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HYDROFLUOROCARBON-404A 71 opmental study in which fetal toxicity was observed (Hodge et al. 1979a). However, fetal toxicity is not as a relevant an end point for setting an exposure level for use on submarines, which have no female crew members. In 1996, the NRC used a 2-year chronic toxicity study (Hext and Parr- Dobrzanski 1993) in male rats to derive a 90-day CEGL for HFC-134a. At the highest concentration of 50,000 ppm in the study, increases in testicular weight and benign Leydig tumors were reported. However, the increases in testicular weight were not considered to be an adverse effect in itself, and the increase in Leydig tumors is not applicable to humans, because those tumors are related to a peculiar aspect of rodent metabolism. Thus, the NOAEL for the study was 50,000 ppm. That value was divided by an uncertainty factor of 10 to account for interspecies variability. That product was then multiplied by 1/4 (to account for exposure for 6 hr per day) and by 5/7 (to account for exposure five times per week), which yielded a 90-day CEGL of about 900 ppm. The subcommittee agrees with this earlier determination of the CEGL. SUMMARY In summary, the toxicity profiles of the three components of HFC-404a indicate that these chemicals are practically nontoxic and, therefore, there is only marginal concern for potential health hazard. Absorption and metabolism studies in laboratory animals show little uptake of all three components and that metabolism is primarily by oxidative and defluorination pathways. Pharmacokinetic studies in humans with HFC-134a indicate rapid elimination from the body. Under acute exposure conditions, cardiac sensitization to epinephrine challenge appears to be the most sensitive end point of biological importance. The NOAELs for cardiac sensitization are 50,000, 75,000, and 250,000 ppm for HFC-134a, HFC-125, and HFC-143a, respectively. For all three components, much higher concentrations (i.e., greater than 500,000 ppm) are required to produce acute lethal or adverse clinical effects. For subchronic exposures, developmental and reproductive toxicity effects are the most sensitive indicators of biological significance. The NOAELs for developmental and reproductive effects are 2,500, 15,000, and 40,000 ppm for HFC-134a, HFC-125, and HFC-143a, respectively. However, slight maternal toxicity in the absence of other adverse effects might not be a suitable indicator for health- hazard evaluation in Navy vessels with no female crew members. Several general toxicity studies ranging from 2 to 13 weeks duration were conducted on the three components. The NOAELs
HYDROFLUOROCARBON-404A 72 for these subchronic studies are 40,000, 50,000, and 50,000 ppm for HFC-143a, HFC-134a, and HFC-125, respectively. Numerous in vitro and in vivo genotoxicity studies were performed on the three HFCs. Results indicate that none of the components are genotoxic. These genotoxicity results are in agreement with the tumor bioassays that have been performed on two of the three components. Both HFC-143a and HFC-134a showed no significant increase in the incidence of neoplasms in all organs and tissues evaluated. Because HFC-404a is a gaseous mixture of three halocarbons (52% HFC-143a, 44% HFC-125, and 4% HFC-143a), the possibility of toxic interaction should be considered in evaluating the toxic potential of this mixture, in addition to evaluating the potential adverse health effects of the individual components. Combined exposures to multiple chemicals could result in interactions leading to a significant increase or decrease (synergism or antagonism, respectively) in overall toxicity of the mixture compared with the summation of the toxicity of individual components (Krishnan and Brodeur 1991; Mehendale 1994). However, for a large number of chemicals, the overall toxicity of a mixture can be represented by the summation of the effects of the individual components (additive effect). There are three approaches for risk assessment of chemical mixtures (Mumtaz et al. 1994). In two of these approaches, mixtures with stable composition, semi-characterized mixtures, or specially formulated mixtures are treated as a single chemical when data are available on the mixture itself. In cases when testing has been done only on the components of the mixture and not on the mixture itself, the primary method used is the hazard index (HI) approach. The HI approach is based on the principle of dose addition and uses the toxicity data available for the various components of the mixture (EPA 1986; Mumtaz et al. 1994; Teuschler and Hertzberg 1995). It is well established that some chemical components of a mixture have the potential to influence the toxicity of other components of the mixture (Groten et al. 1996). However, the HI approach does not allow the use of available interaction data. To overcome this fundamental shortcoming of the HI approach, a weight-of-evidence (WOE) method has been proposed to integrate available interaction data (Mumtaz and Durkin 1992). Recent experimental studies have shown that the WOE method is useful in assessing the toxicity of low-concentration exposures to chemical mixtures (Mumtaz et al. 1998). Because HFC-404a is an azeotrope composed of similar compounds, it is assumed that the components of the mixture would have additive effects. It is suggested that studies of HFC-404a be conducted to determine if this is a valid assumption.
