Time extrapolation in regulatory risk assessment: The impact of study differences on the extrapolation factors.

In human risk assessment, time extrapolation factors (EFs) account for differences in exposure duration of experimental studies. We calculated EFs based on N(L)OEL (no (lowest) observed effect level) ratios, dividing shorter-term by longer-term values. The 'oral' datasets comprised 302 EFs (subacute-subchronic) and 1059 EFs (subchronic-chronic).

Finding synergies for the 3Rs - Repeated Dose Toxicity testing: Report from an EPAA Partners' Forum.

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners' Forum on repeated dose toxicity (RDT) testing to identify synergies between industrial sectors and stakeholders along with opportunities to progress these in existing research frameworks. Although RTD testing is not performed across all industrial sectors, the OECD accepted tests can provide a rich source of information and play a pivotal role for safety decisions relating to the use of chemicals. Currently there are no validated alternatives to repeated dose testing and a direct one-to-one replacement is not appropriate.

Derivation of an inhalation TTC for the workplace based on DNEL values reported under REACH.

The Threshold of Toxicological Concern (TTC) concept defines a generic tolerable exposure for chemicals of unknown toxicity below which the risk of adverse health effects is considered very small. The original concept was refined and extended over the years, based either on differentiated structural classes or on additional information on certain toxicological endpoints. Initially, the focus of the TTC application was only on systemic toxic effects after repeated oral intake and consisted of one value.

Interspecies extrapolation based on the RepDose database--a probabilistic approach.

Repeated dose toxicity studies from the RepDose database (DB) were used to determine interspecies differences for rats and mice. NOEL (no observed effect level) ratios based on systemic effects were investigated for three different types of exposure: inhalation, oral food/drinking water and oral gavage. Furthermore, NOEL ratios for local effects in inhalation studies were evaluated.

Evaluation of time extrapolation factors based on the database RepDose.

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.