Methacrylonitrile is an aliphatic
nitrile used extensively in the preparation of homo- and copolymers,
elastomers, and plastics and as a chemical intermediate in the preparation of
acids,
amides,
esters, and other
nitriles. This aliphatic
nitrile is also used as a replacement for
acrylonitrile in the manufacture of an
acrylonitrile/
butadiene/
styrene-like
polymer.
Methacrylonitrile was nominated for toxicity and carcinogenicity testing by the National Cancer Institute due to its high production volume and extensive use, the lack of chronic or carcinogenicity data, and its structural resemblance to the known rat
carcinogen acrylonitrile. The current 13-week studies were conducted as part of an overall effort by the NTP to assess the toxicity and carcinogenicity of
methacrylonitrile. During the 13-week studies, groups of 20 male and 20 female F344/N rats were administered 0, 7.5, 15, 30, 60, or 120 mg
methacrylonitrile/kg
body weight in deionized, purified water by gavage. Groups of 20 male and 20 female B6C3F1 mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg/kg
methacrylonitrile. Ten male and ten female rats and mice from each group were evaluated on day 32. The results of these studies clearly revealed that male rats are more sensitive than females to
methacrylonitrile treatment. In the rat study, 19 males and one female administered 120 mg/kg and two males administered 60 mg/kg died during the first week of the study. Males in the 60 mg/kg group at the 32-day interim evaluation and at 13 weeks and females in the 120 mg/kg group at 13 weeks had significantly lower final mean
body weights and
body weight gains than did the vehicle controls; the surviving male in the 120 mg/kg group also weighed less than the controls at the 32-day interim evaluation. Clinical findings of toxicity were dose dependent and included
lethargy, lacrimation,
tremors, convulsions,
ataxia, and abnormal breathing. There was hematologic evidence indicating that administration of
methacrylonitrile induced minimal, normocytic, normochromic
anemia. At the 32-day interim evaluation, a minimal dose-related
anemia was evidenced by decreases in hematocrit values,
hemoglobin concentrations, and erythrocyte counts in male and female rats. The
anemia ameliorated by week 13. Administration of
methacrylonitrile resulted in dose-related increases in serum
thiocyanate and blood
cyanide concentrations of male and female rats. These changes were expected and would be consistent with the in vivo metabolism of
methacrylonitrile to
cyanide. Blood
cyanide concentrations were generally higher in males than in females, which may explain the higher sensitivity of males to the lethal effect of
methacrylonitrile. There was also biochemical evidence of increased hepatocellular leakage and/or altered function in dosed male rats, suggesting that the liver may be a target organ for toxic effects of
methacrylonitrile. Minimal, but significant, decreases in absolute right kidney and thymus weights (32-day interim evaluation) and increases in liver and stomach weights (week 13) occurred in male rats that received 60 mg/kg compared to the vehicle controls. In female rats, stomach weights of the 60 and 120 mg/kg groups were significantly greater and thymus weights of the 120 mg/kg group were significantly less than those of the controls on day 32 and at week 13; liver weights were also significantly greater in females in the 120 mg/kg group than in the vehicle controls on day 32. Male and female rats administered 60 mg/kg and females administered 120 mg/kg had significantly greater incidences of
metaplasia of the nasal olfactory epithelium on day 32 and at the end of the study than did the vehicle controls; incidences of olfactory epithelial
necrosis were also significantly greater in females in the 60 and 120 mg/kg groups than in the vehicle controls on day 32. Incidence and/or severity increased with increasing dose in females; however, the mortality in male rats administered 120 mg/kg made it difficult to assess the dose-response relationship in males. The no-observed-adverse-effect level for the nasal cavity of rats was 30 mg/kg. Female rats administered 60 or 120 mg/kg
methacrylonitrile had significantly longer estrous cycles than did the vehicle controls. Females in the 60 mg/kg group spent more time in diestrus than the vehicle controls. One male and one female mouse in the 12 mg/kg groups died early.
Methacrylonitrile administration caused no significant differences in final mean
body weights or
body weight gains. Clinical findings included
lethargy,
tremors,
ataxia, convulsions, and abnormal breathing. At the 32-day interim evaluation, stomach weights of males administered 3 mg/kg or greater were significantly greater and thymus weights of males in the 12 mg/kg group were significantly less than those of the vehicle controls. At week 13, however, the stomach weights of only males in the 12 mg/kg group were increased relative to the vehicle controls. No treatment-related histopathologic lesions occurred in mice.
Methacrylonitrile did not induce mutations in any of several strains of Salmonella typhimurium, with or without S9 activation, and did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster fed
methacrylonitrile during the larval stage. Results of in vivo bone marrow micronucleus tests with
methacrylonitrile in male rats and mice were also negative. In summary, gavage administration of
methacrylonitrile to rats and mice resulted in dose-dependent
lethargy,
tremors, lacrimation, convulsions, and abnormal breathing. However, these effects were more pronounced in rats than mice; these differences may be attributed to the higher doses of
methacrylonitrile administered to rats.
Body weight gain and survival data of rats demonstrated that males are more sensitive to
methacrylonitrile dosing than females. There is an apparent correlation between blood
cyanide concentrations and survival rates, with males having greater
cyanide concentrations and lower survival rates than female rats administered
methacrylonitrile. Microscopically, the only target of
methacrylonitrile toxicity was the olfactory epithelium of the nasal cavity. Necrotic and metaplastic effects were induced in male and female rats that received 60 or 120 mg/kg per day. No similar lesions were observed in mice administered
methacrylonitrile. The no-observed-adverse-effect level for olfactory epithelial lesions in male and female rats administered
methacrylonitrile for 13 weeks was 30 mg/kg per day. No clear chemical-related effects were observed in male or female mice administered
methacrylonitrile for 13 weeks by gavage at doses up to 12 mg/kg per day.