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HYDROFLUOROCARBON-404A 57 was the only fluorinated metabolite detected in the urine. The total amount of trifluoroacetic acid detected ranged from none to 5,186 ng (0.00039% of the inhaled dose), which indicates that oxidative metabolism of HFC-134a occurs in humans but accounts for only a small fraction of the administered dose. In another study (Pike et al. 1995), seven subjects were exposed to HFC-134a at a dose of 75 mg using a metered-dose inhaler, and the absorption, distribution, and retention of HFC-134a was determined using a whole-body γ- counter. HFC-134a was rapidly eliminated in exhaled air within minutes after exposure. An average of 9.6% of the inhaled dose was retained in the body after 5 min. That remaining dose was eliminated with an apparent terminal half-life of 1.5-4.2 hr; on average, less than 1% of the administered dose was retained in the body at 5.8 hr. Approximately 0.0056% of the administered dose of HFC-134a was found in the urine within the first 2 hr, and later samples contained no significant amounts. HFC-134a was distributed to all regions of the body and then cleared without evident accumulation in a specific region. As part of an ascending concentration safety study of HFC-134a (described later in this chapter), Emmen and Hoogendijk (1999) collected pharmacokinetic data from human subjects. Four men and four women were exposed (whole body) to HFC-134a at concentrations of 1,000, 2,000, 4,000, and 8,000 ppm for 1 hr. A summary of the pharmacokinetic data are presented in Table 4-3. The mean maximum blood concentration of HFC-134a ranged from 1.02 to 7.22 µg/ mL. Blood concentrations increased in an exposure-related but nonlinear pattern. Blood concentrations of HFC-134a were higher in males than in females. The total amount of HFC-134a absorbed (expressed as the area under the curves extrapolated to infinity, AUC0-â) also suggests an exposure-related pattern, with higher values for males than for females. These findings are supported by measurements taken during exposure, after exposure, and for both periods combined. The distribution phase of the elimination half-life for HFC-134a was approximately 9 min for females and 10 min for males, and the terminal phase of the elimination half-life was about 43 min for females and 42 min for males. No exposure-related patterns were observed for these values. Toxicity Information Human Studies HFC-134a is being developed for use in pharmaceutical applications. The International Pharmaceutical Aerosol Consortium for Toxicity Testing
TABLE 4-3 Human Pharmacokinetic Data on HFC-134a from the Emmen and Hoogendijk (1999) Studya Exposure Cmax (µg/mL) T½ (min) (D) T½ (min) (T) AUC0-â AUD1 AUD2 AUDT Concentration, ppm (µg*min/mL) (µg*min/mL) (µg*min/mL) (µg*min/mL) Females 1,000 1.02 (0.17) 5.70b (0.76) 39.10 (19.74) 74.14 (7.88) 49.37 (5.91) 20.51 (6.98) 69.88 (10.27) 2,000 1.44 (0.38) 9.74c (1.83) 57.57 (63.56) 110.46 (47.57) 62.94 (16.91) 27.33 (4.74) 90.28 (20.79) 4,000 3.06 (0.18) 11.08b (3.89) 31.78 (10.14) 209.35 (9.30) 135.52 (12.98) 57.84 (14.88) 193.36 (5.49) 8,000 5.95 (0.53) 9.44c (3.88) 44.45 (34.14) 462.21 (42.74) 280.20 (21.12) 125.54 (8.96) 405.75 (16.50) Males 1,000 1.02 (0.18) 9.81 (4.25) 37.95 (12.72) 73.64 (10.82) 48.72 (9.22) 17.58 (5.30) 66.30 (9.65) 2,000 1.92 (0.40) 9.00c (1.73) 34.34 (12.72) 141.96 (28.00) 92.86 (22.87) 38.94 (9.62) 131.80 (27.04) HYDROFLUOROCARBON-404A 4,000 3.79 (0.47) 11.21 (4.23) 57.76 (34.70) 304.93 (81.29) 173.96 (29.05) 73.37 (22.91) 247.33 (24.10) 8,000 7.22 (0.70) 8.34 (1.18) 38.29 (2.33) 534.22 (82.43) 342.87 (45.02) 139.66 (24.94) 482.53 (67.98) aValues are mean (SD), n = 4 bValue is mean of n = 3. No T (D) could be calculated for one subject. ½ cValue is mean of n = 2. No T (D) could be calculated for two subjects. ½ Abbrievations: n, number of subjects; SD, standard deviation; Cmax, highest concentration; T½(D), distribution half-life (elimination phase) (α); T½ (T), terminal half-life (elimination phase) (β); AUC0-â, area under the curve - extrapolation from last measured data point; AUD1, area under the data - during exposure; AUD2, area under the data - after exposure; AUDT, area under the data - during and after exposure. 58
HYDROFLUOROCARBON-404A 59 (IPACTI) is conducting a development program to satisfy regulatory requirements for the use of HFC-134a in drug applications. Harrison et al. (1996) evaluated the safety and tolerability of HFC-134a in a 28-day double- blind inhalation aerosol study using healthy, nonsmoking males between 18 and 55 years of age. Subjects used a metered-dose inhaler and received either four inhalations (puffs) four times per day for 14 days or eight inhalations four times a day for 14 days. The subjects were then crossed over to the alternative exposure regimen with the same propellant for the next 14-day period. The metered-dose inhaler contained HFC-134a as a propellant, ethanol as a co- solvent, and oleic acid as a surfactant. Subjects were instructed to hold their breath for 10 sec following each inhalation and to wait 30 sec before taking the next puff. There were no clinically significant changes in blood pressure, heart rate, electrocardiograms (ECGs), pulmonary function, hematology, or serum chemistry. One of eight subjects in the HFC-134a group had elevated eosinophil counts throughout the study. There were no serious or unexpected adverse events due to inhalation of HFC-134a. Headache was the most frequent adverse event reported by subjects in the double-blind study groups. Vinegar et al. (1997) exposed human volunteers to HFC-134a via inhalation for the purpose of collecting pharmacokinetic data to validate a human physiologically based pharmacokinetic model. The intended exposure was 4,000 ppm for 30 min. A nonrebreathing valve system was used to deliver HFC-134a, and a catheter was inserted in the antecubital vein of subjects to collect blood samples. Subjects were monitored for ECG, blood pressure, and pulse rate throughout the exposure. Exposures were terminated for safety reasons following unexpected and uncontrollable changes in pulse rate during the inhalation exposure. Due to the small sample size and experimental design, no conclusion or speculation about cause and effect was offered. Subsequent to the interim report by Vinegar et al. (1997), a consortium of producers and pharmaceutical industry users initiated a human inhalation exposure study with HFC-134a (Emmen and Hoogendijk 1999). Four men and four women were exposed (whole body) to four concentrations of HFC-134a ranging from 1,000 to 8,000 ppm for 1 hr periods. Subjects were assigned to a randomized ascending concentration exposure regimen that included two air- only exposures and two CFC-12 (dichlorodifluoromethane) exposures. Exposures were administered once per week for 8 consecutive weeks. ECG, pulse rate, blood pressure (diastolic and systolic), and pulmonary function (peak expiratory flow) were evaluated. Blood concentrations of HFC-134a and CFC-12 were measured before, during, and after each expo
