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45912101.der.pdf
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45912101
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Coumaphos
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56-72-4
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036501
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Sheets, L.; Stuart, B. (2003) A Developmental Neurotoxicity Screening Study with Technical Grade Coumaphos in Wistar Rats: Lab Project Number: 01-D72-DK: 200501: 01-D72-DKP3. Unpublished study prepared by Bayer CropScience LP. 1121 p. {OPPTS 870.6300}
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2003.0
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In a developmental neurotoxicity study (MRID 45912101), Coumaphos (94.5-94.7% a.i., batch # 795-010-112) was administered to 30 parent female Wistar rats/dose in the diet at concentrations of 0, 1.0, 5.0 or 30 ppm from gestation day 0 through postnatal day 21. The average daily intake of Coumophos was 0, 0.09, 0.47, and 2.77 mg/kg/day during gestation and 0, 0.22, 1.06, and 7.40 mg/kg/day during lactation, for the 0, 1.0, 5.0, and 30 ppm groups, respectively. A Functional Operational Battery (FOB) was performed on 30 dams/dose on gestation days 6 and 20, and on 10 dams/dose on lactation days 11 and 21. On postnatal day 4, litter sizes were reduced to yield four males and four females (as closely as possible). Offspring representing at least 20 litters/dose were allocated for detailed clinical observations (abbreviated FOB), assessment of motor activity, assessment of auditory startle response habituation, assessment of learning and memory, opthalmology, and neuropathology at study termination (day 75 of age). On postnatal day 21, the whole brain was collected from 10 pups/sex/dietary level for micropathologic examination and morphometric analysis. [These 21 day old pups were flushed with sodium nitrite followed by fixation with 1% gluteraldehyde and 4% paraformaldehyde.] The remaining pups in this set were sacrificed on postnatal day 21 for measurement of cholinesterase activity. Brain, erythrocyte, and plasma cholinesterase activities were measured in offspring (20/dose group) on days 4 and 21 and in dams (10/dose group) on postnatal day 21. Pup physical development was assessed by body weight, and sexual maturation of females was assessed by age at vaginal opening. Maturation of males was assessed by age at completion of balano-preputial separation.
In dams during gestation and lactation, no treatment-related effects on mortality, clinical signs, body weight, body weight gain, food consumption, or FOB parameters were noted.Cholinesterase activity was inhibited (p<=0.05) in maternal animals at 5.0 and 30 ppm. Inhibitions were 21% and 78% at 5.0 ppm, for plasma and erythrocyte cholinesterase activities, respectively, and 68%, 85%, and 36% at 30 ppm, for plasma, erythrocyte and brain cholinesterase activities, respectively.
For maternal systemic toxicity, the NOAEL is 30 ppm (2.77 mg/kg/day), the highest dose tested. A LOAEL was not established.
For maternal cholinesterase inhibition the NOAEL is 1.0 ppm (0.09 mg/kg/day). The LOAEL is 5.0 ppm (0.47 mg/kg/day) based on inhibition of plasma and erythrocyte cholinesterase activities.
In offspring, treatment had no adverse effects on survival, clinical signs, body weight, birth weight, body weight or body weight gain pre- or post-weaning, food consumption, developmental landmarks, pupil constriction, FOB parameters, motor/locomotor, auditory startle response, passive avoidance/latency, learning and memory/latency tests or ophthamology [ophthalmology]. At necropsy, there were no treatment-related gross or micropathological effects and no effect on absolute or relative brain weight. Brain morphometry revealed statistically significant decreases in the parietal cortex thickness (7%) and cerebellum height (4%) in male offspring at the highest dose (30 ppm) on PND 21. No other treatment-related changes were seen in either sex at any time period at any dose. Cholinesterase activity was not affected at any dose level in offspring on PND 4. For the day 21 offspring, all three cholinesterase activities were affected in high-dose animals. Only plasma cholinesterase activity was inhibited significantly (p<=0.05, 30% inhibition) in high-dose males; whereas, plasma, erythrocyte, and brain cholinesterase activities were inhibited (p<=0.05) 27%, 33%, and 8%, respectively, in high-dose females.
For offspring systemic toxicity, the NOAEL is 5.0 ppm (0.47 mg/kg/day). The LOAEL is 30 ppm (2.77 mg/kg/day) based on morphometric changes in the brain of PND21 males.
For offspring cholinesterase inhibition, the NOAEL is 5.0 ppm (0.47 mg/kg/day). The LOAEL is 30 ppm (2.77 mg/kg/day) based on inhibition of plasma, erythrocyte and brain cholinesterase activities.
This study is classified Acceptable and may be used for regulatory purposes, however it does not satisfy the guideline requirement for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6); OECD 426 (draft) at this time pending a comprehensive review of all available 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, 08/18/05]
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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 0 thru Postnatal Day 21
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51861.0
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2005-08-18
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2005-08-23
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Added by
Madison Feshuk
on Apr 25, 2022
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