4-Chloro-ortho-toluidine and its hydrochloride salt were produced commercially in substantial amounts as intermediates in the manufacture of azo dyes and chlordimeform, an insecticide. Since the 1980s, production and use of 4-chloro-ortho-toluidine have been discontinued in most countries.
Three small cohort studies of workers exposed to 4-chloro-ortho-toluidine, one each among dye, 4-chloro-ortho-toluidine and chlordimeform production workers, were available. Two of them showed high relative risks of bladder cancer. Despite problems in the cohort definitions in these two studies, the high relative risks observed for bladder cancer most likely represent a true excess. However, confounding cannot be excluded due to the presence of other exposures including potential bladder carcinogens. The third study had limited power to detect a risk due to use of mortality data only in a small cohort.
4-Chloro-ortho-toluidine or its hydrochloride was tested for carcinogenicity by oral administration in two experiments in mice and in two experiments in rats. The compounds increased the incidence of haemangiosarcomas in the spleen and adipose tissue in both male and female mice, but no increase in the incidence of tumours was observed in rats.
4-Chloro-ortho-toluidine undergoes extensive metabolism in rodents in vivo. Like other aromatic amines, it undergoes metabolic activation via initial formation of the N-hydroxy derivative. The further metabolic processing of this metabolite has not been investigated.
In humans, 4-chloro-ortho-toluidine induces acute toxicity in the urinary bladder and causes methaemoglobinaemia. In rodents, 4-chloro-ortho-toluidine and/or its metabolites bind to macromolecules in liver cells.
4-Chloro-ortho-toluidine gave variable results in the majority of bacterial tests for mutagenicity. While most of the mammalian tests were positive, chromosomal aberration assays gave conflicting results. These data overall indicate that 4-chloro-ortho-toluidine causes DNA damage in mammalian cells.
There is limited evidence in humans for the carcinogenicity of 4-chloro-ortho-toluidine.
There is sufficient evidence in experimental animals for the carcinogenicity of4-chloro-ortho-toluidine.
4-Chloro-ortho-toluidine is probably carcinogenic to humans (Group 2A).