Estimation of intravenous TTC (TTCiv) for Extractables and Leachables (E&Ls) by applying a modifying factor based on blood concentration predicted using an open-source PBPK model

Pharmaceutical manufacturing and storage processes pose the potential risk of chemicals migrating from the packaging materials into pharmaceuticals. These migrants, known as extractables and leachables (E&Ls), consist of various chemicals that may pose a risk to patients during therapeutic use. Although exposure to E&Ls via the intravenous route is of greater concern, there is almost no toxicity information for these chemicals to determine the Permitted Daily Exposure (PDE). The purpose of this study was to establish the Threshold of Toxicological Concern for intravenous route exposure (TTCiv) for risk management of E&Ls contained in pharmaceuticals. First, we derived the oral PDEs of 287 chemicals from a list of 923 known E&Ls. Then, the modifying factor (α) for estimating the intravenous PDE from each oral PDE was calculated based on the ratio of the predicted blood concentrations (area under the curve (AUC) and maximum blood concentration (C_max)) after oral and intravenous administration using the Integrated Chemical Environment (ICE) PBPK model. Additionally, due to uncertainty of the predictions without bioavailability information, the intravenous PDE was calculated using modifying factor 3 based on the maximum value of the root mean square error (RMSE) reported in varification of the High-Throughput Toxicokinetics (HTTK) model. In conclusion, by analyzing the distribution of the intravenous PDE for 287 chemicals, we propose a TTCiv of 27 µg/day/human, based on the ratio of C_max. Our route extrapolation approach could contribute to the establishment of scientifically valid TTCs for not only E&Ls, but also for other impurities without toxicity information.