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HYDROFLUOROCARBON-404A 55 Toxicokinetics Finch et al. (1995a) studied the absorption of HFC-134a by exposing (head only) male and female rats to 150,000 ppm for 1 hr and using 19F nuclear magnetic resonance (NMR) imaging. The study showed that HFC-134a reached a steady state after 25 min of exposure, at which 58.3 ± 11.9 mg had been absorbed per rat (100-225 g). HFC-134a was rapidly eliminated after exposure; the elimination half-life was 4.6 ± 0.6 min in male rats and 4.9 ± 1.5 min in female rats. In another study with rats, the mean half life of HFC-134a was 7.8 ± 1.5 min after a 10-sec exposure and 8.1 ± 1.7 min after a 10-min exposure (Finch et al. 1995b). Ellis et al. (1993) exposed male and female rats to [U-14C]HFC-134a at a concentration of 10,000 ppm for 1 hr. Of the inhaled dose, approximately 1% was recovered in the recovered in the urine, feces, and expired air, indicating that absorption of HFC-134a was poor. Approximately two-thirds of the recovered [U-14C]HFC-134a were exhaled within 1 h after exposure as unchanged HFC-134a, and the remainder was detected in carbon dioxide or excreted in the urine or feces as trifluoroacetic acid. About 0.15% of the inhaled dose of [U-14C]HFC-134a was retained in the body 5 days after exposure. The highest concentrations were found in the lung followed by the heart and then plasma, liver, and spleen. Total metabolism was about 0.37% of the inhaled dose. Trifluoroacetic acid was the only fluorinated metabolite detected in the urine by 19F NMR spectroscopy. In vitro studies with hepatocytes from rats and liver microsomes from humans, rats, and rabbits indicate that HFC-134a is metabolized by cytochrome P-450 (Olson et al. 1990a,b; Olson and Surbrook 1991). The maximal rate of HFC-134a metabolism by human microsomes was low, showed little interindividual variation among the samples evaluated, and did not exceed that observed with rat or rabbit microsomes. The cytochrome P-450 isoform CYP 2E1 is the major isoform that catalyzes the biotransformation of HFC-134a in rat and human liver microsomes, but isoforms CYP 2B1 (phenobarbitol inducible), CYP 1A2 (β-naphthoflavone inducible), and CYP 1A1 also catalyze the biotransformation of HFC-134a (Olson et al. 1991; Surbrook and Olson 1992). On the basis of the in vitro and in vivo metabolic data, the fate of HFC-134a can be described by the scheme shown in Figure 4-1. Monte et al. (1994) studied the metabolism of HFC-134a in humans using 19F NMR spectroscopy. Four male volunteers were administered HFC-134a as a single 1,200-mg dose using a metered-dose inhaler. Trifluoroacetic acid
HYDROFLUOROCARBON-404A FIGIURE 4-1 Metabolic fate of HFC-134a. 1, HFC-134a; 2, 1,3,3,3-tetrafluoroethanol; 3, trifluoroacetaldehyde; 4, trifluoroacetic acid; 5, carbon dioxide. 56
