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47377101.der.pdf
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47377101
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Triadimefon
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43121-43-3
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109901
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Sheets, L.; Gilmore, R.; Hoss, H. (2008) A Developmental Neurotoxicity Study with Technical Grade Triadimefon in Wistar Rats. Project Number: 07/D72/IL, 201766. Unpublished study prepared by Bayer CropScience. 1179 p.
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2008.0
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Triadimefon: In a developmental neurotoxicity study (MRID 47377101) Triadimefon (95.7% a.i., Lot # PF00001KAW) was administered in the diet to 30 mated female Wistar rats/dose at nominal dose levels of 0, 100, 300, or 800 ppm from gestation day (GD) 6 through lactation day (LD) 21. Doses were adjusted during lactation to achieve a more consistent dosage throughout exposure. The mean daily intake during gestation and lactation was 0, 8.0, 23.9, and 71.3 mg/kg/day. Dams were allowed to deliver naturally and were killed on LD 21, following weaning of their respective litters. Any females that were found to be sperm positive and/or with a vaginal plug, but did not deliver, were sacrificed on GD 24. On postnatal day (PND) 4, litters were standardized to 8 pups/litter (4/sex); the remaining offspring and dams were sacrificed and discarded without further examinations. Subsequently, 1 pup/litter/group (at least 10 pups/sex/dose when available) were allocated to subsets for FOB, motor activity, acoustic startle response, learning and memory evaluation, and neuropathological examination.
No treatment-related effects were observed on mortality, clinical signs of toxicity, food consumption, FOB parameters, or reproductive parameters in the dams. At 800 ppm, treatment-related effects were limited to decreases in body weights on GD 13 and LD 0 (5% each, p<0.05), and body weight gain during GD 0-20 (6%, not significant).
The maternal LOAEL is 800 ppm (equivalent to 71.3 mg/kg/day), based on decreases in body weight on GD 13 and LD 0 and body weight gain during GD 0-20. The maternal NOAEL is 300 ppm (equivalent to 23.9 mg/kg/day).
No treatment-related effects on viability/survival, litter parameters, pre-weaning clinical signs, sexual maturation, age of onset of surface righting or pupil constriction, FOB parameters, motor activity, water maze, ophthalmoscopic lesions, gross or microscopic lesions, or brain morphometric measurements were observed in the F1 pups.
At 800 ppm, deviated snout was noted in 3 females and 1 male during post-weaning. Pre-weaning body weights (males and females combined) were decreased (not significant, NS) by 4-5% on PND 11-21; combined body weight gains were decreased (p<0.05) by 6-7% on PND 4-11 and 4-17; and overall (PND 0-21) combined body weight gains (calculated by reviewers) were decreased by 5%. Post-weaning body weights were decreased (p<0.05) by 5-7% in the males during the last 2 weeks of the study, and by 8% (NS) at termination. During the auditory startle reflex habituation test, a treatment-related increase (p<0.05) in total session (blocks 1-5) peak amplitude was observed in the females (54%) on PND 60. Increased (47-70%) peak amplitude was noted during all test blocks in this group compared to controls; however, statistical significance (p<0.05) was only achieved during Block 5 (incr 70%). During the passive avoidance test, an increase (p<0.05) in the mean number of trials to criterion (2.8 treated vs. 2.1 controls) was noted in the females during the retention phase on PND 30.
Additionally at 800 ppm, absolute (perfused) brain weights were decreased (p<0.05) by 4% in the males at termination. The Sponsor stated that this finding was considered to be secondary to the decreased terminal body weight (8%, NS) in this group; however, the reviewers consider this finding equivocal for toxicity.
No treatment-related effects were observed at 300 ppm or below in either sex.
The offspring LOAEL is 800 ppm (equivalent to 71.3 mg/kg/day), based on post-weaning clinical signs (deviated snout); decreases in pre-weaning body weight (PND 11, 17, and 21) in both sexes, preweaning body weight gain in both sexes; increased peak amplitude during auditory startle reflex testing in females; and increased number of trials to criterion during the retention phase of the passive avoidance test in females. The offspring NOAEL is 300 ppm (equivalent to 23.9 mg/kg/day).
This study is classified (Acceptable/Nonguideline) and may be used for regulatory purposes, however it does not satisfy the guideline requirements for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6) OECD 426 (draft) pending the evaluation of the submitted positive control data.
[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, 08/04/2009]
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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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52825.0
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2009-08-04
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2017-09-06
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Added by
Madison Feshuk
on Apr 25, 2022
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