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48811401.der.pdf
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48811401
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Pyridaben
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96489-71-3
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129105
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Patten, R. (2007) Pyridaben: Developmental Neurotoxicity Study in the CD Rat by Dietary Administration. Project Number: NAS/699/053379, NAS/699. Unpublished study prepared by Huntingdon Life Sciences, Ltd. 688p.
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2007.0
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Pyridaben: In a developmental neurotoxicity study (MRID 48811401), Pyridaben (99.2% a.i.; Batch no. 129T950808) was administered to 24 mated female Crl:CD® (SD) IGS BR rats per dose in the diet from gestation day (GD) 3 through lactation day (LD) 20 at dietary concentrations of 0, 25, 50, or 100 ppm (equivalent to 0, 2.2, 4.2, and 8.4 mg/kg bw/day during gestation and 0, 4.3, 8.6, and 17.7 mg/kg bw/day during lactation). Dams were euthanized on LD 21, at which time the F1 offspring were weaned onto the basal diet and maintained on the study through up to postnatal day (PND) 65. Evaluated maternal parameters included the following: clinical observations, body weights, weight gains, and food consumption; a Functional Observational Battery (FOB) on GDs 12 and 18 and LDs 4, 11, and 20; and gross pathology, including brain weights. Evaluated offspring parameters included the following: clinical observations; survival; body weights and weight gains; FOB (PNDs 4, 11, 21, 35, 45, and 60); auditory startle habituation and pre-pulse inhibition (PNDs 23/24 and 61/62); motor activity (PNDs 13, 17, 22, and 59); evaluation of learning and memory via Morris maze testing (PNDs 23/24 and 60-62); evaluation for sexual development (balanopreputial separation and vaginal patency); brain weight (PNDs 11, 21, and 63); and brain length/width measurement, morphometry, and neuropathology (PNDs 21 and 63).
Relative to controls, mid- and high-dose dams had decreased body weight gains during GD 3-14 (-18% and -33%, respectively; p<0.01), and high-dose dams also gained less weight during GD 14-20 (-13; p<0.01), with the magnitude of the difference most marked during GD 3-6 (-33% and -73% for mid- and high-dose, respectively) and decreasing thereafter. Mid- and high-dose dams also had decreased cumulative body weight gain for GDs 3-20 (-10% and -21%, respectively; p<0.01). The differences resulted in small, but statistically significant, decreases in mean absolute body weights during GDs 6-20 (mid-dose: 3-5%; high-dose: 5-8% less than controls). Recovery was seen during lactation, with cumulative LD 1-21 weight gain increased in mid- and high-dose females (+10% and +32%, respectively; p<0.5 at high-dose only) due to increased weight gain by high-dose dams during LDs 7-14 (+60%), and small weight gains in mid- and high-dose dams during LDs 14-21, while controls lost weight (-2 g, -5 g, +3 g, and +8 g in ascending group order). Mean food consumption of the mid- and high-dose females was significantly decreased during GDs 3-13 for high-dose dams (-9% to -14%; p<0.01) and during GDs 10-13 for mid-dose dams (-13%; p<0.01) and essentially unaffected during lactation. There were no treatment-related effects on maternal survival, clinical signs, FOB parameters, gestation index, gestation length, brain weight, or gross pathology.
The maternal toxicity NOAEL is 25 ppm (equivalent to 2.2 mg/kg/day during gestation and 4.3 mg/kg/day during lactation) and the LOAEL is 50 ppm (equivalent to 4.2 mg/kg/day during gestation and 8.6 mg/kg/day during lactation) based on decreased body weight and food consumption.
High-dose pups of both sexes had decreased body weight gains during PNDs 7-21 (-16% to -22%), decreased cumulative PNDs 1-21 weight gain (-17% in both sexes; p<0.01), and decreased mean absolute body weights on PNDs 11-21 in males and PNDs 14-21 in females (-8% to -15%; p<0.05 or p<0.01) with the magnitude of the decrement increasing over time. Mid-dose pups of both sexes had decreased body weight gains during PNDs 14-21 (-15% to -17%), decreased in cumulative PNDs 1-21 weight gain (-8% to -9%), and decreased mean absolute body weights on PND 21 (-7% to -8%). Recovery was evident following weaning and cessation of treatment on PND 21. By PND 28, the group mean body weights of the treated offspring of both sexes were within ±10% of those of their respective controls, although at the high dose the differences did remain statistically significant.
High-dose males exhibited altered motor activity on PND 22. Relative to controls, the mean subsession low beam breaks of the high-dose males were significantly increased (p<0.05 or p<0.01) 2.6- to 3.1-fold during the 49-54 and 55-60 minute subsessions, and this group failed to demonstrate habituation, which should have been present by this time point. At the PND 23/24 time point, high-dose females had an increased percentage auditory startle pre-pulse inhibition (+55%; p<0.05) with a decreased acoustic startle peak amplitude following a stimulus with a pre-pulse (-19%; p<0.05).
There were no treatment related effects on offspring viability, clinical signs, sexual maturation, FOB parameters, Morris maze testing results, brain weight, length, or width, macroscopic pathology, histopathology, or brain morphometry.
The offspring toxicity NOAEL is 25 ppm (equivalent to 2.2 mg/kg/day during gestation and 4.3 mg/kg/day during lactation) and the LOAEL is 50 ppm (equivalent to 4.2 mg/kg/day during gestation and 8.6 mg/kg/day during lactation) based on decreased body weight.
This study is classified Acceptable/Guideline and satisfies the guideline requirement for a developmental neurotoxicity study (OCSPP 870.6300).
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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 3 through LD 20
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57105.0
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2015-10-02
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2018-04-26
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Added by
Madison Feshuk
on Apr 25, 2022
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