Mustard reproductive toxicity

The Army s interim RfD of 7 x 10 mg/kg per day for sulfur mustard was based on an oral two-generation reproductive toxicity study in rats, in which thickening of the forestomach epithelium was observed. The subcommittee agrees that this study is the best available one from which to derive the RfD for sulfur mustard and concludes that the interim RfD for sulfur mustard is scientifically valid. However, the subcommittee recommends adjustments in two of the uncertainty factors used to derive that RfD. Although the adjustments do not change the RfD for sulfur mustard, the subcommittee believes that they are scientifically justified and should be reflected in the Army s supporting documentation for the RfD. 

Agent HD (Sulfur Mustard). RfDe = 7 x 10 mg kg d. A LOiAEL was identified in a two-generation reproductive toxicity study conducted in rats. A total uncertainty factor of 3000 was applied to account for protection of sensitive subpopulations (10), animal-to-human extrapolation (10), LOAEL-to-NOAEL extrapolation (3), and extrapolation from a subchronic to chronic exposure (10). A LOAEL-to-NOAEL UF of 3, instead of the default value of 10, was used because the critical effect (stomach lesions) was considered to be mild in severity and may have been enhanced by the vehicle used (sesame oil in which sulfur mustard is fully soluble) and the route of administration (gavage), which is more likely to result in localized irritant effects. The key study did identify a toxic effect that is consistent with the vesicant properties of sulfur mustard. In none of the other available studies was there any indication of a different effect occurring at a lower exposure level. 

The data base for sulfur mustard contains two developmental toxicity studies in different species, a reproductive bioassay and a standard subchronic toxicity study in one species. In addition, chronic inhalation studies have been conducted on sulfur mustard using rats, mice, guinea pigs and dogs. The principal study identifies a toxic effect that is consistent with the vesicant properties of sulfur mustard. There is no evidence that any other experimental species would be more sensitive to ingested sulfur mustard therefore, additional oral toxicity studies in other species are not considered critical. 

Studies in animals have shown that sulfur mustard may induee developmental and reproductive effects (reviewed in NRC, 1999, 2003). Acute exposures resulting in systemic uptake may have effects on reproductive organs, including inhibition of spermatogenesis. Fetal anomalies were observed in tests with rats given sulfur mustard during gestation but only at maternally toxic doses. 

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