© 1983 Oxford University Press
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Comparison of the Teratogenic Potential of Two Aliphatic Nitriles in Hamsters: Succinonitrile and Tetramethylsuccinonitrile1,2
ADepartment of Pharmacology and Toxicology, Dartmouth Medical School Hanover, New Hampshire 03755 BDepartment of Anatomy/Cytology, Dartmouth Medical School Hanover, New Hampshire 03755
Comparison of the Teratogenic Potential of Two Aliphatic Nitriles in Hamsters: Succinonitrile and Tetramethyl-succinonitrile. Doherty, P.A., Smith, R.P. and Ferm, V.H. (1983). Fundam. Appl. Toxicol. 3:41-48. Succinonitrile (SN) and tetramethylsuccinonitrile (TMSN) were evaluated and compared for their teratogenic potential. Groups of 3 to 20 pregnant hamsters received a single ip injection of either SN, at doses ranging from 0.78 to 6.24 mmol/kg, or TMSN, at doses ranging from 0.036 to 0.147 mmol/kg, on the morning of day 8 of gestation. Other groups of animals received in addition to either nitrile a total of 8.06 mmol/kg thiosulfate, a cyanide antagonist, or 3.49 mmol/kg trimethadione, an anticonvulsant. Examination of offspring on day 11 of gestation indicated that SN produced a significant incidence of malformations, including exencephaly, encephalocoele and runting. Signs of maternal toxicity, including dyspnea, hypothermia and ataxia, occurred in about 20% of the mothers at doses where teratogenic effects were observed. Thiosulfate provided significant protection against maternal toxicity at both 4.56 and 6.24 mmol/kg SN, but against terata only at the lower dose. Trimethadione had no effect on SN toxicity or teratogenicity. In nonpregnant animals, dose related concentrations of cyanide were measured in whole blood after SN treatment. Similar fetal and maternal effects have been produced by other aliphatic nitriles, amygdalin and cyanide itself. Tetramethylsuccinonitrile was not teratogenic at any of the doses tested. At 0.147 mmol/kg signs of maternal toxicity included clonic-tonic convulsions and death occurred in 37% of the animals treated. Malformations were observed only rarely and included exencephaly and fetal runting. The incidence of such anomalies was not different from controls. Pretreatment with the anticonvulsant trimethadione prevented toxicity in 55% of the mothers while thiosulfate had no effect on either fetal malformations or maternal toxicity after TMSN. Only trace amounts of cyanide were measured in whole blood of non-pregnant animals treated with 0.147 mmol/kg TMSN. We conclude that SN produces its teratogenic effects through metabolically released cyanide. The toxicity of TMSN is not due to cyanide, but may be due to the parent compound or some other unidentified metabolite.