Toxicology and Carcinogenesis Studies of Succinic Anhydride (CAS No. 108-30-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies)
Chemical Formula: C4H4N3
Succinic anhydride, a food additive, is also used in the manufacture of polymeric materials, pharmaceuticals, and agricultural and industrial chemicals. Toxicology and carcinogenesis studies were conducted by administering suspensions of succinic anhydride (97% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 or 20 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells.
Twenty-Day or Sixteen-Day and Thirteen-Week Studies:
In the 20-day studies in rats, doses of succinic anhydride given on 14 exposure days ranged from 47 to 750 mg/kg. Compound-related deaths occurred in the groups of males that received 375 mg/kg or higher doses and in females that received 187 mg/kg or higher doses. Necrosis and inflammation of the upper respiratory tract were seen in 3/10 male and 3/10 female rats given 750 mg/kg and 2/10 female rats given 375 mg/kg.
In the 16-day studies in mice, doses of succinic anhydride given on 12 exposure days ranged from 219 to 3,500 mg/kg. All animals that received 875 mg/kg or higher doses of succinic anhydride died before the end of the studies. No compound-related lesions were seen in male or female mice examined from the 438 mg/kg dose group.
In the 13-week studies in rats, doses of succinic anhydride ranged from 25 to 400 mg/kg for males and from 12.5 to 200 mg/kg for females. Deaths of 8/10 male rats that received 400 mg/kg and 4/10 males and 5/10 females that received 200 mg/kg were compound related. At necropsy, the mean body weights of male rats that received 200 or 400 mg/kg were 9% or 15% lower than that of vehicle controls, whereas the mean body weights of dosed and vehicle control female rats were similar. No compound-related gross or microscopic lesions were observed.
In the 13-week studies in mice, doses of succinic anhydride ranged from 37 to 600 mg/kg. All 10 males and 8/10 females that received 600 mg/kg and 2/10 males and 2/10 females that received 300 mg/kg died before the end of the studies. The final mean body weights of mice that received 150 or 300 mg/kg were 13% or 9% lower than that of vehicle controls for males and 8% or 7% lower for females. Mild inflammation of the stomach was observed in 7/10 male mice that received 150 mg/kg and 5/10 males that received 300 mg/kg compared with 2/10 vehicle controls.
Based primarily on the effects of administration of succinic anhydride on survival and mean body weights of rats and mice, doses for the 2-year studies were 0, 50, or 100 mg/kgto groups of 60 rats of each sex; 0, 38, or 75 mg/kg to groups of 50 male mice; and 0, 75, or 150 mg/kg to groups of 50 female mice. Succinic anhydride was administered as a suspension in corn oil by gavage, 5 days per week for 103 weeks.
Body Weights and Survival in the Two-Year Studies:
Mean body weights of high dose rats were 5%-11% lower than those of vehicle controls during the second year of the studies. No significant differences in survival after 2 years were observed between any groups of rats of either sex (male: vehicle control, 36/60; low dose, 33/60; high dose, 32/60; female: 31/60; 27/60; 27/60). For mice, mean body weights of high dose males were generally 5%-12% lower than those of vehicle controls throughout the study. Mean body weights of high dose female mice were 10%-32% lower than those of vehicle controls; mean body weights of low dose female mice were 10%-20% lower than those of vehicle controls. The survival of high dose male mice was significantly greater than that of vehicle controls after week 77 (survival after 2 years--male: 27/50; 30/50; 42/50; female: 37/50; 38/50; 41/50). No other differences in survival were observed between any groups of mice of either sex.
Nonneoplastic and Neoplastic Effects in the Two-Year Studies:
At no site in rats or mice was there a chemical-related increase in the incidence of nonneoplastic or neoplastic lesions. A sufficient number of animals in each dose group lived long enough to allow evaluation of the potential carcinogenicity of succinic anhydride.
Succinic anhydride was not mutagenic in S. typhimurium with or without exogenous metabolic activation. The chemical did not induce sister chromatid exchanges or chromosomal aberrations in cultured CHO cells in the presence or absence of exogenous metabolic activation.
Under the conditions of these 2-year studies, there was no evidence of carcinogenic activity of succinic anhydride for male or female F344/N rats given 50 or 100 mg/kg succinic anhydride. There was no evidence of carcinogenic activity for male B6C3F1 mice given 38 or 75 mg/kg succinic anhydride or for female B6C3F1 mice given 75 or 150 mg/kg.
Synonyms: butanedioic anhydride; dihydro-2,5-furandione; 2,5-diketotetrahydrofuran; succinic acid anhydride; succinyl anhydride; succinyl oxide; tetrahydro-2,5-dioxofuran
Report Date: January 1990