Review Article Monomethylarsonic Acid and Dimethylarsinic Acid: Developmental Toxicity Studies With Risk Assessment

BACKGROUND: The toxicity of arsenic compounds is highly dependent on the valence and methylation state of the compound. Although there is extensive published literature on the potential developmental toxicity of inorganic arsenic compounds, little exists on organic arsenic compounds and, in particular, studies conducted in accordance with conventional regulatory guidelines appropriate for risk assessment are rare. The organic arsenic compounds, monomethylarsonic acid (MMA V ) and dimethylarsinic acid (DMA V , also called cacodylic acid), are the active ingredients in pesticide products that are used mainly for weed control. MMA V and DMA V are also metabolites of inorganic arsenic formed intracellularly by most living organisms (animals, plants and bacteria). In mammals, this occurs predominantly in liver cells. METHODS: Conventional developmental toxicity studies of orally administered MMA V and DMA V in the Sprague–Dawley rat and New Zealand White rabbit were conducted in commercial contract laboratories in the late 1980s for regulatory compliance. The results of these studies are summarized and presented to broaden the data available in the public domain. RESULTS: In both species, data shows an absence of dose-related effects at organic arsenic exposures that were not maternally toxic. MMA V doses of 0, 10, 100, and 500mg/kg/day (rat) and 0, 1, 3, 7, and 12mg/kg/day (rabbit) and DMA V doses of 0, 4, 12, and 36mg/kg/day (rat) and 0, 3, 12, and 48mg/kg/day (rabbit) were administered by oral gavage daily during organogenesis (Gestation Day [GD] 6–15, rat; GD 7–19, rabbit) and the litters examined at maternal sacrifice (GD 20, rat; GD 29, rabbit). After treatment with MMA V , maternal and fetal toxicity were observed at the highest doses of 500mg/kg/day (rat) and 12mg/kg/day (rabbit), but no treatment-related developmental toxicity at the lower doses, even in the presence of minimal maternal toxicity in the rat at 100mg/kg/d. There was no evidence of teratogenicity associated with MMA V treatment. With DMA V , maternal and developmental toxicity were observed in the rat at 36mg/kg/day, with a higher than spontaneous incidence of fetuses with diaphragmatic hernia. In the rabbit at 48mg/kg/day, there was marked maternal toxicity, culminating for most females in abortion and with no surviving fetuses for evaluation. There was no treatment-related maternal or developmental toxicity in the rat or rabbit at 12mg/kg/day. Based on pregnancy outcome, the developmental toxicity no observed adverse effect level (NOAEL) for orally administered MMA V were 100 and 7mg/kg/day in the rat and rabbit, respectively, and for DMA V were 12mg/kg/day in both species. CONCLUSIONS: Margins of exposure estimated based on conservative estimates of daily intakes of arsenic in all of its forms indicate that exposure to MMA V or DMA V at environmentally relevant exposure levels, by the oral route (the environmentally relevant route of exposure) is unlikely to pose a risk to pregnant women and their offspring. Birth Defects Res (Part B) 77:53–68, 2006. r 2006 Wiley-Liss, Inc.