Toxicology and carcinogenesis studies of isophorone (greater than 94% pure), a widely used solvent and chemical intermediate, were conducted by administering 0, 250, or 500 mg isophorone/kg body weight per day by gavage in corn oil to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week for 103 weeks. Doses selected for the 2-year studies were based on the 16-day studies in which rats and mice of each sex received doses of 0-2,000 mg/kg per day and on 13-week studies in which rats and mice of each sex received doses ranging from 0 to 1,000 mg/kg per day by gavage in corn oil. No chemically related gross or histopathologic effects were observed in the 16-day or 13-week studies, but 1/5 high dose male rats, 4/5 high dose female rats, and all high dose male and female mice died during the 16-day studies. During the 13-week studies, 1/10 high dose female rats and 3/10 high dose female mice died. The high dose for the 2-year studies was set at 500 mg/kg per day for each sex of rats and mice, based mainly on the deaths in the 13-week studies.
Throughout the 2-year study, the mean body weights of the high dose male rats averaged 5% lower than those of the vehicle controls. During the second year, the mean body weights of the female high dose rats averaged 8% lower than those of the vehicle controls, and the high dose female mice averaged 5% lower. The survival of high dose male rats was significantly lower than that of the vehicle controls after week 96 (final survival: vehicle control, 33/50; low dose, 33/50; high dose, 14/50). The survival of dosed female rats was poor (30/50; 23/50; 20/50), due in part to 20 gavage-related accidental deaths of dosed animals. The survival of male mice was also low (16/50; 16/50; 19/50), but there was a significant trend toward increased survival of dosed female mice relative to that of the vehicle controls (26/50; 35/50; 34/50).
Dosed male rats showed a variety of proliferative lesions of the kidney (tubular cell hyperplasia: 0/50; 1/50; 4/50; tubular cell adenoma: 0/50; 0/50; 2/50; tubular cell adenocarcinoma: 0/50; 3/50; 1/50; epithelial hyperplasia of the renal pelvis: 0/50; 5/50; 5/50). Dosed male rats also exhibited increased mineralization of the medullary collecting ducts (1/50; 31/50; 20/50), and low dose male rats showed a more severe nephropathy than is commonly seen in aging F344/N rats. Carcinomas of the preputial gland were increased in high dose male rats (0/50; 5/50; 5/50). With the exception of a moderate increase in nephropathy (21/50; 39/50; 32/50), female rats did not show chemically related increased incidences of neoplastic or nonneoplastic lesions.
In high dose male mice, isophorone exposure was associated with increased incidences of hepatocellular adenomas and carcinomas (18/48; 18/50; 29/50) and of mesenchymal tumors of the integumentary system (fibroma, fibrosarcoma, neurofibrosarcoma, or sarcoma: 6/48; 8/50; 14/50). An increased incidence of lymphomas or leukemias was noted in low dose male mice (8/48; 18/50; 5/50). Coagulative necrosis (3/48; 10/50; 11/50) and hepatocytomegaly (23/48; 39/50; 37/50) were observed more frequently in the livers of dosed male mice than in vehicle controls. No compound-related neoplastic or nonneoplastic lesions associated with isophorone exposure were seen in female mice.
Isophorone was not mutagenic in strains TA100, TA1535, TA1537, or TA98 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9. Isophorone was weakly mutagenic in the mouse L5178Y/TK+/- assay in the absence of S9; it was not tested in the presence of S9. Isophorone induced sister-chromatid exchanges in the absence of S9 in Chinese hamster ovary cells; it did not induce sister-chromatid exchanges in the presence of Aroclor 1254-induced male rat liver S9, and it did not induce chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of S9.
An audit of the experimental data was conducted for the 2-year toxicology and carcinogenesis studies of isophorone. No data discrepancies were found that influenced the final interpretations.
Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenicity of isophorone in male F344/N rats as shown by the occurrence of renal tubular cell adenomas and adenocarcinomas in animals given 250 or 500 mg/kg per day; carcinomas of the preputial gland were also observed at increased incidence in male rats given 500 mg/kg. There was no evidence of carcinogenicity in female F344/N rats given 250 or 500 mg/kg per day. For male B6C3F1 mice, there was equivocal evidence of carcinogenicity of isophorone as shown by an increased incidence of hepatocellular adenomas or carcinomas (combined) and of mesenchymal tumors in the integumentary system in animals given 500 mg/kg per day and by an increase in malignant lymphomas in animals given 250 mg/kg per day. There was no evidence of carcinogenicity of isophorone in female B6C3F1 mice given 250 or 500 mg/kg per day.