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45499501.DER.pdf
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45499501
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Tribufos
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78-48-8
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074801
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Lake, S. (2001) A Developmental Neurotoxicity Screening with Technical Grade Tribufos (DEF) in Wistar Rats: Lab Project Number: 00-D72-AG: 00-D72-AS. Unpublished study prepared by Bayer Corporation. 1281 p. {OPPTS 870.6300}
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2001.0
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In a developmental neurotoxicity study (MRID 45499501), Tribufos (98.0-98.1% a.i., batch # 503-0087 5102025) was administered to parent female Wistar rats in the diet at concentrations of 0, 4, 40 or 200 ppm from gestation day 0 through postnatal day 21. The average daily intake of Tribufos was 0, 0.4, 3.4-3.5, and 16.4-18.2 mg/kg bw/day during gestation and 0, 0.6-1.0, 6.1-9.9, and 33.5-55.4 mg/kg/day during lactation, for the 0, 4, 40, and 200 ppm groups, respectively. Two studies, with a two-week difference in start date, were conducted under similar conditions. The main study (00-D72-AG) included 20 parent females/dose level, and the satellite study (00-D2-AS) included 10 parent females/dose level and was utilized to provide samples to assess cholinesterase activity. A Functional Operational Battery (FOB) was performed on 10 dams/dose from the main study on gestation days 6, 13, and 20 and on and lactation days 4, 11, and 21. On postnatal day 4, litters were culled to yield four males and four females (as closely as possible). Offspring from the main study, 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, electroretinography, and neuropathology at study termination (day 75 of age). Animals from the satellite study were used to provide blood and brain samples for the offspring (postnatal days 11 and 21) and dams (lactation day 21) for measurement of cholinesterase activity. 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.
No treatment-related effects were seen on survival, food consumption or reproductive parameters. Dams exhibited clinical signs of toxicity, slight tremors, at parturition which are likely associated with the observed cholinesterase inhibition. Maternal body weight during lactation was decreased at each time point recorded for the high-dose group, with average differences of 8-12% compared to the control.
The maternal systemic LOAEL is 200 ppm (16.4 mg/kg/day) based on clinical signs (tremor) and decreased body weight during lactation. The maternal systemic NOAEL is 40 ppm (3.4 mg/kg/day).
Cholinesterase activity was decreased (p<0.05) in maternal animals at 40 and 200 ppm. Decreases were 66%, 76%, and 22% at 40 ppm, and 88% 87%, and 74% at 200 ppm compared to control for plasma, erythrocyte and brain cholinesterase activities, respectively.
The maternal cholinesterase LOAEL 40 ppm (3.4 mg/kg/day) based on decreases in plasma, erythrocyte and brain cholinesterase activity. The maternal cholinesterase NOAEL is 4 ppm (0.4 mg/kg bw/day).
Treatment had no adverse effects on offspring survival. No treatment-related effects on body weight or body weight gains were seen at 4 or 40 ppm pups. At the high dose (200 ppm), pups weighed an average of 16% less than controls on PND 4, 21% on PND 11 and 22% by PND 21. From birth to PND4, high-dose pups gained 37-38% less than controls, and decreased body weight gain continued to be observed for high-dose pups throughout the lactation period. For males, body weights were 21% below controls on day 27, and had partially recovered by the end of the study, to approximately 12% below controls. For high-dose females, body weights were 20% below controls on day 6, and had partially recovered by the end of the study, to approximately 8% below controls. Preputial separation for high-dose males was delayed relative to controls. Additionally, the development of a surface-righting reflex in high dose animals was significantly (p <= 0.05) delayed. The average day of a surface righting was 6.0 days for control and 7.2 days for the high-dose animals.
Motor activity was decreased in males (15%) and females (46%) at the high dose on PND 13. Conversely, motor activity was increased in males (12%) and females (43%) at the high dose on PND 17. Changes occurred in both directions or at a lower magnitude at the low and mid dose groups for both sexes on PND 13 and PND 17. There were no apparent effects on motor activity in males or females on PND 21 and PND 60.
Startle response amplitude for high-dose males and females was decreased compared to controls on day 21, but not on subsequent test days. No treatment-related effects were seen on learning and memory. Absolute brain weights of high-dose males and females were decreased (4-13%) compared to controls on days 11 and 21. The anterior to posterior lengths of the cerebrum were marginally decreased (p<0.05) for high-dose males and females compared to controls on PND 11. The anterior to posterior length for the cerebellum was also marginally decreased in high-dose males and females, although the effect did not reach statistical significance.
The offspring systemic LOAEL is 200 ppm (16.4 mg/kg/day), based on decreased body weight, body weight gain, delay in preputial separation, delayed surface righting reflex, decreased motor activity, decreased startle response amplitude, decreased absolute brain weights, and changes in the brain morphometrics (cerebrum and cerebellum). The offspring systemic NOAEL is 40 ppm (3.4 mg/kg/day).
For the day 21 offspring, the only effect was a 21-22% decrease in plasma cholinesterase in high-dose males and female. RBC and brain cholinesterase activity was not adversely affected in the offspring. In accordance with the current policy inhibition of plasma cholinesterase activity alone in the absence of clinical signs is not considered to be appropriate for use as the basis for a LOAEL.
The offspring cholinesterase NOAEL is 200 ppm (16.4 mg/kg/day), the highest dose tested. An offspring cholinesterase NOAEL was not established.
This study is classified Acceptable/Non Guideline 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, 09/13/2005]
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Developmental-Neurotoxicity
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NA [83-6, Developmental Neurotoxicity]
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Oral
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No Duration Period; GD 0 to PND 21
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50231.0
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2005-09-13
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2012-04-13
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Added by
Madison Feshuk
on Apr 25, 2022
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