Citation:

MURPHY, S. R., C. H. FARR, C. B. COPELAND, R. W. LUEBKE, V. C. MOSER, K. EHMAN, AND J. DEWITT. TOXICOLOGY OF MONO- AND DI-ALKYLTIN CHLORIDES. Presented at U.S. EPA/NCEA Toxicology and Risk Assessment Conference, Cincinnati, OH, April 24 - 27, 2006.

Description:

Mono- and di-alkyltin chlorides are reactive compounds used in the production of stabilizers for polyvinyl chloride (PVC) plastics, primarily used for water distribution pipes. Health effects data were compiled or developed by the manufacturers for the EPA's HPV Challenge program for methyltin trichloride, (MMTC, CAS# 993-16-8), dimethyltin dichloride (DMTC, CAS# 753-73-1), butyltin trichloride (MBTC, CAS# 1118-46-3) and dibutyltin dichloride (DBTC, CAS# 683-18-1). These compounds are negative in the Ames test and negative to weakly positive in the mouse micronucleus test. In 90 day feeding or drinking water studies in rats the nervous system is the primary target organ for methyltins. Microscopic changes were observed; NOAEL values were ~10 (MMTC) and 0.6 mg/kg (DMTC). Dietary administration of MMTC to rats for 2 weeks premating, then until gestation day (GD) 4 resulted in decreased numbers of pups and increased pup mortality. DMTC caused a dose-dependent reduction of maternal weight gain of dams treated orally on GD 7-17. Pups demonstrated a reduction in mean BW and skeletal and visceral malformations. The NOAEL for both dams and pups was ~10 mg/kg for both MMTC and DMTC. 90-day dietary administration of MBTC caused increased liver weights, clinical chemistry changes and thymic atrophy. NOAELs were 525 mg/kg (90d, MBTC) and 0.4 mg/kg (28d, DBTC). MBTC demonstrated a reproductive & developmental NOAEL of 525 mg/kg. DBTC exposure (NOAEL) decreased numbers of pups delivered (2 mg/kg), increased pup mortality, and reduced of dam BW gain and food intake (0.3 mg/kg).

Moser and Ehman reported that to assess developmental neurotoxicity using MMT, DMT, and DBT, female Sprague-Dawley rats were exposed via drinking water through most of gestation and all of lactation; two studies included exposure prior to mating. Various neurobehavioral tests were used to assess neuromotor development and cognitive function from before weaning to adulthood. Two MMT studies, using concentrations up to 500 ppm, showed no effects on any measure of growth, development, or cognitive function. The neuropathological evaluation revealed mild cortical vacuolation. Two studies of DMT also revealed few developmental effects; however, both studies demonstrated a reproducible effect on spatial learning (mid-concentration, 15 ppm, only), and mild cortical vacuolation was observed in one study. Brain weight was decreased in DBT-exposed offspring (25 ppm) at weaning. Assays of apoptosis revealed changes in the DMT and DBT-treated rats at several ages, indicating an altered progression of naturally-occurring cell death processes; however, these findings were not supported using another measure of apoptosis. Overall, these studies showed that:1) MMT is the least biologically active organotin of the three tested; 2) both DMT and DBT produced some neurotoxicologically significant changes, but 3) the pattern of effects was quite different for these two compounds.

In immunotoxicity studies conducted by DeWitt, Copeland, and Luebke, BW, immune organ weights, delayed-type hypersensitivity (DTH) responses, and natural killer (NK) cell activity were not affected in adults exposed to either 10 or 25 mg DBTC/L or 20 or 40 mg DMTC/L of drinking water for 28 days. Antibody responses in males exposed to DBTC as adults differed in two replicate experiments: IgG was elevated at the highest dose in one replicate whereas IgM was suppressed in the second. No changes were observed in DMTC-exposed adults. Immune organ weights, DTH responses, and NK cell activity were not affected in offspring exposed pre- and post-natally via maternal dosing only (maternal, 10 or 25 mg DBTC/L of drinking water) or via the dam plus ten direct doses by oral gavage from post-natal day 3-24 (maternal, 10 or 25 mg DBTC/L of drinking water; direct, 1.0 or 2.5 mg/kg BW/dose). BW gain of offspring in the maternal + direct 25 mg DBTC/L group was decreased relative to controls. IgM synthesis was suppressed only in maternal + direct female offspring. In contrast, IgG synthesis was elevated in maternal only male offspring. In adults and offspring, these effects on antibody production occurred at 25 mg DBTC/L of drinking water, a concentration several orders of magnitude higher than DBTC levels reported in drinking water. Effects on antibody synthesis only occurred at 25 mg DBTC/L, a concentration several orders of magnitude higher than levels reported in drinking water. The apparently contradictory effects on humoral immune function suggest that DBTC is unlikely to cause immunosuppression at levels demonstrated in drinking water. Furthermore, although the developing immune system is generally more sensitive than that of adults, our DBTC results suggest that at calculated levels of human exposure, developmental immunotoxicity is unlikely.

This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.

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