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Predicting chemicals that may cause skin allergy - validated non-animal methods do not miss chemicals requiring activation

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Mar 01, 2016
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In order to inform ongoing discussions at the regulatory level in the EU, the JRC's European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), supported by a group of experts, analysed the extent to which validated non-animal methods are able to correctly identify chemicals that need to be activated to acquire skin sensitisation potential.

Significant progress has been made in the development, validation and regulatory acceptance of in chemico and in vitro test methods for skin sensitisation. Although these methods have been shown to perform well when compared to conventional animal tests (Local Lymph Node Assay, LLNA) and available human data, concerns have been raised on the regulatory acceptability of negative results since it was questioned whether these methods are able to predict chemicals that need to be activated to act as sensitisers.

At an expert meeting hosted by EURL ECVAM on 10-11 November 2015, a group of experts analysed a list of 127 chemicals with available LLNA and in vitro data. Of these, 22% were considered to be pre-haptens (i.e. chemicals requiring abiotic activation) and/or pro-haptens (i.e. chemicals requiring enzyme-mediated activation) to act as sensitisers. The pre-haptens, constituting the vast majority of chemicals requiring activation, were mostly correctly identified by both the in chemico and in vitro cell-based assays whereas the pro-haptens, which represent a small subset of sensitising chemicals, were identified correctly by at least one of the cell-based assays.

It was concluded that negative in vitro data should be accepted unless there is sufficient evidence to demonstrate that a substance is likely to be a pro-hapten that is only activated through metabolic biotransformation.

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Silvia Casati, Karin Aschberger, David Asturiol, David Basketter, Sabcho Dimitrov, Coralie Dumont, Ann-Therese Karlberg, Jean-Pierre Lepoittevin, Grace Patlewicz, David W. Roberts and Andrew Worth; Ability of non-animal methods for skin sensitisation to detect pre- and pro-haptens: Report and recommendations of an EURL ECVAM expert meeting; EUR 27752 EN; doi:10.2788/01803