The potential reproductive toxicity of methacrylonitrile in Sprague-Dawley rats was evaluated using the Reproductive Assessment by Continuous Breeding (RACB) protocol. Based on decreased body weights and feed consumption, increased water consumption, and mortality noted during Task 1, dose levels for the continuous breeding phase for this study were set at 2, 7, and 20 mg/kg in deionized water by oral gavage.
Exposure to methacrylonitrile by gavage (20 rats/sex/group) did not affect the reproductive performance of F0 rats (Task 2) or F1 rats (Task 4) where only the controls and high-dose groups were evaluated. In Task 4, estrous cyclicity of the F1 animals was not affected by methacrylonitrile administration.
Slight but consistent decreases (3-6%) were noted in the 20 mg/kg F0 male body weights, although none of these reached statistical significance. F0 female body weights were unchanged. Body weights of the F1 20 mg/kg males and females were consistently less (6-10%) than controls and were occasionally statistically significant. Daily mean feed consumption was decreased by 8-11% in the 20 mg/kg F1 males; F0 male and female and F1 female feed consumption values were unchanged.
No treatment-related changes were noted in hematology or clinical chemistry parameters for either the F0 or F1 animals. At necropsy, no differences were noted in F0 or F1 animals absolute organ weights; however, relative liver weight was increased in the 20 mg/kg males and females from both generations by ~12% when compared to controls. No treatment-related gross or microscopic lesions were observed in either the F0 or F1 animals.
The percent normal sperm was decreased slightly (by ~1%) in the 2 and 20 mg/kg F0 males while no differences were seen in F0 epididymal sperm density. In the F1 generation, epididymal sperm density was decreased by 19% at 20 mg/kg but epididymal sperm morphology was unchanged. F0 and F1 sperm motion parameters and testicular spermatid head counts were unchanged.
Results of this study show that methacrylonitrile is not a selective reproductive toxicant, because the decreases in epididymal sperm density occurred concomitant with those doses that reduced body weight. The no-observable-adverse-effect level (NOAEL) in this study was 7 mg/kg. The ~1% change in epididymal sperm abnormalities at 2 and 20 mg/kg is believed to be "noise" and not a treatment-related response because the historical control range of percent abnormal sperm is 0.1-1.4% in this laboratory. A maximum tolerated dose (MTD) was reached in this study based on the decreases in F0 and F1 body weight and increases in relative liver weights. Methacrylonitrile may be a slight developmental toxicant in males at 20 mg/kg based on the decreased epididymal sperm density in the F1 males.
REPRODUCTIVE TOXICANT:
Male - Yes, slight based on decreased epididymal sperm density noted in the F1 males.
Female - No.
NTIS # PB97-176390