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      Retrospective analysis of the Draize test for serious eye damage/eye irritation: importance of understanding the in vivo endpoints under UN GHS/EU CLP for the development and evaluation of in vitro test methods

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          For more than two decades, scientists have been trying to replace the regulatory in vivo Draize eye test by in vitro methods, but so far only partial replacement has been achieved. In order to better understand the reasons for this, historical in vivo rabbit data were analysed in detail and resampled with the purpose of (1) revealing which of the in vivo endpoints are most important in driving United Nations Globally Harmonized System/European Union Regulation on Classification, Labelling and Packaging (UN GHS/EU CLP) classification for serious eye damage/eye irritation and (2) evaluating the method’s within-test variability for proposing acceptable and justifiable target values of sensitivity and specificity for alternative methods and their combinations in testing strategies. Among the Cat 1 chemicals evaluated, 36–65 % (depending on the database) were classified based only on persistence of effects, with the remaining being classified mostly based on severe corneal effects. Iritis was found to rarely drive the classification (<4 % of both Cat 1 and Cat 2 chemicals). The two most important endpoints driving Cat 2 classification are conjunctiva redness (75–81 %) and corneal opacity (54–75 %). The resampling analyses demonstrated an overall probability of at least 11 % that chemicals classified as Cat 1 by the Draize eye test could be equally identified as Cat 2 and of about 12 % for Cat 2 chemicals to be equally identified as No Cat. On the other hand, the over-classification error for No Cat and Cat 2 was negligible (<1 %), which strongly suggests a high over-predictive power of the Draize eye test. Moreover, our analyses of the classification drivers suggest a critical revision of the UN GHS/EU CLP decision criteria for the classification of chemicals based on Draize eye test data, in particular Cat 1 based only on persistence of conjunctiva effects or corneal opacity scores of 4. In order to successfully replace the regulatory in vivo Draize eye test, it will be important to recognise these uncertainties and to have in vitro tools to address the most important in vivo endpoints identified in this paper.

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          Most cited references 39

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          Hen's egg chorioallantoic membrane test for irritation potential.

           N.P. Luepke (1985)
          The increasingly large number of chemicals introduced onto the market and into the environment has necessitated the monitoring of environmental materials and specimen banking, as well as the development of rapid and reliable methods for the evaluation of toxicity. The Hen's Egg Test, or Hühner-Embryonen-Test (HET) is a rapid, sensitive and inexpensive toxicity test and can give information on embryotoxicity, teratogenicity, systemic and immunopathological effects, metabolic pathways and now, in developed form, on mucous-membrane irritation potencies of chemical substances. Testing with incubated hen's eggs is a borderline case between in vivo and in vitro systems and does not conflict with ethical and legal obligations especially animal protection laws. In the special field of mucous-membrane irritation testing, a specific score and classification scheme was developed for the HET, which allows risk assessments analogous to the Draize scheme. There is a good correlation between the results for HET tests on a variety of pyrithiones, phenols and isothiazolinones, and the corresponding data based on Draize tests. HET chorioallantoic membrane testing should and could not entirely replace current irritation tests in mammals, but it can diminish the number of investigations with mammals, as well as limit or eliminate pain and injury during animal experiments and allow regulators to set priority and toxicity categories.
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            Study of intra- and interlaboratory variability in the results of rabbit eye and skin irritation tests.

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              Prevalidation of a new in vitro reconstituted human cornea model to assess the eye irritating potential of chemicals.

              This multicentre study aimed at evaluating the reliability (reproducibility) and relevance (predictivity) of a new commercially available human corneal epithelial (HCE) model (SkinEthic Laboratories, Nice, France) to assess acute ocular irritation. A prevalidation approach (protocol optimisation, transfer and performance) was followed and at each of the four participating laboratories, 20 coded reference chemicals, covering the whole range of irritancy, were tested. The compounds were applied topically to the HCE cultures and the level of cytotoxicity (tissue viability and histological analysis) was determined. Once a standardised protocol was established, a high level of reproducibility between the laboratories was observed. In order to assess the capability of the HCE model to discriminate between irritants (I) and non-irritants (NI), a classification prediction model (PM) was defined based on a viability cut-off value of 60%. The obtained in vitro classifications were compared with different in vivo classifications (e.g. Globally Harmonised System) which were calculated from individual rabbit data described in the ECETOC data bank. Although an overall concordance of 80% was obtained (sensitivity = 100% and specificity = 56%), the predictivity of the HCE model substantially increased when other sources of in vivo and in vitro data were taken into account.

                Author and article information

                +39-332-785843 ,
                Arch Toxicol
                Arch. Toxicol
                Archives of Toxicology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                28 December 2013
                28 December 2013
                : 88
                : 701-723
                [ ]Adriaens Consulting BVBA, Bellem, Belgium
                [ ]Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra, VA Italy
                [ ]The Procter & Gamble Company, Egham, Surrey, UK
                [ ]L’Oréal Research & Innovation, Aulnay Sous Bois, France
                [ ]Laboratoire Pierre Fabre, Castres, France
                [ ]Janssen Research & Development, Beerse, Belgium
                [ ]Henkel AG & Co. KGaA, Düsseldorf, Germany
                [ ]Beiersdorf AG, Hamburg, Germany
                [ ]LVMH Recherche, St. Jean De Braye Cedex, France
                [ ]Services & Consultation on Alternative Methods Sagl (SeCAM), Agno, Switzerland
                [ ]seh consulting + services, Paderborn, Germany
                © The Author(s) 2013

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                In Vitro Systems
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