Rats were exposed by inhalation, 6 hr/day, 5 days/week, to target vapor concentrations of 2000, 1000, or 0 ppm of methyl isoamyl ketone (MIAK) for 12 exposures spanning 16 days, and 2000, 1000, 200, or 0 ppm for 69 exposures spanning 96 days. Body weights, hematology, and serum clinical chemistry determinations were comparable to controls in both inhalation studies. Clinical signs of toxicity were lethargy and decreased aural response (2000 ppm, 2-week study; 2000 and 1000 ppm, 90-day study) and nasal and eye irritation (2000 and 1000 ppm, 90-day study). In addition, the excretion of gel-like casts in seminal fluid was seen in males exposed to 2000 and 1000 ppm in both studies. Increases in absolute and relative liver and kidney weights were observed in both sexes following exposure to 2000 and 1000 ppm in the 2-week and 90-day studies. Liver weight increases were exposure dependent and in the 90-day study reflected hepatocyte hypertrophy observed on microscopic examination. Microscopic kidney changes were hyalin degeneration or hyalin droplet formation in males in the 2-week (2000 and 1000 ppm) and 90-day (2000 ppm) studies; and minor to moderate regeneration of tubular epithelium (2000 and 1000 ppm) in both studies. Minor tubular epithelium regeneration was seen in females exposed to 2000 ppm for 90 days. The toxicity of MIAK following inhalation exposure was not as extensive or severe as that resulting from a prior study in which male rats were dosed orally with 2000 mg/kg/day (a dose comparable to 2000 ppm) for 13 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)