Arch Toxicol (2014) 88:701–723 DOI 10.1007/s00204-013-1156-8
IN VITRO SYSTEMS
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 Els Adriaens · João Barroso · Chantra Eskes · Sebastian Hoffmann · Pauline McNamee · Nathalie Alépée · Sandrine Bessou‑Touya · Ann De Smedt · Bart De Wever · Uwe Pfannenbecker · Magalie Tailhardat · Valérie Zuang Received: 2 July 2013 / Accepted: 29 October 2013 / Published online: 28 December 2013 © The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract 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)
Els Adriaens and João Barroso have contributed equally to this work.
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 ( 0 at 7 ≤ day 0 on day 21 on any tissue in any animal)
13
705
Arch Toxicol (2014) 88:701–723
scores (COMaj, IRMaj, CRMaj and CCMaj) were determined for each study to examine if the majority of the animals (i.e. 2 out of 3, 3 out of 4, 3 out of 5 or 4 out of 6 animals) had a mean tissue score less than, equal to or greater than the defined threshold value(s) for classification. An UN GHS/EU CLP Category 1 (Cat 1) was assigned based on COMaj ≥ 3 and/or IRMaj > 1.5 and/or CO = 4 (observed at any time point in any rabbit during the observation period, before day 21) and/or a persistent effect (score >0 on day 21 on any tissue in any animal). An UN GHS/EU CLP Category 2 (Cat 2) classification was assigned based on 1 ≤ COMaj
IN VITRO SYSTEMS
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 Els Adriaens · João Barroso · Chantra Eskes · Sebastian Hoffmann · Pauline McNamee · Nathalie Alépée · Sandrine Bessou‑Touya · Ann De Smedt · Bart De Wever · Uwe Pfannenbecker · Magalie Tailhardat · Valérie Zuang Received: 2 July 2013 / Accepted: 29 October 2013 / Published online: 28 December 2013 © The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract 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)
Els Adriaens and João Barroso have contributed equally to this work.
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 ( 0 at 7 ≤ day 0 on day 21 on any tissue in any animal)
13
705
Arch Toxicol (2014) 88:701–723
scores (COMaj, IRMaj, CRMaj and CCMaj) were determined for each study to examine if the majority of the animals (i.e. 2 out of 3, 3 out of 4, 3 out of 5 or 4 out of 6 animals) had a mean tissue score less than, equal to or greater than the defined threshold value(s) for classification. An UN GHS/EU CLP Category 1 (Cat 1) was assigned based on COMaj ≥ 3 and/or IRMaj > 1.5 and/or CO = 4 (observed at any time point in any rabbit during the observation period, before day 21) and/or a persistent effect (score >0 on day 21 on any tissue in any animal). An UN GHS/EU CLP Category 2 (Cat 2) classification was assigned based on 1 ≤ COMaj
