2-nitrotoluene

Carcinogenicity

Justification for classification or non-classification

Harmonised classification:

The substance is classified in Category 1B (H350 ) according to the Regulation (EC) No. 1272/2008 (CLP). 

Additional information

EU Risk Assessment 2008:

Only a long-term feed carcinogenicity study in rodents was available (NTP, 2002), performed in essence according to OECD guideline 451 and GLP compliant, and therefore considered adequate for risk assessment. There was clear evidence of carcinogenic activity of 2-nitrotoluene in rats, based on increased incidences of malignant mesothelioma, subcutaneous skin neoplasms, mammary gland fibroadenoma and liver neoplasms in males and increased incidences of subcutaneous skin neoplasms and mammary gland fibroadenoma in females. The increased incidences of lung neoplasms in males and of hepatocellular adenoma in females were also considered to be exposure related. Malignant mesotheliomas occurred with incidences of 33%, 48% and 73% in the 625, 1250 and 2000 ppm core study male rat groups, respectively. The incidences of malignant mesotheliomas were 73% and 90% in the 2000 and 5000 ppm stop-exposure male rat groups. The incidence of mesothelioma was higher in the 2000 stop-exposure group than in the 625 ppm even though the latter group received approximately 50% more total exposure to 2-nitrotoluene. The incidences of mesotheliomas were similar in the 2000 ppm core study and stop-exposure groups of male rats. Thus, critical events leading to mesothelioma occurred early in the study, and this damage was irreversible. The molecular patogenesis of mesotheliomas is not well understood. Decreased incidences of mononuclear cell leukaemia and of testicular interstitial cell adenoma in exposed groups were related to splenic and testicular toxicity, respectively. There was clear evidence of carcinogenic activity of 2-nitrotoluene in male and female mice based on increased incidences of hemangiosarcoma, carcinoma of the large intestine (cecum), and hepatocellular neoplasms (females only because males died early due to the development of hemangiosarcomas). The occurrence of p53 or ß¿catenin mutations in 2-nitrotoluene induced hemangiosarcomas, but not in spontaneous hemangiosarcomas, suggest that the pathways leading to 2-nitrotoluene-induced cancer differ from the pathways in spontaneous hemangiosarcomas. No 2-nitrotoluene epidemiology studies on carcinogenesis have been reported in the literature. However, according to Ward et al., 1991 (cited in NTP, 2002) excess cancers have been found in workers exposed to a related chemical, o-toluidine. In summary, there is a good evidence of an increase in tumour incidence at multiple sites in both rats and mice. There is also evidence that time to onset is very short. These observations are consistent with genotoxic aetiology, which is consistent with the findings from the genotoxicity studies.