Carcinogenicity of benzidine, N,N'-diacetylbenzidine, and N-hydroxy-N,N'-diacetylbenzidine for female CD rats.

To evaluate the role of metabolism in benzidine (BZ) carcinogenesis, BZ and 2 or its metabolites, N,N'-diacetylbenzidine and N-hydroxy-N,N'-diacetylbenzidine (NOHDABZ), were given by i.p. injection to female CD rats twice weekly for 4 weeks beginning at 30 days of age. A preliminary dose-response test showed that NOHDABZ was the most toxic compound; it caused chemical peritonitis and death in each of 4 animals given 70 mumol/kg body weight/injected. Toxicity was low in a 46-week carcinogenicity test which used either 10 or 30 mumol of each compound/kg body weight/injection; of 30 treated animals per groups, the effective number of rats was at least 28 per group. In the high dose BZ rats, the incidences of mammary gland and Zymbal's gland tumors were 41% (fibroadenoma plus adenocarcinoma) and 21% (adenoma plus carcinoma), respectively, and these incidences were significantly greater than those in control animals. The metabolites were approximately equipotent with BZ in mammary and Zymbal's gland, but the amount of NOHDABZ actually reaching these organs may have been diminished by local reactions of NOHDABZ within the peritoneum. Thus, of 60 NOHDABZ-treated rats, there were 2 toxicity-related early deaths, 6 rats with adhesions between visceral organs, and 5 tumors in tissues exposed directly to the compound. Since these effects were not present in other treatment groups, NOHDABZ may present an activate carcinogenic form of BZ.