Exposure-triggered reproductive toxicity testing under the REACH legislation: a proposal to define significant/relevant exposure.

Under the new REACH legislation, toxicological testing is required in relation to annual tonnages produced or imported. Requirements for toxicological information increase when production volume increases. The respective information requirements are laid down in the REACH Annexes VII-X. Concerning human toxicology, certain toxicological tests may be waived under specific conditions. Aside from waiving criteria such as technical feasibility, exposure plays a decisive role in the waiving process with the consequence that toxicological testing will not be required in case of "no relevant exposure", "limited exposure", "no exposure" or "no significant exposure" (as expressed in the documents). However, up to now criteria are lacking which precisely define these terms. Attempts have been made to establish cut-off criteria between "non-relevant" and "relevant" (detrimental) exposure based on external exposure concentrations and the threshold of toxicological concern (TTC) principle. In this paper we make a proposal and describe a strategy how to define the currently insufficiently described terms "relevant/significant" exposure. We propose to define relevant/significant exposure based on an endpoint-specific TTC approach, starting from a comparison of the tentative external exposure to the specific TTC. This can be followed by a refinement of exposure estimates and may culminate in the experimental determination of internal and target tissue exposure. This strategy enables a well-founded assessment of what "no relevant exposure" is and safeguards an appropriate level of protection of the general population. The feasibility of the approach is demonstrated for reproductive toxicity endpoints.