Acute toxicity and anticholinesterase action of O,O-dimethyl O-[4-(methylthio)- m-tolyl] phosphorothioate (DMTP; Baytex) and related compounds

Abstract

The acute toxicity of O,O-dimethyl O-[4-(methylthio)- m-tolyl] phosphorothioate (DMTP; Baytex; Bayer 29493) was studied. By the intraperitoneal route the LD 50 values ranged from 125 mg/kg to 325 mg/kg for mice, guinea pigs, and rats. By the oral route the LD 50 values ranged from 190 mg/kg to 310 mg/kg. The sulfoxide and sulfone derivatives of DMTP exhibited toxicity similar to that of the parent compound. Measurements of the anticholinesterase action of DMTP in vivo demonstrated that the enzyme activity of the brain and peripheral tissues exhibit similar susceptibility and the inhibitory effect is of long duration. The oxygen analog of DMTP was about 13 times more toxic than the parent compound by the intraperitoneal route to rats. The sulfoxide derivative of the oxygen analog was equal to the oxygen analog in toxicity, but the sulfone derivative was about 3 times more toxic than the oxygen analog. These possible metabolites of DMTP exerted a strong anticholinesterase action in vitro and the effects in vivo were much more rapidly reversible than those of DMTP. The S-methyl isomer was about 6 times more toxic than DMTP and differed in its in vivo anticholinesterase action by inhibiting the cholinesterase activity of the brain to a much lesser extent than peripheral tissues. Repeated daily injection of DMTP demonstrated that it has a marked tendency to produce cumulative toxic effects leading to mortality. Potentiation of acute toxicity was observed in rats when DMTP was given simultaneously with Delnav, Co-Ral, or malathion.