VOL.: 77 (2000) (p. 267)ortho-Toluidine
Chem. Abstr. Name: 2-Methylbenzenamine hydrochloride
5. Summary of Data Reported and Evaluation
5.1 Exposure data
ortho-Toluidine and its hydrochloride salt have been widely produced commercially throughout the twentieth century for use in manufacture of dyestuffs, pigments, optical brighteners, rubber chemicals, pharmaceuticals and pesticides. Human exposure has been reported during its use in production of dyestuffs and rubber chemicals. Non-occupational exposure to ortho-toluidine may result from its occurrence in certain foods and from exposure to tobacco smoke.
5.2 Human carcinogenicity data
Five studies were available for evaluation. Two mortality studies were conducted in the 1980s among dye production workers in Italy and in the United States. In each case, the subgroups of workers exposed to ortho-toluidine were small. Two recent cohort studies in Germany, the United Kingdom and a larger study in the United States among workers in 4-chloro-ortho-toluidine production and in rubber chemical manufacturing looked at bladder cancer incidence. Of these five studies, four observed a very high excess of bladder cancer among ortho-toluidine-exposed workers. The fifth study had limited power to detect a risk. In the two studies with data on duration of exposure to ortho-toluidine, the highest risk was observed in the subgroup with the longest duration of exposure. In none of these studies, however, could confounding by concomitant exposure to various other potential bladder carcinogens be ruled out with confidence, although co-exposures differed between studies.
5.3 Animal carcinogenicity data
ortho-Toluidine was tested for carcinogenicity as its hydrochloride salt in two experiments in mice and in three experiments in rats and as the free base in one limited experiment in hamsters. After oral administration to mice, it induced an increased incidence of haemangiomas and haemangiosarcomas and hepatocellular carcinomas or adenomas. In rats, oral administration of ortho-toluidine increased the incidence of tumours in multiple organs, including fibromas, sarcomas, mesotheliomas, mammary fibroadenomas and transitional-cell carcinomas of the urinary bladder.
5.4 Other relevant data
ortho-Toluidine undergoes extensive metabolism in vivo, with the bulk of the dose being excreted in the urine within 24 h. Like other aromatic amines, it is thought to undergo metabolic activation initially via N-hydroxylation, leading to covalent binding to tissue macromolecules. Evidence that ortho-toluidine undergoes metabolic activation in vivo is supported by the fact that it forms both haemoglobin and albumin adducts in laboratory animals and haemoglobin adducts in humans.
In rats, repeated administration of ortho-toluidine led to haemosiderosis, splenic congestion, bone marrow and splenic proliferation and splenic fibrosis consistent with a response to erythrocyte destruction.
Bacterial or bacteriophage assay systems showed negative or inconsistent data or, at most, weakly positive results. In the yeast Saccharomyces cerevisiae, ortho-toluidine caused reverse mutation at some loci and occasionally recombinational events. It caused gain or loss of whole chromosomes and mutation of mitochondrial DNA. In cultured mammalian cells, it generally caused sister chromatid exchanges and sometimes also increased gene mutations, chromosomal aberrations and micronuclei. It induced aneuploidy and increased cell transformation in such cells. ortho-Toluidine may inhibit intercellular communication. It has been demonstrated to be a mutagen but not a recombinogen in Drosophila melanogaster. In rodent models in vivo, it enhanced sister chromatid exchanges but gave equivocal results for micronuclei and sperm morphology.
There is limited evidence in humans for the carcinogenicity of ortho-toluidine.
There is sufficient evidence in experimental animals for the carcinogenicity of ortho-toluidine.
ortho-Toluidine is probably carcinogenic to humans (Group 2A).For definition of the italicized terms, see Preamble Evaluation.
Previous evaluations: Vol. 16 (1978); Vol. 27 (1982); Suppl. 7 (1987)
See Also: Toxicological Abbreviations ortho-toluidine (ICSC) ortho-Toluidine (IARC Summary & Evaluation, Supplement7, 1987)