Subchronic Toxicity of Tetramethylsuccinonitrile

Subchronic Toxicity of Tetramethylsuccinonitrile. JOHANNSEN,F. R., AND LEVINSKAS, G. J. (1986). Fundam Appl. Toxicol. 7,41-48. The acute rat oral LD50 for tetramethylsuccinonitrile (TMSN)is 38.9 ± 7.4 mg/kg. A series of three 90-day subchronictoxicity studies were conducted with Sprague-Dawley-derivedalbino rats. In each study, rats were administered corn oilsolutions of TMSN by intubation. In the first study, groupsof 15 male and 15 female rats were given 0, 1, 3, or 10 mg/kgTMSN. Significant reductions in weight gain were observed at10 and 3 mg/kg/day. Survival, demeanor, food consumption, hematology,and urinalysis were not affected. Except for a reduction infasting blood glucose in the 10 mg/kg test group, no effectswere observed in clinical pathology parameters. Absolute andrelative liver weights were increased at 10 mg/kg (both sexes)and 3 mg/kg (males). Both absolute and relative kidney weightswere increased and treatment-related morphological lesions,characterized as tubular nephrosis, were observed in all testgroups of males, but not in females. Other TMSN-related microscopicobservations were limited to liver changes in both sexes at10 mg/kg. Two subsequent 90-day studies, each conducted with15 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 observedat 1.0 mg/kg TMSN. Microscopic renal lesions similar to thoseseen 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-relatedmicroscopic lesions of the kidney were observed in groups ofmale rats given 3.0 mg/kg TMSN by gavage for 90 days and thenremoved from treatment for 14 days. Thus, tubular nephrosisproduced by subchronic exposure to TMSN is reversible in themale rat. Groups of 15 male rats also were exposed to 1,5, or10 ppm TMSN in drinking water for 90 days. No adverse effectson in vivo parameters or clinical pathology were observed. Increasesin kidney weights were seen at 10 and 5 ppm TMSN. Histopathologicchanges characteristic of tubular nephrosis were noted in ratsfrom all treatment groups. Dogs administered capsules containingTMSN for 90 days at levels equivalent to 0.3, 1.0 and 3.0 mg/kg/dayexhibited slight suppressions of body weight gain at the twohigher dosage levels and a small increase in blood thiocyanateat 3 mg/kg. No other functional or morphological changes relatedto treatment were observed in any organs evaluated, includingliver and kidney.