Comparative developmental toxicities of aliphatic nitriles: in vivo and in vitro observations

The effects on embryonic development of a series of eight saturated (acetonitrile, propionitrile, and n-butyronitrile) and unsaturated (acrylonitrile, methacrylonitrile, allylnitrile, cis-2-pentenenitrile, and 2-chloroacrylonitrile) nitriles were compared in vitro using the whole embryo culture system. Day 10 rat embryos were cultured for 46 h in rat serum in the presence of either of these chemicals. All the tested chemicals produced concentration-dependent decreases in growth and differentiation and increases in the incidences of morphologically abnormal embryos. A wide range of embryotoxic potency was observed, with 2-chloroacrylonitrile and acetonitrile at the extremes (lowest effect levels of 50 microM and 40 mM, respectively). No common pattern could be drawn for all the eight nitriles tested in vitro, although there were some similarities between the malformations elicited by propionitrile and n-butyronitrile or between those elicited by the five unsaturated nitriles. Presence of a rat hepatic microsomal fraction and NADPH in the culture medium enhanced the embryotoxic effects of the five unsaturated nitriles tested but had no effects on saturated nitriles embryotoxicity. In addition to these in vitro experiments, pregnant rats were given a single oral dose of each compound on Day 10 of gestation and the embryos were evaluated on Day 12 of gestation, i.e., at a time of development corresponding to the developmental stage at the end of the whole embryo culture. All the nitriles investigated produced the characteristic defects developed by embryos exposed to sodium cyanide in utero or in culture. Our results provide further evidence that maternal production of cyanide may contribute to the developmental toxicity of saturated and unsaturated nitriles and suggest that distinct metabolites derived from microsomal metabolism of unsaturated nitriles may also play a role.