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The potential of emamectin benzoate (EB) to cause developmental neurotoxicity in Sprague-Dawley rats was assessed using a study design 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 day (GD) 6 to lactational day (LD) 20 to groups of 25 mated females each. Between GD 17 and 20 the high dose was reduced to 2.5 mg/kg/day because of pup tremors observed at this dose level in a concurrent two-generation study. Females were allowed to deliver and the young were evaluated for survival, growth, development, behavior, and histological changes to brain, spinal cord, peripheral nerve, and skeletal muscle. Behavioral assessment of the offspring consisted of open field motor activity, auditory startle habituation, and passive avoidance tests; each 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 significant increases in average F0 maternal body weight gains during gestation in the 0.6 and 3.6/2.5 mg/kg/day groups, but no other effects were observed in pregnant females of these or the low-dose groups during the study. Beginning on PND 6, tremors were observed in high-dose pups, and this was followed by hindlimb splay in all high-dose pups by PND 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 F1 offspring. Beginning on PND 11, progressive decreases in preweaning average weights were observed in the high-dose group (to 42% below control in females on PND 21). Average weight gain during the postweaning period 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 group. A significant increase in PND 13 average horizontal motor activity was due to stereotypical movements. Average horizontal activity was decreased on PND 17 and in adult females, but there was 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 passive avoidance test, relative brain weights, or in the histological examination (including morphometry) of the nervous system. These results demonstrate that the high-dose EB exposure during gestation and lactation to rats produced evidence of neurotoxicity in the F1 offspring, and a clear No Observed Adverse Effect Level (NOAEL) for developmental neurotoxicity of EB was determined to be 0.6 mg/kg/day.

Based on the literature to-date, the potential of acrylamide (ACRL) to cause developmental neurotoxicity in laboratory animals has not been assessed. We examined this potential in Sprague-Dawley rats using a study design similar to that proposed by the USEPA. Dosages of 0 (deionized water), 5, 10, 15, or 20 mg/kg/day were administered at 5 ml/kg by oral gavage from gestational day 6 to lactational day 10 to groups of 12 mated females each. Females were allowed to deliver and the offspring were evaluated for survival, growth, development, behavior, and histological changes to brain, spinal cord, and peripheral nerve. Behavioral assessments consisted of open-field motor activity, auditory startle habituation, and passive avoidance tests during both the preweaning and adult periods (1 animal/sex/litter). All F0 and F1 animals in the 20 mg/kg/day group were euthanized early in the lactation period due to high pup mortality. Significantly increased pup mortality was also present in the 15 mg/kg/day group. There were dose-related decreases in average F0 maternal body weight gains during the dosing period in the 10, 15, and 20 mg/kg/day groups, and characteristic hindlimb splaying was observed in dams of the two highest dosage groups. Pup body weight proved to be the most sensitive indicator of developmental toxicity. Dose-related decrease in preweaning average weights were observed at all dose levels, although only transiently in the 5 mg/kg/day group. Average weight gain during the postweaning period was significantly decreased only in males of the 15 mg/kg/day group. Significant decreases in average horizontal motor activity and auditory startle response were observed only in weanlings of the 15 mg/kg/day group. The only behavioral effect in F1 adult animals was a decrease in auditory startle response in females of the 15 mg/kg/day group. There were no effects in the passive avoidance test or in the histological examination of the nervous system of preweaning pup or adult animals. Based on these results, the NOAEL (No Observed Adverse Effect Level) for developmental toxicity is less than 5 mg/kg/day, the NOAEL for maternal toxicity is 5 mg/kg/day, and that for developmental neurotoxicity is 10 mg/kg/day. Thus behavioral changes in the offspring were observed only at a dose which was also maternally toxic. These results suggest that acrylamide may be a selective developmental toxicant but not a selective developmental neurotoxicant, because a conventional measure of offspring toxicity (i.e., pup body weight) was affected at a dosage lower than that which produced maternal effects or offspring behavioral effects.