The potential of
o-nitrotoluene and
p-nitrotoluene to cause
cancer in mammalian species was studied in male and female F344/N rats and B6C3F1 mice. These chemicals are on the EPA list of high production chemicals and there is potential for human exposure (High Production Volume Chemical List (2000) http://oaspub.cpa.gov/opptintr/chemrtk/volchall.htm.).
o-Nitrotoluene, administered in the feed for up to 2 years, caused clear evidence for
cancer at multiple sites in rats and mice. Male rats, receiving
o-nitrotoluene in the feed ( approximately 0, 25, 50, or 90 mg/kg per day), developed treatment-related
mesotheliomas, subcutaneous
skin neoplasms, mammary gland
fibroadenomas, and
liver neoplasms. By 2 years,
mesotheliomas, skin, liver, mammary gland and liver
tumors also occurred in 'stop-study' male rats that received
o-nitrotoluene at 125 or 315 mg/kg per day for only the first 3 months of study. These 'stop-studies' showed that the critical events leading to
tumor formation occurred after 3 months of dosing, and these events were irreversible and eventually led to
cancer at multiple sites.
o-Nitrotoluene given in the feed to female rats (approximately 0, 30, 60, or 100 mg/kg per day) and to male and female mice (approximately 0, 150, 320, or 700 mg/kg per day) also caused a carcinogenic response. In female rats, treatment-related subcutaneous
skin neoplasms and mammary gland
fibroadenomas occurred.
Hemangiosarcomas and
carcinomas of the large intestine (cecum) were seen in treated male and female mice. In contrast to
o-nitrotoluene,
p-nitrotoluene given in the feed over approximately the same exposure levels caused only equivocal evidence of carcinogenic activity in male rats (subcutaneous
skin neoplasms); some evidence of carcinogenic activity in female rats (clitoral gland
neoplasms); equivocal evidence of carcinogenic activity in male mice (
lung neoplasms); and no evidence of carcinogenic activity in female mice. Differences in the
o-nitrotoluene and
p-nitrotoluene carcinogenic activity may be due to differences in the metabolism of the parent compound to carcinogenic metabolites.