3-chloro-o-toluidine

Endpoint summary

Description of key information

Oral: No data available for the test substance.
read across: CAS 95-79-4: LOAEL = 31.5 mg/kg bw/day (target organ: liver; rat, subacute study, NCI 1979)
                                                 LOAEL = 125 mg/kg bw/day (target organ: liver; rat, chronic study, NCI 1979)
read across: CAS 95-74-9: NOAEL = 560 mg/kg bw/day (highest dose tested; rat, subacute study, NCI 1978)
                                                 NOAEL = 80 mg/kg bw/day (target organ: liver, spleen; rat, chronic study, NCI 1978)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

LOAEL

31.5 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

Oral: No data available for the test substance. Reliable data are given for two substances which are structural similar to the test substance and thus, suitable for read-across purpose.

5 -chloro-o-toluidine (CAS 95 -79 -4):

Subacute: In the context of a carcinogenicity study of the National Cancer Instiute (1979) subacute dose finding studies were done. For this purpose male and female Fischer 344 rats and B6C3F1 mice in groups of five each were used. The feed contained the substance and the treatment lasted four weeks with a post exposure period of two weeks. The feed for the rats contained the substance in following concentrations: 0, 315, 680, 1465, 3155, and 6800 mg/kg and for mice: 0, 255, 550, 1180, 2550, and 5500 mg/kg.

In the highest dose group a reduced body weight gain in male and female rats were observed. None of the rats died during this study. In all dose groups all rats had mottled livers. Male rats additionally showed spotted kidneys. This results leads to a LOAEL of 31.5 mg/kg bw/day which in turn leads to a classification STOT RE 2 with the liver as target organ.

The results from the study done with mice were different. The survival rate for female mice in the highest dose group was 100% whereas it was 0% for the male mice. In all other dose groups all mice survived. The body weight gain was normal for all mice and no abnormalities were detected. This results lead to a NOAEL for females of 825 mg/kg bw/day and for males of 375 mg/kg bw/day.

Chronic: From a carcinogenicity study (NCI 1979) an evaluation of repeated dose toxicity is possible. A bioassay for the possible carcinogenicity of 5-chloro-o-toluidine was conducted using Fischer 344 rats and B6C3F1 mice. 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 5000 and 2500 mg/kg diet for rats and 4000 and 2000 mg/kg diet 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 no associations between the concentrations of 5-chloro-o-toluidine administered and mortality among male and female rats. Distinct mean body weight depression was apparent when dosed female rats were compared to their controls. 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. Female rats also showed a fatty liver in both dose groups. These observations lead to LOAEL of at least 125 mg/kg bw/day (corresponds to 2500 mg/kg diet).

There were significant positive associations between the concentrations of 5-chloro-o-toluidine administered and mortality among male and female mice. Distinct mean body weight depression was apparent dosed mice of both sexes were compared to their controls. Furthermore, female mice showed a clear increase of myelosclerosis in both dose groups. In male mice of both dose groups hyperplasia in the liver and in the high dose group glomerulonephritis were observed. In mice of both sexes in both dose groups cytoplasmic changes in the liver were observed. These results lead to an LOAEL of at least 300 mg/kg bw/day (corresponds to 2000 mg/kg diet).

 

3 -chloro-p-toloudine (CAS 95 -74 -9):

Subacute: In the context of a carcinogenicity study of the National Cancer Institute (1978) subacute dose finding studies were done. For this purpose male and female Fischer 344 rats and B6C3F1 mice in groups of five each were used. The feed contained the substance and the treatment lasted four weeks with a post exposure period of two weeks. The feed for the rats contained the substance in following concentrations: 0, 315, 680, 1465, 3155, and 6800 mg/kg diet and for mice: 0, 810, 1180, 1740, 2550, and 3750 mg/kg diet.

At the highest dose all rats showed a reduced body weight gain of 9% compared to the controls. In the second highest dose group the male rats had 17% more weight gain than the controls and the female rats had 6% less weight gain than the controls. No deaths were reported for any rat group. This result leads to a NOAEL of 680 mg/kg bw/day (corresponds to 6800 mg/kg diet).

At the end of the subacute test, mean body weight gain among male mice receiving 1740 mg/kg diet was the same as that of their controls, while female mice receiving the same concentration displayed a mean weight gain 5 percent less than that of their controls. The mean body weight gain among male mice receiving 1180 mg/kg diet was the same as that of their controls, while female mice receiving the same concentration displayed a mean body weight gain 3 percent less than that of their control. No deaths were reported in any mouse group. This result leads to a NOAEL for males of 560 mg/kg bw/day (corresponds to 3750 mg/kg diet) and a NOAEL for females of 260 mg/kg bw/day (corresponds to 1740 mg/kg diet).

Chronic: From a carcinogenicity study (NCI 1978) an evaluation of repeated dose toxicity is possible. 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 high and low dietary concentrations of 3-chloro-p-toluidine were 3269 and 1635 mg/kg diet for rats, 300 and 600 mg/kg diet for female mice, and 600 and 1200 mg/kg diet for male mice. The compound was administered for 78 weeks to both rats and mice, followed by an observation period of up to 24 to 25 weeks for rats and 12 weeks for mice.

In the high dose group all rats showed a slight reduction (<10%) of body weight gain. The survival rate was not reduced. The rats of both dose groups showed a high incidence to develop a fatty liver and fibrosis of splenic capsula. These observations lead to a NOAEL of 80 mg/kg bw/day (corresponds to 1635 mg/kg diet).

The survival rate was not reduced in the study with mice. Male mice showed a clear dose dependent reduction of body weight gain. Female mice showed only in the high dose group a reduction of the body weight gain. Differences concerning pathologic changes in the treated mice compared to the control animals were not observed. These results lead to an LOAEL of 90 mg/kg bw/day (corresponds to 600 mg/kg diet). Conclusion: In almost all studies effect on the liver were observed in rats after subacute and chronic oral exposure. For 5 -chloro-o-toluidine (CAS 95 -79 -4) a LOAEL of 31.5 mg/kg bw/day was found from the subacute study. This result leads to a STOT RE 2. Therefore the test substance 3 -chloro-o-toluidine has also to be classified for repeated dose toxicity.

Inhalation: One subacute inhalation study with the test substance on one cat is available (Lehmann 1933). The cat was whole-body exposed for 21 days 8 hours per day. The cat lost weight but after 3 weeks of recovery no abnormalities were detected. Since the study data are only available as secondary quotation, they were considered insufficient for a reliable evaluation of the long-term inhalative toxicity potential of the test substance.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

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 substance (CAS 95 -79 -4 and CAS 95 -74 -9) which are structurally similar to the test substance. As a result the substance is considered to be toxic after repeated oral exposure (R48) under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC.

 

Classification, Labeling, 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 substance (CAS 95 -79 -4 and CAS 95 -74 -9) which are structurally similar to the test substance. As a result the substance is considered to be toxic after repeated oral exposure (STOT RE 2) under Regulation (EC) No. 1272/2008.