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47166501.de.pdf
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47166501
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Spirodiclofen
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148477-71-8
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124871
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Gilmore, R.; Sheets, L.; Hoss, H. (2007) A Developmental Neurotoxicity Study with Technical Grade Spirodiclofen (BAJ 2740) in Wistar Rats. Project Number: 201673, 06/D72/GL. Unpublished study prepared by BioSTAT Consultants, Inc. and Bayer Corp. 529 p.
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2007.0
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Spirodiclofen: In a developmental neurotoxicity study conducted in 2004 with Spirodiclofen (MRID 46324901) treatment related effects in the memory phase of the water maze test were seen at the lowest dose tested (6.5 mg/kg/day) in female offspring on post natal day 60. Additionally, treatment-related changes were seen at the highest dose tested (135.9 mg/kg/day) in several brain morphometric parameters (caudate putamen, parietal cortex, hippocampal gyrus, and dentate gyrus). Consequently, evaluations were requested for these parameters at the mid and low dose groups. However, the Registrant has informed that the brain tissues were not appropriately preserved and therefore additional brain morphometric analyses at the mid and low doses are not possible (verbal communication between PMRA and HED) (TXR No. 0052758).
Because of the concerns observed in the study discussed above, the Registrant conducted an abbreviated study in which behavioral assessments (learning and memory) and brain morphometry analyses were conducted. The Executive Summary for this abbreviated study is presented below.
In this abbreviated developmental neurotoxicity study (MRID 47166501), technical Spirodiclofen (97.5-98.3 % a.i., batch 06480/0002) was administered in the diet to 30 female Wistar Han Crl:WI (Han) rats per dose at dose levels of 0, 70, 350 or 1500 ppm (average daily intake of 0, 5.4, 28.6 and 119.2 mg/kg/day, respectively, during gestation and 0, 13.0, 65.7 and 262.1 mg/kg/day, respectively, during lactation) from gestation day (GD) 0 through lactation day (LD) 21. Because of increased food consumption during lactation, dietary levels were adjusted to achieve a more consistent mg/kg/day dosage throughout the exposure period. On postnatal day (PND) 4, litters were culled to yield four males and four females (as closely as possible). Offspring were allocated for clinical observations, body weight measurements, ophthalmic examinations and assessment of learning and memory (water maze testing using M-Maze and Cincinnati Water Maze). Whole-brain tissue was collected from 10/sex/dose level on PND 21 and at study termination (PND 75 ±5) for morphometry.
No deaths or clinical signs of toxicity were observed in parental females. The slight decrease in food consumption (4-5% as compared to controls) during lactation produced a minimal decrease in body weight gain (4% as compared to controls) for LDs 0-20. The findings are not considered adverse due to the low magnitude of the changes and the lack of statistical significance. No treatment-related effects on reproduction were reported.
No clinical signs of toxicity were observed in offspring during lactation or postweaning. Litter size and viability were not affected by treatment. Beginning on PND 17, a decrease in body weight was observed in the high-dose group, with statistically significant decreases of 8% and 7% in males and females as compared to controls, respectively, on PND 21. Statistically significant decreases in body weight gain were observed in high dose males and females for the periods PND 4-21 (9-10%), PND 11-21 (13%) and PND 17-21 (21%). During postweaning, body weight was decreased (5-6% as compared to controls) in high-dose males on PND 29 through PND 50, which was statistically significant on PNDs 35 and 42.
No treatment-related effects on learning and memory were observed in either the M-Maze or the Cincinnati Water Maze testing. When tested at the same dose levels, the changes observed in the memory phase in the previous study were not replicated in this study. Similarly, changes seen in the brain morphometric parameters in the previous study were not seen in this study.
The maternal LOAEL for Spirodiclofen in rats was not established. The maternal NOAEL is 1500 ppm (119.2 and 262.1 mg/kg/day during gestation and lactation, respectively).
The offspring LOAEL for Spirodiclofen in rats is 1500 ppm (119.2 and 262.1 mg/kg/day during gestation and lactation, respectively) based on decreased preweaning body weight and body weight gain in males and females and decreased post-weaning body weight in males. The offspring NOAEL is 350 ppm (28.6 and 65.7 mg/kg/day during gestation and lactation, respectively).
This developmental neurotoxicity is classified as Acceptable/Non-Guideline 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 (draft) due to the pending review of the positive control data.
[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, 12/20/2007]
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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 0 to LD 21
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54354.0
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2007-12-20
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2018-03-27
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Added by
Madison Feshuk
on Apr 25, 2022
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