FLUOROACETATE-MEDIATED TOXICITY OF FLUORINATED ETHANES

A series of 1-(di)halo-2-fluoroethanes reported in the literature to b e nontoxic or of low toxicity were found to be highly toxic by the inh alation route. Experiments were performed that showed the compounds, 1 ,2-difluoroethane, 1-chloro-2-fluoroethane, 1-chloro-1,2-difluoroethan e, and 1-bromo-2-fluoroethane to be highly toxic to rats upon inhalati on for 4 hr. All four compounds had 4-hr approximate lethal concentrat ions of less than or equal to 100 ppm in rats. In contrast, 1,1-difluo roethane (commonly referred to as HFC-152a) has very low acute toxicit y with a 4-hr LC50 of >400,000 ppm in rats. Rats exposed to the select ed toxic fluoroethanes showed clinical signs of fluoroacetate toxicity (lethargy, hunched posture, convulsions). 1,2-Diffuoroethane, 1-chlor o-2-fluoroethane, 1-chloro-1,2-difluoroethane, and 1-bromo-2-fluoroeth ane were shown to increase concentrations of citrate in serum and hear t tissue, a hallmark of fluoroacetate intoxication. F-19 NMR analysis confirmed that fluoroacetate was present in the urine of rats exposed to each toxic compound. Fluorocitrate, a condensation product of fluor oacetate and oxaloacetate, was identified in the kidney of rats expose d to 1,2-difluoroethane. There was a concentration-related elevation o f serum and heart citrate in rats exposed to 0-1000 ppm 1,2-difluoroet hane. Serum citrate was increased up to 5-fold and heart citrate was i ncreased up to Ii-fold over control citrate levels, Metabolism of 1,2- diffuoroethane by cytochrome P450 (most likely CYP2E1) is suspected be cause pretreatment of rats or mice with SKF-525A, disulfiram, or dimet hyl sulfoxide prevented or delayed the toxicity observed in rats not p retreated. Experimental evidence indicates that the metabolism of the toxic fluoroethanes is initiated at the carbon-hydrogen bond, with met abolism to fluoroacetate via an aldehyde or an acyl fluoride. The resu lts of these studies show that 1-(di)halo-2-fluoroethanes are highly t oxic to rats and should be considered a hazard to humans unless demons trated otherwise. (C) 1996 Society of Toxicology