Linking internal dosimetries of the propyl metabolic series in rats and humans using physiologically based pharmacokinetic (PBPK) modeling

The metabolic series approach has successfully linked internal dosimetries of metabolically related compounds reducing cost and time for chemical risk assessments. Here, we developed a physiologically based pharmacokinetic (PBPK) model in rats and humans for the propyl metabolic series including propyl acetate, 1-propanol, propionaldehyde, and propionic acid. Manufacturers use these compounds as organic solvents and intermediates during chemical synthesis. Public exposures can occur through using consumer products containing propyl compounds like cosmetics, aerosol sprays, or foods, and occupational exposures can occur at manufacturing facilities. To develop the PBPK model, we measured in vitro metabolism of propyl acetate in blood and liver S9 fractions. We measured concentrations of propyl compounds in blood following intravenous (iv) infusion of 13C-propanol or 13C-propionic acid and closed chamber inhalation exposures to propyl acetate or propanol in rats. Using these studies and other published data, we modified an existing PBPK model for the butyl metabolic series to simulate time course concentrations of propyl compounds in rats and humans. Consistent with measured in vitro and in vivo data, the optimized propyl series model predicts rapid clearance of propyl acetate, higher concentrations of propanol in blood from propyl acetate inhalation compared to propanol inhalation in rats but not in humans, and low concentrations of propionic acid in blood from exposures to propyl acetate or propanol. Regulators can use this model as a tool for propyl compound risk assessment by linking internal dosimetries under various exposure scenarios.