|Methyl Ethyl Ketone Peroxide||C8H16O4|
Methyl ethyl ketone peroxide (MEKP) is an unstable organic peroxide used in the manufacture of acrylic resins, as a hardening agent for fiberglass-reinforced plastics, and as a curing agent for unsaturated polyester resins. It is commercially available as a 40% to 60% solution in dimethyl phthalate (DMP). Because exposure to MEKP is typically through dermal contact, 2-week and 13-week toxicity studies were conducted by topical application of MEKP in DMP (45:55 w/w) to the clipped dorsal region of male and female Fischer 344/N rats and mice. Animals were evaluated for histopathology and for reproductive endpoints. In vitro genetic toxicity studies of MEKP included assessments of mutagenicity in Salmonella typhimurium and in mouse lymphoma L5178Y cells and analysis of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells. In addition, the peripheral blood of mice from the 13-week study was evaluated in the micronucleus assay.
In the 2-week studies, groups of 5 animals of each species and sex were administered MEKP in DMP for 5 days per week at doses of 50.6, 101.3, 202.5, 405, and 810 mg/kg body weight per day for rats and 112.5, 225, 450, 900, and 1800 mg/kg body weight per day for mice. Control groups received DMP or no treatment. No rats died during the studies, but at least 1 mouse in each group receiving MEKP died. Body weight gains of rats decreased with increasing doses of MEKP; body weight gains of mice were not affected by treatment. The primary effects of topical administration of MEKP in both rats and mice were an extensive coagulative necrosis of the epidermis and dermis, variable degrees of inflammation of the adnexa, and epidermal regeneration and hyperplasia at the application site. Lesions considered secondary to the dermal lesions included increased hematopoiesis in the spleen in rats and mice and increased myeloid hyperplasia of the bone marrow in mice, primarily at the higher doses. Mice showed a marked, dose-related increase in liver weight.
In the 13-week dermal studies, groups of 10 rats and 10 mice of each sex were administered MEKP in DMP for 5 days per week at doses of 1.07, 3.57, 10.7, 35.7, and 107 mg/rat and 0.357, 1.19, 3.57, 11.9, and 35.7 mg/mouse. All high-dose mice, 3 high-dose female rats, and 1 female mouse in the 11.9 mg/animal group died or were sacrificed during the first week of the studies. Skin lesions similar to those seen in the 2-week studies were judged of sufficient severity to warrant early termination of surviving rats and mice in the 2 highest dose groups. All rats and mice in the remaining dose groups survived to the end of the studies, and weight gains were generally lower with increasing doses of MEKP. Skin lesions at the application site for the remaining animals (rats and mice) in the 10.7 mg/rat and 3.57 mg/mouse dose groups involved a spectrum of necrosis, inflammation, and acanthosis (epidermal hyperplasia). Lesions in the lower dose groups were limited to acanthosis and hyperkeratosis in rats (1.07 and 3.57 mg/rat) and acanthosis in mice (0.357 and 1.19 mg/mouse). While splenic and bone marrow lesions similar to those described in the 2-week studies were seen in animals that died early in the 13-week studies and in the rats and mice that showed ulcerative or necrotic injury, no other systemic changes were noted in animals that did not show ulcerative skin lesions.
In genetic toxicity studies, MEKP in DMP (45:55 w/w) was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98, with or without S9activation. A positive response was obtained in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells without S9. In cytogenetic tests with Chinese hamster ovary cells, MEKP induced sister chromatid exchanges and chromosomal aberrations, with and without S9. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples obtained from male and female mice at the termination of the 13-week toxicity study.
In summary, topical administration of MEKP in DMP resulted in a spectrum of necrotic, inflammatory, and regenerative skin lesions limited to the application site. Histopathologic changes in the spleen and bone marrow were also seen in rats and mice with ulcerative skin lesions, and were considered a secondary response. A no-observed-adverse-effect level (NOAEL) for histopathologic skin lesions could not be determined from these studies, as lesions were observed with administration of daily doses as low as 1.07 mg for rats and 0.357 mg for mice.
Methyl Ethyl Ketone Peroxide Synonyms: 2-Butanone Peroxide
Dimethyl Phthalate Synonyms: 1,2-Benzenedicarboxylic acid dimethyl ester; phthalic acid dimethyl ester; methyl phthalate; dimethyl 1,2-benzene- dicarboxylate; DMP
Report Date: February 1993