Subchronic toxicity of tetramethylsuccinonitrile

Abstract

The acute rat oral LD50 for tetramethylsuccinonitrile (TMSN) is 38.9 ± 7.4 mg/kg. A series of three 90-day subchronic toxicity studies were conducted with Sprague-Dawley-derived albino rats. In each study, rats were administered corn oil solutions of TMSN by intubation. In the first study, groups of 15 male and 15 female rats were given 0, 1, 3, or 10 mg/kg TMSN. Significant reductions in weight gain were observed at 10 and 3 mg/kg/day. Survival, demeanor, food consumption, hematology, and urinalysis were not affected. Except for a reduction in fasting blood glucose in the 10 mg/kg test group, no effects were observed in clinical pathology parameters. Absolute and relative liver weights were increased at 10 mg/kg (both sexes) and 3 mg/kg (males). Both absolute and relative kidney weights were increased and treatment-related morphological lesions, characterized as tubular nephrosis, were observed in all test groups of males, but not in females. Other TMSN-related microscopic observations were limited to liver changes in both sexes at 10 mg/kg. Two subsequent 90-day studies, each conducted with 15 male rats per group, used levels of 0, 0.001, 0.01, 0.1, 0.3, or 1.0 mg/kg/day TMSN. Renal weight increases were observed at 1.0 mg/kg TMSN. Microscopic renal lesions similar to those seen in the first study were observed down to 0.1 mg/kg TMSN. A no-effect level was established at 0.01 mg/kg TMSN. No treatment-related microscopic lesions of the kidney were observed in groups of male rats given 3.0 mg/kg TMSN by gavage for 90 days and then removed from treatment for 14 days. Thus, tubular nephrosis produced by subchronic expsure to TMSN is reversible in the male rat. Groups of 15 male rats also were exposed to 1, 5, or 10 ppm TMSN in drinking water for 90 days. No adverse effects on in vivo parameters or clinical pathology were observed. Increases in kidney weights were seen at 10 and 5 ppm TMSN. Histopathologic changes characteristic of tubular nephrosis were noted in rats from all treatment groups. Dogs administered capsules containing TMSN for 90 days at levels equivalent to 0.3, 1.0 and 3.0 mg/kg/day exhibited slight suppressions of body weight gain at the two higher dosage levels and a small increase in blood thiocyanate at 3 mg/kg. No other functional or morphological changes related to treatment were observed in any organs evaluated, including liver and kidney.