Evaluation of time extrapolation factors based on the database RepDose

Abstract

In chemical risk assessment for many substances only short-term animal studies are available for the evaluation of long-term human exposure. Therefore usually extrapolation factors (EF) are used to extrapolate NOAELs from existing short-term studies to NOAELs for long term exposure. In this report time EFs are derived, based on NOEL/C or LOEL/C ratios (short term N(L)OEL/long term N(L)OEL) from the large datasets of the database RepDose (www.fraunhofer-repdose.de) on repeated dose toxicity for oral or inhalation administration. Within a tiered approach several sources of variability, e.g. use of LOEL/C ratios or differences in dose spacing were analyzed and if needed subsequently excluded. The reduction of data variability resulted in “final” EFs datasets, which are as far as possible based on compound-specific, time-dependent differences in toxicity. For distribution functions of oral repeated dose toxicity studies characterised by GM, GSD and 90th percentiles the following data are obtained: subacute-to-subchronic – GM 1.3, GSD 2.4, 90th 4.0, subacute-to-chronic – GM 3.4, GSD 3.7, 90th 18.2, and subchronic-to-chronic – GM 1.4, GSD 2.1, 90th 3.6. The number of data for inhalation exposure is limited, but with regard to systemic toxicity the derived EFs confirm the respective oral EFs.