The Inhalation Toxicology, Genetic Toxicology, and Metabolism of Difluoromethane in the Rat

Difluoromethane (HFC32) is under development as a replacementfor chlorofluorocarbons (CFCs) in some refrigeration applications.It has been evaluated by standard studies of toxicity, developmentaltoxicity, and genotoxicity. In addition, the metabolism anddisposition of HFC32 was investigated and a physiologicallybased pharmacokinetic (PB-PK) model constructed. Inhalationof HFC32 (up to 50,000 ppm) caused no organ-specific effects,but resulted in slight maternal toxicity to the pregnant ratand rabbit and some fetotoxicity to the rat. HFC32 did not sensitizethe heart to adrenaline. The pharmacokinetics of [¹⁴C]difluoromethane(10,000 to 50,000 ppm/6 hr) revealed that about 2.1% of theinhaled HFC32 was absorbed and that steady state blood levelswere achieved within 2 hr and were proportional to dose. Carbondioxide was the major metabolite of HFC32 at all exposure levels.Carbon monoxide was not detected. The in vivo data were usedto validate a PB-PK model to describe the uptake and metabolismof HFC32. Absorption and distribution are adequately describedusing rat blood:air and tissue:air partition coefficients. Metabolism,which was linear across the dose range, was described by a firstorder rate constant (K_f=8.98 hr^–1). Of the absorbed HFC32,about 63% was metabolized at all doses; however, when metabolismwas expressed as a percentage of the inhaled dose it was muchlower, being about 1.4% of the HFC32 entering the airways. Overall,the results indicate that HFC32 is of very low toxicity andshould be an acceptable alternative to CFCs.