Human safety and pharmacokinetics of the CFC alternative propellants HFC 134a (1,1,1,2-tetrafluoroethane) and HFC 227 (1,1,1,2,3,3,3-heptafluoropropane) following whole-body exposure

HFC 134a (1,1,1,2-tetrafluoroethane) and HFC 227 (1,1,1,2,3,3,3-heptafluoro propane) are used to replace chlorofluorocarbons (CFCs) in refrigerant and aerosol applications, including medical use in metered-dose inhalers. Produ ction and consumption of CFCs are being phased out under the Montreal Proto col on Substances that Deplete the Ozone Layer. The safety and pharmacokine tics of HFC 134a and HFC 227 were assessed in two separate double-blind stu dies. Each HFC (hydro fluorocarbon) was administered via whole-body exposur e as a vapor to eight (four male and four female) healthy volunteers. Volun teers were exposed, once weekly for 1 h, first to air and then to ascending concentrations of HFC (1000, 2000, 4000, and 8000 parts per million (ppm), interspersed with a second air exposure and two CFC 12 (dichlorodifluorome thane) exposures (1000 and 4000 ppm). Comparison of either HFC 134a or HFC 227 to CFC 12 or air gave no clinically significant results for any of the measured laboratory parameters. There were no notable adverse events, there was no evidence of effects on the central nervous system, and there were n o symptoms of upper respiratory tract irritation. HFC 134a, HFC 227, and CF C 12 blood concentrations increased rapidly and in an exposure-concentratio n-dependent manner, although not strictly proportionally, and approached st eady state. Maximum blood concentrations (C-max) tended to be higher in mal es than females; in the HFC 227 study, these were statistically significant ly (P < 0.05) higher in males for each HFC 227 and CFC 12 exposure level. I n the HPC 134a study, the gender difference in C-max was only statistically significant CP < 0.05) for CFC 12 at 4000 ppm and HFC 134a at 8000 ppm. Fo llowing the end of exposure, blood concentrations declined rapidly, predomi nantly biphasically and independent of exposure concentration. For the HFC 134a study, the t(1/2)alpha (alpha elimination half-life) was short for bot h CFC 12 and HFC 134a (<11 min). The t(1/2)<beta> (beta elimination half-li fe) across all exposure concentrations was a mean of 36 and 42 min for CFC 12 and HFC 134a, respectively. Mean residence time (MRT) was an overall mea n of 42 and 44 min for CFC 12 and HFC 134a, respectively. In the HFC 227 st udy, by t(1/2)alpha for both CFC 12 and HFC 227, at each exposure level, wa s short (<9 min) and tended to be lower in males than females. For CFC 12 m ean t(1/2)<beta> ranged from 23 to 43 min and for HFC 227 the mean range wa s 19-92 min. The values tended to be lower for females than males for HFC 2 27. For both CFC 12 and HFC 227, MRT was statistically significantly lower (P < 0.05) in males than females and independent of exposure concentration. For CFC 12, MRT was a mean of 37 and 45 min for males and females, respect ively, and for HFC 227 MRT was a mean of 36 and 42 min, respectively. Expos ure of healthy volunteers to exposure levels up to 8000 ppm HFC 134a, 8000 ppm HFC 227, and 4000 ppm CFC 12 did not result in any adverse effects on p ulse, blood pressure, electrocardiogram, or lung function. (C) 2000 Academi c Press.