Nonlinear kinetics of inhaled propylene glycol monomethyl ether in Fischer 344 rats following single and repeated exposures.

The kinetics of propylene glycol monomethyl ether (PGME) and its demethylated metabolite, propylene glycol (PGLY), were investigated with the aim of describing concentration- and treatment-related changes in absorption and clearance. Groups of Fischer 344 rats received either 1 or 10 daily 6-hr inhalation exposures to PGME. Single exposures were performed using both nose-only (300, 750, 1500, and 3000 ppm) and whole-body (300 and 3000 ppm) inhalation techniques, whereas multiple exposures (300 and 3000 ppm) were confined to the whole-body procedure. PGME blood levels failed to plateau during a 6-hr inhalation exposure, indicating that absorption was limited by respiration. The clearance of PGME from the blood could be described as a pseudo-zero-order process following each exposure concentration and treatment regimen examined. PGLY blood levels indicated that the demethylation of PGME to PGLY was saturated at exposure concentrations exceeding 1500 ppm. PGME blood levels were higher in male than in female rats receiving a single 3000 ppm exposure. Unlike the results from a single exposure, PGME elimination was essentially complete 24 hr after the last of 10 consecutive 3000 ppm exposures. The changes in PGME elimination following multiple 3000 ppm exposures were associated with higher in vitro levels of cytochrome P-450 and mixed-function oxidase activity. Multiple exposures to 300 ppm did not affect PGME elimination or in vitro microsomal metabolism.