In the 14-week studies, groups of 10 male and 10 female rats and mice were exposed to methyl methacrylate at concentrations of up to 5,000 ppm. All male and female rats and eight male and eight female mice exposed at 5,000 ppm died, one male and nine female rats and four male and no female mice exposed at 3,000 ppm died, and one male and three female rats and two male and one female mouse exposed at 2,000 ppm died; all rats and mice exposed at 500 or 1,000 ppm survived. Compared with the controls, the body weights of the exposed male and female rats and mice were lower. Compound-related lesions included inflammation associated with necrosis and loss of olfactory epithelium in the nasal turbinates in both male and female rats; malacia and gliosis in female rats; inflammation of the nasal turbinates and nasal epithelium metaplasia in both male and female mice; and renal cortical necrosis, renal cortical tubular degeneration, renal focal mineralization, and liver necrosis in male mice. Based on these results, 2-year inhalation toxicology and carcinogenesis studies were conducted in which groups of 50 male rats were exposed to methyl methacrylate at 0, 500, or 1,000 ppm; female rats at 0, 250, or 500 ppm; and male and female mice at 0, 500, or 1,000 ppm.
In the 2-year studies, the body weights of the low dose and high dose male and female rats were within 10% of those of the controls. There was no difference in survival between the dosed male and female rats and the controls. Incidences of inflammation of the nasal cavity and degeneration of the olfactory sensory epithelium were greater in the dosed male and female rats than in the controls, with lesions seen in virtually all high dose animals.
An increased incidence of mononuclear cell leukemia was observed in female rats exposed to methyl methacrylate at 500 ppm compared with the controls (control, 11/50; 250 ppm, 13/50; 500 ppm, 20/50). This increase was not significant by life table tests, the method of analysis most appropriate for this fatal neoplasm.
The mean body weights of dosed male and female mice were 5%-8% lower than those of the controls at the end of the 2-year studies. However, during most of the second year of the studies, body weights of dosed male mice and high dose female mice were 10%-18% lower than those of the controls. Survival rates of the dosed and control mice were similar.
Incidences of inflammation and epithelial hyperplasia of the nasal cavity and degeneration of the olfactory sensory epithelium were significantly greater in all dosed groups of male and female mice compared with those of the controls. Compound-related neoplastic lesions were not found in the dosed mice.
Significant dose-related decreases were observed in the incidences of pituitary gland and preputial gland tumors in male rats, alveolar/bronchiolar adenomas or carcinomas (combined) in male mice, hepatocellular adenomas in both male and female mice, and pituitary gland adenomas or adenocarcinomas (combined) and uterine adenocarcinomas in female mice.
Methyl methacrylate was not mutagenic in strains TA100, TA1535, TA97, or TA98 of Salmonella typhimurium in the presence or absence of male rat or hamster liver S9 when assayed by a preincubational protocol but gave a positive response in L5178Y/TK+/- mouse lymphoma cells in the presence or absence of male rat liver S9. In cultured Chinese hamster ovary cells, methyl methacrylate produced a reproducible, dose-related increase in the frequency of sister-chromatid exchanges, both with and without rat liver S9. A slight, dose-related increase in chromosomal aberrations was also induced in cultured Chinese hamster ovary cells in the absence of S9; in the presence of S9, an increase in the frequency of aberrations was seen only at the highest, near-lethal dose of 5 mg/ml.
An audit of the experimental data was conducted for the 2-year carcinogenesis studies on methyl methacrylate. No data discrepancies were found that influenced the final interpretations.
Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenicityof methyl methacrylate for male F344/N rats exposed at 500 or 1,000 ppm, for female F344/N rats exposed at 250 or 500 ppm, or for male and female B6C3F1 mice exposed at 500 or 1,000 ppm. Inhalation of methyl methacrylate was associated with inflammation of the nasal cavity and degeneration of the olfactory sensory epithelium in male and female rats and mice; epithelial hyperplasia of the nasal cavity was also observed in exposed mice.