INHALATION TOXICITY STUDY OF A HALOALKENE DEGRADANT OF SEVOFLURANE, COMPOUND A(PIFE), IN SPRAGUE-DAWLEY RATS

Background: Under certain circumstances in the clinical setting, conta ct of the anesthetic sevoflurane with a CO2 absorbant (e.g., soda lime , Baralyme) leads to the formation of a degradant designated as pentaf luoroisopropenyl fluoromethyl ether (PIFE; Compound A). Previous studi es have shown that the kidney is the primary target organ for toxicity in the rat. This study was designed to determine the impact of PIFE o n rat renal histology correlated with functional changes. The findings are discussed in terms of probable mechanism of action and relevance to humans. Methods: Male and female Sprague-Dawley rats were exposed t o 0, 30, 61, 114, or 202 ppm PIFE for a single 3-h period via nose-onl y inhalation. Rats were observed daily for behavioral changes or exter nal physical signs of toxicity (i.e., lacrimation, dyspnea, piloerecti on, etc.) and body weights were recorded at 6, 4, and 1 day preexposur e and 1, 3, 7, and 13 days postexposure. Animals were evaluated for he matologic, clinical chemistry and/or urinalysis changes immediately po stexposure and/or at 1, 4, and 14 days postexposure. Rats were killed, subjected to a macroscopic postmortem examination, and evaluated for histopathologic changes in all major tissues and organs at 1, 4, and 1 4 days postexposure. Results: Labored breathing was observed in 3 of t he 20 and 2 of the 20 rats in the 114 ppm and 202 ppm groups, respecti vely, during the 3-h exposure period. No significant reductions in bod y weight gain were noted during the 2-week study period. Clinical chem istry evaluations revealed Increases in blood urea nitrogen and creati nine 1 day postexposure in males and females exposed to 202 ppm PIFE. Changes in urinary glucose, protein and N-acetyl-beta-glucoaminidase/c reatinine were evident one day postexposure in males and females expos ed to 202 ppm and in males exposed to 114 ppm PIFE. Most values were w ithin normal ranges by 4 or 14 days postexposure. No drug-related alte rations in hematolologic parameters were noted. Evidence of olfactory epithelial degeneration and desquamation in the nasal turbinates was n oted at 4 days postexposure in male and female rats exposed to 202 ppm PIFE. Concentration-dependent renal tubular necrosis and tubular cell hyperplasia, in the corticomedullary border, were observed In males a nd females exposed to 114 and 202 ppm PIFE. The severity of tubular ne crosis in both males and females was considered minimal to slight at t he 114 ppm exposure concentration and slight to moderate at the 202 pp m exposure. Both the numbers of affected animals and severity were red uced over time. The most marked changes in serum and urine chemistry w ere associated with the animals described as having moderate renal nec rosis. Male rats appeared more susceptible to nephropathy than female rats. There were no other PIFE-related histopathologic findings. Concl usions: The renal histopathologic findings in this study are consisten t with those reported In previous acute studies hn rats after PIFE adm inistration. Functional changes in the kidney, as evidenced by serum c hemistry and urinalyses, were observed at exposure concentrations that induced morphologic alterations.