REACH, non-testing approaches and the urgent need for a change in mind set.

The objectives of REACH cannot be achieved under the current risk assessment approach. A change in mind set among all the relevant stakeholders is needed: risk assessment should move away from a labor-intensive and animal-consuming approach to intelligent and pragmatic testing, by combining exposure and hazard data effectively and trying to group chemicals (category approaches). The focus should be on reducing the overall uncertainties of 30,000 chemicals while acknowledging the existence of the uncertainty paradox: reducing uncertainty in the assessment of individual chemicals following the classical chemical-by-chemical approach as we have in previous decades will result in a prolongation of uncertainty for the entire group of 30,000 chemicals as a whole. With the first REACH registration deadline (2010) rapidly approaching, a mind set change is urgently needed. We can speed up the regulatory acceptance process, starting with the maximum use of currently available exposure and hazard data, tools and models. Optimal use should also be made of experimental exposure and hazard data generated under REACH. Only such an approach will make it possible to obtain a sufficient level of information within the time frame of REACH. A much more intensive dialogue between stakeholders is necessary.

Improving the applicability of (Q)SARs for percutaneous penetration in regulatory risk assessment.

The new regulatory framework REACH (Registration, Evaluation, and Authorisation of Chemicals) foresees the use of non-testing approaches, such as read-across, chemical categories, structure-activity relationships (SARs) and quantitative structure-activity relationships (QSARs). Although information on skin absorption data are not a formal requirement under REACH, data on dermal absorption are an integral part of risk assessment of substances/products to which man is predominantly exposed via the dermal route. In this study, we assess the present applicability of publicly available QSARs on skin absorption for risk assessment purposes. We explicitly did not aim to give scientific judgments on individual QSARs. A total of 33 QSARs selected from the public domain were evaluated using the OECD (Organisation for Economic Co-operation and Development) Principles for the Validation of (Q)SAR Models. Additionally, several pragmatic criteria were formulated to select QSARs that are most suitable for their use in regulatory risk assessment. Based on these criteria, four QSARs were selected. The predictivity of these QSARs was evaluated by comparing their outcomes with experimentally derived skin absorption data (for 62 compounds). The predictivity was low for three of four QSARs, whereas one model gave reasonable predictions. Several suggestions are made to increase the applicability of QSARs for skin absorption for risk assessment purposes.

Inhalation toxicity studies: OECD guidelines in relation to REACH and scientific developments.

The OECD Health Effects Test Guidelines (TGs) provide guidance concerning the use of methods for the identification and characterization of hazards from chemical substances. These TGs are largely based on tests in routine use for many years and are known to yield information relevant to various types of toxicity. They have proven their value in practice and will remain of paramount importance for decades to come. However, the TGs describe mostly animal assays, and there is an increasingly strong urge to reduce animal testing on ethical grounds. In addition, assessment procedures are generally considered too slow and too rigid, which has resulted in elaborate testing of a relatively small number of chemicals, while virtually nothing is known about the vast majority of compounds. The major objectives of Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) are to improve the knowledge about the properties and use of chemicals and to speed up the procedure of risk assessment. The REACH text contains information requirements that can be met by OECD TGs but REACH also provides rules for adaptation of the standard testing regime. Also, various components of "Intelligent Testing Strategies" are described in order to limit animal testing. This paper briefly describes the OECD TGs for inhalation toxicity studies, including those in preparation, and their role in future hazard identification. This will be discussed in relation to the evaluation of the safety of thousands of chemicals in a relatively short period of time and scientific developments, including the use of alternatives to animal testing.

Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients.

The threshold of toxicological concern (TTC) has been used for the safety assessment of packaging migrants and flavouring agents that occur in food. The approach compares the estimated oral intake with a TTC value derived from chronic oral toxicity data for structurally-related compounds. Application of the TTC approach to cosmetic ingredients and impurities requires consideration of whether route-dependent differences in first-pass metabolism could affect the applicability of TTC values derived from oral data to the topical route. The physicochemical characteristics of the chemical and the pattern of cosmetic use would affect the long-term average internal dose that is compared with the relevant TTC value. Analysis has shown that the oral TTC values are valid for topical exposures and that the relationship between the external topical dose and the internal dose can be taken into account by conservative default adjustment factors. The TTC approach relates to systemic effects, and use of the proposed procedure would not provide an assessment of any local effects at the site of application. Overall the TTC approach provides a useful additional tool for the safety evaluation of cosmetic ingredients and impurities of known chemical structure in the absence of chemical-specific toxicology data.

Development of a QSAR for worst case estimates of acute toxicity of chemically reactive compounds.

Future EU legislations enforce a fast hazard and risk assessment of thousands of existing chemicals. If conducted by means of present data requirements, this assessment will use a huge number of test animals and will be neither cost nor time effective. The purpose of the current research was to develop methods to increase the acceptability of in vitro data for classification and labelling regarding acute toxicity. For this purpose, a large existing database containing in vitro and in vivo data was analysed. For more than 300 compounds in the database, relations between in vitro cytotoxicity and rat or mouse intravenous and oral in vivo LD50 values were re-evaluated and the possibilities for definition of mechanism based chemical subclasses were investigated. A high in vitro-in vivo correlation was found for chemicals classified as irritants. This can be explained by a shared unspecific cytotoxicity of these compounds which will act as the predominant mode of action for both endpoints, irritation and acute toxicity. For this subclass, which covered almost 40% of all compounds in the database, the LD50 values after intravenous dosing could be predicted with high accuracy. A somewhat lower accuracy was found for the prediction of oral LD50 values based on in vitro cytotoxicity data. Based on this successful correlation, a classification and labelling scheme was developed, that includes a hazard based definition of the applicability domain (irritants) and a prediction of the labelling of compounds for their acute iv and oral toxicity. The scheme was tested by an external validation.

In vitro predictions of skin absorption of caffeine, testosterone, and benzoic acid: a multi-centre comparison study.

To obtain better insight into the robustness of in vitro percutaneous absorption methodology, the intra- and inter-laboratory variation in this type of study was investigated in 10 European laboratories. To this purpose, the in vitro absorption of three compounds through human skin (9 laboratories) and rat skin (1 laboratory) was determined. The test materials were benzoic acid, caffeine, and testosterone, representing a range of different physico-chemical properties. All laboratories performed their studies according to a detailed protocol in which all experimental details were described and each laboratory performed at least three independent experiments for each test chemical. All laboratories assigned the absorption of benzoic acid through human skin, the highest ranking of the three compounds (overall mean flux of 16.54+/-11.87 microg/cm(2)/h). The absorption of caffeine and testosterone through human skin was similar, having overall mean maximum absorption rates of 2.24+/-1.43 microg/cm(2)/h and 1.63+/-1.94 microg/cm(2)/h, respectively. In 7 out of 9 laboratories, the maximum absorption rates of caffeine were ranked higher than testosterone. No differences were observed between the mean absorption through human skin and the one rat study for benzoic acid and testosterone. For caffeine the maximum absorption rate and the total penetration through rat skin were clearly higher than the mean value for human skin. When evaluating all data, it appeared that no consistent relation existed between the diffusion cell type and the absorption of the test compounds. Skin thickness only slightly influenced the absorption of benzoic acid and caffeine. In contrast, the maximum absorption rate of testosterone was clearly higher in the laboratories using thin, dermatomed skin membranes. Testosterone is the most lipophilic compound and showed also a higher presence in the skin membrane after 24 h than the two other compounds. The results of this study indicate that the in vitro methodology for assessing skin absorption is relatively robust. A major effort was made to standardize the study performance, but, unlike in a formal validation study, not all variables were controlled. The variation observed may be largely attributed to human variability in dermal absorption and the skin source. For the most lipophilic compound, testosterone, skin thickness proved to be a critical variable.