title: The inhalation toxicology, genetic toxicology, and metabolism of difluoromethane in the rat.
abstract: Difluoromethane (HFC32) is under development as a replacement for chlorofluorocarbons (CFCs) in some refrigeration applications. It has been evaluated by standard studies of toxicity, developmental toxicity, and genotoxicity. In addition, the metabolism and disposition of HFC32 was investigated and a physiologically based pharmacokinetic (PB-PK) model constructed. Inhalation of HFC32 (up to 50,000 ppm) caused no organ-specific effects, but resulted in slight maternal toxicity to the pregnant rat and rabbit and some fetotoxicity to the rat. HFC32 did not sensitize the heart to adrenaline. The pharmacokinetics of [14C]difluoromethane (10,000 to 50,000 ppm/6 hr) revealed that about 2.1% of the inhaled HFC32 was absorbed and that steady state blood levels were achieved within 2 hr and were proportional to dose. Carbon dioxide was the major metabolite of HFC32 at all exposure levels. Carbon monoxide was not detected. The in vivo data were used to validate a PB-PK model to describe the uptake and metabolism of HFC32. Absorption and distribution are adequately described using rat blood:air and tissue:air partition coefficients. Metabolism, which was linear across the dose range, was described by a first order rate constant (Kf = 8.98 hr-1). Of the absorbed HFC32, about 63% was metabolized at all doses; however, when metabolism was expressed as a percentage of the inhaled dose it was much lower, being about 1.4% of the HFC32 entering the airways. Overall, the results indicate that HFC32 is of very low toxicity and should be an acceptable alternative to CFCs.
authors.affiliation: Zeneca Central Toxicology Laboratory, Macclesfield, United Kingdom.
authors.forename: M K
authors.initials: MK
authors.lastname: Ellis
authors.forename: R
authors.initials: R
authors.lastname: Trebilcock
authors.forename: J L
authors.initials: JL
authors.lastname: Naylor
authors.forename: K
authors.initials: K
authors.lastname: Tseung
authors.forename: M A
authors.initials: MA
authors.lastname: Collins
authors.forename: P M
authors.initials: PM
authors.lastname: Hext
authors.forename: T
authors.initials: T
authors.lastname: Green
mesh_terms: D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D005260:Female; D006321:Heart / Q000187:drug effects; D006845:Hydrocarbons, Fluorinated / Q000493:pharmacokinetics* / Q000633:toxicity*; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008954:Models, Biological; D009152:Mutagenicity Tests; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013723:Teratogens / Q000633:toxicity*; D018675:Toxicity Tests
chemical_list: D006845:Hydrocarbons, Fluorinated; D013723:Teratogens; C102075:difluoromethane