Carcinogenesis in F-344 rats induced by nitrosohydroxyalkyl-chloroethylureas

Summary

The two isomeric N-nitroso derivatives of 1-chloroethyl-3-(2-hydroxyethyl)-urea and of 1-chloroethyl-3-(2-hydroxypropyl)-urea were prepared and isolated. They were given by gavage in ethyl acetate/corn oil to groups of 20 male and female F-344 rats. The two nitroso-1-chloroethyl compounds were nephrotoxic and most animals died within 20 weeks; no neoplasms were seen in any of these animals. Nitroso-1-hydroxyethyl-3-chloroethylurea was given at 2 concentrations, 21 and 10.5 mg/ml; in both groups almost all animals died with neoplasms related to the treatment. These included hepatocellular and cholangiocellular neoplasms of the liver; many of the former metastasized. Many rats also had tubular cell neoplasms in the kidney. Nitroso-1-(2-hydroxypropyl)-3-chloroethylurea was a less potent carcinogen at equimolar doses, inducing fewer liver neoplasms than the nitrosohydroxyethyl analog and only few kidney neoplasms. Both of these carcinogens were less effective in female rats than in males, although the females, which were smaller, received a higher dose per unit body weight. The spectrum of neoplasms induced by the nitrosohydroxyalkyl-chloroethylureas was quite different from that induced by equimolar doses of each corresponding nitrosohydroxyalkylurea, neither of which induced neoplasms of the liver, although they were potent inducers of neoplasms in other organs.