Neurotoxicity and carcinogenicity of N-methylolacrylamide in F344 rats and B6C3F1 mice.
Toxicology and carcinogenicity studies of N-methylolacrylamide were conducted by administering the chemical by gavage in water to both sexes of F344/N rats and B6C3F1 mice 5 times per week for 16 d, 13 wk, or 2 yr. In 16-d studies, rats receiving doses of 200 mg/kg or higher and mice receiving 400 mg/kg died. In 13-wk studies, all rats given 100 mg/kg or higher doses died. Rats receiving 50 mg/kg or higher doses developed hindlimb ataxia progressing to paralysis. In neurobehavioral assessments, decreased forelimb and hindlimb grip strength occurred in rats at doses as low as 12.5 mg/kg. Landing footspread was also increased in dosed rats compared to controls. Axon filament and myelin sheath degeneration in the spinal cord and/or peripheral nerves occurred in rats receiving doses of 25 mg/kg or higher. Necrosis in the granular cell layer of the cerebellum was seen in rats given 200 mg/kg. Mice receiving 200 mg/kg in 13-wk studies died. Decreased grip strength was noted in mice at doses as low as 25 mg/kg, and rotarod performance was also affected by N-methylolacrylamide administration, but no neuropathology was seen microscopically. Testicular weights were decreased at doses as low as 12.5 mg/kg, and hepatocellular necrosis, thymic lymphocyte necrosis, and hemorrhage, necrosis, and mineralization of the zona reticularis of the adrenal gland were seen in mice that died (200 mg/kg). In 2-yr studies, survival and weight gains in male and female rats receiving doses of 6 or 12 mg/kg/d were minimally affected. No biologically important clinical signs or neoplastic or nonneoplastic lesions were attributed to N-methylolacrylamide administration to rats, suggesting that higher doses could have been tolerated. In mice, survival was not different between dosed and control groups (0, 25, or 50 mg/kg/d). Body weights were higher by as much as 25% in dosed compared to control groups. No compound-related clinical signs were observed, but increases in neoplasms of the harderian gland, liver, and lung were clearly related to chemical administration in both sexes of mice. Benign granulosa-cell neoplasms of the ovary were also increased in dosed female mice.
Bucher
J R
JR
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Huff
J
J
Haseman
J K
JK
Eustis
S L
SL
Peters
A
A
Toft
J D
JD
D000178:Acrylamides / Q000633:toxicity*; D000311:Adrenal Glands / Q000187:drug effects; D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000139:chemically induced*; D009420:Nervous System / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D010243:Paralysis / Q000139:chemically induced; D051381:Rats; D011916:Rats, Inbred F344; D013737:Testis / Q000187:drug effects; D013950:Thymus Gland / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects
D000178:Acrylamides; C066443:N-methylolacrylamide