necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization.
Concise International Chemical Assessment Document 7
o-TOLUIDINE
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
Please note that the layout and pagination of this pdf file are not identical to the printed CICAD
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) 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-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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iii
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 . . . 5
6.2 Human exposure . . . 5
7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS . . . 6
8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . 6
8.1 Single exposure . . . 6
8.2 Irritation and sensitization . . . 6
8.3 Short-term exposure . . . 6
8.4 Chronic exposure and carcinogenicity . . . 6
8.5 Genotoxicity and related end-points . . . 8
8.6 Reproductive and developmental toxicity . . . 8
8.7 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 . . . 10
11.2 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 . . . 10
13.2 Advice to physicians . . . 10
13.3 Health surveillance advice . . . 10
13.4 Spillage . . . 10
14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS . . . 10
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
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 character- ization 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.
While every effort is made to ensure that CICADs represent the current status of knowledge, new informa- tion 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 infor- mation 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 high- quality evaluations of toxicological, exposure, and other data that are necessary for assessing risks to human health and/or the environment.
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 thorough review. Authors are required to take reviewers’ comments 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;
– to provide guidance to those responsible for the preparation of CICADs on how to resolve any remaining issues if, in the opinion of the Board, the author has not adequately addressed all comments of the reviewers; and
– to approve CICADs as international assessments.
Board members serve in their personal capacity, not as representatives of any organization, government, or industry. They are selected because of their expertise in human and environmental toxicology or because of their experience in the regulation of chemicals. Boards are chosen according to the range of expertise required for
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).
S E L E C T I O N O F H I G H Q U A L I T Y N A T I O N A L / R E G I O N A L A S S E S S M E N T D O C U M E N T ( S )
CICAD PREPARATION FLOW CHART
FIRST DRAFT P R E P A R E D
P R I M A R Y R E V I E W A T P R O D U C E R L E V E L
(1-2 OTHER DOCUMENT PRODUCERS) 1
P R O D U C E R
REVIEW BY IPCS CONTACT POINTS
FINAL REVIEW BOARD 3
FINAL DRAFT 4
EDITING
APPROVAL BY DIRECTOR, IPCS
PUBLICATION
R E S P O N S I B L E O F F I C E R
( R O ) 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 at the 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
a meeting and the need for balanced geographic representation.
Board members, authors, reviewers, consultants, and advisers who participate in the preparation of a CICAD are required to declare any real or potential conflict of interest in relation to the subjects under discussion at any stage of the process. Representatives of nongovernmental organizations may be invited to observe the proceedings of the Final Review Board.
Observers may participate in Board discussions only at the invitation of the Chairperson, and they may not participate in the final decision-making process.
N H2 CH3
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 Inter- national 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 temper- ature. It is used primarily in the manufacture of dye- stuffs, 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-tolui- dine. The principal signs of toxicity following acute and short-term exposure to this chemical are methaemo- globinaemia and related effects in the spleen. These effects 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 was a significant increase in the incidence of benign and malignant tumours in various tissues. o-Toluidine is generally not mutagenic in standard bacterial mutageni- city 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 associ- ated 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-tolui- dine.
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:
Although some toxicological studies on o-toluidine have employed its hydrochloride salt (o-toluidine hydro- chloride), 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 chroma- tography. 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 poten- tial for skin absorption. Methods for biological monitor- ing 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 condi- tions, followed by brominated ether extraction and subsequent analysis using gas chromatography with electron capture detection (detection limit 0.1–0.6 :g/litre). The analysis of o-toluidine in sediment may involve steam distillation under alkali conditions with quantitation by gas chromatography coupled with elec- tron capture detection (detection limit 0.002–0.012 :g/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 :g/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 :g/litre) at levels ranging from 0.14 to 20 :g/litre; 27 samples of sediment collected in the same year con- tained 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. Informa- tion 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 esti- mated to result in a daily o-toluidine intake of approxi- mately 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 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 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 subcuta- neous 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 haemato- poiesis in the spleen (all likely associated with met- haemoglobinaemia) 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 iden- tified. 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 admin- istered 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
7 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 myo- cardial 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 haemangiosarco- mas, 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 hydro- chloride (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 haemangio- sarcomas 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) (esti- mated intakes of 1800 and 3600 mg/kg body weight per
day, assuming 30 g for the body weight of mice con- suming 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 con- ducted 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-tolui- dine 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 clasto- genicity 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 descrip- tion of the study precludes the drawing of definitive conclusions (Cesarone et al., 1982). Despite some sug- gestions 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 immuno- logical 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% confi- dence interval [CI] = 2.13–5.73). The SIRs for bladder cancer 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 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 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 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; 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–response assessment
Available data are inadequate to allow the poten- tial risks of reproductive or developmental effects on human health to be assessed. Carcinogenicity is consid- ered, however, to be the critical effect associated with potential exposure to o-toluidine. In several experimental studies, the oral administration of o-toluidine hydro- chloride increased the incidence of benign and/or malignant tumours in various tissues in rats (spleen sarcomas 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 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 dye- stuffs and rubber industries found that exposure to chemicals, including o-toluidine, appears to be associ- ated 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-tolui- dine would not result in some risk to human health.
1Source: EnviChem Data Bank of Environmental Properties of Chemicals. Helsinki, Finland, Finnish Environment Agency, version 1.0, 1995.
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 environ- ment, 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% methaemo- globinaemia, further administer intravenously 1000 cc of a 5% glucose solution containing ascorbic acid; above 60% 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 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 deci- sions 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.
Prepared in the context of cooperation between the International Programme on Chemical Safety and the European Commission
© IPCS 1999
IPCS
International
March 1995
CAS No: 95-53-4 RTECS No: XU2975000 UN No: 1708
EC No:
1-Amino-2-methylbenzene 2-Aminotoluene
o-Methylaniline C7H9N / C6H4CH3NH2 Molecular mass: 107.2
TYPES OF HAZARD/
EXPOSURE
ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING
FIRE Combustible. Gives off irritating or toxic fumes (or gases) in a fire.
NO open flames. NO contact with nitric acid.
Powder, AFFF, foam, carbon dioxide.
EXPLOSION Above 85C explosive vapour/air mixtures may be formed.
Above 85C 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 A
DOCTOR!
Inhalation Blue lips or finger nails. Blue skin.
Confusion. Dizziness. Headache.
Shortness of breath. Weakness.
Ventilation, local exhaust, or breathing protection.
Fresh air, rest. Artificial respiration if indicated. Refer for medical attention.
Skin MAY BE ABSORBED! Redness.
Blue lips or fingernails. Blue skin (Further see Inhalation).
Protective gloves. Protective clothing.
Remove contaminated clothes.
Rinse and then wash skin with water and soap. Refer for 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. Blue skin.
Dizziness. Headache. Laboured breathing (further see Inhalation).
Do not eat, drink, or smoke during work.
Rinse mouth. Induce vomiting (ONLY IN CONSCIOUS PERSONS!). Refer for medical attention.
SPILLAGE DISPOSAL PACKAGING & LABELLING
Collect leaking and spilled liquid in sealable containers as far as possible. Absorb remaining liquid in sand or inert absorbent and remove to safe place (extra personal protection: complete
protective clothing including self-contained breathing apparatus).
Symbol R:
S:
UN Hazard Class: 6.1 UN Pack Group: II
Do not transport with food and feedstuffs.
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: 200C Melting point: -16C
Relative density (water = 1): 1.01 Solubility in water: poor
Vapour pressure, kPa at 20C: 0.2 Relative vapour density (air = 1): 3.7
Relative density of the vapour/air-mixture at 20C (air = 1): 1.00 Flash point: 85C c.c.
Auto-ignition temperature: 482C Explosive 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 information0341 ortho-TOLUIDINE
IMPORTANT DATA
Physical State; Appearance
COLOURLESS TO YELLOW LIQUID, TURNS
REDDISH-BROWN ON EXPOSURE TO AIR AND LIGHT.
Chemical Dangers
The substance decomposes on heating or on burning producing toxic fumes including nitrogen oxides. Reacts with strong oxidants, especially nitric acid.
Occupational Exposure Limits
TLV: 2 ppm; 8.8 mg/m3 (as TWA) A2 (skin) (ACGIH 1994-1995).
Routes of Exposure
The substance can be absorbed into the body by inhalation and through the skin, and by ingestion.
Inhalation Risk
Evaporation at 20C is negligible; a harmful concentration of airborne particles can, however, be reached quickly on spraying.
Effects of Short-term Exposure
The substance irritates the eyes and the skin. The substance may cause effects on the blood, bladder and kidneys, resulting in tissue lesions, impaired functions and formation of
methaemoglobin. Exposure to high concentrations may result in damage to kidneys and bladder. The effects may be delayed. Medical observation is indicated. See Notes.
Effects of Long-term or Repeated Exposure
The substance may have effects on the blood, resulting in the formation of methaemoglobin (see Notes). This substance is possibly carcinogenic to humans.
PHYSICAL PROPERTIES
ENVIRONMENTAL DATA
The substance is harmful to aquatic organisms.
NOTES
Depending on the degree of exposure, periodic medical examination is 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.
ADDITIONAL INFORMATION
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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 — 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)
