Developmental neurotoxicity evaluation of the avermectin pesticide, emamectin benzoate, in Sprague-Dawley rats.
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.
Wise
L D
LD
Merck Research Laboratories, Department of Safety Assessment, West Point, PA 19486, USA. david_wise@merck.com
Allen
H L
HL
Hoe
C M
CM
Verbeke
D R
DR
Gerson
R J
RJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D005260:Female; D017408:Guidelines as Topic; D007306:Insecticides / Q000633:toxicity*; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D007306:Insecticides; D007559:Ivermectin; C108024:emamectin benzoate