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45215701.der.pdf
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45215701
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Isoxaflutole
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141112-29-0
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123000
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Nemec, M. (2000) An Oral Developmental Neurotoxicity Study of Isoxaflutole (IFT) in Rats: Lab Project Number: WIL-21153. Unpublished study prepared by WIL Research Laboratories, Inc. 1519 p. {OPPTS 870.6300}
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2000.0
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Isoxaflutole: In a developmental neurotoxicity study (MRID 45215701), Isoxaflutole (99.15% a.i.; Lot/Batch # IFT98-196) in 1% methylcellulose was administered by gavage in a volume of 5 mL/kg to pregnant Crl:CD(SD)IGS BR rats (25/dose) from GD 6 to LD 10 at doses of 0, 5, 25 or 250 mg/kg/day. P dams were allowed to deliver naturally. All P females were killed on LD 21. On PND 4, eight pups/litter were randomly selected in order to reduce variability among the litters; the remaining offspring were weighed and euthanized. Following weaning, the F1 offspring remained together as a litter through PND 28 or 29. Subsequently, ten pups/sex/group were selected for neurobehavioral testing and neuropathological examination. Morphometric analyses were not performed. Pups not selected for behavioral and neuropathological evaluations were sacrificed on PND 28 or 29. Positive control data that validate the procedures and observers of the performing lab to assess motor activity, neurotoxicity and behavioral effects were not provided.
No unscheduled maternal deaths occurred during the study. Clinical signs, gross pathology, pregnancy rate, number of implantations/dam, gestation length, and sex ratio were unaffected by treatment. Reproductive function was not evaluated. No treatment-related differences in live litter size, post-natal survival, sex ratios, clinical signs, or sexual maturation were observed in any treated group.
In the 250 mg/kg dams, body weights were slightly decreased (p<=0.05) during GDs 9-15 (decr 4-6%) and LDs 1-10 (decr 7-10%). Body weight gains were decreased (p<=0.01) during GDs 6-9 (decr 91%) and 9-12 (decr 39%). Body weight gains were also decreased for the entire gestation treatment interval (GDs 6-20; decr 14%, p<=0.01) and overall gestation (GDs 0-20; decr 11%, p<=0.05). During the lactation treatment interval (LDs 1-10), body weight gains were comparable to controls in all treated groups. Body weight gains were increased (p<=0.01) during post-treatment (LDs 10-21; inc 133%), resulting in increased body weight gains during the overall lactation interval (LDs 1-21; inc 46%). Absolute (g/animal/day) food consumption was reduced (p<=0.05) during GDs 6-15 (decr 9-23%), 6-20 (decr 9%), and 0-20 (decr 9%). Absolute food consumption was also decreased during LDs 1-4 (decr 17%, p<=0.01). Relative (g/kg/day) food consumption was reduced (p<=0.01) during the GD intervals 6-9 (decr 19%), 9-12 (decr 14%), and 15-20 (decr 11%). In addition, relative food consumption was increased (p<=0.05) post-treatment during LDs 10-16 (incr 9%) and 10-21 (incr 6%). No treatment-related findings were observed in dams treated with 25 or 5 mg/kg a.i.
The maternal LOAEL is 250 mg/kg/day based on decreased body weights, body weight gains, and food consumption. The maternal NOAEL is 25 mg/kg/day.
No treatment-related differences in live litter size, post-natal survival, sex ratios, clinical signs, or sexual maturation were observed in any treated group. Pup swimming ability, learning, memory, motor activity, auditory startle response, brain weights and dimensions, and neuropathology were unaffected by the test substance.
In the 250 mg/kg pups, body weights were decreased (p<=0.05) in the males from PND 1 to 28 (decr 7-12%) and from PND 49 to 63 (decr 4-5%). In the females, body weights were decreased (p<=0.05) sporadically between PND 1 and 35 (decr 5-12%). Decreased (p<=0.05) body weight gains were observed sporadically in the males between PNDs 1 and 28 (decr 6-21%) and only during PNDs 4-7 in the females (decr 15%). Absolute brain weights were also reduced (11-12%) in males and females on PND 11 at 250 mg/kg/day, an effect likely related to the decreased body weights and body weight gains observed in these animals. Body weights of offspring at the 5 and 25 mg/kg/day groups were comparable to that of the controls.
A NOAEL/LOAEL for offspring cannot be determined due to the lack of morphometric analyses in this study.
This study is classified as Unacceptable/Guideline due to the lack of morphometric analyses and therefore does not satisfy the guideline requirement (OPPTS 870.6300; OECD 426) for a developmental neurotoxicity study in rats.
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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; GD 6 to LD 10
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50815.0
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2008-10-01
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2013-11-05
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Added by
Madison Feshuk
on Apr 25, 2022
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