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46695725.de.pdf
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46695725
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Tembotrione
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335104-84-2
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012801
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Sheets, L.; Gilmore, R.; Hoss, H. (2005) A Developmental Neurotoxicity Screeing Study with Technical Grade AE0172747 in Wistar Rats. Project Number: 04/D72/UE, 201310. Unpublished study prepared by Bayer Corp. 1105 p.
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2005.0
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Tembotrione: In a developmental neurotoxicity study (MRID 46695725) technical grade AE 0172747 (94% a.i., Batch #s PFI 0215 and OP2250027) was administered to approximately 30 mated female Wistar rats per dose in the diet at nominal dose levels (gestation) of 0, 10, 200, or 1500 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, 0.8, 16.3, and 118 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; eight treated dams were examined for pregnancy status. On postnatal day (PND) 4, litters were standardized to 8 pups/litter; 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) was 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 or reproductive parameters or at necropsy in dams. At ¿16.3 mg/kg/day, corneal opacity was observed during lactation in dams both upon clinical examination and during the FOB. Body weight in dams was decreased by 5-7% during gestation and by 3-5% during lactation at ¿16.3 mg/kg/day. Overall body weight gain in dams was decreased by 13-17% during gestation at ¿16.3 mg/kg/day. Overall body weight gain during lactation was similar to controls at all doses. During gestation, no treatment-related differences in food consumption were observed. During lactation, food consumption in dams was decreased by 8-12% for part (¿16.3 mg/kg/day) or all (118 mg/kg/day) of the pre-weaning period.
The maternal LOAEL is 16.3 mg/kg/day, based on corneal opacity during lactation. The maternal NOAEL is 0.8 mg/kg/day.
In pups, no compound-related effects were observed on litter parameters (including litter size), vaginal patency, motor or locomotor activity, and learning and memory assessments. In addition, no clinical signs of toxicity were observed during pre-weaning at any dose. During post-weaning, increased incidences of corneal opacity were observed in pups at ¿16.3 mg/kg/day at the time of clinical observations and during the FOB. Offspring pre-weaning body weights were decreased by 7-14% at ¿16.3 mg/kg/day for most days of lactation. Body weight gains were also decreased by 8-32% at ¿16.3 mg/kg/day throughout most pre-weaning intervals. Offspring post-weaning body weights remained decreased by 5-16% in both sexes throughout the study at ¿16.3 mg/kg/day. Decreases (5-6%) in post-weaning body weight in the 0.8 mg/kg/day males were also considered treatment-related since they were observed many weeks after treatment was discontinued and therefore appeared to be delayed-onset effects. Preputial separation was delayed by 2.1 days in the 118 mg/kg/day males.
On PND 60, overall acoustic startle peak amplitude was decreased in males by 40-50% at ¿16.3 mg/kg/day. In addition, in males on PND 60, the interval peak amplitude values were decreased by 40-50% during most or all blocks at ¿16.3 mg/kg/day. At 0.8 mg/kg/day, mean peak amplitude was decreased by 38% (p<0.05) during block 2 only. PND 21 absolute brain weights were decreased in males by 6-9% at ¿16.3 mg/kg/day and in females by 6% at 118 mg/kg/day; terminal body weight was also decreased in both sexes. PND 75 absolute brain weights were decreased in both sexes by 6-7% at 118 mg/kg/day either with (males) or without (females) corresponding reductions in terminal body weights. Changes were observed in several morphometric parameters in adult animals at ¿0.8 mg/kg/day; however, statistical analysis of brain morphometry data for PND 21 and 70 males and females was inappropriate. Measurements at each dose level were compared separately to those in controls (i.e., 2-group comparisons) using individual t-tests. More appropriate is the use of Dunnett¿s test (as used for brain weights) for group comparisons against a single control.
The offspring LOAEL is 0.8 mg/kg/day, based on decreased post-weaning body weight (males), decreased acoustic startle response on PND 60 (males), and brain morphometric changes on PND 75 (males and females). The offspring NOAEL was not determined.
This study is classified Acceptable/non-guideline and may be used for regulatory purposes. It does not, however, satisfy the guideline requirement for a developmental neurotoxicity study in rats [OPPTS 870.6300, §83-6; OECD 426 (draft)] due to the pending review of the 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, 03/13/08]
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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; GD6 - LD21
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54231.0
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2008-03-13
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2018-03-02
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Added by
Madison Feshuk
on Apr 25, 2022
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