Studies on the mechanism of acute toxicity of nitriles in mice.

Abstract

Acute toxicity and metabolism of 21 nitriles in mice were studied in relation to their chemical structures. All the test nitriles liberated cyanide ions both in vivo and in vitro, with the exception of benzonitrile , although the extent of liberation and the effect of carbon tetrachloride (CCl4) pretreatment on the mortality of animals differed among nitriles. From these results, test compounds were tentatively divided into three groups. In group 1 (13 compounds), acute toxicity was greatly reduced by CCl4 pretreatment, in group 2 (seven compounds), toxicity was not significantly changed or was somewhat enhanced, and in group 3, benzonitrile only, toxicity was clearly enhanced. The amount of cyanide was higher (0.68-0.80 microgram CN/g brain) at death in the brains of mice given group-1 compounds, the level being comparable to that found in mice killed by dosing with potassium cyanide. After oral doses of each nitrile, the time course for cyanide levels in the liver varied among the compounds. The difference between group-1 and -2 compounds lay in the dose-cyanide liberation relationship in liver, and in the kinetics for cyanide liberation in the hepatic microsomal enzyme system. Double-reciprocal plots of enzyme activity showed a linear relationship for nitriles of group 1 and a non-linear one for group 2. The relationship between log (1/LD50) and log P for the compounds in group 1 fitted a parabolic plot, while that for compounds in group 2 was linear.