___

Hackett RB, McDonald TO. Eye Irritation. In Advances in Modern Toxicology. Editors: Marzulli FN, Maibach HI, Hemisphere Publishing Corporation. Washington, DC, USA. 1991, pp. 749–815.



Wilhelmus KR. The Draize eye test. Surv Ophthalmol 2001; 45: 493–515.

Shaw A, Balls M, Clothier R, Bateman N. Predicting ocular irritancy and recovery from injury using Madin–Darby canine kidney cells. Toxicol in vitro 1991; 5: 569–71.



Wilson SL, Ahearne M, Hopkinson A. An overview of current techniques for ocular toxicity testing. Toxicology 2015;327:3246.

Stephens ML, Mak NS. History of the 3Rs in toxicity testing: from Russell and Burch to 21st century toxicology, Reducing, Refining and Replacing the Use of Animals in Toxicity Testing. Editors: Allen D, Walters M, RSC Publishing. Cambridge, UK. 2013, pp. 1–39.



Russell WMS, Burch RL, Hume CW. The Principles of Humane Experimental Technique. Methuen, London, UK. 1959.

European Commision (EC) Cosmetics Directive: Council Directive of 27 July 1976 on the approximation of the laws of the Member States relating to cosmetic products (76/768/ EEC) 1976.



SCCP. The SCCP’S Notes Of Guıdance For The Testıng Of Cosmetıc Ingredıents And Theır Safety Evaluatıon, 6th Revısıon Scientific Committee On Consumer Products 2006.



European Union (EU). Council Directive 93/35/EEC of 14 June 1993 amending for the sixth time Directive 76/768/ EEC on the approximation of the laws of the Member States relating to cosmetic products. OJ L151, 1993, 32–7.

Rogiers V, Pauwels M. Curr Probl Dermatol 36: Safety Assessment of Cosmetics in Europe. S. Karger, Basel, Switzerland. 2008.

Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther 1944; 82: 377–90



Calabrese EJ. Principles of Animal Extrapolation. Wiley Interscience, New York. 1987.



Huhtala A, Salminen L, Tähti H. Uusitalo H. Corneal models for the toxicity testing of drugs and drug releasing materials. In: Topics in multifunctional biomaterials and devices. Editors: Ashammakhi N. Biomaterials and Tissue Engineering Group. 2008.



Organisation for Economic Co-operation and Development (OECD). Acute Eye Irritation/Corrosion Guideline for Testing of Chemicals No. 405. Organisation for Economic Cooperation and Development, Paris 2014.



Barile FA. Validating and troubleshooting ocular İn vitro toxicology tests. J Pharm Toxicol Methods 2010; 61: 136–45.



Davila JC, Rodriguez RJ, Melchert RB, Acosta SL. Predictive value of İn vitro model systems in toxicology. Annu Rev Pharmacol Toxicol 1998; 38: 63–96.



Curren RD, Harbell, JW. Ocular safety: a silent (in vitro) success story. Altern Lab Anim 2002; 30: 69–74.



Prinsen MK. The Draize eye test and in vitro alternatives; a left-handed marriage? Toxicol in vitro 2006; 20: 78–81.



Maurer JK, Parker RD, Jester JV. Extent of initial corneal injury as the mechanistic basis for ocular irritation: Key findings and recommendations for the development of alternative assays. Regul Toxicol Pharmacol 2002; 36: 106–17.



NRC, Principles and Procedures for Evaluating the Toxicity of Household Substances. National Academy of Sciences Publication, Washington, DC. 1977.

Griffith JF, Nixon GA, Bruce RD, Reer PJ, Bannan EA. Dose– response studies with chemical irritants in the albino rabbit eye as a basis for selecting optimum testing conditions for predicting hazard to the human eye. Toxicol Appl Pharmacol 1980; 55: 501–13.



Lambert LA, Chambers WA, Green S, Gupta KC, Hill RN, Hurley PM, Lee CC, Lee JK, Liu PT, Lowther DK, Roberts CD, Seabaugh VM, Springer JA, Wilcox NL. The use of lowvolume dosing in the eye irritation test. Food Chem Toxicol 1993; 31: 99–103.



Jester JV, Li L, Molai A, et Maurer JK. Extent of corneal ınjury as a mechanistic basis for alternative eye irritation tests. Toxicol in vitro 2001; 15: 115–30.



Freeberg F, Griffith J, Bruce R, Bay P. Correlation of animal test methods with human experience for household products. Cutan Ocul Toxicol 1984; 3: 53–64.



Freeberg F, Hooker D, Griffith J. Correlation of animal eye test data with human experience for household products: an update. Cutan Ocul Toxicol 1986; 5: 115–23.



Ghassemi A, Sauers, L, Bruner L, Reer P, Hall R. Demonstrating the human safety of a new household cleaning (HSC) product using alternatives to the Draize eye irritation test. Presentation made at the US Society of Toxicology meeting. 1993



The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM). International Association for Soaps, ICCVAM LVET Test Method Evaluation Report: Recommendation to Discontinue Use of the Low Volume Eye Test for Ocular Safety Testing. National Institute of Environmental Heath Sciences, Triangle Park, NC NIH Publication. 2010.



Freeberg F, Nixon G, Reer P, Weaver J, Bruce R, Griffith J, Sanders III P. Human and rabbit eye responses to chemical insult. Fundam Appl Toxicol 1986; 7: 626–34.



Ubels JL, Clousing DP. In vitro alternatives to the use of animals in ocular toxicology testing. Ocul Surf 2005; 3: 126– 42.

Bagley DM, Casterton PL, Dressler WE, Edelhauser HF, Kruszewski FH, McCulley JP, Nussenblatt RB, Osborne R, Rothenstein A, Stitzel KA. Proposed new classification scheme for chemical injury to the human eye. Regul Toxicol Pharm 2006; 45: 206–13.



Hartung T. Toxicology for the twenty-first century. Nature 2009; 460: 208–12.



Organisation for Economic Co-operation and Development (OECD). Test No. 438: Isolated chicken eye test method for identifying ocular corrosives and severe irritants. OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing, Paris 2009.

Organisation for Economic Co-operation and Development (OECD). Test number 437: Bovine corneal opacity and permeability test metjod for identifying) chemicals induscing serious eye damage and ii) chemicals not requiring classification for eye irritation and serious eye damage. OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing, Paris 2009.



Burton AB, York M, Lawrence RS. The in vitro assessment of severe eye irritants. Food Cosmet Toxicol 1981; 19: 471–80.



Gautheron P, Dukic M, Alix D, Sina JF. Bovine corneal opacity and permeability test: An in vitro assay of ocular irritancy. Fundam Appl Toxicol 1992; 18: 442–9.



Prinsen MK. The chicken enucleated eye test (CEET): A practical (pre)screen for the assessment of eye irritation/ corrosion potential of test materials. Food Chem Toxicol 1996; 34: 291–6.



Griffith M, Osborne R, Munger R, Xiong X, Doillon CJ, Laycock NL, Hakim M, Song Y, Watsky MA. Functional human corneal equivalents constructed from cell lines. Science 1999; 286: 2169–72.



Takahashi Y, Koike M, Honda H, Ito Y, Sakaguchi H, Suzuki H, Nishiyama N. Development of the short time exposure (STE) test: An in vitro eye irritation test using SIRC cells. Toxicol in vitro 2008; 22: 760–70.



Organisation for Economic Co-operation and Development (OECD Fluorescein Leakage Test Method for Identifying Ocular Corrosives and Severe Irritants. OECD Guideline for the Testing of Chemicals No. 460. Organisation for Economic Cooperation and Development, Paris, France 2012.



Reader SJ, Blackwell V, O’Hara R, Clothier RH, Griffin G, Balls M. Neutral red release from pre-loaded cells as an İn vitro approach to testing for eye irritancy potential. Toxicol in vitro 1990; 4: 264–6.



Guo X, Yang XF, Yang Y, Hans R, Cai JH, Xue JY, Tan XH, Xie XP, Xiong, XK, Huang JM. Prediction of ocular irritancy of 26 chemicals and 26 cosmetic products with isolated rabbit eye (IRE) test. Biomed Environ Sci 2012; 25: 359–66.



The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM). Editor: N.I.o.E.H. Sciences, NIH Publication. ICCVAM Recommended Test Method Protocol Isolated Rabbit Eye Test Method. National Institute of Environmental Heath Sciences, Triangle Park, NC, 2010, pp. 1–15.



Organisation for Economic Co-operation and Development (OECD). Test No. 438: Isolated Chicken Eye Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage. OECD Publishing, Paris 2013.



Muir C. A simple method to assess surfactant-induced bovine corneal opacity in vitro: Preliminary findings. Toxicol Lett 1984; 22: 199–203.



Muir C. Surfactant-induced opacity of bovine isolated cornea: An epithelial phenomenon? Toxicol Lett 1987; 38: 51–4.



Tchao R. Trans-epithelial permeability of fluorescein in vitro as an assay to determine eye irritants. In: Alternative Methods in Toxicology. Editor: Goldbery A. Mary Ann Liebert, New York. 1988, pp. 271–283.



Türkiye İlaç Ve Tıbbi Cihaz Kurumu Kozmetik Ürünler Üzerinde Yapılan Hayvan Deneylerine Alternatif Test Metotlarına İlişkin Kılavuz. PDF dokümanı.



Organisation for Economic Co-operation and Development (OECD). In: Guidleines, O. (Ed.), Test No. 437: Bovine Corneal Opacity and Permeability Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage. OECD Publishing, Paris 2013.



Eskes C, Bessou S, Bruner L, Curren R, Harbell J, Jones P, Kreiling R, Liebsch M, McNamee P, Pape W. Eye irritation. Altern Lab Anim 2005; 33: 47-81.



Reichl S, Muller-Goymann CC. The use of a porcine organotypic cornea construct for permeation studies from formulations containing befunolol hydrochloride. Int J Pharm 2003; 250: 191–201.



Reichl S, Bednarz J, Muller-Goymann CC. Human corneal equivalent as cell culture model for in vitro drug permeation studies. Br J Ophthalmol 2004; 88: 560–5.



Luepke NP, Kemper FH. The HET-CAM test: An alternative to the draize eye test. Food Chem Toxicol 1986; 24: 495-6.

NICEATM, Current Status of in vitro Test Methods for Identifying Ocular Corrosives and Severe Irritants: Hen’s Egg Test– Chorioallantoic Membrane Test Method. Editor: D.o.H.a.H. Services, ICCVAM Publication, NIEHS Publication, North Carolina. 2006.



United Nations (UN). United Nations Globally Harmonized System of Classification and Labelling of Chemicals (GHS). ST/SG/AC.10/30, Fifth Revised Edition, New York and Geneva: United Nations 2013.



European Union (EU). Regulation (EC) No 1272/2008 of the European Parliament and of the 533 Council of 16 December 2008 on classification, labelling and packaging of 534 substances and mixtures, amending and repealing Directives 67/548/EEC and 535 1999/45/EC, and amending Regulation (EC) No. 1907/2006. OJEU L 2008; 353: 1–1354.



Globally harmonised system of classification and labelling of chemicals (GHS) United Nations, New York, Geneva 2011, 133-145



Courtellemont P, Pannetier M, Biesse JP, Larnicol M, Baret JP, Breda B. Evaluation of the EYTEX(TM) system in the COLIPA eye irritation program. Toxicol in vitro 1999; 13: 295–304.



Gordon VC, Kelly CP, Bergman HC. Applications of the EYTEX method. Toxicol in vitro 1990; 4:314–7.



Matsukawa K, Masuda K, Kakishima H, Suzuki K, Nakagawa Y, Matsushige C, Imanishi Y, Nakamura T, Mizutani A, Watanabe R, Shingai T, Kaneko T, Hirose A, Ohno Y. Interlaboratory validation of the in vitro eye irritation tests for cosmetic ingredients. (11) EYTEX(TM). Toxicol in vitro 1999; 13: 209–17.



Eskes C, Hoffmann S, Facchini D, Ulmer R, Wang A, Flego M, Vassallo M, Bufo M, van Vliet E, d’Abroscat F. Validation study on the Ocular Irritection 1 assay for eye irritation testing. Toxicol in vitro 2014; 28: 1046–65.



Kojima H, Hayashi K, Sakaguchi H, Omori T, Otoizumi T, Sozu T, Kuwahara H, Hayashi T, Sakaguchi M, Toyoda A. Second-phase validation study of short time exposure test for assessment of eye irritation potency of chemicals. Toxicol in vitro 2013; 27: 1855–69.



Takahashi Y, Hayashi K, Abo T, Koike M, Sakaguchi H, Nishiyama N. The short time exposure (STE) test for predicting eye irritation potential: intra- laboratory reproducibility and correspondence to Globally Harmonized System (GHS) and EU eye irritation classification for 109 chemicals. Toxicol in vitro 2011; 25: 1425–34.



Organisation for Economic Cooperation and Development 2012a. Draft OECD Guideline for (OECD). the Testing of Chemicals: The Cytosensor Microphysiometer Test Method: An İn vitro Method for Identifying Ocular 3corrosive and Severe Irritant Chemicals as Well as Chemicals Not Classified as Ocular Irritants. OECD Publishing, Paris 2012.



Engelke M, Zorn-Kruppa M, Gabel D, Reisinger K, Rusche B, Mewes K. A human hemi-cornea model for eye irritation testing: quality control of production, reliability and predictive capacity. Toxicol in vitro 2013; 1: 458–68.



Pfannenbecker U, Bessou-Touya S, Faller C, Harbell J, Jacob T, Raabe H, Tailhardat M, Alépée N, De Smedt A, De Wever B, Jones P, Kaluzhny Y, Le Varlet B, McNamee P, MarrecFairley M, Van Goethem F. Cosmetics Europe multi-laboratory pre-validation of the EpiOcular™ reconstituted human tissue test method for the prediction of eye irritation. Toxicol in vitro 2013; 27: 619-26.



Scott L, Eskes C, Hoffmann S, Adriaens E, Alépée N, Bufo M, Clothier R, Facchini D, Faller C, Guest R, Harbell J, Hartung T, Kamp H, Le Varlet B, Meloni M, McNamee P, Osborne R, Pape W, Pfannenbecker U, Prinsen M, Seaman C, Spielman H, Stokes W, Trouba K, Van den Berghe C, Van Goethem F, Vassallo M, Vinardell P, Zuang V. A proposed eye ırritation testing strategy to reduce and replace in vivo studies using bottom-up and top-down approaches. Toxicol in vitro 2010; 24: 1-9.



Fox DA, Boyes WK. Toxic Responses of the Ocular and Visual System. In Cassaret and Doull’s Toxicology: The Basic Science of Poisons. Editor: Klaassen CD. 7th Edition, Withby, ON, McGraw-Hill Ryerson. Canada. 2008, pp. 665–697.



Jester JV, Li HF, Petroll WM, Parker RD, Cavanagh HD, Carr GJ, Smith B Maurer JK. Area and depth of surfactant ınduced corneal ınjury correlates with cell death. Invest Ophthalmol Vis Sci 1998; 39: 922–36.

Jester JV, Petroll WM, Bean J, Parker RD, Carr GJ, Cavanagh HD, Maurer JK. Area and depth of surfactant-ınduced corneal injury predicts extent of subsequent ocular responses. Invest Ophthalmol Vis Sci 1998; 39: 2610–25.



Jester JV. Extent of corneal ınjury as a biomarker for hazard assessment and the development of alternative models to the draize rabbit eye test. Cutan Ocul Toxicol 2006; 25: 41–54.

Castro-Munozledo F. Corneal epithelial cell cultures as a tool for research, drug screening and testing. Exp Eye Res 2008; 86: 459–69.

Freeman, SJ, Alépée N, Barroso J, Cole T, Compagnoni A, Rubingh C, Eskes C, Lammers J, McNamee P, Pfannenbecker U, Zuang V. Prospective validation study of reconstructed human tissue models for eye irritation testing. ALTEX 27, Special Issue 2010; 261-266.

EC EURL ECVAM. Eye Irritation Validation Study (EIVS): Statistical Analysis of the Data Generated Under SOP ver 8.0 of EpiOcular™ EIT (Solid Test Substances, Laboratory Beiersdorf), 2014, pp. 21.

EC EURL ECVAM. Validation Study Report on the EURL ECVAM - Cosmetics Europe Prospective Validation Study of Reconstructed Human Corneal Epithelium-Based Test Methods for Identifying Chemicals not Requiring Classification and Labelling for Serious Eye Damage/Eye Irritation Testing. 2014.

EC EURL ECVAM. (Eye Irritation İn vitro Assay Validation: Selection of Test Item Chemicals (EpiOcular™ Eye Irritation Test and SkinEthic™ Human Cornea Epithelium). Validation Management Group report. 2014.



TNO. Eye Irritation Validation Study on Human Tissue Models: Statistical Analysis and Reporting on the EpiOcular™ EIT. TNO Report TNO2013 R10396 Final, pp. 165. (Manuscript in Preparation) 2014.



Organisation for Economic Cooperation and Development 2012a. Draft OECD Guideline for (OECD). Reconstructed human Cornea-like Epithelium (RhCE) test method for identifying chemicals not requiring classification and labelling for eye irritation or serious eye damage No. 492. Organisation for Economic Cooperation and Development, Paris 2015.



Kaluzhny Y, Kandárová H, Hayden P, Kubilus J, d’ArgembeauThornton L, Klausner M. Development of the EpiOcular™ eye ırritation test for hazard ıdentification and labelling of eye iritating chemicals in response to the requirements of the EU cosmetics directive and REACH legislation. Altern Lab Anim 2011; 9: 339-64.



Kaluzhny Y, Kandárová H, d’Argembeau-Thornton L, Hayden De Luca J, Hayden P, Hunter P, Klausner M. Optimization of the EpiOcularTM eye irritation test for hazard identification and labelling of chemicals in response to the requirements of the EU Cosmetic Directive and REACH Legislation, Congress of the European Societies of Toxicology (EUROTOX) 2013; 222: 156.



Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55-63.



Doucet O, Lanvin M, Thillou C, Linossier C, Pupat C, Merlin B, Zastrow L. Reconstituted human corneal epithelium: a new alternative to the Draize eye test for the assessment of the eye irritation potential of chemicals and cosmetic products. Toxicol in vitro 2006; 20: 499–512.



Van Goethem F, Adriaens E, Alepee N, Straube F, De Wever B, Cappadoro M, Catoire S, Hansen E, Wolf A, Vanparys P. Prevalidation of a new in vitro reconstituted human cornea model to assess the eye irritating potential of chemicals. Toxicol in vitro 2006; 20: 1–17.



Zuang V, Schäffer M, Tuomainen AM, Amcoff P, Bernasconi C, Bremer S, Casati S, Castello P, Coecke S, Corvi R, Griesinger C, Janusch Roi A, Kirmizidis G, Prieto P, Worth A, Munn S, Berggren E, Whelan M. In: European Commission JRC, Editor: Institute for Health and Consumer Protection, EURL ECVAM Progress Report on the Development, Validation and Regulatory Acceptance of Alternative Methods (20102013). Prepared in the Framework of Directive 76/768/EEC and Regulation (EC) No 1223/2009 on Cosmetic Products. Publications Office of the European Union, Luxembourg, 2013, pp. 1–63.

Jung KM, Lee SH, Ryu YH, Jang WH, Jung HS, Han JH, Seok SH, Park JH, Son Y, Park YH. A new 3D reconstituted human corneal epithelium model as an alternative method for the eye irritation test. Toxicol in vitro 2011; 25: 403–10.



McLaughlin CR, Tsai RJF, Latorre MA, Griffith M. Bioengineered corneas for transplantation and İn vitro toxicology. Front Biosci 2009; 14: 3326–37.

86. Wilson SE, Liu JJ, Mohan RR. Stromal–epithelial interactions in the cornea. Prog Retin Eye Res 1999; 18: 293–309.

Wilson SL, Yang Y, El Haj AJ. Corneal stromal cell plasticity: İn vitro regulation of cell phenotype through cell–cell interactions in a three-dimensional model. Tissue Eng Part A 2014; 20: 225–38.

Netzlaff F, Lehra CM, Wertzb PW, Schaefera UF. The human epidermis models EpiSkinw, SkinEthicw and EpiDerm: An evaluation of morphology and their suitability for testing phototoxicity, irritancy, corrosivity, and substance transport.  Eur J Pharm Biopharm 2005; 60: 167–78.

Vinardell MP. The use of non-animal alternatives in the safety evaluations of cosmetics ingredients by the Scientific Committee on Consumer Safety (SCCS). Regul Toxicol Pharmacol 2015; 71: 198-204.