Cupferron, an N-nitroso hydroxylamine derivative used primarily as a reagent in analytical chemistry, was selected for bioassay by the National Cancer Institute because of the suspected carcinogenicity of nitrosamines.
A bioassay of cupferron for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. Cupferron was administered in the feed, at either of two concentrations, to groups of 49 or 50 male and 50 female animals of each species. The time-weighted average high and low dietary concentrations of cupferron were, respectively, 0.30 and 0.15 percent for male and female rats, and 0.4 and 0.2 percent for male and female mice. After a 78-week period of compound administration, observation of the rats continued for an additional period of up to 28 weeks and observation of the mice continued for an additional period of up to 18 weeks.
For each species, 50 animals of each sex were placed on test as controls and fed only the basal diet.
Among both sexes of rats and mice there was a significant positive association between the dose of cupferron administered and mortality; however, in all groups of animals sufficient numbers survived long enough to establish the carcinogenicity of this compound.
There were significant positive associations between the concentrations of cupferron administered to male and female rats and the incidences of: squamous-cell carcinomas of the forestomach, hepatocellular carcinomas and neoplastic nodules, and hemangiosarcomas. When a binomial distribution and a spontaneous incidence rate correspondingto the appropriate historical control incidence were assumed, the incidences of auditory sebaceous gland neoplasms in female rats and female mice were significant. There were significant positive associations between the concentrations administered and the incidences of hepatocellular carcinomas in female mice, the incidences of hemangiosarcomas in both sexes of mice, and the incidence of Harderian gland adenomas in both sexes of mice.
Under the conditions of this bioassay cupferron was carcinogenic in Fischer 344 rats, causing hemangiosarcomas, hepatocellular carcinomas, and squamous-cell carcinomas of the forestomach in males and females as well as carcinomas of the auditory sebaceous gland in females. The chemical was also carcinogenic in B6C3F1 mice, causing hemangiosarcomas in males and hepatocellular carcinomas, carcinomas of the auditory sebaceous gland, a combination of hemangiosarcomas and hemangiomas, and adenomas of the Harderian gland in females.