An Integrated Decision-tree Testing Strategy for Eye Irritation with Respect to the Requirements of the EU REACH Legislation

Grindon, Christina; Combes, Robert; Cronin, Mark T.D.; Roberts, David W.; Garrod, John F.

doi:10.1177/026119290803600109

Cited by 8 publications

(5 citation statements)

References 72 publications

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“…Substances belonging to the 1 to 10 ton per annum tonnage band should use in vitro methods; above this tonnage the use of the Draize test is recommended (Grindon et al, 2008). Recent progress in the validation of alternative methods (Vinardell and Mitjans, 2008; Hartung, 2010) supports their use in weight-of-evidence evaluations, but no method to fully replace the animal test has yet been accepted.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Draize eye irritation testing and its prediction by mining publicly available 2008-2014 REACH data

Luechtefeld

2016

ALTEX

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SummaryPublic data from ECHA online dossiers on 9,801 substances encompassing 326,749 experimental key studies and additional information on classification and labeling were made computable. Eye irritation hazard, for which the rabbit Draize eye test still represents the reference method, was analyzed. Dossiers contained 9,782 Draize eye studies on 3,420 unique substances, indicating frequent retesting of substances. This allowed assessment of the test’s reproducibility based on all substances tested more than once. There was a 10% chance of a non-irritant evaluation after a prior severe-irritant result according to UN GHS classification criteria. The most reproducible outcomes were the results negative (94% reproducible) and severe eye irritant (73% reproducible).To evaluate whether other GHS categorizations predict eye irritation, we built a dataset of 5,629 substances (1,931 “irritant” and 3,698 “non-irritant”). The two best decision trees with up to three other GHS classifications resulted in balanced accuracies of 68% and 73%, i.e., in the rank order of the Draize rabbit eye test itself, but both use inhalation toxicity data (“May cause respiratory irritation”), which is not typically available.Next, a dataset of 929 substances with at least one Draize study was mapped to PubChem to compute chemical similarity using 2D conformational fingerprints and Tanimoto similarity. Using a minimum similarity of 0.7 and simple classification by the closest chemical neighbor resulted in balanced accuracy from 73% over 737 substances to 100% at a threshold of 0.975 over 41 substances. This represents a strong support of read-across and (Q)SAR approaches in this area.

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Section: Introductionmentioning

confidence: 99%

Analysis of Draize eye irritation testing and its prediction by mining publicly available 2008-2014 REACH data

Luechtefeld

2016

ALTEX

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“…We have proposed several integrated testing schemes (ITS) for toxicity testing, 68 based on the recommendations made by the authors of the various chapters in the book, as well as on previously published ITS that were developed as part of a research project to generate testing strategies for prioritisation of chemicals for further evaluation in the EU REACH legislation. [69][70][71][72][73][74][75][76][77] These schemes are for: general chemicals (Fig. 1); cosmetic ingredients (Fig.…”

Section: Integrated Testing Strategiesmentioning

confidence: 99%

“…This ITS scheme could be used, for example, for compliance with the EU REACH system and US HPV system, to provide the required comprehensive set of information for new chemicals and so-called 'missing' information for existing chemicals. It is based on proposals made during the FRAME/Liverpool John Moores University/Defra REACH project, [69][70][71][72][73][74][75][76][77] and some of the other chapters in this book, and incorporates some of the ITS proposed as part of that project. These individual ITS schemes, which can be downloaded free from www.frame.org.uk, include animal tests, but these should only be used as a last resort (as explained in box 13, above).…”

Section: Integrated Testing Strategiesmentioning

confidence: 99%

“…In the case of the scheme for general chemicals, in vitro carcinogenicity testing is followed by relevant in vitro target organ toxicity tests, according to published ITS strategies, with the above corollary. These tests are to be selected and used in relation to previous data on target organs and are as follows: acute systemic toxicity; 70 skin sensitisation; 76 skin corrosion and irritation; 75 eye irritation; 73 and developmental and reproductive toxicity. 72 In addition, the chemical needs to be tested for environmental toxicity.…”

Section: Integrated Testing Strategiesmentioning

confidence: 99%

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The Use of Integrated and Intelligent Testing Strategies in the Prediction of Toxic Hazard and in Risk Assessment

Balls

Combes²,

Bhogal

2012

Advances in Experimental Medicine and Biology

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There is increasing concern that insurmountable differences between humans and laboratory animals limit the relevance and reliability for hazard identification and risk assessment purposes of animal data produced by traditional toxicity test procedures. A way forward is offered by the emerging new technologies, which can be directly applied to human material or even to human beings themselves. This promises to revolutionise the evaluation of the safety of chemicals and chemical products of various kinds and, in particular, pharmaceuticals. The available and developing technologies are summarised and it is emphasised that they will need to be used selectively, in integrated and intelligent testing strategies, which, in addition to being scientifically sound, must be manageable and affordable. Examples are given of proposed testing strategies for general chemicals, cosmetic ingredients, candidate pharmaceuticals, inhaled substances, nanoparticles and neurotoxicity.

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“…An introduction to integrated testing has been given by van Leeuwen et al (7). Many ITS have been proposed in the scientific literature (8)(9)(10)(11)(12)(13)(14), although relatively few have been agreed at the regulatory level and published in regulatory guidance documents (15). While the details of published ITS differ, they are all based on the concept of combining the use of different testing and non-testing methods in an optimal manner, in order to: a) increase the efficiency and effectiveness of hazard and risk assessments; b) minimise costs; and c) reduce, replace and refine animal testing where possible, while at the same time ensuring sufficient protection of human health and the environment.…”

Section: The Concept Of Integrated Testing Strategiesmentioning

confidence: 99%

Overcoming Barriers to Validation of Non-animal Partial Replacement Methods/Integrated Testing Strategies: The Report of an EPAA–ECVAM Workshop

et al. 2009

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The use of Integrated Testing Strategies (ITS) in toxicological hazard identification and characterisation is becoming increasingly common as a method for enabling the integration of diverse types of toxicology data. At present, there are no existing procedures and guidelines for the construction and validation of ITS, so a joint EPAA WG5–ECVAM workshop was held with the following objectives: a) to investigate the role of ITS and the need for validation of ITS in the different industry sectors (pharmaceuticals, cosmetics, chemicals); b) to formulate a common definition of ITS applicable across different sectors; c) to explore how and when Three Rs methods are used within ITS; and d) to propose a validation rationale for ITS and for alternative methods that are foreseen to be used within ITS. The EPAA provided a platform for comparing experiences with ITS across different industry sectors. It became clear that every ITS has to be adapted to the product type, R&D stage, and regulatory context. However, common features of ITS were also identified, and this permitted the formulation of a general definition of ITS in a regulatory context. The definition served as a basis for discussing the needs, rationale and process of formal ITS validation. One of the main conclusions was that a formal validation should not be required, unless the strategy will serve as full replacement of an in vivo study used for regulatory purposes. Finally, several challenges and bottlenecks to the ITS validation were identified, and it was agreed that a roadmap on how to address these barriers would be established by the EPAA partners.

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An Integrated Decision-tree Testing Strategy for Eye Irritation with Respect to the Requirements of the EU REACH Legislation

Cited by 8 publications

References 72 publications

Analysis of Draize eye irritation testing and its prediction by mining publicly available 2008-2014 REACH data

Analysis of Draize eye irritation testing and its prediction by mining publicly available 2008-2014 REACH data

The Use of Integrated and Intelligent Testing Strategies in the Prediction of Toxic Hazard and in Risk Assessment

Overcoming Barriers to Validation of Non-animal Partial Replacement Methods/Integrated Testing Strategies: The Report of an EPAA–ECVAM Workshop

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