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46801917.der.pdf
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46801917
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Pyrasulfotole Technical
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365400-11-9
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000692
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Gilmore, R.; Sheets, L.; Hoss, H. (2006) A Developmental Neurotoxicity Screening Study with Technical Grade AE 0317309 in Wistar Rats. Project Number: 04/D72/YE, 201439. Unpublished study prepared by Bayer Corp. 1083 p.
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2006.0
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Pyrasulfotole: In a developmental neurotoxicity study (MRID 46801917), AE 0317309 (95.7% w/w a.i., batch Op. 1-4) was administered from gestation day 6 through postnatal day 21 to 30 female Wistar rats per dose in the diet at nominal concentrations of 0, 45, 450, or 4500 ppm during gestation and 0/0/0, 24/20/16, 237/196/161, or 2368/1957/1607 ppm during weeks 1/2/3 of lactation. These concentrations provided an average daily intake of 0, 3.8, 37, or 354 mg/kg bw/day over gestation and lactation. Offspring were not dosed directly in this study. Dams were observed for clinical signs at least once daily. FOB (functional observational battery) tests were conducted on GDs 13 and 20 and LDs 11 and 21. Body weight and food consumption were measured on GDs 6, 13, and 20 and on LDs 0, 7, 14, and 21. On LD 4 litters were culled to eight pups, with four male and four female pups wherever possible. Dams were sacrificed on LD 21 following weaning of their litters, and a gross necropsy examination was conducted. Offspring were allocated for FOB and assessment of motor activity, auditory startle reflex habituation, learning and memory (passive avoidance and watermaze testing), and neuropathology (including brain weights). Offspring were monitored daily throughout lactation for clinical signs or morbidity and were weighed individually on LDs 0, 4, 11, 17, and 21 and weekly thereafter. The age of sexual maturation (vaginal opening in females and preputial separation in males) was also recorded.
There were no treatment-related effects on mortality, clinical signs during gestation, or body weight in dams. During lactation, ocular opacities were observed in up to 5/21 dams from LD 9 at 37 mk/kg/day and in up to 14/20 females from LD 10 at 354 mg/kg/day. During the FOB, ocular opacities were observed on LD 11 in 3/10 dams at 37 mk/kg/day and in 7/10 dams at 354 mg/kg/day; and on LD 21 in 2/10 and 7/10 dams at 37 and 354 mg/kg/day, respectively. Food consumption was reduced in dams during weeks 1-2 of lactation at 37 (12-19%) and 354 (9-20%) mg/kg/day, however without a corresponding effect on body weight. The fertility index was decreased (NSS) at 37 mg/kg/day (3%) and 354 mg/kg/day (13.3%); however, this observation was not considered treatment-related, since dosing began on GD 6. All other reproductive parameters were unaffected by treatment.
The maternal LOAEL is 37 mg/kg/day, based on ocular opacities during lactation. The maternal NOAEL is 3.8 mg/kg/day.
There were no treatment-related effects on litter size, viability/mortality, or other litter parameters in offspring. Clinical signs and body weight were unaffected during lactation. During post-weaning, ocular opacities were observed in 6/58 males at 354 mg/kg/day on or after PND 29, as well as in 2/63 females at 37 mg/kg/day and 1/60 females at 354 mg/kg/day on or after PND 30. Body weight was decreased in males and females by 6-9% and 4-8% each at 37 mg/kg/day and by 8-13% and 8-11% each at 354 mg/kg/day. Preputial separation was delayed at 37 mg/kg/day (46.0 days) and 354 mg/kg/day (46.7 days, P< 0.01), compared to controls (44.1 days). Vaginal patency was unaffected by treatment. During the FOB, ocular opacity was observed in 1/15 females at both 37 mg/kg/day and 354 mg/kg/day. These changes were first noted on postnatal days 45 and 35, respectively, and persisted in both cases through postnatal day 60.
No treatment-related effects were observed on motor activity or auditory startle response. For PND 22 animals tested for passive avoidance, an increase (P<0.05) in the number of trials to criterion, as well as dose-dependent decreases in trials 1 and 2 latencies, were observed at ¿37 mg/kg/day during the learning session. During the retention session, an increase (P<0.05) in the number of trials to criterion and reduced latency at trial 1 were observed at 354 mg/kg/day. There were no treatment-related effects on acquisition and retention in either adult males or females during the water maze testing. An increase in the mean time required to complete trial 1 was observed in the retention phase in males at 37 mg/kg/day; however, the result was not considered treatment-related in the absence of dose response and treatment-related effects on the number of trials to reach criterion.
During ophthalmoscopic examinations, retinal degeneration was observed in 4/10 males at 354 mg/kg/day. Retinal degeneration was also observed in 0/13, 1/13, 3/11, and 4/10 females at 0, 3.8, 37, and 354 (P<0.05) mg/kg/day, respectively. The increase in one female animal at the low dose was not considered treatment-related based on the low incidence and lack of statistical significance in the current study and since retinal degeneration was not observed at a similar dose in F1 or F2 offspring in the 2-generation reproduction study. Absolute fixed brain weight on PND 21 was statistically significantly decreased for males (8%) at 354 mg/kg/day and for females at 37 mg/kg/day (6%) and 354 mg/kg/day (11%). Absolute fixed brain weight on PND 75 was also decreased for females at 354 mg/kg/day (5%). At necropsy, an increased incidence of opacity was observed in the eyes of 3/10 PND 75 males at 354 mg/kg/day. During macroscopic morphometry at PND 21, cerebellum length was decreased (P<0.05) in perfused males (6%) and females (7%) at 354 mg/kg/day. Cerebrum length was also decreased (P<0.05) in females at 37 (4%) and 354 (5%) mg/kg/day. At PND 75, cerebellum length was decreased in males (5%, P<0.05) and females (4%, NSS) at 354 mg/kg/day. During microscopic morphometry on PND 21, cerebellum height was decreased (P<0.05) in males at 37 mg/kg/day (7%) and 354 mg/kg/day (8%) and in females at 354 mg/kg/day (10%). The hippocampal gyrus was decreased (P<0.05) by 11% and 9% in males and females, respectively, at 354 mg/kg/day on PND 21. On PND 75, cerebellum height was changed at the mid and high doses in males (¿14% and ¿6%, respectively) and females (¿13% and ¿6%); however, in the absence of a consistent change across dose, the findings were not considered toxicologically significant.
The offspring LOAEL is 37 mg/kg/day, based on ocular opacity (post-weaning), decreased body weight, delayed preputial separation (males), increase in the number of trials to criterion and decreases in trial latencies (passive avoidance; PND 22 males), retinal degeneration at ophthalmoscopy (females), decreased brain weight (PND 21 females), decreased cerebrum length (PND 21 females), and decreased cerebellum height (PND 21 males). The offspring NOAEL was 3.8 mg/kg/day.
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. The following deficiencies were noted in the report: 1) litter data were reported for only 20-23 dams/group. An explanation as to why litter data were not reported for the remaining 6-8 dams/group (after accounting for non-pregnant animals) that underwent ¿elective sacrifice¿ is requested; 2) SE (rather than SD) was used as the measure of variability around sample means.
[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, 03/25/2009]
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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 6 through LD 21
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54227.0
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2009-03-25
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2019-09-10
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Added by
Madison Feshuk
on Apr 25, 2022
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