Unexpected brain lesions in lactating Sprague-Dawley rats in a Two-generation Inhalation Reproductive Toxicity Study with pentafluoropropane (HFC-245fa)

Abstract

The study presented was conducted following the reproductive study guideline OECD Guideline 416 Two-Generation Reproduction Toxicity Study. Sprague-Dawley rats were exposed to 2000, 10,000 and 50,000 ppm of HFC-245fa. There was an unexpected mortality of lactating dams in the medium and high dose group beginning at day 10 of lactation. Statistically significant histopathological alterations were observed in the cerebellum of a total of 9/30 females of the high dose group of the F0-generation and in 10/27 females of the high dose group of the F1-generation. In contrast there were no brain lesions found in males or non-pregnant females of all dose groups. Neuronal necrosis and degeneration in the cerebellar cortex were observed as the most severe finding. Furthermore vacuolation of the neuropil in different degrees was diagnosed in 7/30 females of the F0-generation and in 9/30 females of the F1-generation. Acute hemorrhages - in particular perivascular - occurred in 5/30 females of the F0- and in 5/30 females of the F1-generation indicating a disturbed vascular integrity. The main lesions found in the cerebrum were glial scars in the corpus callosum and restricted to 2/30 females of the F0-generation of the high dose group. The increased incidence of myocardial fibrosis and mononuclear cell infiltration in males - indicating myocarditis - was only seen in the F0-generation of the high dose group. Females of the F1-generation of the high dose group showed an increased incidence of minimal myocardial fibrosis. In summary, histopathology revealed that the brain, particularly the cerebellum, and to a minor degree the heart turned out to be the toxicological target organs of the substance. Presumably substance-related energy deprivation may be responsible for the observed changes. One of the metabolites, 3,3,3-trifluoropropanoic acid has been shown to be capable of causing this effect.

Keywords: Brain lesions; HFC-245a; Lactation; Mortality; Pentafluoropropane; Reproduction.