Toxicity and carcinogenicity of methyl isobutyl ketone in F344N rats and B6C3F1 mice following 2-year inhalation exposure

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 1800ppm by inhalation, 6h/day, 5 days per week for 2 years. Survival was decreased in male rats at 1800ppm. Body weight gains were decreased in male rats at 900 and 1800ppm and in female mice at 1800ppm. 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 1800ppm 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 1800ppm; 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 alpha2micro-globulin-dependent or -independent mechanisms. An increase in mononuclear cell leukemia at 1800ppm was an uncertain finding. Adrenal medulla hyperplasia was increased at 1800ppm, 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 1800ppm, indicating that CPN was increased by mechanisms in addition to those related to alpha2micro-globulin. There were renal mesenchymal tumors, which have not been observed in historical control animals, in two female rats at 1800ppm. 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 1800ppm. There were also treatment-related increases in multiple adenomas in both sexes.

Exploratory Study Using Urinary Volatile Organic Compounds for the Detection of Hepatocellular Carcinoma

“…The mechanism for this was found to be due to the induction of the CYP450 system [ 41 , 42 , 43 ]. Chronic inhalation of an isomer of 2-hexanone (methyl isobutyl ketone, MIBK) was found to cause hepatocellular adenomas and HCC in mice [ 44 , 45 , 46 ]. This was shown to be in part due to the activation of the pregnane X and constitutive androstane nuclear receptors; these receptors are responsible for the regulation of CYP450 activity [ 44 ].…”

Food-Borne Chemical Carcinogens and the Evidence for Human Cancer Risk

“…Carcinogenicity : Currently, no studies assessed carcinogenicity of MIBK following oral exposure. Some evidence of carcinogenic activity were observed in inhalation studies, which reported increased incidences of renal tubule neoplasms in rats and hepatocellular neoplasms in mice at the highest tested dose of 1800 ppm (equivalent to 1725 mg/kg/day for rats and 3171 mg/kg/day for mice) [ 115 , 842 , 844 , 845 , 846 ].…”

From sugars to FDCA: a techno-economic assessment using a design concept based on solvent selection and carbon dioxide emissions

“…This will result in further costs to ensure the health and safety of personnel and the working environment, as well as the additional cost of installing a flare system in the plant. MIBK is a low boiling point, flammable organic solvent with high toxicity to humans through inhalation, 101 although it does not represent an issue in WWT since it is highly biodegradable. Control measures must be in place to minimise the emission of this solvent to the atmosphere.…”