1,1,1,2-Tetrafluoroethane (HFC-134a): Acute Exposure Guideline ...

SUMMARY

Hydrofluorocarbon-134a or 1,1,1,2-Tetrafluoroethane (HFC-134a) has been developed as a replacement for fully halogenated chlorofluorocarbons because, compared with chlorofluorocarbons, its residence time in the atmosphere is shorter and its ozone depleting potential is insignificant. HFC-134a is used in refrigeration and air conditioning systems, as a blowing agent for polyurethane foams, and as a propellant for medical aerosols. Yearly production is estimated at 175,000 tons. HFC-134a is a colorless gas with a faint ethereal odor that may go unnoticed by most individuals.

HFC-134a has a very low acute inhalation toxicity. Both uptake and elimination are rapid, but uptake is low, and most of the compound is exhaled unchanged. Consequences of acute HFC-134a inhalation have been studied with human subjects and several animal species, including the monkey, dog, rat, and mouse. Considerable inhalation data from controlled studies with healthy human subjects as well as patients with respiratory diseases are available. Studies addressing repeated and chronic exposures, genotoxicity, carcinogenicity, neurotoxicity, and cardiac sensitization were also available. At high concentrations, halogenated hydrocarbons may produce cardiac arrhythmias; this end point was considered in development of AEGL values.

Adequate data were available for development of the three AEGL classifications. Inadequate data were available for determination of the relationship between concentration and time for a fixed effect. Based on the observations that (1) blood concentrations in humans rapidly approach equilibrium with negligible metabolism and tissue uptake and (2) the end point of cardiac sensitization is a blood-concentration related threshold phenomenon, the same concentration was used across all AEGL time periods for the respective AEGL classifications.

The AEGL-1 concentration was based on a 1-hour (h) no-effect concentration of 8,000 parts per million (ppm) in healthy human subjects (Emmen et al. 2000). This concentration was without effects on pulmonary function, respiratory parameters, the eyes (irritation), or the cardiovascular system. Because this concentration is considerably below that causing any adverse effect in animal studies, an intraspecies uncertainty factor (UF) of 1 was applied. The intraspecies UF of 1 is supported by the absence of adverse effects in therapy tests with patients with severe chronic obstructive pulmonary disease and adult and pediatric asthmatics who were tested with metered-dose inhalers containing HFC-134a as the propellant. Because blood concentrations in this study approached equilibrium following 55 minutes (min) of exposure and effects are determined by blood concentrations, the value of 8,000 ppm was made equivalent across all time periods. The AEGL-1 of 8,000 ppm is supported by the absence of adverse effects in experimental animals that inhaled considerably higher concentrations. No adverse effects were observed in rats exposed at 81,000 ppm for 4 h (Silber and Kennedy 1979) or in rats exposed repeatedly at 50,000 or 100,000 ppm for 6 h/day (d). Adjustment of the 81,000 ppm value by interspecies and intraspecies UFs of 3 each, for a total of 10, results in essentially the same concentration (8,100 ppm) as the AEGL-1 based on human data.

The AEGL-2 concentration was based on the no-effect concentration of 40,000 ppm for cardiac sensitization in dogs (Hardy et al. 1991). The cardiac sensitization model with the dog is considered an appropriate model for humans. Because the dog heart is considered an appropriate model for the human heart, an interspecies UF of 1 was applied. Because the cardiac sensitization test is highly sensitive as the response to exogenous epinephrine is optimized, an intraspecies UF of 3 was applied to account for sensitive individuals. Cardiac sensitization is concentration-dependent; duration of exposure does not influence the concentration at which this effect occurs. Using the reasoning that peak circulating concentration is the determining factor in HFC-134a cardiac sensitization, and exposure duration is of lesser importance, the resulting value of 13,000 ppm was applied to all time periods.

The AEGL-3 concentration was based on a concentration of 80,000 ppm, which caused marked cardiac toxicity but no deaths in dogs (Hardy et al. 1991). The cardiac sensitization model with the dog is considered an appropriate model for humans; therefore, an interspecies UF of 1 was applied. Because the cardiac sensitization test is highly sensitive as the response to epinephrine is optimized, an intraspecies UF of 3 was applied to account for sensitive individuals. Cardiac sensitization is concentration-dependent; duration of exposure does not influence the concentration at which this effect occurs. Using the reasoning that peak circulating concentration is the determining factor in HFC-134a cardiac sensitization, and exposure duration is of lesser importance, the resulting value of 27,000 ppm was applied to all time periods.

Values are summarized in Table 3–1.

TABLE 3–1

Summary of AEGL Values for HFC-134a (ppm [mg/m3]).