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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

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Author: Emmen, H.H. · Hoogendijk, E.M.G. · Klöpping-Ketelaars, W.A.A. · Muijser, H. · Duistermaat, E. · Ravensberg, J.C. · Alexander, D.J. · Borkhataria, D. · Rusch, G.M. · Schmit, B.
Institution: Centraal Instituut voor Voedingsonderzoek TNO
Source:Regulatory Toxicology and Pharmacology, 1, 32, 22-35
Identifier: 56887
doi: doi:10.1006/rtph.2000.1402
Keywords: Nutrition · Apaflurane · Cfc 12 · Chlorofluorocarbon · Dichlorodifluoromethane · Hfc 227 · Norflurane · Unclassified drug · Adult · Aerosol · Blood pressure · Central nervous system disease · Clinical trial · Concentration response · Controlled clinical trial · Controlled study · Double blind procedure · Drug blood level · Drug delivery system · Drug elimination · Drug excretion · Drug safety · Electrocardiogram · Exposure · Female · Human · Human experiment · Lung function · Male · Metered dose inhaler · Normal human · Priority journal · Pulse rate · Respiratory tract disease · Sex difference · Steady state · Vapor · Administration, Inhalation · Adult · Aerosol Propellants · Atmosphere Exposure Chambers · Blood Pressure · Chlorofluorocarbons, Methane · Dose-Response Relationship, Drug · Double-Blind Method · Electrocardiography · Female · Half-Life · Humans · Hydrocarbons, Fluorinated · Inhalation Exposure · Male · Respiratory Function Tests · Safety · Sex Characteristics


HFC 134a (1,1,1,2-tetrafluoroethane) and HFC 227 (1,1,1,2,3,3,3-heptafluoropropane) are used to replace chlorofluorocarbons (CFCs) in refrigerant and aerosol applications, including medical use in metered-dose inhalers. Production and consumption of CFCs are being phased out under the Montreal Protocol on Substances that Deplete the Ozone Layer. The safety and pharmacokinetics of HFC 134a and HFC 227 were assessed in two separate double-blind studies. Each HFC (hydrofluorocarbon) was administered via whole-body exposure as a vapor to eight (four male and four female) healthy volunteers. Volunteers 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 (dichlorodifluoromethane) 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 no symptoms of upper respiratory tract irritation. HFC 134a, HFC 227, and CFC 12 blood concentrations increased rapidly and in an exposure-concentration-dependent mariner, although not strictly proportionally, and approached steady state. Maximum blood concentrations (C(max)) tended to be higher in males than females; in the HFC 227 study, these were statistically significantly (P < 0.05) higher in males for each HFC 227 and CFC 12 exposure level. In the HFC 134a study, the gender difference in C(max) was only statistically significant (P < 0.05) for CFC 12 at 4000 ppm and HFC 134a at 8000 ppm. Following the end of exposure, blood concentrations declined rapidly, predominantly biphasically and independent of exposure concentration. For the HFC 134a study, the t( 1/2 )α (α elimination half-life) was short for both CFC 12 and HFC 134a (<11 min). The t( 1/2 )β (β elimination half-life) 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 mean of 42 and 44 min for CFC 12 and HFC 134a, respectively. In the HFC 227 study, t( 1/2 )α for both CFC 12 and HFC 227, at each exposure level, was short (<9 min) and tended to be lower in males than females. For CFC 12 mean t( 1/2 )β ranged from 23 to 43 min and for HFC 227 the mean range was 19-92 min. The values tended to be lower for females than males for HFC 227. For bath 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, respectively, and for HFC 227 MRT was a mean of 36 and 42 min, respectively. Exposure 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 pulse, blood pressure, electrocardiogram, or lung function. (C) 2000 Academic Press. Chemicals/CAS: Aerosol Propellants; Chlorofluorocarbons, Methane; dichlorodifluoromethane, 75-71-8; HFA 134a, 431-89-0; Hydrocarbons, Fluorinated; norflurane, 811-97-2