DEVELOPMENTAL NEUROTOXICITY EVALUATION OF THE AVERMECTIN PESTICIDE, EMAMECTIN BENZOATE, IN SPRAGUE-DAWLEY RATS

The potential of emamectin benzoate (EB) to cause developmental neurot oxicity in Sprague-Dawley rats was assessed using a study design propo sed by the US EPA. Dosages of 0 (deionized water), 0.1, 0.6, or 3.6 mg /kg/day were administered at 5 ml/kg by oral gavage from gestational d ay (GD) 6 to lactational day (LD) 20 to groups of 25 mated females eac h. Between GD 17 and 20 the high dose was reduced to 2.5 mg/kg/day bec ause of pup tremors observed at this dose level in a concurrent two-ge neration study. Females were allowed to deliver and the young were eva luated for survival, growth, development, behavior, and histological c hanges to brain, spinal cord, peripheral nerve, and skeletal muscle. B ehavioral assessment of the offspring consisted of open field motor ac tivity, auditory startle habituation, and passive avoidance tests; eac h was conducted on weanling and adult animals (one animal/sex/litter). Histopathological examination of the CNS and PNS was conducted on one animal/sex/litter on postnatal days (PND) 11 and 60. There were signi ficant increases in average F-0 maternal body weight gains during gest ation in the 0.6 and 3.6/2.5 mg/kg/day groups, but no other effects we re observed in pregnant females of these or the low-dose groups during the study. Beginning on PND 6, tremors were observed in high-dose pup s, and this was followed by hindlimb splay in all high-dose pups by PN D 15-26. Both of these physical signs disappeared by PND 34 (i.e., 10- 11 days after weaning). There were no compound-related deaths in F-1 o ffspring. Beginning on PND 11, progressive decreases in preweaning ave rage weights were observed in the high-dose group (to 42% below contro l in females on PND 21). Average weight gain during the postweaning pe riod was significantly decreased in the 3.6/2.5 mg/kg/day group. There were EB-related effects in behavioral tests only in the high-dose gro up. A significant increase in PND 13 average horizontal motor activity was due to stereotypical movements. Average horizontal activity was d ecreased on PND 17 and in adult females, but there were no effects on PND 21. Average peak auditory startle response amplitude was decreased on PND 22 and in adults. There were no EB-related effects in the pass ive avoidance test, relative brain weights, or in the histological exa mination (including morphometry) of the nervous system, These results demonstrate that the high-dose EB exposure during gestation and lactat ion to rats produced evidence of neurotoxicity in the F-1 offspring, a nd a clear No Observed Adverse Effect Level (NOAEL) for developmental neurotoxicity of EB was determined to be 0.6 mg/kg/day. (C) 1997 Elsev ier Science Inc.