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46055701.DER.pdf
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46055701
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Fentin hydroxide
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76-87-9
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083601
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Myers, D. (2003) TPTH Developmental Neurotoxicity Study in the CD Rat by Oral Administration. Project Number: LDA/038/032055, LDA/038, 032055. Unpublished study prepared by Huntingdon Life Sciences, Ltd. 1035 p.
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2003.0
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TPTH (Fentin hydroxide; Triphenyltin hydroxide): In a developmental neurotoxicity study (2003, MRID 46055701), Fentin hydroxide (TPTH; 97.5% a.i., Lot/Batch # ZVRAM.928K) in corn oil was administered to pregnant CD (Crl:CD®[SD]BR IGS) rats (24/dose) by gavage at dose levels of 0, 1, 2.5, or 5 mg/kg/day from gestation day (GD) 6 through lactation day (LD) 20. Groups of 10 dams/dose were subjected to a functional observational battery (FOB) during gestation and lactation. On postnatal day (PND) 4, litters were standardized to 4 pups/sex pups/litter, and 1 pup/litter/group were allocated to subsets for assessment of FOB and motor activity, auditory startle response, learning and memory evaluation, and neuropathological examination.
Maternal Toxicity: A single dam in the 2.5-mg/kg/day dose group was sacrificed on GD day 18 due to poor condition (pallor, piloerection, red discharge from the vagina and low body temperature). Six high-dose dams were sacrificed with similar poor clinical conditions between GDs 21 to 23. Three high-dose dams showed total litter death in utero, while some of the other three had obvious problems with parturition. There were 24, 24, 23, and 17 dams with viable litters for the control, low-, mid-, and high-dose groups. During the FOB assessment, the high-dose group was judged to have different grades for ease of handling (reactivity, reduced rearing and activity levels). Body weight gains were decreased (17%) in the high-dose group during gestation and increased (138% for days 1 - 21) during lactation, but food consumption generally decreased (up to 22%) during either gestation or lactation. There were 23, 23, 22, and 16 litters for the control, 1-, 2.5-, and 5-mg/kg/day dose groups, respectively, that provided pups for the developmental aspects of this study.
The maternal LOAEL is 2.5 mg/kg/day, based on clinical condition (requiring sacrifice) in one animal with conditions similar to dams at the next higher dose. The maternal NOAEL is 1 mg/kg/day.
Developmental Toxicity: Starting at about day 49 and persisting to termination, the low- (4.4 to 5.5% for males, and 4.7 to 5% for females, p<0.05 or 0.01) and mid- (4.8 to 6.5% for males and 3.7% to 4.6% for females, p<0.05 or 0.01) dose group body weights were decreased. Mean body weight gain over the period of days 28 to 65 were also decreased for the low- (6%, both sexes, p<0.01) and mid- (6% females and 7% males, both p<0.01) dose groups. The mean litter size was similar at birth for all groups but mean pup weight at birth was slightly lower (¿9% for males and ¿6% for females, both p<0.05) in the high-dose group. During lactation, the high-dose group pups reached 14 to 15% lower body weights and weight gain during lactation was reduced (15% for males and 20% for females for days 1 to 7). The high-dose group maintained a 7 to 10% difference in post weaning body weight until day 65 accompanied with a decrease of 11% in body gain over this period. Treatment had no adverse effects on survival, clinical signs, food consumption, developmental landmarks, motor activity, auditory startle response, learning and memory, brain weights, brain morphology, or neuropathology at any dose.
The offspring LOAEL is 5 mg/kg/day based on decreases in body weight and body weight gain. The offspring NOAEL is 2.5 mg/kg/day. Note: The apparent differences in body weight in the low- and mid-dose group were not included in the LOAEL because of a lack of dose response and they were not considered definitely related to treatment.
This study is classified Acceptable/Non Guideline 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 Acceptable. This study does not satisfy the guideline requirment for a developmental neurotoxicity study and is classified as Non-Guideline pending review of all available positive control data. J. Rowland, 10/03/2005].
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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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No Duration Period; gavage; GD 6 to LD 20
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52163.0
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2005-10-03
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2016-01-04
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Added by
Madison Feshuk
on Apr 25, 2022
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