Assessment of the metabolism and toxicity of the dichloroacetamide safener benoxacor

Benoxacor is a chiral dichloroacetamide safener that is often co-formulated with the chloroacetanilide herbicide metolachlor. The main function of benoxacor is to induce metabolic enzymes such as cytochrome P450s (CYPs), carboxylesterases (CESs) and glutathione S-transferases (GSTs) within crops, such as maize, to provide protection from metolachlor toxicity. While previous studies have determined that benoxacor along with other dichloroacetamide safeners are found in the surface water in the Midwest United States, the enantioselective metabolism and toxicity of benoxacor has not been previously studied in mammalian systems.

Benoxacor was incubated in microsomes and cytosol from rats, monkeys, humans, and mice. The co-factors nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) were added to the incubations to determine the metabolism of benoxacor by CYPs and GSTs respectively. CES metabolism was monitored in incubations without the addition of co-factor. These incubations studies showed that benoxacor was enantioselectively metabolized by CYPs, CESs, and GSTs in all of the species tested; however, many interspecies and sex differences were noted.

Benoxacor was also tested for toxicity in C57Bl/6 mice following an acute oral exposure. Following benoxacor exposure there were significant changes to the bodyweight-adjusted weights of the testes and livers of the exposed animals and 163 genes were differentially expressed. The profile of differentially expressed genes closely matched the profile of expression as a result of dichloroacetic acid which is a likely metabolite of benoxacor hydrolysis. Minimal overall toxicity was noted in this study, but the results from this study warrant further investigation. While these studies provided a foundation for understanding the metabolism and potential toxicity of benoxacor, many further studies need to be conducted to determine the metabolites of benoxacor and further understand any toxic effects.