Upper respiratory tract toxicity of inhaled methylvinyl ketone in F344 rats and B6C3F1 mice

The National Toxicology Program is conducting a chemical class study to inv estigate the structure-activity relationships for the toxicity of alpha,bet a -unsaturated ketones. Methylvinyl ketone (MVK) was selected for study bec ause it is a representative straight-chain aliphatic alpha,beta -unsaturate d ketone and because of its extensive use and widespread exposure. Short-te rm inhalation studies of MVK were conducted to provide toxicity data for co mparison with other alpha,beta -unsaturated ketones and for use in designin g chronic toxicity and carcinogenicity studies. In 2-week studies, rats and mice were exposed to 0, 0.25, 0.5, 1, 2, 4, or 8 ppm MVK 6 h/day, 5 days/w eek for 12 exposures. Morbidity and early deaths occurred in all male and f emale rats after 1 exposure and in 2 male mice after 10 exposures to 8 ppm. Rats exhibited nasal cavity toxicity and lung necrosis at 4 ppm. No toxici ty was observed in animals exposed to less than 2 ppm. Based on these resul ts a 13-week study was conducted at 0, 0.5, 1, and 2 ppm MVK. As observed i n the 2-week study, the nasal cavity was the main target organ and rats wer e more sensitive than mice. Respiratory and olfactory epithelial necrosis w ere prominent by day 21 in the rat. At study termination these lesions were still evident but not as severe as noted earlier. Additionally, changes su ch as olfactory epithelial regeneration and metaplasia (respiratory) as wel l as respiratory epithelial hyperplasia and metaplasia (squamous) were clea rly evident. Nasal lesions in mice were limited to a subtle squamous metapl asia of transitional and/or respiratory epithelium covering predominantly t he tips of naso- and maxilloturbinates in Levels I and II. A transient, leu kopenia was observed in rats exposed to 2 ppm, however, this effect was not present after 13 weeks of exposure. In mice, leukocyte counts were signifi cantly decreased at all exposure concentrations after 13 weeks of exposure. Absolute testicular and epididymal weights and sperm counts were decreased at the high dose only. MVK can be characterized as a reactive, direct-acti ng gaseous irritant. MVK exposure causes the same nasal cavity lesions as t he cyclic alpha,beta -unsaturated ketone, 2-cyclohexen-1-one, although at l ower exposure concentrations.