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45516601.DER.pdf
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45516601
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Thiacloprid
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111988-49-9
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014019
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Hoberman, A. (2001) Oral (Diet) Developmental Neurotoxicity Study of YRC 2894 in CRL:CD(SD)IGS BR VAF/Plus: Lab Project Number: 99C-D72-ER: 110834. Unpublished study prepared by Argus Research Laboratories, Inc. 838 p. {OPPTS 870.6300}
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2001.0
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In a developmental neurotoxicity study (MRID 45516601) YRC 2894 (Thiacloprid; 99.2% a.i., 898013001) was administered to 25 female Crl:CD®(SD)IGS BR VAF/Plus® rats per dose in the diet at dose levels of 0, 50, 300, or 500 ppm (0, 4.4, 25.6, and 40.8 mg/kg/day during gestation; 0, 8.2, 49.4, and 82.8 mg/kg/day during lactation) from gestation day (GD) 0 through lactation day (LD) 22. The day that litter delivery was completed was designated postnatal day (PND) 1 (or LD 1). Body weight and food consumption data were recorded for dams. Detailed clinical observations, including assessments of autonomic function, were conducted daily during gestation and on LD 1, 5, 8, 14, and 22. Dams were killed and necropsied on LD 22. 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 23-25 and 30-32) and water maze testing (on PND 59-63 and 66-70) (20/sex/group); 3) motor activity testing (on PND 14, 18, 22, and 58-60) and auditory startle habituation (on PND 23 and 59-61) (20/sex/group); 4) detailed clinical exam outside the home cage on PND 12 and weekly during the postweaning period (20/sex/group), fixed brain weights and neuropathological evaluation on PND 68-79 (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).
There were no treatment-related effects on maternal survival, clinical or functional observations, reproductive function, or gross pathology at any dietary level. Treatment-related decreases (p<= 0.05) in maternal body weight gain were observed in the 300 and 500 ppm dams during GDs 0-6 (decr. 31-56%), and in the 500 ppm dams during LDs 1-4 (decr. 67%). Treatment-related decreases in food consumption (p<= 0.01) were also noted in the 300 and 500 ppm dams during GDs 0-6 (decr. 16-30%) and in the 500 ppm dams during LD 4-7 (decr. 11%). Significant decreases (p<= 0.01) in relative food consumption on GD 0-6 at 300 (decr. 14%) and 500 ppm (decr. 27%) support the conclusion that the effects on body weight gain in early gestation were not solely related to palatability. The maternal LOAEL is 300 ppm (25.6 mg/kg/day), based on decreased body weight gain and food consumption during early gestation (GD 0-6). The maternal NOAEL is 50 ppm (4.4 mg/kg/day).
Offspring survival, assessments of autonomic function, watermaze, brain weights, and qualitative histopathology were unaffected by treatment. Suggestive effects on motor activity and auditory startle were seen in the 300 and 500 ppm groups. Increased incidences (p<=0.01) of malaligned incisors and chromodacryorrhea were observed at postpartum week 10 in 500 ppm offspring. These findings were considered to be treatment-related, perhaps a latent expression of a developmental anomaly. In the 300 and 500 ppm offspring, preweaning body weights were decreased (p<= 0.01) on PNDs 8-22 (decr. 5-15%). In addition, postweaning body weights were decreased (p<= 0.01) in these animals (decr. 4-15%). Sexual maturation was delayed (p<= 0.05) in the 300 and 500 ppm male pups (48.2 days each treated vs. 46.7 days controls), and in the 500 ppm female pups (34.7 days treated vs. 33.4 days controls). Passive avoidance testing revealed significant increases in Trial 2 latency during the first testing session in 300 and 500 ppm females (p<= 0.05 and p<= 0.01, respectively) in weanling offspring. Also at these doses, examination of the individual data indicated slower responses, and an adverse effect on retention of behaviors learned in Session 1. At histopathological evaluation, in the 500 ppm males, the size of the corpus striatum (decr. 4%) and corpus callosum (decr. 14%) were decreased (p<= 0.05) from controls on PND 12. At study termination, the corpus striatum (decr. 4%) and dentate gyrus (decr. 5%) were smaller (p<= 0.05) than controls.
A definitive NOAEL was not established for these findings. The offspring LOAEL is tentatively set at 300 ppm (25.6 mg/kg/day), based on decreased preweaning and postweaning body weights in both sexes and delayed sexual maturation in the males, and altered performance in passive avoidance testing. The tentative offspring NOAEL is 50 ppm (4.4 mg/kg/day).
This study is classified unacceptable/guideline and does not satisfy the guideline requirement for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6); OECD 426 (draft). This study can be upgraded following the submission of acceptable morphometric histopathology data to establish a definitive NOAEL for alterations in brain development, procedural information for functional observation assessments, and adequate positive control data.
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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; dams: GD 0 - LD 22
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50517.0
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2003-03-19
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2006-09-21
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Added by
Madison Feshuk
on Apr 25, 2022
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