hazard classification

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Acute Oral Toxicity Testing: Scientific Evidence and Practicability Should Govern Three Rs Activities

Roland Buesen, Uwe Oberholz, Ursula G. Sauer and Robert Landsiedel

Acute oral toxicity is determined for regulatory hazard classification or non-classification. The European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) recommends the following modules for acute oral toxicity testing: a) the use of the in vitro 3T3 Neutral Red Uptake (NRU) test to identify substances not requiring classification and to estimate starting doses for in vivo acute oral toxicity studies; and b) the use of data from sub-acute toxicity studies to identify substances not requiring classification. However, the application of these modules in a regulatory context would require a predefined, validated and formally accepted testing strategy and data interpretation procedure, which are not available. Furthermore, the application of the 3T3 NRU assay for starting dose estimations could in fact increase the number of animals used. Finally, only very few substances exist for which data from sub-acute or other repeated dose studies are available, but data from acute studies are not. Therefore, in practice, the prediction of acute toxicity by using sub-acute toxicity data is generally irrelevant. It could even lead to a risk of overdosing in the range-finding study, which may result in the death of many or all of the animals used.

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Local Tolerance Testing Under REACH: Accepted Non-animal Methods Are Not on Equal Footing with Animal Tests

Ursula G. Sauer, Erin H. Hill, Rodger D. Curren, Susanne N. Kolle, Wera Teubner, Annette Mehling and Robert Landsiedel

In general, no single non-animal method can cover the complexity of any given animal test. Therefore, fixed sets of in vitro (and in chemico) methods have been combined into testing strategies for skin and eye irritation and skin sensitisation testing, with pre-defined prediction models for substance classification. Many of these methods have been adopted as OECD test guidelines. Various testing strategies have been successfully validated in extensive in-house and inter-laboratory studies, but they have not yet received formal acceptance for substance classification. Therefore, under the European REACH Regulation, data from testing strategies can, in general, only be used in so-called weight-of-evidence approaches. While animal testing data generated under the specific REACH information requirements are per se sufficient, the sufficiency of weight-of-evidence approaches can be questioned under the REACH system, and further animal testing can be required. This constitutes an imbalance between the regulatory acceptance of data from approved non-animal methods and animal tests that is not justified on scientific grounds. To ensure that testing strategies for local tolerance testing truly serve to replace animal testing for the REACH registration 2018 deadline (when the majority of existing chemicals have to be registered), clarity on their regulatory acceptance as complete replacements is urgently required.

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