Reproductive Toxicity Evaluation of Methylethyl Ketoxime by Gavage in CD Rats

Methylethyl ketoxime (CAS No. 96-29-7; MEKO; 2-butanone oxime),an antioxidant agent used in paints, resins, and adhesives,was tested for reproductive toxicity in a two-generation studywith CD (Sprague-Dawley) rats. Thirty-eight-week-old rats/sex/group(F0) were administered MEKO in water, by gavage, at 0, 10, 100,or 200 mg/kg/day (at a dosing volume of 2 ml/kg), 5 days/weekfor 10 weeks with vaginal cytology evaluation (VCE) of F0 femalesduring the last 3 weeks of the prebreed period. Animals weremated within groups for 3 weeks with dosing during mating, gestation,and lactation for 7 days/week. F0 parents and F1 weanlings,10/sex/dose, were necropsied (after a 2-week postwean VCE inF0 females) with hematologic evaluation (including methemoglobin)and histology of adult livers, spleens, and reproductive organs.F1 weanlings, 30/sex/dose, were dosed for 11 weeks and matedas described above. Because of poor reproductive performance,not treatment related, F1 animals with no F2a litters were rebredto produce F2b litters. F1 parents and F2a weanlings, 10/sex/dose,were necropsied and evaluated as described above. Inguinal mammaryglands were examined histologically from all nonselected F1and F2 (a and b) female weanlings. Adult toxicity was observedin both generations and both sexes at all doses. Treatment-relatedparental deaths occurred at 200 mg/kg/day. At 100 and 200 mg/kg/day,parents exhibited dose-related reduced body weights and weightgains, reduced feed consumption, clinical signs of toxicity,and anemia with concomitant extramedul-lary hematopoiesis andhemosiderosis in livers and spleens (and increased spleen weights).At 10 mg/kg/day, only adult liver and spleen histologic effectswere present. There was no evidence of reproductive organ ormammary gland pathology or of reproductive or postnatal toxicityat any dose tested. There was no adult "no observable adverseeffect level" (NOAEL) established; the NOAEL for reproductiveand postnatal toxicity was at least 200 mg/kg/day for rats inthis study.