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45377901.de.pdf
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45377901
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Cymoxanil
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57966-95-7
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129106
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York, R. (2001) Oral (Gavage) Developmental Neurotoxicity Study of Cymoxanil in Crl:CD (SD)IGS BR VAF/Plus Presumed Pregnant Rats: Lab Project Number: WR12453: 975: DUPONT 3146. Unpublished study prepared by Argus Research Laboratories, Inc.1211 p. {OPPTS 870.6300}
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2001.0
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Cymoxanil: In a developmental neurotoxicity study (MRID 45377901) Cymoxanil (97.2% a.i.; lot #19062-02) was administered to 25 mated female Crl:CD®(SD)IGS BR VAF/Plus® rats per group in aqueous 0.5% methylcellulose by gavage (dosing volume 10 mL/kg bw) at dose levels of 0, 5, 50, or 100 mg/kg bw/day from gestation day (GD) 6 through postnatal day (PND) 21. Although the dams were not subjected to a formal functional observational battery (FOB), detailed clinical observations included most of the FOB parameters. On PND 5, litters were standardized to yield 5 males and 5 females (as closely as possible), and 10 randomly selected pups/sex/group were subjected to detailed clinical examination outside the home cage. On PND 12, pups were randomly assigned to each of the following four subsets: 1) fixed brain weights and/or neuropathological evaluation on PND 12 (10/sex/group); 2) passive avoidance testing (on PND 24-25 and 31-32) and water maze testing (on PND 59-61 and 66-68) (20/sex/group); 3) motor activity testing (on PND 14, 18, 22, and 60) and auditory startle habituation (on PND 23 and 61) (20/sex/group); 4) detailed clinical exam outside the home cage on PND 12 and weekly during PND 22-79 (20/sex/group), fixed brain weights and neuropathological evaluation on PND 80-83 (10/sex/group). In addition, the pups from subsets 2-4 were observed for the age of attainment of balanopreputial separation or vaginal patency (60/sex/group).
Maternal toxicity: No maternal toxicity was observed at the doses tested. A slight decrease in mean body weight (4-6%), body weight gain (17% less than controls for GD 6-21), and food consumption was observed at 100 mg/kg/day. Due to the small magnitude of the mean body weight decrease (less than 10% below controls), these changes were not considered adverse. The maternal NOAEL is 100 mg/kg/day. The maternal LOAEL was not determined (>100 mg/kg/day).
Offspring toxicity: At 5 mg/kg/day, there were decreases in retention of the passive avoidance task in weanling animals of both sexes (latency 54-75% of control values).However, this finding by itself was not considered to be a toxicologically significant effect.
At 50 mg/kg/day, there was a slight (non-statistically significant) decrease in pup survival between PND 2-5. The number of fetuses/litters affected, from control to high dose, respectively, was 3/3, 4/3, 9/8 and 46/13. The decrease in survival was considered treatment-related, as a dose-related response was observed at the highest two doses. Statistically significant decreases in anterior/posterior cerebrum measurements for males, and decreases in retention of the passive avoidance task in weanling animals of both sexes (latency 50-52% of control values) were observed but were not considered of toxicological significance.
At 100 mg/kg/day, there were decreases in pup survival, slight decreases in pup weight during early lactation (less than 6%), increases in morphometric measurements (anterior/posterior cerebrum for males, cerebellar height for females) at PND 79-83, slight decreases in auditory startle reflex amplitude in PND 23 females (61-71% of control levels), decreased performance in passive avoidance in post-weanling animals of both sexes (latency 68-85% of control levels), and decreased retention in the water maze task for adult females (latency 158% of control levels).
Although substantial changes in motor activity were seen in several groups and time points (for example, decreases up to 52% in PND 18 males, increases up to 129% in PND 22 males), no statistically significant changes were seen. The failure to find statistical significance may be attributable to large variance for many values. In addition, motor activity levels for control pups during lactation were substantial below historical control levels. These findings raise questions about the validity of the motor activity assessments during lactation. For adult time points, motor activity was similar for all doses among treated and control animals.
The offspring LOAEL is 50 mg/kg/day, based on decreased pup survival. The offspring NOAEL is 5 mg/kg/day.
This study is classified as Acceptable/Nonguideline and does not satisfy the guideline requirement for a developmental neurotoxicity study in rats (OCSPP 870.6300, §83-6). However, the study provides information on the effects of cymoxanil on the nervous system during development and is acceptable for regulatory purposes. Classification may be upgradable to guideline upon submission of additional information to address deficiencies listed below, including: 1) procedural information for functional observation procedures; 2) appropriate positive control data; 3) additional morphometric measurements, as described; 4) additional information regarding motor activity data, as described; 5) additional information regarding temperature excursion; 6) explanation of statistical procedures, as described.
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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
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57514.0
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2017-06-08
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2020-03-04
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Added by
Madison Feshuk
on Apr 25, 2022
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