3-chloro-o-toluidine

Carcinogenicity

Description of key information

No data are available for the test substance.
Read across from CAS 75-79-4: oral: rat: No dose related tumors were found: NOAEL = 250 mg/kg bw/day (highest dose tested, NCI, 1979)
                                                                   mouse: LOAEL < 300 mg/kg bw/day, haemangiosarcoma and hepatocellular carcinoma were observed in both dose groups (NCI, 1979)
Read across from CAS 75-74-9: No dose related tumors were found in studies with rats and mice.
oral: rat: NOAEL = 165 mg/kg bw/day (highest dose tested, NCI, 1978)
         mouse: NOAEL = 90 mg/kg bw/day (highest dose tested, NCI, 1978)

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. The evaluation is based on two read across substances 5 -chloro-o-toluidine and 3 -chloro-p-toluidine (CAS 95 -79 -4 and CAS 95 -74 -9) which are structural similar to the test substance. As a result the substance is not considered to be classified for carcinogenicity under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC.

 

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008.

The evaluation is based on two read across substances 5 -chloro-o-toluidine and 3- chloro-p-toluidine (CAS 95 -79 -4 and CAS 95 -74 -9) which are structural similar to the test substance. As a result the substance is not considered to be classified for carcinogenicity under Regulation (EC) No. 1272/2008.

Additional information

No data are available for the test substance 3 -chloro-o-toluidine. Carcinogenicity studies with the substances which have structural similarity with the test substance are considered suitable for read across prupose, and are described below:

CAS 95 -79 -4: A bioassay for the possible carcinogenicity of 5-chloro-o-toluidine was conducted using Fischer 344 rats and B6C3F1 mice (NCI, 1979). 5-Chloro-o-toluidine was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of 5-chloro-o-toluidine were 250 and 125 mg/kg bw/day for rats and 600 and 300 mg/kg bw/day for mice. The compound was administered for 78 weeks to both rats and mice, followed by an observation period of up to 26 weeks for rats and 13 weeks for mice. There were significant positive associations between the concentrations of 5-chloro-o-toluidine administered and mortality among male and female mice, but not among rats of either sex. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Distinct mean body weight depression was apparent when dosed female rats and dosed mice of both sexes were compared to their controls, indicating that the concentrations administered to these animals in this bioassay may have approximated the maximum tolerated concentrations. Since no mean body weight depression, relative to controls, no significantly accelerated mortality, and no signs of toxicity other than fatty metamorphosis of the liver were associated with administration of 5-chloro-o-toluidine to male rats, it is possible that these animals may have been able to tolerate a higher dietary concentration. There was a significant positive association between the concentration of 5-chloro-o-toluidine administered to male rats and the incidence of adrenal pheochromocytomas in these animals; however, neither of the Fisher exact comparisons was significant. None of the other statistical tests for tumors at any site in male or female rats indicated a significant positive association between dosage and incidence. In mice of both sexes there were significant positive associations between concentration administered and the incidence of hemangiosarcomas. In addition, the high dose to control Fisher exact comparisons for both sexes were significant. The Cochran-Armitage tests were also significant and positive for the incidences of hepatocellular carcinomas in both sexes of mice. For males and females, the high dose to control Fisher exact comparisons were significant, and for females the low dose to control comparison was also significant. Under the conditions of this bioassay, 5-chloro-o-toluidine was carcinogenic to B6C3F1 mice, inducing hemangiosarcomas and hepatocellular carcinomas in both males and females. There was no conclusive evidence of the carcinogenicity of the compound in Fischer 344 rats.

CAS 95 -74 -9: A bioassay for the possible carcinogenicity of 3-chloro-p-toluidine was conducted using Fischer 344 rats and B6C3F1 mice. 3-Chloro-p-toluidine was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The time-weighted average dietary concentrations of 3-chloro-p-toluidine administered to rats of both sexes were 165 and 80 mg/kg bw/day for the high and low dose groups, respectively. The high and low dietary concentrations of 3-chloro-p-toluidine administered to mice were, respectively, 180 and 90 mg/kg bw/day for males and 90 and 180 mg/kg bw/day for females. The compound was administered in the diet for 78 weeks, followed by an observation period of 24 weeks for high dose male rats, 25 weeks for all other dosed rats, and 12 weeks for mice. There were no significant positive associations between the concentrations of 3-chloro-p-toluidine administered and mortality in either species. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Mean body weight depression, relative to controls, was observed in high dose rats and mice of both sexes, indicating that the concentrations administered to these animals may have approximated the maximum tolerated dosages. The unusual incidences of nonneoplastic spleen and liver lesions in high dose rats supports this assumption. Under the conditions of this bioassay there was no convincing evidence for the carcinogenicity of 3-chloro-p-toluidine in Fischer 344 rats or B6C3F1 mice.

Conclusion: Since only one study done with 5 -chloro-o-toluidine in mice showed positive result and all other studies done with 5 -chloro-o-toluidine and 3 -chloro-p-toluidine in rats and mice were negative there is no clear evidence that 3 -chloro-o-toluidine would be a carcinogen. Also taken into account that data provided by mouse carcinogenicity study in terms of cancer and noncancer NOEL's contribute little or nothing to human health based risk assessments (Billington et al., Criticial Reviews in Toxicology, 2010; 40(1):35 -49). Furthermore, 3 -chloro-o-toluidine did not show any potential for genetic toxicity. Therefore, 3 -chloro-o-toluidine is not considered to be carcinogenic.