant tumours in various tissues. 
     o-Toluidine is generally not mutagenic in standard bacterial
    mutagenicity tests, but it is clastogenic in mammalian cells 
     in vitro.  There is uncertainty concerning the genotoxicity of
     o-toluidine  in vivo; however, some positive results have been
    reported.  Based upon the wide distribution of tumours observed in 
     o-toluidine-exposed animals, as well as the clastogenic activity
    observed in mammalian  in vitro assays,  o-toluidine may be acting
    as a genotoxic carcinogen.  Information relevant to assessing the
    risks of reproductive or developmental effects of  o-toluidine was
    not identified.

         Owing to the lack of relevant data on exposure, it was not
    possible to assess risks to human health associated with indirect
    exposure to  o-toluidine present in the general environment.  In the
    occupational environment, there is the potential for significant risks
    of carcinogenic and genotoxic effects.  Useful data on concentrations
    of  o-toluidine in various environmental media and on its effects on
    aquatic and terrestrial organisms were not identified, and therefore
    it was not possible to assess the risks of exposure of environmental
    organisms to  o-toluidine.

    2.  IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

          o-Toluidine (CAS no. 95-53-4; C7H9N; 1-amino-2-methylbenzene,
    2-aminotoluene,  o-methylaniline), a synthetic chemical described as
    having an "aromatic" odour, exists at ambient temperature as a light
    yellow liquid that rapidly darkens on exposure to air and light.  
     o-Toluidine has a boiling point of 200°C, a melting point of -16°C,
    and a vapour pressure of 0.2 kPa at 20°C.  o-Toluidine is completely
    miscible with ethanol and diethyl ether; its solubility in water is
    poor.  Additional physical/chemical properties are presented in the
    International Chemical Safety Card reproduced in this document.  The
    structural formula for  o-toluidine is:

    CHEMICAL STRUCTURE 1

    Although some toxicological studies on  o-toluidine have employed its
    hydrochloride salt  (o-toluidine hydrochloride), this is unlikely to
    significantly alter the observed health effects of the parent
    chemical.

    3.  ANALYTICAL METHODS

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

         The analytical monitoring of urine for  o-toluidine and its
    metabolites may be a useful means of assessing occupational exposure,
    especially where there is potential for skin absorption.  Methods for
    biological monitoring of occupationally exposed individuals have been
    reported (Brown et al., 1995; Ward et al., 1996).  These techniques
    employ urine sampling for the determination of  o-toluidine and its
     N-acetyl metabolites and blood sampling for the detection of
     o-toluidine-haemoglobin adducts.

         The determination of  o-toluidine in water samples may involve
    extraction under acidic and alkali conditions, followed by brominated
    ether extraction and subsequent analysis using gas chromatography with
    electron capture detection (detection limit 0.1-0.6 µg/litre).  The
    analysis of  o-toluidine in sediment may involve steam distillation
    under alkali conditions with quantitation by gas chromatography
    coupled with electron capture detection (detection limit 0.002-0.012
    µg/g dry matter).

    4.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         The principal use of  o-toluidine worldwide is in the
    manufacture of dyestuffs, although it is also used in the production
    of rubber, chemicals, and pesticides and as a curing agent for epoxy
    resin systems.  o-Toluidine is also used as a corrosion inhibitor in
    paint formulations and possibly has limited uses in analytical
    laboratory procedures.  There are no known domestic or household uses
    for  o-toluidine.

         Global production data for  o-toluidine were not identified.  In
    the USA in 1975, more than 900 t of the chemical were produced, and
    another 1000 t were imported.  Total production of  o-toluidine in
    Great Britain is approximately 6000 t per year, 90% of which is
    exported.  Approximately 610 and 545 t of  o-toluidine were imported
    into Japan in 1992 and 1993, respectively.

    5.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         Using an equilibrium model to assess partitioning between
    environmental media, Yoshida et al. (1983) estimated the distribution
    of  o-toluidine to be 14.5% to air, 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 was
    estimated to be about 1 day (Zoeteman et al., 1980).

    6.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    6.1  Environmental levels

          o-Toluidine was detected in 3/46 samples of Rhine River water
    collected at the Germany-Netherlands border in 1979; the mean and
    maximum concentrations were 0.03 and 1.8 µg/litre, respectively
    (Wegman & de Korte, 1981).   o-Toluidine was detected in water
    collected from a shallow aquifer contaminated by coal tar wastes in
    the USA; however, concentrations were not reported (Pereira et al.,
    1983).

         In Japan, 8/68 samples of surface water collected in 1976
    contained  o-toluidine (detection limit 0.1-0.6 µg/litre) at levels
    ranging from 0.14 to 20 µg/litre; 27 samples of sediment collected in
    the same year contained  o-toluidine (detection limit 0.002-0.012
    mg/kg) at concentrations ranging from 0.002 to 0.013 mg/kg dry weight
    (J. Sekizawa, personal communication, 1996).   o-Toluidine was not
    detected (detection limit 0.05-150 ng/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-toluidine present in
    the environment could not be estimated, owing to the lack of relevant
    data on levels of this chemical in air, drinking-water, and
    foodstuffs.  Information on human exposure to  o-toluidine is limited
    to occupational settings.

         In the United Kingdom in 1992, approximately 120 individuals were
    potentially exposed to  o-toluidine during activities involving its
    manufacture and use; about a quarter of these were maintenance rather
    than process workers.  Eight-hour time-weighted-average exposures to
     o-toluidine in seven different industries in the 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 mg/m3)  o-toluidine was measured at a site involving
    centrifugation at high temperature.  If it is assumed that a worker
    weighing 70 kg breathes 10 m3 of air during a typical working day and
    that inhaled  o-toluidine is completely absorbed, exposure to 
     o-toluidine at a concentration of 1.3 mg/m3 in workplace air can be
    estimated to result in a daily  o-toluidine intake of approximately
    0.2 mg/kg body weight.  Exposure to  o-toluidine associated with some
    processes conducted at elevated temperatures (i.e. exposure to 
     o-toluidine at 11.8 mg/m3) can be estimated to result in a daily
     o-toluidine intake of approximately 1.7 mg/kg body weight.  Dermal
    exposure to  o-toluidine may also occur in the occupational
    environment; however, quantitative data were not identified.

    7.  COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS
        AND HUMANS

         Biological monitoring to assess human exposure to  o-toluidine
    indicates that absorption may occur through inhalation and dermal
    contact; however, quantitative information was not identified. 
     o-Toluidine binds to haemoglobin (Ward et al., 1996).  
     N-acetylated metabolites of  o-toluidine are eliminated in the
    urine (Brown et al., 1995).

         In laboratory animals, studies on the kinetics and metabolism of
     o-toluidine have involved rats exposed orally or via dermal contact. 
    There is extensive absorption (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 the structure of  o-toluidine
    suggests that, like other aromatic amines, it is lipid soluble and
    therefore likely to be readily absorbed through the skin.  Oral and
    subcutaneous studies have revealed that  o-[14C]toluidine and its
    metabolites are excreted mainly in the urine, with at least 90% of the
    administered radioactivity appearing in the urine within 72 hours
    after exposure (Son et al., 1977; Cheever et al., 1980).  Small
    amounts of radioactivity were also detected in the faeces and exhaled
    carbon dioxide.  Up to one-third of the  o-toluidine administered was
    recovered unchanged in the urine.  The metabolism of  o-toluidine is
    characterized principally by ring hydroxylation and  N-acetylation,
    the major metabolites being 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 over
    glucuronide conjugates.  Binding of  o-toluidine metabolites to
    haemoglobin has also been observed in rats (Birnier & Neumann, 1988).

    8.  EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

    8.1  Single exposure

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

    8.2  Irritation and sensitization

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

    8.3  Short-term exposure

         A 13% decrease in body weight, a 1.5- to 3.0-fold increase in
    spleen weight, increased methaemoglobin levels, and congestion,
    haemosiderosis, and haematopoiesis in the spleen (all likely
    associated with methaemoglobinaemia) were observed in rats orally
    administered  o-toluidine for 5 days at a dose of 225 mg/kg body
    weight per day (Short et al., 1983); no other doses were tested, and a
    no-effect level was not identified.  Relevant toxicity studies
    involving short-term inhalation or dermal exposure to  o-toluidine
    were not identified.

    8.4  Chronic exposure and carcinogenicity

         Increased incidences of benign and malignant tumours have been
    observed in rats and mice administered  o-toluidine hydrochloride in
    the diet.

         In one study, groups of 50 male and 50 female F344 rats were
    given diets containing 3000 or 6000 ppm (mg/kg)  o-toluidine
    hydrochloride for 101-104 weeks (equivalent to intakes of
    approximately 150 and 300 mg/kg body weight per day, based on a body
    weight of 400 g and the consumption of 20 g of food per day) (NCI,
    1979; Goodman et al., 1984).  Controls consisted of 20 animals of each
    sex.  In addition to routine clinical observations, gross and
    microscopic examinations were conducted on all major tissues and
    organs and on all gross lesions.  Exposure to  o-toluidine
    hydrochloride was associated with a dose-related decrease in body
    weight gain and survival.  In the control, low-dose, and high-dose
    groups, the combined incidence of sarcomas, angiosarcomas, and
    osteosarcomas of the spleen was 0/20, 9/49  (p = 0.36), and 12/49
     (p = 0.01), respectively, in females 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, and 21/49 
     (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.  In females, the incidence of 
    transitional cell carcinomas of the 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 tumour 
    was not significantly increased in the male rats.  The incidence of 
    malignant mesothelioma of the serous covering 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 control 
    animals, splenic fibromas were noted in the exposed animals; however, 
    the incidence was significantly increased only for males in the 
    low-dose group (10/49;  p = 0.024).  For animals in the control, 
    low-dose, and high-dose groups, the incidence of skin fibromas among 
    males was 0/20, 28/50  (p < 0.001), and 27/49  (p < 0.001), 
    respectively, and the incidence of mammary gland fibroadenomas among 
    females was 6/20, 20/50, and 35/49  (p = 0.002), respectively.

         Non-neoplastic effects that were not observed in control animals
    included splenic fibrosis (in 12-27% and 6-12% of exposed males and
    females, respectively), splenic mesothelial hyperplasia (in 12-37% and
    24-65% of exposed males and females, respectively), hyperplasia of the
    urinary bladder epithelium (in 16-18% and 28-47% of exposed males and
    females, respectively), and myocardial fibrosis (in 17-34% of exposed
    males).  Liver necrosis was noted in 24-35% of exposed males (10% in
    controls) and in 2-31% of exposed females (0% in controls).

         In a study in which groups of 30 male F344 rats received 0 or 62
    mg  o-toluidine hydrochloride in the diet each day for 72 weeks
    (approximately 470 and 130 mg/kg body weight per day at the beginning
    and end of the study, respectively), followed by a 16-week recovery
    period, exposure to  o-toluidine reduced survival (6/30 and 18/30
    survivors in the exposed and control groups, respectively) (Hecht et
    al., 1982).  Incidences of the following tumours (in the control and
    exposed groups, respectively) were: bladder epithelial cell tumours,
    0/30 and 4/30; skin fibromas, 1/30 and 25/30; splenic fibromas, 0/30
    and 10/30; mammary tumours, 0/30 and 13/30; and peritoneal tumours,
    2/30 and 14/30.  Although neither the statistical significance of
    these results nor the incidence of non-neoplastic effects was
    discussed in this report, the results reveal an increased occurrence
    of a variety of tumour types in animals administered  o-toluidine
    hydrochloride for 72 weeks.

         In another study in which several chemicals were examined, groups
    of 25 male Charles River CD rats were given diets containing
     o-toluidine hydrochloride at concentrations of 8000 or 16 000 ppm
    (mg/kg) for 3 months (estimated intakes of approximately 800 and 1600
    mg/kg body weight per day, assuming 200 g for the body weight of rats
    consuming 20 g of food per day) (Weisburger et al., 1978).  Excessive
    toxicity, based upon increased mortality and reductions in body

    weight, resulted in the concentrations being reduced to 4000 and 8000
    ppm (mg/kg) (with estimated intakes of 400 and 800 mg/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 were
    necropsied.  Data on survival or general toxicity were not provided. 
    Controls included one matched group  (n = 16 animals) used for this
    portion of the overall study, as well as the pooled controls 
     (n = 111) from the entire investigation.  There was a statistically
    significant increase in the incidence (0/16, 18/111, 18/23, and 21/24
    in the matched control, pooled control, low-dose, and high-dose
    groups, respectively) of subcutaneous fibroma and fibrosarcoma in 
     o-toluidine-exposed animals.  The incidence of bladder transitional
    cell carcinoma was 0/16, 5/111, 3/23, and 4/24 in the matched control,
    pooled control, low-dose, and high-dose groups, respectively.

         Statistically significant increases in hepatocellular carcinomas
    and adenomas, as well as haemangiosarcomas, were observed in a study
    in which groups of 50 male and 50 female B6C3F1 mice were given diets
    containing 1000 or 3000 ppm (mg/kg)  o-toluidine hydrochloride
    (estimated intakes of 110 and 340 mg/kg body weight per day, assuming
    30 g for the body weight of mice consuming 3.4 g of food per day) for
    101-104 weeks (NCI, 1979).  Twenty animals of each sex served as
    unexposed controls.  In the control, low-dose, and high-dose groups,
    the incidences of hepatocellular carcinoma (in females),
    hepatocellular adenoma (in females), and haemangiosarcoma (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 haemangiosarcomas and
    haemangiomas were observed in a study in which groups of 25 male and
    25 female CD-1 mice were given diets containing  o-toluidine
    hydrochloride at concentrations of 16 000 or 32 000 ppm (mg/kg)
    (estimated intakes of 1800 and 3600 mg/kg body weight per day,
    assuming 30 g for the body weight of mice consuming 3.4 g of food per
    day) for 3 months (Weisburger et al., 1978).  Excessive toxicity,
    based upon increased mortality and reductions in body weight, resulted
    in the concentrations being reduced to 8000 and 16 000 ppm (mg/kg) for
    a further 15 months, followed by a 3-month observation and recovery
    period.  Only animals that survived 6 months or more were necropsied. 
    Controls included one matched group used for this portion of the
    overall study, as well as the pooled controls from the entire
    investigation.  In the matched control, pooled control, low-dose, and
    high-dose groups, the incidence of abdominal haemangiosarcomas and
    haemangiomas was 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 conducted and/or reported)
    dermal and parenteral studies conducted in various species and from an
    oral toxicity study in dogs (Morigami & Nisimura, 1940; Steinhoff,
    1981; Hecht et al., 1983) do not contribute meaningfully to the
    assessment of  o-toluidine.

    8.5  Genotoxicity and related end-points

         Based upon the results of assays conducted in  Salmonella 
     typhimurium and  Escherichia coli, o-toluidine was not considered
    to be mutagenic in standard bacterial 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 Ames test have been
    observed when norharman was added to the test system (Nagao et al.,
    1978; Nagao & Takahashi, 1981; Sugimura & Nagao, 1981).  Results from
    several cytogenetic studies have indicated that  o-toluidine is
    clastogenic 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 been adequately
    tested only in mice.  No evidence of clastogenicity was observed in
    several high-quality studies (a bone marrow cytogenetic assay and
    three bone marrow micronucleus tests) in which the chemical was
    injected intraperitoneally (Salamone et al., 1981; Tsuchimoto &
    Matler, 1981; McFee et al., 1989).  Although there was no reporting of
    bone marrow toxicity in these studies, use of an intraperitoneal
    injection with elevated dose levels would suggest that  o-toluidine
    probably reached the target tissue (bone marrow).  In contrast, in the
    best conducted bone marrow sister chromatid exchange assay, high doses
    of  o-toluidine apparently produced positive results in mice (McFee
    et al., 1989).  A positive result has also been reported for the
    induction of DNA single strand breaks in mice; however, the poor
    description of the study precludes the drawing of definitive
    conclusions (Cesarone et al., 1982).  Despite some suggestions of
    clastogenicity, the genotoxic potential of  o-toluidine  in vivo 
    remains uncertain.

    8.6  Reproductive and developmental toxicity

         Relevant information on the reproductive and developmental
    toxicity of  o-toluidine in laboratory animals was not identified.

    8.7  Immunological and neurological effects

         Relevant toxicological studies in which immunological or
    neurological effects were assessed were not available.  However,
    evidence of specific adverse immunological and neurological effects
    has not been reported in general toxicity studies.

    9.  EFFECTS ON HUMANS

         Relevant case reports on adverse health effects associated with
    exposure to  o-toluidine were not available.

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

         Exposure to chemicals including  o-toluidine in the dyestuffs
    industry and more recently in the rubber industry has been reported to
    be associated with an increased incidence of bladder cancer.  For
    example, expected and observed cases of bladder cancer were recorded
    in a thorough, well conducted retrospective cohort study at a rubber
    chemical plant in upstate New York (Ward et al., 1991).  The cohort
    consisted of all 1749 male and female workers employed at the plant
    between 1973 and 1988.  The work-force was relatively young; 72% were
    born after 1 January 1939.  It was estimated that cohort members were
    "slightly more likely" than the general population of the USA to be
    current or former smokers.  These workers were exposed primarily to
     o-toluidine and aniline.  In 1988, airborne  o-toluidine and
    aniline levels were <1 ppm (<4.4 mg/m3 for  o-toluidine).

         Based upon 13 identified cases of bladder cancer among all 1749
    employees, compared with 3.61 cases expected (estimated from the rate
    in the population of the state of New York, excluding New York City),
    the standardized incidence ratio (SIR) was 3.6 (90% confidence
    interval [CI] = 2.13-5.73).  The SIRs for bladder cancer among workers
    "definitely exposed"  (n = 708), "possibly exposed"  (n = 288), and
    "probably unexposed"  (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 of bladder cancer increased with duration of
    exposure and time since first exposure.  The SIRs for bladder cancer
    among the "definitely exposed" workers with <5, 5-9.99, and >10
    years of exposure to these chemicals were 0 (0 observed cases), 8.8
    (90% CI = 0.45-41.7; 1 observed case), and 27.2 (90% CI = 11.8-53.7;
    6 observed cases), respectively.  The SIRs for bladder cancer among
    workers with <10, 10-20, and >20 years since their first employment
    in the "definitely exposed" department of the 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 was calculated that
    smoking was unlikely to account for the increased incidence of bladder
    cancer in this group of workers.  The mean latency period for the
    group of seven "definitely exposed" workers with bladder cancer was 23
    years.  Although the carcinogenic potential of  o-toluidine
    specifically cannot be definitively determined from this study, the
    findings merit considerable concern.

         Other studies of workers employed in the dyestuffs industry
    include those by Vigliani & Barsotti (1961), Khlebnikova et al.
    (1970), Zavon et al. (1973), Conso & Pontal (1982), and Rubino et al.
    (1982).  However, as in the study of rubber chemical workers, it was
    not possible to definitively link the increased incidence of bladder
    cancer specifically to  o-toluidine because of concurrent exposure to
    other chemicals.

    10.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         Relevant information on the effects of  o-toluidine on aquatic
    or terrestrial organisms was not identified.  However, toxicity
    thresholds for the inhibition of algal growth  (Microcystis 
     aeruginosa, 0.31 mg/litre;  Scenedesmus quadricauda, 6.3 mg/litre)
    have been reported.1


              

    1 Source: EnviChem Data Bank of Environmental Properties of
    Chemicals. Helsinki, Finland, Finnish Environment Agency, version 1.0,
    1995.

    11.  EFFECTS EVALUATION

    11.1  Evaluation of health effects

    11.1.1  Hazard identification and dose-response assessment

         Available data are inadequate to allow the potential risks of
    reproductive or developmental effects on human health to be assessed. 
    Carcinogenicity is considered, however, to be the critical effect
    associated with potential exposure to  o-toluidine.  In several
    experimental studies, the oral administration of  o-toluidine
    hydrochloride increased the incidence of benign and/or malignant
    tumours in various tissues in rats (spleen sarcomas and fibromas in
    males and females, mesotheliomas of the scrotum in males, transitional
    cell carcinomas of the urinary bladder in females, skin fibromas and
    mammary gland fibroadenomas in males and females, respectively). 
    Clear evidence of carcinogenicity has also been observed in oral
    studies in mice (hepatocellular carcinomas and adenomas,
    haemangiosarcomas, and haemangiomas).  Even where the increased tumour
    incidences were not statistically significant, they were considered to
    be of biological significance in view of the low incidences of such
    tumours in historical controls (Haseman et al., 1990).   o-Toluidine
    is genotoxic  in vitro; although the genotoxicity studies conducted
     in vivo do not allow definite conclusions to be drawn, there is some
    evidence of genotoxic potential.  Carcinogenicity studies in rats and
    mice have yielded tumours in both sexes and in multiple organs;
    therefore, the possibility of involvement of a genotoxic mechanism
    cannot be eliminated.

         Several studies of workers employed in the dyestuffs and rubber
    industries found that exposure to chemicals, including  o-toluidine,
    appears to be associated with an increased incidence of bladder
    cancer.  Although it is difficult to draw definite conclusions
    regarding the carcinogenic potential of  o-toluidine in humans from
    these studies of workers exposed to multiple chemicals, this evidence,
    together with data from experimental carcinogenicity bioassays, raises
    concern about the risk of cancer in exposed humans.  It would
    therefore be prudent to consider that  o-toluidine is probably
    carcinogenic in humans, possibly through involvement of a genotoxic
    mechanism.

    11.1.2  Criteria for setting guidance values for o-toluidine

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

    11.1.3  Sample risk characterization

         It is recognized that there are a number of different approaches
    to assessing the risks to human health posed by genotoxic and
    carcinogenic substances.  In some jurisdictions, there are models for
    characterizing potency, which may be of some benefit in 
    priority-setting schemes.

         The example here is from the occupational environment, as the
    lack of available data precludes the characterization of potential
    cancer risks for the general population.  In the United Kingdom, a
    Maximum Exposure 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 Maximum Exposure Limit was based on a level of
    control that was deemed (by tripartite agreement) to be reasonably
    practicable under workplace conditions within the United Kingdom.  In
    the United Kingdom, there is a continuing remit to reduce exposure
    levels as much as reasonably practicable with the technology that is
    currently available.

    11.2  Evaluation of environmental effects

         The lack of available information precludes adequate assessment
    of potential risks to environmental organisms.

    12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

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

         Information on international hazard classification and labelling
    is included in the International Chemical Safety Card reproduced in
    this document.

    13.  HUMAN HEALTH PROTECTION AND EMERGENCY 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 could induce
    methaemoglobinaemia.  After long-term or repeated exposure, 
     o-toluidine is considered possibly carcinogenic to humans.

    13.2  Advice to physicians

         If splashed with  o-toluidine, it is crucial to remove all wet
    or contaminated clothing and wash the entire body with soap and water. 
    Following such an incident, the degree of methaemoglobinaemia needs to
    be determined hourly until a decrease is well established.  Above 30%
    methaemoglobinaemia, administer oxygen under continuous observation;
    above 50% methaemoglobinaemia, further administer intravenously 1000
    cc of a 5% glucose solution containing ascorbic acid; above 60%
    methaemoglobinaemia, further administer intravenously 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 health surveillance
    programme should include regular urinary cytology, with more specific
    procedures in the case of positive results.

    13.4  Spillage

         In the event of spillage, measures should be undertaken to
    prevent this chemical from reaching drains and watercourses.

    14.  CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

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

         The reader should be aware that regulatory decisions about
    chemicals taken in a certain country can be fully understood only in
    the framework of the legislation of that country.  The regulations and
    guidelines of all countries are subject to change and should always be
    verified with appropriate regulatory authorities before application.



        INTERNATIONAL CHEMICAL SAFETY CARD
    ortho-TOLUIDINE                                                                                                  ICSC: 0341

                                                                ortho-TOLUIDINE
                                                            1-Amino-2-methylbenzene
                                                                2-Aminotoluene
                                                                o-Methylaniline
                                                               C7H9N/C6H4CH3NH2
                                                             Molecular mass: 107.2
    CAS #       95-53-4
    RTECS #     XU2975000
    ICSC #      0341
    UN #        1708

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

    FIRE                       Combustinble. Gives off         NO open flames. NO contact      Powder, AFFF, foam, carbon
                               irritating or toxic fumes (or   with nitric acid.               dioxide.
                               gases) in a fire.

    EXPLOSION                  Above 85°C explosive            Above 85°C use a closed         In case of fire: keep drums,
                               vapour/air mixtures may be      system, ventilation.            etc., cool by spraying with
                               formed.                                                         water.

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

    * INHALATION               Blue lipsor finger nails.       Ventilation, local exhaust,     Fresh air, rest. Artificial
                               Blue skin. Confusion.           or breathing protection.        respiration if indicated.
                               Dizziness. Headache.                                            Refer for medical attention.
                               Shortness of breath.
                               Weakness.
                                                                                                                                        

    INTERNATIONAL CHEMICAL SAFETY CARD (continued)

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

    * SKIN                     MAY BE ABSORBED! Redness.       Protective gloves. Protective   Remove contaminated clothes.
                               Blue lips or fingernails.       clothing.                       Rinse and then wash skin with
                               Blue skin (Further see                                          water and soap. Refer for
                               inhalation).                                                    medical attention.

    * EYES                     Redness. Pain.                  Safety goggles.                 First rinse with plenty of
                                                                                               water for several minutes
                                                                                               (remove contact lenses if
                                                                                               easily possible), then take
                                                                                               to a doctor.

    * INGESTION                Blue lips or fingernails.       Do not eat, drink, or smoke     Rinse mouth. Induce vomiting
                               Blue skin. Dizziness.           during work.                    (ONLY IN CONSCIOUS PERSONS!).
                               Headache. Laboured breathing                                    Refer for medical attention.
                               (further see inhalation).
                                                                                                                                        

    INTERNATIONAL CHEMICAL SAFETY CARD (continued)

                                                                                                                                        

    SPILLAGE DISPOSAL                             STORAGE                                   PACKAGING & LABELLING

                                                                                                                                        
    Collect leaking and spilled liquid in         Separated from strong oxidants, strong    Do not transport with food and
    sealable containers as far as                 acids, food and feedstuffs. Cool. Dry.    feedstuffs.
    possible. Absorb remaining liquid in          Well closed. Ventilation along the
    sand or inert absorbent and remove to         floor.                                    UN Hazard Class: 6.1
    safe place (extra personal protection:                                                  N Packing Group: II
    complete protective clothing including
    self-contained breathing apparatus).

                                                                                                                                        

    IMPORTANT DATA      PHYSICAL STATE; APPEARANCE:                          EFFECTS OF SHORT-TERM EXPOSURE:
                        COLOURLESS TO YELLOW LIQUID, TURNS                   The substance irritates the eyes and the skin.
                        REDDISH-BROWN ON EXPOSURE TO AIR AND LIGHT.          The substance may cause effects on the blood,
                                                                             bladder and kidneys, resulting in tissue
                        CHEMICAL DANGERS:                                    lesions, impaired functions and formation of
                        The substance decomposes on heating or on            methaemoglobin. Exposure to high concentrations
                        burning producing toxic fumes including              may result in damage to kidneys and bladder.
                        nitrogen oxides. Reacts with strong oxidants,        The effects may be delayed. Medical observation
                        expecially nitric acid.                              is indicated. See Notes.

                        OCCUPATIONAL EXPOSURE LIMITS (OELs):                 EFFECTS OF LONG-TERM OR REPEATED EXPOSURE:
                        TLV: 2 ppm; 8.8 mg/m3 (as TWA) A2 (skin)             The substance may have effects on the blood,
                             (ACGIH 1994-1995.                               resulting in the formation of methaemoglobin
                                                                             (see Notes). This substance is possibly
                        ROUTES OF EXPOSURE:                                  carcinogenic to humans.
                        The substanec can be absorbed into the body by
                        inhalation and through the skin, and by
                        ingestion.

                        INHALATION RISK:
                        Evaporation at 20°C is negligible; a harmful
                        concentration of airborne particles can,
                        however, be reached quickly on spraying.
                                                                                                                                        

    INTERNATIONAL CHEMICAL SAFETY CARD (continued)

                                                                                                                                        

    PHYSICAL            Boiling point:                         200°C         Flash point:                          85°C c.c.
    PROPERTIES          Melting                               -16°C          Auto-ignition temperature:            482°C
                        Relative density (water = 1):          1.01          Explosive limits, vol% in air:        1.5-?
                        Solubility in water:                   poor          Octanol/water partition coefficient
                        Vapour pressure, kPa at 20°C:          0.2           as log Pow:                           1.32
                        Relative vapour density (air = 1):     3.7
                        Relative density of the vapour/
                        air-mixture at 20°C (air = 1):         1.00

                                                                                                                                        

    ENVIRONMENTAL       The substance is harmful to aquatic organisms.
    DATA                

                                                                                                                                        

    NOTES               Depending on the degree of exposure, periodic medical examination is indicated.
                        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.
                        Also consult ICSC #0342, meta-Toluidine and 0343, para-Toluidine.

    ICSC: 0341 1.1                                                                                                 NFPA Code: H3; F2; R0
                                                                                                                                        
    

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    APPENDIX 1 - SOURCE DOCUMENT

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

         The authors' draft version was initially reviewed internally by a
    group of approximately 10 Health & Safety Executive experts œ mainly
    toxicologists, but also experts in other relevant disciplines (e.g.
    epidemiology, occupational hygiene).  The toxicology section of the
    amended draft was then reviewed by toxicologists from the United
    Kingdom Department of Health.  Subsequently, the entire Criteria
    Document was reviewed by a tripartite advisory committee to the United
    Kingdom Health & Safety Commission, the Working Group for the
    Assessment of Toxic Chemicals (WATCH).  This committee is composed of
    experts in toxicology and occupational health and hygiene from
    industry, trade unions, and academia.

         The members of the WATCH committee at the time of the 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 to
    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:

         BASF Aktiengesellschaft, Ludwigshafen, Germany

         Bayer AG, Leverkusen, Germany

         Department of Health, London, United Kingdom

         Department of Public Health, Albert Szent-Gyorgyi University
         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 Affairs Division,
         Government of Japan, Tokyo, Japan

         National Food Agency of Denmark, Institute of Toxicology,
         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 of
         Pollution Prevention and Toxics; National Center for
         Environmental Assessment, Office of Research and Development;
         Office of Drinking Water)

    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 Regulation Unit, Health
    & Safety Executive, Merseyside, United Kingdom

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

    Dr C. DeRosa, Director, Division of Toxicology, Agency for Toxic
    Substances 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 Environmental Assessment,
    Office of Research and Development, US Environmental Protection
    Agency, Washington, DC, USA  (Chairperson)

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

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

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

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

    Dr T. Lakhanisky, Head, Division of Toxicology, Institute of Hygiene
    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, Environmental Health
    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, National Institute
    of Hygienic Sciences, Tokyo, Japan

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

    Professor S. Tarkowski, Department of Environmental Health Hazards,
    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 Ecotoxicology and
    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 and Nuclear
    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 and Development,
    Environment Division, Paris, France

              

    1 Invited but unable to attend.

    Secretariat

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

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

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

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

    RÉSUMÉ D'ORIENTATION

         Ce CICAD (document international succinct sur l'évaluation des
    risques chimiques) relatif à l' ortho-toluidine  (o-toluidine) est
    fondé sur une étude, menée par le United Kingdom Health & Safety
    Executive (Gregg et al., 1996), des principaux problèmes posés par
    cette substance du point de vue de l'hygiène industrielle, étude qui
    prenait en compte les données connues en mars 1992.  Des informations
    complémentaires ont été incorporées à ce CICAD lors de l'examen par
    les pairs, puis par le Comité d'Évaluation finale.  Les informations
    relatives à la préparation du document initial et à son examen par les
    pairs figurent à l'appendice 1.  Les renseignements concernant
    l'examen du CICAD par les pairs font l'objet de l'appendice 2.  La
    publication de ce CICAD a été approuvée à une réunion du Comité
    d'Évaluation finale qui s'est tenue à Bruxelles (Belgique) du 18 au
    20 novembre 1996.  La liste des participants à cette réunion figure à
    l'appendice 3.  La fiche d'information sur la sécurité chimique de
    l' o-toluidine (ICSC 0341), préparée par le Programme international
    sur la sécurité chimique (IPCS, 1993), est également reproduite dans
    le présent document.

         L' o-toluidine (CAS N° 95-53-4) est un produit chimique de
    synthèse qui se présente à la température ambiante sous la forme d'un
    liquide jaune pâle.  Elle est utilisée principalement dans la
    fabrication de colorants, mais aussi de caoutchouc, de produits
    chimiques et de pesticides.  C'est également un agent de
    polymérisation des résines époxy.

         La toxicité aigue de l' o-toluidine est modérée à faible.  
    L' o-toluidine est très légèrement irritante pour la peau et
    légèrement irritante pour les yeux.  On ne possède pas d'information
    sur le potentiel de sensibilisation cutanée ou respiratoire.  Les
    principaux signes de toxicité à la suite d'une exposition massive et
    de courte durée sont une méthémoglobinémie et des effets connexes sur
    la rate.  Ces effets ont été observés chez des rats soumis à une dose
    de 225 mg/kg de poids corporel par jour pendant cinq jours.  Il n'a
    pas été établi de dose sans effet observé.

         Dans plusieurs études de cancérogénicité, au cours desquelles de
    l' o-toluidine avait été administrée par voie orale à des rats et à
    des souris, on a noté une augmentation significative de l'incidence
    des tumeurs bénignes et malignes dans divers tissus.  L' o-toluidine
    n'est généralement pas mutagène dans les épreuves classiques de
    mutagénicité bactérienne, mais elle est clastogène dans les cellules
    mammaliennes  in vitro.  Sa génotoxicité n'a pas été établie avec
    certitude  in vivo, encore que des résultats positifs aient été
    signalés.  Compte tenu de la large distribution des tumeurs observées
    chez les animaux exposés, ainsi que de l'activité clastogène constatée
    dans les épreuves  in vitro sur des systèmes mammaliens, on peut
    considérer que l' o-toluidine se comporte comme un cancérogène
    génotoxique.  On ne dispose pas de données permettant d'évaluer le
    risque d'effets indésirables sur la reproduction ou le développement.

         En raison de l'absence de données pertinentes relatives à
    l'exposition, il n'a pas été possible d'évaluer les risques que
    l'exposition indirecte à l' o-toluidine présente dans l'environnement
    général pourraient poser pour la santé de l'homme.  Dans
    l'environnement professionnel, les risques d'effets cancérogènes et
    génotoxiques pourraient être significatifs.  Il n'a pas été possible
    de recueillir de données utiles sur les concentrations d' o-toluidine
    dans différents milieux et sur ses effets sur les organismes
    aquatiques et terrestres, de sorte que les risques pour les organismes
    en question n'ont pu être évalués.

    RESUMEN DE ORIENTACION

         Esta reseña de la evaluación química internacional de la
    orto-toluidina (o-toluidina) está basada en un análisis del Comité
    Ejecutivo sobre Salud y Seguridad del Reino Unido acerca de los
    aspectos de interés de ese compuesto en relación con la salud humana,
    sobre todo la salud ocupacional (Gregg et al., 1996); el análisis
    abarca los datos obtenidos hasta marzo de 1992. Posteriormente se ha
    incorporado la información adicional pertinente reunida durante el
    examen colegiado internacional de la presente reseña, previo examen
    por el Comité de Revisión Final. En el apéndice 1 se informa sobre la
    preparación y el examen colegiado del documento de partida, y en el
    apéndice 2 sobre el examen colegiado de la presenta reseña. La
    publicación de ésta fue aprobada en una reunión del Comité de Revisión
    Final, celebrada en Bruselas (Bélgica) del 18 al 20 de noviembre de
    1996. El apéndice 3 contiene la lista de los participantes en esa
    reunión. Se ha reproducido asimismo la ficha internacional de
    seguridad quimica (ICSC 0341) de la o-toluidina, elaborada por el
    Programa Internacional de Seguridad de las Sustancias Químicas (IPCS,
    1993).

         La o-toluidina (CAS No.95-53-4) es una sustancia química
    sintética que a temperatura ambiente es un liquido amarillo claro. Se
    utiliza principalmente en la elaboración de pigmentos, aunque también
    para producir caucho, productos químicos y plaguicidas, y como agente
    polimerizante para los sistemas de resinas epoxidicas.

         La o-toluidina tiene una toxicidad entre moderada y baja y puede
    producir una muy ligera irritación cutánea e irritación moderada de
    los ojos. No se dispone de información sobre su potencial de
    sensibilización de la piel o de las vías respiratorias. Los
    principales signos de toxicidad tras la exposición aguda y de corta
    duración a esa sustancia quimica son la metahemoglobinemia y los
    efectos asociados en el bazo. Tales efectos se han observado en ratas
    a las que se había administrado o-toluidina a dosis diarias de 225
    mg/kg de peso corporal durante 5 días; no se ha establecido un nivel
    sin efectos adversos observados.

         En diversos estudios de carcinogenicidad en que se administró
    o-toluidina por vía oral a ratas y ratones se observó un aumento
    significativo de la incidencia de tumores benignos y malignos en
    distintos tejidos. La o-toluidina no suele tener efectos mutagénicos
    en las pruebas habituales de mutagenicidad bacteriana, pero es
    clastogénica en células de mamífero in vitro. No se conoce con certeza
    la genotoxicidad de la o-toluidina in vivo, pero se ha informado de
    algunos resultados positivos. Teniendo en cuenta la amplia
    distribución de los rumores que aparecen en los animales expuestos a
    esa sustancia, así como la actividad clastogénica detectada en ensayos
    in vitro con células de mamífero, es probable que la o-toluidina actúe
    como carcinógeno genotóxico. No se hallaron datos de interés para
    evaluar el riesgo de efectos para la reproducción o el desarrollo.

         Debido a la falta de datos pertinentes sobre la exposición, no se
    han podido evaluar los riesgos para la salud humana asociados a la
    exposición indirecta a la o-toluidina presente en el medio ambiente
    general. En el entorno ocupacional, es posible que haya riesgos
    significativos de efectos carcinogénicos y genotóxicos. No se han
    hallado datos útiles sobre las concentraciones de o-toluidina en
    diversos ambientes y sobre sus efectos en organismos acuáticos y
    terrestres, por lo que no ha sido posible evaluar los riesgos de la
    exposición al compuesto entre los organismos presentes en el medio.






    See Also:
       Toxicological Abbreviations