In vitro dermal absorption rate testing of certain chemicals of interest to the Occupational Safety and Health Administration: Summary and evaluation of USEPA’s mandated testing

Abstract

In 2004, the United States Environmental Protection Agency (USEPA) published a final test rule in the US Federal Register requiring in vitro dermal penetration rate testing for selected industrial chemicals. The test rule described procedures for determining a permeability coefficient (Kp) and two short-term dermal absorption rates at 10 and 60 min using human cadaver skin mounted in an in vitro diffusion cell model. According to the USEPA announcement, the selected chemicals were to be spiked with their radiolabeled form and tested in either water, isopropyl myristate (IPM) or neat depending on their physical character at room temperature, their aqueous solubility, their potential to damage the skin and their ability to achieve the study endpoints as prescribed. Overall, and for the majority of chemicals, the short-term absorption rates were higher at 10 min than at 60 min and the portion of applied dose remaining in the skin at the end of the exposure period was greater than the portion of dose that had penetrated through the skin and was detected in the receptor solution. In contrast to this, the amount of chemical in the receptor solution at study termination for the Kp (steady-state) experiments was greater than the amount remaining in the skin. For the Kp experiments, which lasted from 2 to 48 h, a majority of skins exposed to neat chemical exhibited a reduced barrier function. However, integrity was mostly unaltered for skins from the short-term experiments and Kp experiments using chemicals applied either in water or IPM. Quantitative structure activity relationship (QSAR) model-predicted Kp values were in fair agreement with experimental data for those chemicals that were applied in a water vehicle when the integrity of the skin was not compromised. However, QSAR-derived Kp values were not predictive for those chemicals when applied in IPM vehicle or neat. Absorption predictions, based on the measured Kp and steady-state flux data for chemicals applied in water or neat, respectively, were comparable to measured values at both 10 and 60 min. Kp data for chemicals applied in water and the flux values for neat chemicals will be useful for making estimates of skin absorption in occupational settings. Kp measurements for chemicals applied in IPM vehicle are not envisioned to provide useful data for estimating the risk from dermal exposure to chemicals in the workplace. When available, in vitro dermal flux measurements should be combined with toxicity information in order to improve the utility of chemical skin notations.