A dietary toxicity/oncogenicity study of tributyl phosphate in the rat

Tri-n-butyl phosphate (TBP, CAS No. 126-73-8), an industrial chemical, was administered in the diet at concentrations of 0, 200, 700 and 3000 ppm to groups of 50 male and 50 female Sprague-Dawley rats for 2 years. Body weights and food consumption were measured weekly for the first 13 weeks and monthly thereafter. Hematology was performed at 12, 18 and 24 months; urinalyses were performed at 3 weeks and 3, 6, 12 and 18 months. All surviving animals were euthanized after 24 months of treatment. Macroscopic postmortem examinations were performed on all animals; complete histopathological evaluation was performed on control and high dose animals; target organs were examined in all dose groups. Significant decreases in body weight gain occurred in males and females receiving the 3000 ppm concentration and a slight decrease in weight gain occurred in females receiving the 700 ppm concentration. The only clinical sign attributed to TBP was an increased incidence of red discoloration of the urine in some high-dose males. Survival, hematology and urinalysis parameters were unaffected by treatment at any concentration. A dose-related increase in the incidence and severity of urinary bladder hyperplasia and the incidence of urinary bladder papillomas was evident in male and female rats receiving the 700 and 3000 ppm concentrations. Transitional cell carcinomas were present in six of 49 males and two of 50 females and a squamous cell carcinoma was present in one of 49 males in the group which received 3000 ppm. The oncogenic effects showed a clear threshold of 700 ppm in the diet. The NOEL (no observable effect level) for chronic toxicity was 200 ppm. Mean intake of TBP was 9 and 12 mg/kg/day for males and females, respectively, receiving 200 ppm; 33 and 42 mg/kg/day for males and females, respectively, receiving 700 ppm, and 143 and 182 mg/kg/day for males and females, respectively, receiving 3000 ppm. TBP was negative in genotoxicity tests, suggesting that the tumors are induced by nongenotoxic mechanisms.