Derivation of evidence-based oral-to-parenteral uncertainty factors for medical device toxicological risk assessment.

Uncertainty factors (UFs) are used in toxicological risk assessment to address uncertainty when extrapolating from available data to intended exposure scenarios. In medical device biocompatibility evaluation, oral toxicity data are frequently extrapolated to parenteral exposures, for which ISO 10993-17 specifies a default oral-to-parenteral UF of 10. Although the standard permits lower values when bioavailability data are available, such data are uncommon for medical device constituents. In this study, in silico physiologically based pharmacokinetic (PBPK) modeling was used to estimate oral bioavailability for 7697 chemicals identified in a published medical device constituent database. Single-dose oral and intravenous exposures were modeled using the National Toxicology Program Integrated Chemical Environment PBPK tool, and plasma area under the curve (AUC) values were used to calculate bioavailability. Most constituents exhibited moderate to high oral bioavailability, with nearly half exceeding 90%. The lower fifth percentile of the bioavailability distribution was 14.56%, corresponding to an oral-to-parenteral UF of 6.87 (rounded to 7). These results support a default oral-to-parenteral UF of 7 for medical device toxicological risk assessment. In addition, as 42.1% of chemicals in the database had bioavailability values modeled, it is highly probable that toxicologists can utilize chemical-specific or structurally similar analogue bioavailability estimates.