Safety Assessment of MIBK (Methyl Isobutyl Ketone)1

Abstract

MIBK (Methyl Isobutyl Ketone) is an aliphatic ketone that functions as both a denaturant and solvent in cosmetic products. Current use in cosmetic products is very limited, but MIBK is reported to be used in one nail correction pen (volume = 3 ml) at a concentration of 21%. The maximum percutaneous absorption rate in guinea pigs is 1.1 µmol/min/cm 2 at 10 to 45 min. Metabolites include 4-hydroxy-4-methyl-2-pentanone (oxidation product) and 4-methyl-2-pentanol (4-MPOL) (reduction product). Values for the serum half-life and total clearance time of MIBK in animals were 66 min and 6 h, respectively. In clinical tests, most of the absorbed MIBK had been eliminated from the body 90 min post exposure. MIBK was not toxic via the oral or dermal route of exposure in acute, short-term, or subchronic animal studies, except that nephrotoxicity was observed in rats dosed with 1 g/kg in a short-term study. MIBK was an ocular and skin irritant in animal tests. Ocular irritation was noted in 12 volunteers exposed to 200 ppm MIBK for 15 min in a clinical test. A depression of the vestibulo-oculomotor reflex was seen with intravenous infusion of MIBK (in an emulsion)at 30 µM/kg/min in female rats. The no-observed-effect level in rats exposed orally to MIBK was 50 mg/kg. Both gross and microscopic evidence of lung damage were reported in acute inhalation toxicity studies in animals. Short-term and subchronic inhalation exposures (as low as 100 ppm) produced effects in the kidney and liver that were species and sex dependent. Dermal doses of 300 or 600 mg/kg for 4 months in rats produced reduced mitotic activity in hair follicles, increased thickness of horny and granular cell layers of the epidermis, a decrease in the number of reactive centers in follicles (spleen), an increase in the number of iron-containing pigments in the area of the red pulp (spleen), and a reduction in the lipid content of the cortical layer of the adrenal glands. Neuropathological changes in the most distal portions of the tibial and ulnar nerves were observed in young adult rats which inhaled 1500 ppm MIBK for up to 5 months. No adverse effects were seen in any other neurological end point by any route of exposure in other studies using rats or other animal species. Clinical tests demonstrated a threshold for MIBK-induced irritation of the lungs at 0.03 to 0.1 mg/L after 1 min of respiration. MIBK was not mutagenic in the Ames test or in a mitotic gene-conversion assay in bacteria. Mammalian mutagenicity test results were also negative in the following assays: mouse lymphoma, unscheduled DNA synthesis, micronucleus, cell transformation, and chromosome damage. MIBK did not induce any treatment-related increases in embryotoxicity or fetal malformations in pregnant Fischer 344 rats or CD-1 mice that inhaled MIBK at concentrations of 300, 1000, or 3000 ppm. There was evidence of treatment-related maternal toxicity only at the highest concentration tested. MIBK applied to the tail of rats daily at doses of 300 or 600 mg/kg for 4 months produced changes in the t...

Catalytic Fractionation of Raw Biomass to Biochemicals and Organosolv Lignin in a Methyl Isobutyl Ketone/H2O Biphasic System

“…Thus, a stable and polar extractive agent for composing the biphasic system is essential. It is well-known that methyl isobutyl ketone (MIBK) is a preferred candidate due to its stability toward acid, medium polarity, lower toxicity, average boiling point, poor miscibility with water, and good extraction ability for polar products. , It has been used as an extracting agent for producing fine chemicals from biomass, as a cosolvent to fractionate organosolv lignin from raw biomass in monophase systems, − and as an extracting agent to isolate lignin from hemicellulose and lignin rich liquors …”

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

“…Occurrence : Methyl isobutyl ketone (MIBK) (4-methylpentan-2-one) ( Figure 8 (5)) is produced from acetone by aldol condensation and is used primarily as denaturant and solvent [ 115 , 842 , 843 ]. It is also a natural constituent of many foods including orange and lemon juice, grapes, papaya, ginger, cooked eggs, meat, milk and cheeses, beer, mushrooms, coffee and tea, as at concentrations ranging from 0.008 to 6.5 mg/kg, and as a flavoring agent in meat products, dairy and non-alcoholic beverages, baked goods and puddings at maximum reported level of 25 mg/kg [ 115 , 844 ].…”

“…Genotoxicity/DNA Binding (Adducts) : MIBK produced overwhelmingly negative results in genotoxicity testing battery in vitro and in vivo [ 115 , 843 , 846 , 847 , 848 , 849 ] and thus, is not considered to be of concern for genotoxicity [ 842 , 844 ].…”

“…Metabolism : MIBK is metabolized in vivo by reduction in the presence of alcohol dehydrogenases to 4-hydroxyMIBK and by oxidation in the presence of CYP-dependent monooxygenase to 4-methyl-2-pentanol [ 843 , 850 , 851 , 852 , 853 ]. The letter metabolite was not detected with oral administration [ 852 , 854 ].…”

“…MoA underlying hepatocarcinogenicity of MIBK in mice is not well understood. While it potentiated hepatotoxicity and cholestasis produced by other chemicals [ 853 , 855 , 856 , 859 , 860 ] no evidence of hepatotoxicity was observed when MIBK was administered alone [ 275 , 843 ]. A study by Hughes and colleagues [ 861 ] suggested involvement of receptor-mediated mechanism, specifically, activation of the CAR/PXR nuclear receptors, which results in hepatocellular proliferation consequently leading to tumor development.…”