NTP Toxicity Studies of Cyclohexanone Oxime Administered by Drinking Water to B6C3F1 Mice (CAS No. 100-64-1)

Cyclohexanone oxime is used primarily as a captive intermediate in the synthesis of caprolactam for the production of polycaprolactam (Nylon-6) fibers and plastics and also in a variety of industrial applications. Cyclohexanone oxime was selected for study because of the potential for human exposure and the interest in oximes as a chemical class. Toxicity studies of cyclohexanone oxime (approximately 99% pure) were carried out in male and female B6C3F1 mice; the compound was administered in drinking water for 2 weeks or 13 weeks. In addition, the genetic toxicity of cyclohexanone oxime was evaluated by determining mutagenicity in Salmonella typhimurium and induction of chromosomal aberrations in cultured Chinese hamster ovary cells in vitro, with and without S9 activation. The frequency of micronucleated normochromatic erythrocytes in the bone marrow and peripheral blood of mice from the 13-week study was also determined. In the 2-week study, groups of five male and five female mice were given drinking water containing 0, 106, 312, 625, 1,250, or 2,500 ppm cyclohexanone oxime. No deaths occurred, and there was no decrease in weight gain in any group. No gross lesions were observed; there were significant increases in relative spleen weights of males and females in the 2,500 ppm group and increases in the relative liver weight of male mice exposed to 312 ppm or greater. In the 13-week studies, groups of 10 male and 10 female mice were given drinking water containing 625, 1,250, 2,500, 5,000 or 10,000 ppm cyclohexanone oxime. Deaths occurred in the 10,000 ppm groups and weight gain was depressed in males and females given 10,000 ppm and in females given 5,000 ppm. There were significant increases in relative spleen weight at exposure levels of 5,000 and 10,000 ppm and significant increases in the relative liver weights of males and females that received 10,000 ppm. Microscopically, hematopoietic cell proliferation was observed in the spleen of males and females in the 5,000 and 10,000 ppm groups. Centrilobular cell hypertrophy was observed in the liver of males in the 2,500, 5,000, and 10,000 ppm groups and in females in the 5,000 and 10,000 ppm groups. Olfactory epithelial degeneration was observed in all exposed groups. Cyclohexanone oxime was mutagenic in Salmonella typhimurium strain TA1535 with S9 activation only; results of mutagenicity testing of cyclohexanone oxime were negative in strains TA97, TA98, and TA100, with and without S9. Cyclohexanone oxime gave equivocal results in a test for induction of chromosomal aberrations in cultured Chinese hamster ovary cells without S9; with S9, results were negative. In vivo, no induction of micronuclei was noted in erythrocytes of mice treated with cyclohexanone oxime either for 13 weeks in drinking water or for 3 days by intraperitoneal injection. In summary, the major targets of cyclohexanone oxime toxicity are the erythrocyte, spleen, liver, and nasal epithelium. The no-effect level for erythrotoxicity is 2,500 ppm following 13 weeks of exposure. The no-effect level for hematopoietic cell proliferation in the spleen is 2,500 ppm. The no-effect level for hepatotoxicity is 1,250 ppm for males and 2,500 ppm for females following 13 weeks of exposure. Some nasal olfactory epithelial degeneration was observed at all exposure levels; only at 625 ppm in males was the incidence of this lesion not significantly different from that in the controls. Cyclohexanone oxime was mutagenic only in Salmonella typhimurium strain TA1535 with S9 activation.