Toxicity and carcinogenicity of methyl isobutyl ketone in F344N rats and B6C3F1 mice following 2-year inhalation exposureToxicology, Volume 244, Issues 2-3, 28 February 2008, Pages 209-219

Matthew D. Stout, Ronald A. Herbert, Grace E. Kissling, Fernando Suarez, Joseph H. Roycroft, Rajendra S. Chhabra, John R. Bucher



Abstract
Methyl isobutyl ketone (MIBK) is primarily used as a denaturant for rubbing alcohol, as a solvent and in the manufacture of methyl amyl alcohol. Inhalation of vapors is the most likely route of exposure in the work place. In order to evaluate the potential of MIBK to induce toxic and carcinogenic effects following chronic exposure, groups of 50 male and 50 female F344/N rats and B6C3F1 mice were exposed to MIBK at concentrations of 0, 450, 900, or 1800 ppm by inhalation, 6 h/day, 5 days per week for 2 years. Survival was decreased in male rats at 1800 ppm. Body weight gains were decreased in male rats at 900 and 1800 ppm and in female mice at 1800 ppm. The primary targets of MIBK toxicity and carcinogenicity were the kidney in rats and the liver in mice. In male rats, there was increased mineralization of the renal papilla at all exposure concentrations. The incidence of chronic progressive nephropathy (CPN) was increased at 1800 ppm and the severity was increased in all exposed groups. There were also increases in renal tubule hyperplasia at all exposure concentrations, and in adenoma and adenoma or carcinoma (combined) at 1800 ppm; these lesions are thought to represent a continuum in the progression of proliferative lesions in renal tubule epithelium. These increases may have resulted from the increased severity of CPN, either through α2μ-globulin-dependent or -independent mechanisms. An increase in mononuclear cell leukemia at 1800 ppm was an uncertain finding. Adrenal medulla hyperplasia was increased at 1800 ppm, and there was a positive trend for increases in benign or malignant pheochromocytomas (combined). In female rats, there were increases in the incidence of CPN in all exposure concentrations and in the severity at 1800 ppm, indicating that CPN was increased by mechanisms in addition to those related to α2μ-globulin. There were renal mesenchymal tumors, which have not been observed in historical control animals, in two female rats at 1800 ppm. The relationship of these tumors to exposure to MIBK was uncertain. Hepatocellular adenomas, and adenoma or carcinoma (combined) were increased in male and female mice exposed to 1800 ppm. There were also treatment-related increases in multiple adenomas in both sexes
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BrooklynDodger(s) comment: This publication of an NTP study left the levels of evidence out of the abstract. These were "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." "Some" evidence is a study finding associations. The nephropathy in female rats undermines the Houdini alpha-2 theory. Liver tumors in both genders of mice is a strong finding. The Dodger(s) would add these findings up to a solid 2B carcinogen at IARC, or reasonably anticipated for the ROC. This is a rare organic vapor that didn't cause lung tumors in mice.