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47443311.der.pdf
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47443311
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Indaziflam
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950782-86-2
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080818
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Sheets, L.; Gilmore, R. ; Hoss, H. (2008) A Developmental Neurotoxicity Study with Technical Grade BCS-AA10717 in Wistar Rats. Project Number: M/303709/01/1, 201877, 07/D72/KC. Unpublished study prepared by Bayer CropScience. 1139 p.
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2008.0
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Indaziflam: In a developmental neurotoxicity study (MRID 47443311) Indaziflam (AE 1170437; BCS-AA10717; 93.14% a.i.; Batch No.: EFIM000511) was administered in the diet to pregnant Wistar Han rats (30/dose) from gestation day (GD) 6 through lactation day (LD) 21 at doses of 0, 150, 1000 or 7000 ppm. Beginning on LD 4, the high dose dietary level was reduced to 4000 ppm. The average test substance intake was 13.0, 83.8 or 432 mg/kg/day. Pups were not directly dosed. Dams were allowed to deliver naturally and were killed at weaning on LD 21. On PND 4, litters were standardized to 4 pups/sex/litter (when possible). The remaining offspring and dams were sacrificed and not examined further. One male and/or female per litter (approximately 16 ¿ 20, minimum 10)/sex/dose, representing at least 20 litters/dose) were assigned to the following sets: motor activity (Set A), auditory startle (Set B), passive avoidance, water maze and functional observational battery (Set C). On PND 21, the whole brain was collected from a separate group of randomly selected offspring (Set D; 10/sex/dietary level; representing 20 litters/dose) for micropathologic examination and morphometric analysis. The remaining pups assigned to Set D (~10/sex/dose) were reserved for possible use as replacement animals or sacrificed on PND 21 without necropsy examination.
In the maternal animals: No treatment-related mortality occurred. Toxicity was only observed in the 7000/4000 ppm group. Treatment-related clinical signs were evident beginning on GD 6 as coarse tremor, dilated pupils, nasal stain and repetitive chewing movements in one animal. In the FOB, treatment-related effects were first evident on GD 6, and included dilated pupils, dilated pupils that were unresponsive to penlight, tremor and repetitive chewing movements.
Body weights were decreased on GD 13 and 20 by 7-13%, resulting in a decreased cumulative body weight gain (GD 0-20) of 42%. Body weights were decreased throughout lactation by 4-14%, but increased cumulative body weight gain (LD 0-21) of 71% was noted. Body weight for females was reduced an average 14% and 11%, compared to controls, on LD 0 and 4, respectively. After LD 4 (when dose was reduced), the difference in body weight for the treated animals compared to controls progressively decreased with time. An effect on food consumption may have been observed during GD 6-13 but this was unclear due to food spillage. There was no effect on food consumption after reduction of the high-dose for the remainder of lactation. The number of litters was decreased by 17%. The maternal LOAEL is 7000/4000 ppm (equivalent to 432 mg/kg/day), based on clinical signs and decreased body weights and body weight gains. The maternal NOAEL is 1000 ppm (equivalent to 83.8 mg/kg/day).
In the offspring: No treatment-related effects were observed on litter size, viability, clinical signs, developmental landmarks, functional observational battery, auditory startle reflex, learning and memory testing, ophthalmology, nervous system morphometric evaluation, or gross or microscopic pathology.
Decreased offspring body weights were noted in both sexes up to PND 4, post-culling (decr 14-17%), and up to PND 21 in both sexes (decr 5-10%). Offspring postweaning male body weights were decreased by 3-8%; treated group female body weights were similar to controls.
Motor activity was decreased in the 7000/4000 ppm males on PND 21 by 29%. Although there was no treatment-related effect on any measure of activity in high-dose males at other ages or in females at any age or dietary level, this difference from controls is considered treatment-related because it was statistically significant and the average results for the high-dose males (228) was below the range of historical control from four developmental neurotoxicity studies (261-341) conducted during the same time period (2005-2007), while the results for controls were well within this range. All other aspects of motor activity, including habituation, were not considered to be affected by treatment. Minor (3-5%) decreases in perfused and/or non-perfused brain weights in 7000/4000 ppm male and female pups were not considered adverse due to their small magnitude and change only at the limit dose: furthermore, most did not achieve statistical significance and in males, decreases were seen at PND 21 but not at termination.
The offspring LOAEL is 7000/4000 ppm (equivalent to 432 mg/kg/day), based on decreased body weights (males and females) and decreased motor activity in male pups on PND 21. The offspring NOAEL is 1000 ppm (equivalent to 83.8 mg/kg/day).
This study is classified as Acceptable/Nonguideline and may be used for regulatory purposes. It does not, however, satisfy the guideline requirement for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6); OECD 426 review of the positive control data.
[Note - This classification scheme is applicable only to Developmental Neurotoxicity (DNT) studies. The DNT Work Group determined that this study can be classified as Acceptable. This study does not satisfy the guideline requirements for a developmental neurotoxicity study and is classified as NonGuideline pending review of all available positive control data. J. Rowland,April 21, 010]
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Developmental-Neurotoxicity
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NA [870.6300, Developmental neurotoxicity study]
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Oral
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No Duration Period; GD 6 to LD 21
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54980.0
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2010-04-21
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2020-03-11
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Added by
Madison Feshuk
on Apr 25, 2022
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