Two-Year Vapor Inhalation Chronic/Oncogenicity Study and Evaluation of Hepatic and Renal Cellular Proliferation, P450 Enzyme Induction and Protein Droplet Nephropathy with Cover Letter dated 06/02/1999

摘要

This study evaluated the potential chronic toxicityloncogenicity and the response of liver and kidney tissue of Fischer 344 rats to propylene glycol monomethyl ether (PGME) at targeted vapor concentrations of 0, 300, 1000 or 3000 ppm. Groups of 50 male and female rats per sex were whole-body exposed under dynamic airflow conditions for 6 hours/day, 5 days/week for up to 2 years. Parameters evaluated included the general appearance and demeanor of animals, in-life body weights, survival, hematology, urinalysis and clinical chemistry determinations, survival, selected organ weights, gross and microscopic pathologic changes and tumor incidence. In addition, the metabolic and morphological bases for PGME-induced sedation, hepatic hypertrophy and renal toxicity were characterized in separate groups of male and female rats exposed to PGME for 6, 12 or 18 months. Hepatic enzyme induction and cellular proliferation, as well as renal cellular proliferation and accumulation of alpha2u-globulin (males only) in the kidneys, were conducted in these separate groups of animals. PGME-induced sedation at 3000 ppm resolved in all animals during the second week of exposure in conjunction with the appearance of adaptive changes in the liver (cytochrome P450 induction and hepatocellular proliferation). Cytochrome P450 (pentoxyresorufin O- demethylase) activities dropped to near control eoncentrations by week 52, coinciding with a return of sedation at 3000 ppmPGMB. In male rats, the loss of metabolic adaptation was followed by a dose-related increase in altered hepatocellular foci after two years of exposure to 1000 or 3000 ppm PGME. The kidney toxicity observed in male rats was confirmed immunohistochemically as an alpha2u- globulin nephropathy. No statistically-identified increases in tumors were observed in any tissue however, a numerical increase in kidney tumors (3/50) was observed in male rats from the intermediate exposure level with 1/50 observed at 3000 ppm PGMB. The lack of statistical significance or a dose response relationship in renal tumors, in conjunction with the induction of the male rat-specific alpha2u- globulin nephropathy, render these minimal renal observations irrelevant for human assessment purposes (EPA, 1991). In conclusion, PGME did not cause a dose-related increase in tumors in male or female rats exposed to 0, 300, 1000 or 3000 ppm PGME vapor for 6 hours/day, 5 days/week for up to two years. A NOEL of 300 ppm PGME was established for this study.