title: Bioassay of p-Nitrosodiphenylamine for Possible Carcinogenicity (CAS No. 156-10-5).
abstract: p-Nitrosodiphenylamine is used to accelerate the vulcanization of rubber. It is also used as an intermediate in the manufacture of dyes and pharmaceutical compounds and as an inhibitor of polymerization during the production of vinyl monomers such as styrene. A bioassay for the possible carcinogenicity of p-nitrosodiphenylamine was conducted using Fisher 344 rats and B6C3F1 mice. p-Nitrosodiphenylamine was administered in the feed, at either of two concentrations, to groups of 50 male and 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 p-nitrosodiphenylamine were, respectively, 5000 and 2500 ppm for rats. The high and low time-weighted average concentrations for mice were 9000 and 4254 ppm, respectively. The compound was administered for 78 weeks to rats, for 50 weeks to high dose mice and for 57 weeks to low dose mice. The period of compound administration was followed by an observation period of 27 weeks for rats and 35 weeks for mice. There were significant positive associations between the concentrations of p- nitrosodiphenylamine administered and mortality among male and female mice, but not for rats of either sex. Although 19/50 high dose male mice and 21/50 high dose female mice died before week 52, adequate numbers of mice and rats survived sufficiently long to be at risk from late-developing tumors. The toxicity observed in mice and the dose-related mean body weight depression apparent in male and female rats indicated that the concentrations of p-nitrosodiphenylamine administered to these animals in this bioassay may have approached or exceeded the maximum tolerated concentrations. In male rats, there was a significant positive association between concentration administered and the incidence of a combination of hepatocellular carcinomas and neoplastic nodules. In addition, both the high dose to control and thelow dose to control Fisher exact comparisons were significant. There was also a significant positive association between concentration administered and the incidence of alveolar/bronchiolar adenomas in male rats; however, neither of the Fisher exact comparisons were significant. There were no positive, significant statistical tests for tumor incidence at any site in female rats. Due to the large number of early deaths among high dose mice of both sexes, the statistical conclusion concerning carcinogenicity was based on comparisons between the low dose and control groups. The incidence of hepatocellular carcinomas was significantly higher among the low dose males than among their controls. Although hepatocellular neoplasms were observed in dosed females, there were no tumors occurring with a statistically increased incidence when low dose females were compared to their controls. Under the conditions of this bioassay, p-nitrosodiphenylamine was carcinogenic when administered in the diet to male B6C3F1 mice, causing hepatocellular carcinomas. The chemical was also carcinogenic in male Fisher 344 rats, causing liver neoplasms. No evidence was provided for the carcinogenicity of p-nitrosodiphenylamine in female B6C3F1 mice or in female Fisher 344 rats. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negative Male Mice: Positive Female Mice: Negative Synonyms: 4-nitroso-N-phenylbenzeneamine; 4-nitrosodiphenylamine; p-nitroso-N-phenylaniline; TKB