| filename |
-
46324901.DE1.pdf
-
46324901
-
Spirodiclofen
-
148477-71-8
-
124871
-
Sheets, L.; Lake, S. (2004) A Developmental Neurotoxicity Screening Study with Technical Grade Spirodiclofen in Wistar Rats. Project Number: 201056, 02/D72/JT, 02/D72/JTP3. Unpublished study prepared by Bayer Corp. 1113 p.
-
2004.0
-
In a developmental neurotoxicity study (MRID 46324901) Spirodiclofen (96.8-97.1% a.i.; Batch #: 06480/0002) was administered in the diet to pregnant Wistar Hannover rats (30/dose) continuously from gestation day (GD) 0 to lactation day (LD) 21 at nominal doses of 0, 70, 350, or 1500 ppm (equivalent to 0/0, 6.5/14.0, 32.1/69.7, and 135.9/273.8 mg/kg/day [gestation/lactation]). On post-natal day (PND) 4, litters were standardized to 4 pups/sex/litter; excess pups were killed and discarded. Pups were weaned on PND 21, after which time all animals received untreated diet. F1 pups were assigned to subgroups (1 pup/litter/group [approximately 16 pups/sex/dose]) in order to evaluate brain weights, neuropathology, learning and memory, motor activity, and acoustic startle habituation. Positive control data were not submitted with this study; however, summaries of positive control data previously submitted to the Agency were reviewed and determined to be inadequate.
No treatment-related effects were observed in the dams on mortality, clinical signs, FOB, serum cholesterol level, reproductive performance and postmortem examinations. No treatment-related differences were noted in body weights, body weight gains, or food consumption during gestation period. During lactation, a statistically significant body weight decrease (decr. 5%, p<=0.05) was observed in the 1500 ppm dams on LD 21. Food consumption was decreased (p<=0.05) by 8% in the 1500 ppm dams during LD 7-14. However, body weight changes within each group did not show significant difference while compared with the control group. The body weight decrease may be treatment-related but was not considered biologically significant.
The maternal NOAEL was 1500 ppm (135.9 mg/kg/day). The maternal LOAEL was not established.
Treatment had no adverse effects on offspring survival, clinical signs, or developmental landmarks. However, the evaluation of viability for PND 0 to PND 4 was limited due to the fact that litters with fewer than 3 pups/sex were sacrificed PND 0. During pre-weaning, body weights were decreased (p<=0.05) by 5-8% in the 1500 ppm animals on PNDs 17 and 21. Body weight gains were decreased (p<=0.05) by 6-18% at 1500 ppm in both sexes at most intervals, and overall (PNDs 0-21) body weight gain was decreased by 9% in each sex at 1500 ppm. During post-weaning, body weights were recovered in the 1500 ppm group. Post-weaning food consumption was similar between the treated and control males.
No treatment-related effects were observed on FOB, motor activity, or auditory startle reflex assessments. No treatment-related differences in the passive avoidance tests were observed at any dose. The trials to criterion for the retention phase of the water maze test for PND 60 females showed a treatment-related effect at all doses (number of animals with < 6 consecutive errorless trials: 14/16, 8/16, 7/16, and 8/16 for the control, low, mid, and high-dose groups, respectively). Four of the high dose females failed to complete five consecutive errorless trials (criterion for success) during the retention phase.
For postmortem examination, no significant differences in absolute brain weight or cerebrum and cerebellum lengths were observed at any dose in either sex at any time-point. The following morphometric measurement differences (p<=0.05, unless identified as NSS for not statistically significant) were noted in the 1500 ppm group: (i) caudate putamen (decr. 3%) and (ii) hippocampal gyrus (incr. 7%, NSS) in the PND 21 females; (iii) parietal cortex (decr. 6%) in the terminal males; and (iv) caudate putamen (incr. 3%) and (v) hippocampal gyrus (incr. 6%, NSS) in the terminal females. Due to these findings, morphometric analyses of the caudate putamen, parietal cortex, hippocampal gyrus, and dentate gyrus at the mid and low doses should be evaluated. However, the Registrant has informed us that the brain tissues were not appropriately preserved and therefore additional brain morphometric analyses at the mid and low doses are not possible (verbal communication between PMRA and HED).
The offspring LOAEL was 70 ppm (equivalent to 6.5 mg/kg/day) based on effects in memory phase of the water maze test in PND 60 females. An offspring NOAEL was not established.
This study is classified Acceptable and may be used for regulatory purposes, however it does not satisfy the guideline requirement for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6); OECD 426 (draft) at this time pending a comprehensive review of all available positive control data.
[Note - 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, July 21, 2005]
-
Developmental-Neurotoxicity
-
NA [870.6300, Developmental neurotoxicity study]
-
Oral
-
No Duration Period; Dosing: GD 0 to LD 21
-
52758.0
-
2005-07-21
-
2005-08-16
-
|
Added by
Madison Feshuk
on Apr 25, 2022
|
|