COMPARATIVE METABOLISM AND DISPOSITION OF ACRYLONITRILE AND METHACRYLONITRILE IN RATS

Aliphatic nitriles are a class of chemicals used in high volumes in th e production of plastics and elastomers, in organic synthesis, and in production of a number of food packaging containers. Toxicity and meta bolism of acrylonitrile (AN) are well characterized. On the other hand , minimal information is available on the toxicity or fate of structur ally related, methacrylonitrile (MAN). In an attempt to predict the to xicity of MAN, the present studies were designed to compare the dispos ition of both nitriles in rats. After gavage administration of equimol ar doses (0.87 mmol/kg) of 2-C-14-MAN or 2-C-14-AN to male F344 rats, both chemicals were well absorbed from the GI tract and distributed to all major tissues. However, major differences in the disposition of t he two nitriles were observed. While approximately 39% of the administ ered MAN dose was eliminated as CO2 in 24 h after dosing, only 11% of an equimolar dose of AN was eliminated as such. In addition, 31% of th e MAN dose was exhaled as organic volatiles in 24 h compared to less t han 2% of an equivalent AN dose. MAN and acetone were identified by HP LC analysis of expired organic volatiles from MAN-treated rats. HPLC a nalysis showed that AN is the only organic volatile exhaled by AN-trea ted rats. Urinary excretion of MAN was 22% compared to 67% of an equiv alent dose of AN. The major urinary metabolite from AN results from di rect conjugation with GSH, whereas the major urinary metabolite from M AN results from conjugation of the epoxide with GSH. Pretreatment with phenobarbital (PB) or SKF 525A (SKF) resulted in quantitative changes in the disposition of bath nitriles. The most striking effect of thes e pretreatments was the increase in AN-derived radioactivity in tissue s following SKF pretreatment. PB pretreatment resulted in decreased am ounts of unchanged MAN elimination in expired air. In summary, the res ults of current work indicate that there are major quantitative differ ences in the metabolism and disposition of MAN and AN; however, it rem ains to be established if these differences reflect a different spectr um of toxicity.