Methyl isobutyl ketone is used as a denaturant for
rubbing alcohol; as a
solvent for paints, varnishes,
nitrocellulose, lacquers, and protective coatings; in industrial extraction processes; in dry-cleaning preparations; and in the synthesis of
methyl isobutyl carbinol.
Methyl isobutyl ketone was nominated for study by the National Cancer Institute and the United States Environmental Protection Agency because of its widespread use, the high potential for worker exposure due to its many industrial applications, and its high production volume. Male and female F344/N rats and B6C3F1 mice were exposed to
methyl isobutyl ketone (greater than 99% pure) by inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium. 2-YEAR STUDY IN RATS: Groups of 50 males and 50 females were exposed to
methyl isobutyl ketone at concentrations of 0, 450, 900, or 1,800 ppm by inhalation, 6 hours plus T(90) (12 minutes) per day, 5 days per week for 104 weeks. Survival of males exposed to 1,800 ppm was significantly less than that of the chamber controls. The mean
body weights of the 900 and 1,800 ppm males were less than those of the chamber controls after weeks 97 and 89, respectively. In the standard evaluation of the kidney, there were slightly increased incidences of renal tubule
adenoma and renal tubule
adenoma or
carcinoma (combined) in males exposed to 900 or 1,800 ppm, and renal tubule
carcinoma in males exposed to 1,800 ppm. The incidences of renal tubule
hyperplasia were also significantly increased in the 450 and 1,800 ppm males, and the severities were greater than in the chamber controls. Chronic nephropathy occurred in all males exposed to 1,800 ppm and in 70% to 88% of exposed females, and the severity was increased in 1,800 ppm males. The incidences of transitional epithelial
hyperplasia of the renal pelvis in males exposed to 900 or 1,800 ppm and mineralization of the renal papilla in all groups of exposed males were significantly increased. In addition, two female rats exposed to 1,800 ppm had renal mesenchymal
tumors. In the extended evaluation of the kidney, renal tubule
adenomas and renal tubule
hyperplasia occurred in all groups of exposed male rats. In the combined single and step section analysis, the incidences of renal tubule
adenoma and renal tubule
adenoma or
carcinoma (combined) were significantly increased in males exposed to 1,800 ppm. The incidences of renal tubule
hyperplasia were also significantly increased in all exposed groups of males. There was a positive trend in the incidences of mononuclear cell
leukemia in males, and the incidence in the 1,800 ppm group was significantly increased. The incidence of adrenal medulla
hyperplasia in the 1,800 ppm males was significantly increased. 2-YEAR STUDY IN MICE: Groups of 50 males and 50 females were exposed to
methyl isobutyl ketone at concentrations of 0, 450, 900, or 1,800 ppm by inhalation, 6 hours plus T(90) (12 minutes) per day, 5 days per week for 105 weeks. Survival of males and females was similar to that of the chamber controls. The mean
body weights of females exposed to 1,800 ppm were less than those of the chamber controls after week 17. The incidences of
hepatocellular adenoma and
hepatocellular adenoma or
carcinoma (combined) were significantly increased in males and females exposed to 1,800 ppm. The incidences of eosinophilic foci were significantly increased in 450 and 1,800 ppm females.
GENETIC TOXICOLOGY: Under the conditions of these 2-year studies, there was some evidence of carcinogenic activity of
methyl isobutyl ketone in male F344/N rats based on increased incidences of renal tubule
neoplasms. Increased incidences of mononuclear cell
leukemia in 1,800 ppm male F344/N rats may have been related to
methyl isobutyl ketone exposure. There was equivocal evidence of carcinogenic activity of
methyl isobutyl ketone in female F344/N rats based on the occurrence of renal mesenchymal
tumors in the 1,800 ppm group. There was some evidence of carcinogenic activity of
methyl isobutyl ketone in male and female B6C3F1 mice based on increased incidences of
liver neoplasms. Exposure to
methyl isobutyl ketone resulted in nonneoplastic lesions of the kidney characteristic of alpha2u-globulin accumulation in male rats and nephropathy in female rats.