Extrapolation for exposure duration in oral toxicity: A quantitative analysis of historical toxicity data

For human risk assessment, experimental data often have to be extrapolated for exposure duration, which is generally done by means of default values. The purpose of the present study was twofold. First, to derive a statistical distribution for differences in exposure duration that can be used in a probabilistic concept for combining assessment factors in risk characterization. Second, to obtain insight in the magnitude of the change in No-Observed-Adverse-Effect-Level (NOAEL) with exposure duration, which will lead to more science-based assessment factors for exposure duration. A large historical database, including 198 substances, was consulted. Ratios were calculated for pairs of NOAELs for systemic toxicity from oral toxicity studies with the same species (rats or mice, various strains) and different exposure duration categories. The Geometric Mean (GM), Geometric Standard Deviation (GSD), and the 90th and 95th percentile values were determined. The traditionally applied default factors for subacute to semichronic (10), for semichronic to chronic (10), and for subacute to chronic exposure (100) corresponded with the 93, 87, and 99-percentiles of the respective distributions. Options are presented for a set of default values and probabilistic distributions for assessment factors for exposure duration based on data from the consulted historical database.