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HomeSCOEL/REC/145 4-Aminotoluene (p-Toluidine)
Recommendation from the Scientific Committee on Occupational Exposure Limits
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Methaemoglobin (MHb) formation is the critical non-neoplastic effect in animals and humans exposed to 4-aminotoluene (4-AT). Depending on the concentration of MHb, methaemoglobinemia may have serious health effects in humans. Quantitative data on the formation of MHb after inhalation of 4-AT in humans or in experimental animals are not available. Experimentally, MHb levels reached between 4.2 % and 6.6 % after 3 months of feeding 40 mg/kg/day of 4-AT in rats (the lowest dosed examined) and were only marginally further increased after 6 months (Jodynis-Liebert and Bennasir 2005). By analogy to tolerable levels of CO-Hb in carbon monoxide exposed persons, a MHb level of 4-5 % has been considered tolerable (Bolt et al 1985; see also REC-153 for aniline). Thus, 40 mg/kg/day 4-AT may be regarded as the LOAEL concerning MHb induction in rats. Comparison of equimolar intravenous doses of 4-AT and aniline in cats indicates that the ability of 4-AT to induce MHb formation is lower and about half as high as the ability of aniline (McLean et al 1969). 4-AT was not mutagenic or genotoxic in most in vitro tests with bacterial or eukaryotic test systems including mammalian cells. DNA damage was observed in human lung cells and unscheduled DNA synthesis in rat hepatocytes. The in vivo database is very limited. A mutagenic response was obtained in a Drosophila test. Strand breaks in liver and kidney of mice and DNA binding in various tissues of rats have been detected. 4-Methylphenylhydroxylamine, an intermediate of 4-AT that is involved in methaemoglobin formation, is mutagenic in bacterial test systems. In summary, a minor genotoxic potential of 4-AT in vivo cannot be ruled out. The database with respect to carcinogenic effects in humans is insufficient. Two cases of bladder papillomas and 6 cases of bladder tumours were identified in an examination of 81 workers with occupational exposure to 4-AT and, most of them, also to 2AT. The latter (o-toluidine) is an established human bladder carcinogen (Khlebnikova et al 1970). Several older animal carcinogenicity studies have been performed in the 1970s. Weekly subcutaneous injections of 4-AT over a period of 2 years led to an increase in malignant tumours at the site of application in both males and females and in benign liver tumours in females. No tumours at the site of application occurred after dermal application of a solution of 4-AT to the skin of mice. 4-AT was not carcinogenic in an 18-month feeding study with male rats, but in the same study, feeding of 4-AT caused a slight increase of liver tumours in male and female mice. From the report it appears likely that these were benign (hepatic adenomas). In the same study, the isomer 2AT (o-toluidine) was clearly carcinogenic under similar conditions (Section 7.7.2). Therefore, although the possibility of metabolic formation of genotoxic N-oxidation products in humans may raise some concern for a genotoxic potential of 4-AT, there is no experimental or epidemiological proof of carcinogenicity at present. Compared to its structural isomer 2AT (o-toluidine), a carcinogenic potential of 4-AT, if such a potential exists, must be distinctly lower. In essence, modern studies on carcinogenicity of 4-AT are needed. Because the available data are not clear, SCOEL does presently not classify 4-AT as to carcinogenicity.
- Dáta foilsithe:
- Údar corparáideach/údair chorparáideacha: Directorate-General for Employment, Social Affairs and Inclusion (An Coimisiún Eorpach) , Scientific Committee on Occupational Exposure Limits
- Téamaí: Sláinte tomhaltóirí
- Ábhar: animal experimentation , carcinogenic substance , classification , consumer protection , health risk , labelling , legislation , occupational health , organic chemical , report , toxic substance
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| ISSN | ISBN 978-92-79-66635-3 | DOI 10.2767/20947 | Uimhir chatalóige KE-02-17-271-EN-N |
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| ISSN | ISBN 978-92-79-66634-6 | DOI 10.2767/118245 | Uimhir chatalóige KE-02-17-271-EN-C |
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