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The monocomponent insulin analog LY275585 was administered to Fischer 344 rats in daily subcutaneous doses of 0, 20, or 200 U/kg for 12 months. Each treatment group consisted of 30 males and 30 females, and the vehicle control group consisted of 35 of each sex. Changes related to the pharmacologic activity of LY275585 included an increase in body weight, body weight gain, food consumption, and efficacy of food utilization in male and female rats given 200 U/kg. Pharmacologically related clinical chemistry effects occurring at 200 U/kg were an increase in mean serum glucose (24 h postdose) of males and females, a slight decrease in mean serum triglyceride of females, and decreased mean serum cholesterol of males and females. Fewer effects occurred in lowdose rats (20 U/kg) and included an increase of efficiency of food utilization only in female rats, a slight decrease in mean serum triglyceride in females, and decreased mean serum cholesterol in low-dose males and females. Three male and two female rats administered 200 U/kg died during the treatment period. Death of one male was attributed to hypoglycemia. Cause of death of four other high-dose rats was either not apparent, or the result of a variety of intercurrent disease processes unrelated to treatment. Survival in the low-dose (20 U/kg) and control groups was similar; one rat in each group died prior to treatment termination. The only compound-related lesion associated with treatment was a non-dose-related enhancement of the degree and incidence of inflammation at the site of subcutaneous injection. There were no compoundrelated changes in background lesions including neoplasms, or in hematologic or urinalysis values. In a comparison study, pharmacokinetic profiles of LY275585 and serum glucose values were determined in groups of 30 male and female rats administered single doses of 20 or 200 U/kg. Plasma levels of LY275585 peaked after 30 min, were dose related, and were similar in male and female rats. The hypoglycemia produced in rats receiving a single dose of 20 U/kg was maximal, suggesting saturation of the insulin receptor sites at this dose. The dose of 200 U/kg of LY275585 was, therefore, a supramaximal pharmacological dose when compared to an average daily human dose of 0.5 U/kg/ d. It is concluded that no toxicologically significant changes, other than moderate injection site inflammation, occurred in Fischer 344 rats treated with LY275585 at doses of 20 and 200 U/kg for 12 months. [ABSTRACT FROM AUTHOR]