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45074301.de.pdf
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45074301
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Tebuconazole
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107534-96-3
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128997
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Parker, R. (2000) Developmental Neurotoxicity Study of Technical Grade Tebuconazole Administered Orally via Diet to Crl: CD BR VAF/Plus Presumed Pregnant Rats: Lab Project Number: 109616: 98-C612-QU: 1702-004. Unpublished study prepared by Primedica Argus Research Labs., Inc. 1405 p. Relates to L0000526. {OPPTS 870.6300}, Sheets, L. (2005) Bayer CropScience's Response to U.S. EPA Data Evaluation Record for a Developmental Neurotoxicity Study with Technical Grade Tebuconazole in Sprague-Dawley Rats. Project Number: 201433. Unpublished study prepared by Bayer Corp. 16 p.
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2000.0
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Tebuconazole: In a developmental neurotoxicity study (MRID 45074301), [46705101] Tebuconazole (96-96.9% a.i.; Lot/Batch #603-0013) in corn oil was administered via the diet to pregnant Crl:CD®BR VAF/Plus® (Sprague Dawley) rats (25/dose) from gestation day (GD) 6 to lactation day (LD) 11 at doses of 0, 100, 300 or 1000 ppm (equivalent to [GD/LD] 0/0, 8.8/16.3, 22.0/41.3, and 65.0/125.4 mg/kg/day). No analytical data were provided. P dams were allowed to deliver naturally. On day 5 postpartum, litters were standardized to a maximum of 10 pups/litter. Pups were assigned to one of 5 Subsets (20 pups/sex/dose in each subset). Physical development landmarks were evaluated for all subsets (including surface righting, eye opening, pinna unfolding, acoustic startle response, and pupil constriction); sexual maturation was evaluated in subsets 2-4. Subset 1 pups were sacrificed on postnatal day 12; brains were weighed for all Subset 1 pups, and histopathological evaluations were performed on 6/sex in control and high dose groups (morphometric analysis was performed on 6/sex in control, mid-dose, and high dose groups). Subset 2 pups were evaluated for learning and memory on day 23-25 (passive avoidance) and on day 59-63 (Water M-maze). Subset 3 pups were evaluated for motor activity (days 14, 18, 22, and 62) and for auditory startle habituation (days 23 and 63). Subset 4 pups received detailed weekly clinical evaluations. In addition, 6 animals/sex/group in Subset 4 were selected for neuropathological evaluations; brains were weighed and the high dose and control animals were evaluated histopathologically on day 83 (morphometric analysis was performed on 6/sex in control, mid dose, and high dose groups). Subset 5 pups were sacrificed and necropsied on day 22.
At 1000 ppm, two P females died as a result of prolonged gestation. Body weights were slightly decreased (p<=0.01) in the P females during gestation (decreased 4-8%) and early lactation (decreased 6-12%). Body weight gains were decreased (p<=0.01 or 0.05) during GDs 6-9 (decreased 400%) and 6-21 (decreased 22%), and during LDs 1-12 (decreased 55-164%). When compared to concurrent controls, absolute (g/animal/day) food consumption was reduced (p<=0.05 or 0.01) in the dams throughout gestation (decreased 9-23%) except during the GD 0-6 interval, and during the LD intervals 4-7 (decreased 20%) and 7-12 (decreased 18%). Relative (g/kg/day) food consumption was reduced (p<=0.05 or 0.01) starting on GD 6 (6-20%) and during early lactation (up to day 12, (decreased 8-12%). There was also an increase in alopecia in high dose dams. The number of live fetuses/dam was decreased relative to concurrent controls (decreased 6%, p<=0.01); while the number of dead fetuses/dam was increased relative to concurrent controls (increased 200%, p<=0.01).
No treatment-related findings were observed in dams at 300 or 100 ppm.
The LOAEL for maternal toxicity is 1000 ppm (equivalent to [GD/LD] 65.0/125.4 mg/kg/day) based on decreased body weights, body weight gains, and food consumption, prolonged gestation with mortality, and an increased number of dead fetuses. The NOAEL is 300 ppm (equivalent to [GD/LD] 22.0/41.3 mg/kg/day).
At 1000 ppm, the stillborn index was increased (increased 200%, p<=0.01) and the number of pup deaths (calculated by reviewers) was increased during days 1-5 (increased 229%). Body weights were decreased (p<=0.01) in the males from PND 5 to 86 (decreased 7-23%) and in the females from PND 5 to 72 (decreased 5- 24%). Pinna unfolding was delayed (increased 19%, p<=0.01) relative to concurrent controls. There were decreases in several morphometric measurements of the brain, including decreased (p<=0.01) thickness of the cerebellum in the males and females on day 12 (decreased 10-14%) and on day 83 (decreased 7- 9%), and an increased thickness of the germinal layer of the cerebellar cortex in the Day 12 males (increased 23%, p<=0.01). Absolute brain weights were decreased in the Day 12 and Day 83 animals (decreased 10-16%, p<=0.01 or 0.05). Relative (to body) brain weights were increased (p<=0.01 or 0.05) in the day 12 males and females (increased 10-15%). There were also statistically significant changes in motor activity on days 14 (43% decrease in males [p<0.01], 24% decrease in females [n.s.]) and 22 (39% increase in males [p<0.05], 19% increase in females [n.s.]), and changes in auditory startle amplitude at both time points (decreased in both sexes on day 23 [14-33%], decreased in females [20%] and increased in males [71%] on day 63).
At 300 ppm, there were also decreases in body weight (3-7%) and body weight gain (4-16%, PND5-23 and 72-86 in males, PND5-51 in females). Pinna unfolding was delayed (increased 16%). There were changes in auditory startle amplitude in both sexes: a dose-related decrease in females on day 23 (decreased 26%), and a dose-related increase in males on day 63 (increased 18%). In addition, there was a decrease in absolute brain weight in both sexes (3-4%) on day 12 (statistically significant for females only), and in brain measurements (anterior/posterior cerebrum).
At 100 ppm, there were decreases in body weight (3-7%) and body weight gain (5-13%) (PND 5- 37 in males, PND 5-51 in females). There were decreases in motor activity (on days 14 and 18 in males [28-35%]) and changes in auditory startle amplitude (decreased 9% in day 14 females, increased 16% in day 63 males, n.s.). There was also a decrease in absolute brain weight in both sexes on day 12 (4%, statistically significant for both sexes), and in brain measurements (anterior/posterior cerebrum).
The LOAEL for offspring toxicity is 100 ppm based on decreases in body weights, decreases in absolute brain weights and measurements, and decreases in motor activity.
The NOAEL is not determined.
This study is classified as acceptable/guideline (§83-6[a]) and satisfies the requirement for a developmental neurotoxicity study in rats, pending submission of additional information regarding analytical data and positive control studies, as described below.
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Developmental-Neurotoxicity
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NA [83-3, Teratogenicity -- 2 Species|870.6300, Developmental neurotoxicity study]
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Oral
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No Duration Period; GD 6 -LD 11
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54053.0
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2006-11-20
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2018-02-07
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Added by
Madison Feshuk
on Apr 25, 2022
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