Nitrofen, a substituted diphenyl ether, is one of several agricultural pesticides selected for bioassay by the National Cancer Institute because of a lack of adequate chronic toxicity data.
A bioassay of technical-grade nitrofen for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Nitrofen was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. The time-weighted average high and low dietary concentrations of nitrofen were 3,656 and 2,300 ppm for male rats, 2,600 and 1,300 ppm for female rats, and 4,696 and 2,348 ppm for both male and female mice, respectively. After a 78-week treatment period, observation of the low dose and control male and all female rats continued for an additional 32 weeks; observation of the high dose male rats continued for an additional 4 weeks. All mice were observed for an additional 12 weeks after the 78-week treatment period.
For each species, 20 animals of each sex were placed on test as controls. No nitrofen was added to their diet.
The incidence of carcinomas of the pancreas had a statistically significant positive association with concentration of nitrofen in the diet of female rats. The incidence of this tumor in high dose female rats was significant when compared to controls. Poor survival related to chemical toxicity precluded the evaluation of the carcinogenicity of nitrofen in male rats.
In mice of both sexes, the incidence of hepatocellular carcinoma at both high and low dose levels was highly significant when compared to the controls. The incidence of hemangiosarcoma of the liver had a statistically significant relationship with nitrofen concentration in the diet for mice of both sexes, and the incidence in high dose male mice was significant when compared to controls.
The results of this study indicate that orally administered technical-grade nitrofen is a liver carcinogen in B6C3F1 mice of both sexes. Nitrofen is also carcinogenic to female Osborne-Mendel rats.