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42851508.der.pdf
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42851508
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Emamectin benzoate
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155569-91-8
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122806
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Wise, D. (1993) MK-0244: Oral Developmental Neurotoxicity Study in Female Rats: Lab Project Number: 618-244-TOX45: TT #91-721-0: 3592. Unpublished study prepared by Merck Research Labs. 554 p.
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1993.0
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Emamectin benzoate (Deoxyavermectin; MK-0244): Groups of 25 impregnated Sprague-Dawley strain rats were given daily doses of 0, 0.1, 0.6, or 3.6/2.5 mg Emamectin per kg body weight in deionized water beginning on gestation day 6 and continuing through lactation day 20. If an animal did not give birth to a litter on gestation day 24, it was sacrificed and examined to determine pregnancy status. Doses were based on the results of a range-finding study, as well as the results of the pup effects in the 2-generation rat reproduction study [MRID 42851511]. The progress of pup development was monitored by observation of weekly body weights during and after lactation, and preputial separation was noted on postnatal days (PND) 39, 43, and 47 in male pups. Vaginal canalization was noted in female pups on PNDs 31, 34, and 37. Selected pups were observed for behavioral changes on PNDs 13, 17, 21, and 59 (±1) for open-field motor activity; PNDs 22 and 59 (±1) for auditory startle habituation, and PNDs 24 and 59 for learning and short term retention of passive avoidance, and PNDs 32 and 66 for long term retention of learned passive avoidance. Other selected pups were sacrificed on PNDs 11 and 60, and body and brain weights were measured. Brain, spinal cord, sciatic nerve, and skeletal muscle tissues from those animals in the control and high dose groups, which were sacrificed on PND 60, were also prepared for microscopic examination.
There were no treatment-related effects on the incidence of clinical observations, the number of implants/dam, the percent postimplantation survival, pup survival during lactation, or the incidence of malformations. There was an increase in maternal body weight gain during gestation at the mid- and high-dose levels (11 and 15% above controls, respectively). A greater decrease in maternal weight gains was observed in the mid- and high-dose groups during lactation. In the absence of clinical signs, no dose-response relationship (33% and 14% body weight gain decreases at the mid- and high-dose groups in comparison to controls, respectively), and the stated reason for selecting and reducing the highest dose level in the main study (excessive pup mortality), it is unlikely that the 3.6/2.5 mg/kg/day dose is associated with maternal toxicity.
The NOEL for maternal toxicity is 3.6/2.5 mg/kg/day (highest dose tested).
At the highest dose tested, pup body weights were decreased in comparison to controls by 14 to 41% on lactation days 11, 17, and 21, and body weight gains after weaning were 16 and 17% less than control values for male and female pups, respectively. In addition, clinical signs including head and body tremors, hindlimb extension and splay, and unkempt coat without alopecia were observed in pups from the high dose group during lactation and postweaning. Tremors were noted as early as PND 6 and persisted through PND 27, and hind limb splay appeared in high dose pups as soon as PND 10 and persisted through PND 34. The developmental landmarks were delayed an average of 3.6 days in both sexes for pups from the high dose. The behavioral changes were observed primarily in pups given the 3.6/2.5 mg/kg/day dose level. Motor activity was increased in both sexes on PND 13 and decreased in both sexes on PND 17. Motor activity was also decreased in females on PND 59. At the mid dose of 0.6 mg/kg/day, female pups exhibited a dose-related decrease in open field motor activity (activity in mid- and high-dose females was decreased by 20.6 and 41.2 from controls, respectively, at PND 17. The auditory startle reflex was also decreased in both sexes from the highest dose tested on PNDs 22 and 59. There were no treatment-related effects in brain weights or neurophysiological findings which could be associated with the developmental behavioral results.
The NOEL for development neurotoxicity is considered to be 0.10 mg/kg/day (LDT). The LEL is 0.6 mg/kg/day based on the dose-related decrease in open field motor activity in females at PND 17.
Core Classification: Supplementary. The study was well conducted with respect to dose selection, and numbers and kinds of observations, but was under-reported, and full statistical analyses, as well as individual animal data, were not presented. Additionally, page 25 of the study report, dealing with the decreased open field motor activity of mid- and high-dose females at PND 17, was missing and is required to be submitted. Also, an explanation of stereotypy time is required. It is noted that there is a 12.5% increase in cerebral cortex measurement in females at the high dose. Individual data were not presented. A 10% change was sustained among females measured on day 58 in brains that were smaller on average. Statistical analysis was not performed. This finding may be an effect of unclear significance.
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Developmental-Neurotoxicity
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NA [83-6, Developmental Neurotoxicity]
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Oral
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No Duration Period; GD6-LD20
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11308.0
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1994-11-03
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2018-05-23
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Added by
Madison Feshuk
on Apr 25, 2022
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