Neurotoxicity evaluation of N,N-diethyl-m-toluamide (DEET) in rats

The neurotoxic potential of N,N-diethyl-m-toluamide (DEET) was evaluated following acute oral administration or following multigeneration plus chronic dietary administration to the rat. For the acute study, rats were administered undiluted DEET at dose levels of 50, 200, or 500 mg/kg by gavage. A dose level of 500 mg/kg was considered to be the highest practical dose that could be evaluated in this study based upon observations of overt toxicity at 500 mg/kg and mortality at 1000 mg/kg in a dose range-finding study. The two measures of neurotoxicity evaluated in the acute study were functional observational battery (FOB) and motor activity measurements. An apparent treatment-related effect in thermal response time (increased) was noted for both sexes 1 hr after dosing at the 500 mg/kg dose level. A questionable effect on rearing activity (decreased) also was noted at the same dose level. For the multigeneration plus chronic dietary administration study, rats were administered DEET at dietary concentrations of 0, 500, 2000, or 5000 ppm continuously over two generations and then chronically for 9 months. A dietary concentration of 5000 ppm meets the criteria for a maximum tolerated dose (MTD) based on traditional chronic toxicology assessments. Evaluations included FOB, motor activity, discriminative acquisition and reversal in an M-maze, acoustic startle habituation, passive avoidance acquisition and retention, and microscopic examination of central and peripheral nervous tissue. The only effect that was considered to be possibly treatment-related was a slight increase in exploratory locomotor activity at the 5000 ppm dose level. Based on the results of these studies, the nervous system does not appear to be a selective target when DEET is administered to rats either as a single oral dose at high dose levels or chronically at the MTD.