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47900401.der.pdf
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47900401
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Ziram
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137-30-4
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034805
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Nemec, M. (2009) A Dietary Developmental Neurotoxicity Study of Ziram in Rats: Final Report. Project Number: WIL/223006. Unpublished study prepared by WIL Research Laboratories, Inc. 1555 p
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2009.0
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Ziram: In a non-guideline developmental neurotoxicity study (MRID 47900401) Ziram (96.75% a.i.; doses adjusted for purity, Batch no. G060600605) was administered in the diet to 25 presumed pregnant female Sprague-Dawley rats/dose at nominal dose levels of 0, 72, 207, and 540/360 ppm (equivalent to 0, 8.6, 24.0, and 46.6 mg/kg/day; calculated by reviewers) from gestation day (GD) 6 through lactation day (LD) 21. Due to the magnitude of maternal toxicity observed, the 540 ppm dietary concentration was reduced to 360 ppm beginning on LD 4. Dams were allowed to deliver naturally and rear their offspring to LD 21. Any females that were found to be sperm positive and/or with a vaginal plug, but did not deliver, were sacrificed on GD 25. Females that delivered were sacrificed and necropsied on LD 21. On postnatal day (PND) 4, litters were standardized to 8 pups/litter (4/sex, when possible); the remaining offspring and dams were sacrificed and discarded without further examinations. Subsequently, 1 pup/litter/group (15 or 20 pups/sex/dose) were allocated to subsets for motor activity, brain weights, and neuropathological examination. Acceptable positive control data were included with this study.
Maternal toxicity: No treatment-related effects were observed on mortality, clinical signs of toxicity, reproductive parameters, or gross lesions in the dams.
At 540/360 ppm, mean maternal body weights were decreased (p<0.01) by 5-15% during GD 7 through 20. This group displayed weight loss during GD 6-9 (-14 g treated vs. 11 g controls), and decreases (p<0.01) in body weight gains of 33-75% compared to controls during GD 9-12, 12-15, and 18-20. Overall (GD 6-20) bodyweight gain was decreased (p<0.01) by 50% compared to controls at this dose. These decreases in body weight and body weight gain corresponded to decreases (14-55%; p<0.01) in food consumption (g/rat/day) observed throughout gestation, with overall (GD 6-20) food consumption being decreased (p<0.01) by 33% compared to controls. During lactation days 1 through 4, decreases (p<0.01) were observed in body weights (decr 14-16%) and food consumption (decr 17%). Body weight gains were also decreased during this interval; however, did not attain statistical significance. Due to the severity of maternal toxicity observed at 540 ppm, the dietary concentration of the test material was reduced to 360 ppm beginning on LD 4. Following the decrease in dietary concentration, body weights remained decreased (p<0.05) by 4-11% compared to controls from LD 5 through 20. However, the reductions in body weight at this dose became less severe over time, and body weight gains at this dose increased (p<0.01) by 225% during LD 4-7 and by 80% overall (LD 1-21) compared to controls. Food consumption at this dose remained decreased (p<0.05) at several intervals; however, there was no significant effect on bodyweight gains.
At 207 ppm, body weights were decreased by 2-4% from GD 7 through 20 and attained statistical significance on GD 15 and 20. Additionally at this dose, body weight gains were decreased (p<0.01) by 82% during GD 6-9 and by 21% during GD 18-20, and overall (GD 6-20) bodyweight gain was decreased (p<0.01) by 16% compared to controls. The decreased bodyweight gain noted during GD 6-9 corresponded to decreased food consumption during this interval (↓15%; p<0.01). During lactation, body weights were decreased (p<0.05) by 4-5% on LD 2-4 only.
No adverse compound-related effects were noted in the 72 or 207 ppm dams.
The maternal LOAEL is 540/360 ppm (equivalent to 46.6 mg/kg/day), based on decreases in body weights, body weight gains, and food consumption during gestation and lactation. The maternal NOAEL is 207 ppm (equivalent to 24 mg/kg/day).
Offspring toxicity: No compound-related effects on viability/survival, litter parameters, clinical signs, post-weaning body weights or body weight gains, sexual maturation (preputial separation or vaginal patency), brain weight or measurements, gross or microscopic lesions, or brain morphometric measurements were observed in the F1 pups. Live birth, viability, and lactation indices were similar to controls at all doses.
At 540/360 ppm, mean pup body weights were decreased in the males (decr 10-19%, p<0.01) throughout pre-weaning (PND 1 through 21) and in the females (decr 11-16%, p<0.05) at all pre-weaning intervals except PND 17. Also at this dose, body weight gains were decreased (p<0.05) by 26-28% in the males during PND 1-4 and 4-7 and by 22% in the females during PND 1-4. On PND 17-21, body weight gains were decreased (p<0.05) by 17-19% in both sexes. Overall pre-weaning (PND 1-21) body weight gains (calculated by reviewers) were decreased by 11-12% in both sexes at this dose. Cumulative locomotor activity counts (combined sexes) were increased (not statistically significant) by 25% (total activity) and 44% (ambulatory activity) on PND 13 and by 31% and 41%, respectively, on PND 17. On PND 21, this group showed less habituation compared to controls, resulting in increased cumulative total (40%, p<0.05) and ambulatory 62%, p<0.05) activity counts.
At 207 ppm, body weight was decreased (p<0.05) by 8% in the males on PND 21. On PND 17-21, body weight gains were decreased (p<0.05) by 15-17% in both sexes (likely due to direct consumption of the test diet). Animals in this group showed less habituation during locomotor activity evaluations on PND 21, resulting in increased cumulative total (47%, p<0.01) and ambulatory activity counts (66%, p<0.05).
At 72 ppm, male pup body weight was decreased by 7% (not statistically significant) on PND 21, and body weight gain was decreased by 13% in the males on PND 17-21. Males and females in this group showed less habituation during locomotor activity sub-session evaluations on PND 21, resulting in increased cumulative total (↑24%) and ambulatory activity counts (↑43%) relative to controls (not statistically significant).
The offspring LOAEL is 72 ppm (equivalent to 8.6 mg/kg/day), based on increased locomotor activity and decreased habituation on PND 21, as well as decreased pup body weight in males. The offspring NOAEL was not defined (<72 ppm).
This study is classified Acceptable/Non-guideline and provides useful data concerning developmental neurotoxicity in rats. The study was considered non-guideline for the following reasons: no functional observational battery was performed on the dams or pups, acoustic startle response testing was not performed, and no form of learning and memory testing (i.e. passive avoidance or water maze) was performed. Nevertheless, the study was considered acceptable.
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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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Treatment Range: 6 (GD)-21 (LD) Dose;
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58080.0
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2020-09-16
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2021-06-02
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Replaced previous memo that had numerous studies with file with only relevant DER (already cleared)
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Added by
Madison Feshuk
on Apr 25, 2022
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