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46590001.DE.pdf
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46590001
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Fenamidone
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161326-34-7
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046679
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Sheets, L; Gilmore, R.; Hoss, H. (2005) A Developmental Neurotoxicity Screening Study with Technical Grade Fenamidone in Wistar Rats. Project Number: 04/D72/UM, 201299. Unpublished study prepared by Bayer Corp. 1200 p.
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2005.0
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Fenamidone: In a developmental neurotoxicity study (MRID 46590001), Fenamidone (99.2% a.i.; batch # OP2250040) was administered in the diet to 30 female mated Wistar Hannover Crl:WI (Glx/BRL/Han) IGS BR rats/dose at nominal concentrations of 0, 60, 250, 1000 or 4700 ppm from gestation day (GD) 6-20. Dietary concentrations were reduced to 0/0/0, 34/28/24, 145/116/95, 584/471/388, or 2716/2222/1844 ppm, during weeks 1/2/3 of lactation, respectively, based on estimated increases in feed consumption during lactation. Average doses to the animals throughout the study were 0, 5.5, 23.2, 92.3, or 429 mg/kg/day, respectively. A Functional Operational Battery (FOB) was performed on 30 dams/dose on GDs 13 and 20, and on 10 dams/dose on LDs 11 and 21. On postnatal day (PND) 4, litters were culled to yield four males and four females (as closely as possible). Offspring were allocated for detailed clinical observations (FOB) and assessment of motor activity, auditory startle reflex habituation, learning and memory (passive avoidance and watermaze testing), and neuropathology at study termination (day 75±5 of age). On PND 21, the whole brain was collected from 10 pups/sex/dose group for micropathologic examination and morphometric analysis. Pup physical development was evaluated by body weight. The age of sexual maturation (vaginal opening in females and preputial separation in males) was assessed.
No maternal deaths or clinical signs of toxicity were observed during the study. FOB testing was unaffected by treatment. Mean body weight during gestation was unaffected by treatment. However, at 4700 ppm mean body weight gain was significantly decreased (8% relative to controls) during GDs 6-20 due to weight gain that was decreased by 27%, relative to controls, during GDs 6-13. Food consumption measurement during GDs 6-13 in the 4700 ppm group was compromised by spillage. Food consumption was decreased at 1000 ppm during GDs 6-13 (7% decrease relative to controls), but without a toxicologically significant change in body weight or body weight gain. Mean body weight during lactation was slightly decreased (3-5% relative to controls) in females at 4700 ppm. Food consumption during lactation was unaffected by treatment. No treatment-related effects were observed on reproductive performance.
Litter viability and clinical signs in offspring were unaffected by treatment. No treatment-related effects were observed at birth; however, body weight was significantly decreased in males (9-10% relative to controls) and females (8-11% relative to controls) at 4700 ppm from PNDs 4-21. Body weight gain during the pre-weaning period was significantly decreased in males (9-20% relative to controls) and females (8-20% relative to controls) at 4700 ppm. Post-weaning (PNDs 28-70) body weight was significantly decreased in males by 5-6%, relative to controls, and females (4-5% relative to controls) at 4700 ppm during the first three weeks. Body weight gain was similar between the treated and control groups during post-weaning. Attainment of vaginal opening in females, preputial separation in males, and pupil constriction response in both sexes was not affected by treatment. No treatment-related effects were observed on FOB, motor/locomotor activity, auditory startle habituation or learning and memory testing (passive avoidance and watermaze performance). No treatment-related effects were reported for ophthalmologic testing. At necropsy, brain weight, macroscopic/ microscopic examination of the nervous system and morphometric measurements were unaffected by treatment.
The maternal systemic and neurotoxicity LOAEL for Fenamidone was not determined. The maternal NOAEL is 4700 ppm (429 mg/kg/day).
The offspring systemic and neurotoxicity LOAEL for Fenamidone in rats is 4700 ppm (429 mg/kg/day) based on decreased body weight (9-11%) and body weight gain (8-20%) during pre-weaning and decreased body weight (4-6%) during post-weaning. The offspring NOAEL is 1000 ppm (92.3 mg/kg/day).
This developmental neurotoxicity study is classified as Unacceptable/Guideline and does not satisfy the guideline requirement for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6); OECD 426. Previously, the Health Effects Division suggested that a preliminary dose-range finding study be conducted if the Crl:CD(SD)BR strain of rat were not utilized in the required DNT study, since the 2-generation reproduction study (MRID 45400014) was conducted with the Crl:CD(SD)BR strain of rat (Memo, PV Shah, 12-Jan-2004, TXR# 0052296). However, the DNT study was conducted with the Wistar Hannover strain of rat. It is therefore not possible to assess whether the decreases in absolute brain weight observed in the F1 and F2 generations in the 2-generation reproduction study using the Crl:CD(SD)BR strain of rat would also be observed in the required DNT paradigm, using the Crl:CD(SD)BR strain of rat.
[The standard DNT classification statement does not apply to this study.]
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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; gestation day (GD) 6-20
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53629.0
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2006-02-23
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2006-04-12
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Added by
Madison Feshuk
on Apr 25, 2022
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