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46336203.der.pdf
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46336203
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Trimethyltin
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1066-45-1
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600007
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Chivers, S. (2004) Trimethyltin chloride: Positive Control Study for Neurotoxicology and Neuropathology in Adult Rats: Final Report. Project Number: WR0492. Unpublished study prepared by Central Toxicology Lab. (Syngenta). 564 p.
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2004.0
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Trimethyltin Chloride: In a study submitted by Central Toxicology Laboratory, Cheshire, UK to demonstrate proficiency in conducting neurotoxicity and neuropathology tests (MRID 46336203), groups of five Alpk:APfSD rats/sex were injected intraperitoneally with 0, 6, or 8 mg/kg trimethyltin chloride (day 1) and killed two weeks later. Originally, 0, 6, or 8 mg/kg were also to be administered on two occasions (day 1 and 7) to groups five animals/sex. Due to excessive toxicity, animals that received two doses were killed 2-3 days following the second dose. For females scheduled to receive two doses, the high dose for the second administration was reduced from 8 mg/kg to 6 mg/kg.
Neurobehavioral assessment (functional observational battery and motor activity testing) and body weight measurements were performed on all animals/sex/group pre-study and on days 1, 7, and 14 (single dose) and pre-study and on days 1, 7, and 8 (repeat dose). On day 14, five animals/sex/group of the animals dosed once were euthanized and perfused in situ for neuropathological examination. Of the perfused animals, all control and treated animals were subjected to histopathological evaluation of brain and peripheral nervous system tissues. Brain weight was measured and morphometric evaluations were performed on multiple brain regions.
No treatment-related clinical signs of toxicity were observed in animals administered one dose of trimethyltin chloride. All animals survived to scheduled termination. However, repeat-dose animals exhibited clinical signs of neurotoxicity 2-3 days following the second dose (decreased activity, clonic convulsions, tremors, reduced response to sound, and aggressive behavior). The body weight of animals administered a single dose was similar to the control groups throughout the study. In the repeat-dose groups, body weight of males was reduced at both dose levels on day 7 (94%-96% of controls) and day 8 (92%-95% of controls).
During the FOB assessments on the day of treatment (day 1), reduced splay reflex was observed in 1/10 animals each in the low- and high-dose male groups and in the low-dose female group. Reduced response to sound was seen on day 1 in 1/10 high-dose females and on day 7 in the low-dose male and female groups (3/10 and 4/10, respectively) and in the high-dose male and female groups (1/10 and 4/10, respectively). Day 8 findings for high-dose males dosed twice included ataxia (1/5) and slight to moderate tremors (4/5). In males dosed once, there was a dose-related increase in time to tail-flick (significant at 8 mg/kg) on day 1. For repeat-dose animals, time to tail-flick latency was increased on day 1 for low-dose females and on days 7 and 8 for low- and high-dose males and females compared to controls. Landing foot splay was significantly increased for low- and high-dose males on day 1. No effects were found on fore- and hind-limb grip strength.
Dose-related reductions in total motor activity were seen in all treatment groups on day 1. For animals dosed once, significant decreases were observed on day 1 in low- and high-dose males (57% and 45%, respectively, of controls) and high-dose females (53% of controls). On day 7, the decreases were significant for low-dose males and females (62% and 64%, respectively, of controls). Significant effects were no longer evident on day 14. For animals in the repeat-dose group, motor activity was not significantly affected for males in either dose group or at any time point. For females, decreased activity was seen on day 1 at the high dose (50% of controls) and on day 7 at the low dose (43% of controls) and high dose (53% of controls).
Gross necropsy was unremarkable. Brain weight was not affected by treatment. Microscopic lesions in the brain, characterized as minimal to mild neuronal degeneration/necrosis and gliosis in the hippocampus and piriform lobe, were observed in both dose groups of both sexes but not in controls. The incidence (severity) of neuronal degeneration/necrosis in the low- and high-dose groups, respectively, was 4/5 (1.00) and 5/5 (2.00) for males and 3/5 (1.00) and 5/5 (1.80) for females. The incidence of gliosis in the low- and high-dose groups, respectively, was 4/5 (1.00) and 5/5 (2.00) for males and 1/5 (1.00) and 5/5 (2.00) for females. An increased incidence, but not severity, of demyelination of peripheral nerves was seen in both dose groups of males (sciatic and tibial nerves) and in high-dose females (sciatic nerve). The width of the dentate gyrus in the hippocampus was significantly decreased in high-dose males (84% of controls) and females (80% of controls). Several other morphometric measures were statistically different from controls, but no consistency was seen between sexes, doses, or multiple measures within a structure.
This study is classified as Acceptable/Non-Guideline. Central Toxicology Laboratory, UK, has demonstrated proficiency in this study for detecting changes in FOB, motor activity, neuropathology, and morphometry due to Trimethyltin Chloride treatment in postweaning (47 days old) Alpk:APfSD rats for the time period around 2003-4 (in life period of study). This positive control study does not satisfy any guideline requirement.
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Other
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NA [870.6200, Neurotoxicity screening battery|870.6300, Developmental neurotoxicity study]
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Intraperitoneal
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No Duration Period; Positive control study
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54596.0
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2012-03-20
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2017-02-10
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Added by
Madison Feshuk
on Apr 25, 2022
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