Trimethylphosphate: A 30-Month Chronic Toxicity/Carcinogenicity Study in Wistar Rats with Administration in Drinking Water

Abstract

Trimethylphosphate (TMPO) was administered to 50 male and 50 female Wistar rats through their drinking water at doses of 0, 1, 10, or 100 mg/kg body weight up to 30 months. The dosage of 100 mg/kg was reduced to 50 mg/kg in week 54 for reasons of tolerance, and the animals were euthanized in week 100. Additional 10 animals per dose and sex were treated for 12 months and then euthanized for interim analysis. Weakness of the hind limbs, increased incidences of sunken flanks, distended abdomen, and poor general condition were observed in both sexes of the 100/50 mg/kg group beginning with week 46. Food intake was reduced in high dose males. At 10 mg/kg body weights were up to 10% (males) and at 100/50 mg/kg up to 20% (males) or 15% (females) lower than in controls. Mortality was not affected in animals receiving up to 10 mg/kg. At 100/50 mg/kg it was markedly increased, reaching about 70% at week 100. Relatively slight hematologic changes (reduced hemoglobin, hematocrit, erythrocyte counts, increased reticulocyte numbers, and thrombocyte counts as well as a shift in the differential blood count) at 100/50 mg/kg are interpreted as changes most probably secondary to the other toxic effects. Increased cholesterol concentrations in plasma, shifts in the serum protein electrophoresis (males), increased organ weights (females), and an increased incidence of necroses and lymphocytic infiltrations point to a treatment-related effect on the liver at 100/50 mg/kg. Slightly increased protein excretion, increased relative kidney weights, and an increased incidence of chronic progressive nephropathy are considered treatment-related but rather secondary effects at 100/50 mg/kg. At 100/50 mg/kg an increased incidence and severity of bilateral tubular atrophy in the testes was diagnosed. The most important toxic effect was neurotoxicity, consisting of degeneration and loss of nerve fibers in the peripheral nerves and the spinal cord, associated with myopathic changes, and occurring at 100/50 mg/kg. The no-observed-adverse-effect-level, based on the suppression of body weight gain, is 1 mg/kg in males and 10 mg/kg in females. The incidence, time of occurrence, spectrum of types, and localizations of tumors provided no indication of a tumorigenic/carcinogenic effect of the test substance. TMPO is therefore considered not to be carcinogenic in Wistar rats.