Muscle necrosis by N-methylated p-phenylenediamines in rats: structure-activity relationships and correlation with free-radical production in vitro.

Certain derivatives of p-phenylenediamine have been shown to cause necrosis of cardiac and skeletal muscle in rats; in vitro, such compounds are known to autoxidize to the corresponding radical cations, with concomitant formation of oxygen free-radicals. In the present study, the autoxidation rates of p-phenylenediamine and its N-methyl, dimethyl, trimethyl and tetramethyl derivatives have been determined and compared with the severity of the muscle necrosis induced by each of these compounds in rats. A close correlation was observed between autoxidation rate in vitro and toxicity in vivo, suggesting that free-radical species may be involved in the initiation of the muscle damage caused by these substances.