cefic-lri expression of interest formmembers.ecetoc.org/.../20140905004640-01-aimt6_prop… ·...

Please note the following: - Limit your proposal to 15 pages.- The text should be submitted as a Microsoft Word document by email (PDF formatted, or print-outs,

documents, will not be accepted).- Additional documents such as curriculum vitae of the Principal Investigator (highlighting evidence of the

expertise, and contributions to the areas of science and technology relevant to this proposal) and additional references/bibliography, are to be sent as annexes

PROJECT PROPOSAL FOR SUBMISSION TO A CEFIC-LRI REQUEST FOR PROPOSALSName of organisation (administering grant if approved)

BASF SE

Contact person details Family Name KolleTitle (Dr, Prof etc.) Dr. First Name Susanne

Address Carl-Bosch-Str. 38

67056 Ludwigshafen

Germany

Telephone No. +49 621 60-56731 Fax No. +49 621 60-58043E-mail [email protected] of the research proposal

Evaluation of animal-free eye irritation test systems for industrial chemicals - increase of database and development of testing strategy

RfP Identifier # LRI-AIMT6RfP Title Eye irritation testing in vitro in practice – Database and testing strategy

Add Collaborators as necessary (names and institutions)

Collaborator 1 Dr. Sylvia Escher

Job title Group Manager Structure Activity Relationships

Affiliation Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM)

Address Nikolai-Fuchs-Strasse 1

30625 Hannover

Germany

Email [email protected]

Telephone No. +49 511 5350-330

Fax No. +49 511 5350-335

Collaborator 2 David J Esdaile

Job title Scientific Director

Affiliation CiToxLAB - Hungary

LRI RfP Expression of Interest of 17 04/05/2023

mailto:[email protected]


Address H-8200 Veszprem

Szabadsagpuszta

Hungary


Telephone No. +36 88 545 242

Fax No. +36 88 545 301

Collaborator 3 Dr. Albrecht Poth

Job title Deputy Director/Scientific Advisor

Affiliation Harlan Laboratories Germany

Address In den Leppsteinswiesen 19

64380 Roßdorf

Germany


Telephone No. +49-6154-807266

Fax No. +49-6154-83399

Collaborator 4 Dr. Kerstin Tegethoff

Job title Regulatory Toxicologist

Affiliation Bayer Pharma AG

Address Aprather Weg 18a

42096 Wuppertal

Germany


Telephone No. +49 202 36 8013

Fax No. +49 202 36 8839

Collaborator 5 Dr. Wera Teubner

Job title Regulatory Toxicologist

Affiliation BASF Schweiz AG

Address Klybeckstrasse 141

CH-4057 Basel

Switzerland


Telephone No. +41 61 63-66399

Fax No. +41 61 63-61304

Collaborator 6 Prof. Dr. Hans-Werner VohrLRI RfP Expression of Interest of 17 04/05/2023





Job title Principal Expert and Head of Immunotoxicology

Affiliation Bayer Pharma AG

Address Aprather Weg 18a

42096 Wuppertal

Germany


Telephone No. +49 202 36 8811

Fax No. +49 202 36 4137

Objectives of Proposed Research

Describe the objectives of the project and the advances that it represents in relation to the current state of the science, including a description of the mechanistic basis for the proposed research.

Currently three in vitro methods for the assessment of eye irritation including the Bovine Corneal Opacity and Permeability (BCOP) test and Isolated Chicken Eye (ICE) test are accepted by authorities for the identification of severe ocular irritants and two for non-irritants. Test methods based on commercially available reconstructed human corneal tissue such as the EpiOcular Eye Irritation Test (EIT) and the Human Cornea Epithelial (HCE) test have been described promising for the identification of ocular irritants and non-irritants. OECD test guidelines for the EIT and the cell based Short-Term-Exposure (STE) Test on rabbit cornea cells are currently being drafted. The Hen’s Egg Test – Chorioallantoic Membrane (HetCam) Test has been accepted in Europe for the identification of severe ocular irritants (former DSD classification R41) but none of the available protocols has been adopted as OECD protocol. While all tests have undergone formal validation, the applicability of the test methods for industrial chemicals is not yet sufficiently analysed and the available database is limited. Therefore, the primary goal of the project is the evaluation of the in vitro eye irritation test methods’ applicability for industrial chemicals to establish testing strategies and therewith improve classification and labelling (C&L) based on in vitro eye irritation data. Besides the in vitro methods, existing computational methods will be evaluated. In total 45 substances with available and reliable in vivo data for eye irritation will be analysed by computational methods (TIMES-SS module for eye irritation, OECD Toolbox BfR eye irritation exclusion rules, expert application of BfR eye irritation rules) and in the six abovementioned in vitro methods. Using a data bank the predictivity of the individual methods will be analysed and if possible a proposal for a (chemical class specific) testing strategy will be made. Further a web application will be developed to give an open access to the data gathered in this project. The data generated in this project will help to better understand the applicability domain of the tests and can also be used to provide more specific guidance in existing or new OECD test guidelines.



Work Content

Give a detailed scientific and technical description of the proposed project identifying the different options available to meet the objectives

In this chapter a detailed description of the work content is given. The project is structured into 4 work packages (WPs), these are:

WP1: Development of a project database and web application

WP2: Test substance selection

WP3: Testing

WP4: Data analysis

The technical description to achieve the workpackge specific objectives are given in the following:

WP1: Development of a project database and web application

Objective: Development of a project database and web application

Complex datasets for each of the six assay types will be generated in this project for 45 test substances. Further existing in vivo data on eye irritation need to be analysed for compound selection in work package 2. We will therefore establish a relational project database, e.g. ACCESS or MYSQL based, to enable an efficient data documentation, exchange and analysis within the project. A database allows to link study results per assay and substance, so that substance specific as well as assay specific analyses can evaluated.

In addition a web application will be developed which will give open access to the data of this project to the public.

The database will consist of two sections:1. Substance identity e.g. CAS- number, name, structural features (smiles),PC parameters, chemical properties

2. Study data per assay (in vivo, in vitro and in silico) such as study design, study parameters/ outcome

In section 2 we will thus have the already existing in vivo data, six different in vitro assay types and in silico data in corresponding tables. Data from above given will be delivered as Excel sheets. Per test system only one type of Excel sheet is expected, in which the data needed for further analysis need to be defined (as outline in the workpackage description).

This data will be analysed relating to a common structure in order to have a comparison of all data. Design of the database will be based on this structure. Basically, data from different test systems will be imported into different database tables. Thereby, it will be possible to evaluate the data statistically within one certain test system as well as among them.

The final project database will serve as basis for the web application. The outline of the web application will be developed within the project in close cooperation with all project partners and CEFIC. The basic building blocks will be orientated to the web-application initially developed for the RepDose DB (www.fraunhofer-repdose.de).

Web pages enable search in the data and presentation of the selected result. The web application will consist of two parts: A MySQL database for the actual data storage and web pages for the presentation. The MySQL LRI RfP Expression of Interest of 17 04/05/2023

Responsibility of Partners

Breakdown overall project into work packages with an indication of partners involved in each work package, their roles and responsibilities. The interrelationship between the partners and work packages should also be indicated

BASF will have overall project management responsibility and financial oversight.

WP1: Database

Partners involved: ITEM

WP2: Test Substance Selection

Partners involved: Bayer, ITEM, BASF

Proposal for test substances will be made by Bayer, ITEM, BASF based on availability of reliable in vivo data, chemical industry’s need and other relevant data gaps identified from available databases such as the ECETOC Eye Irritation: Reference Chemicals Data Bank (ECETOC TR 48(2), 1998). BASF will be responsible for the distribution of the test substances to the partners.

WP3: Testing

Each in vitro test will be performed in a single laboratory as listed below.

WP3.1: Bovine Corneal Opacity and Permeability (BCOP) Test: BASF

WP3.2: Isolated Chicken Eye (ICE) Test: CiToxLAB

WP3.3: EpiOcular Eye Irritation Test (EIT): BASF

WP3.4: Human Cornea Epithelial (HCE) Test: Bayer

WP3.5: Hen’s Egg Test – Chorioallantoic Membrane (HetCam) Test: Bayer

WP3.6: Short-Term-Exposure (STE) Test: Harlan

WP3.7: Computational Prediction: BASF

WP4: Data Analysis

Partners involved: ITEM, BASF, Bayer

Statistical analysis of the predictivity of the in vitro tests will be conducted by ITEM. Based on the outcome testing strategies shall be proposed together with BASF and Bayere.

Project Management Structure

Give a description of the management structure. The use of PERT or GANTT or other diagrams is recommended

Coordinating activities and financial management will be carried out by BASF.

Communication and data exchange is crucial to guarantee a successful collaboration within the consortium and a continuous exchange with CEFIC. The following tools will be used to assure an effective and secure exchange of data and knowledge:

A secured Internet platform will be installed to enable data exchange e.g. the exchange of experimental data in WP 3. This platform includes a version control thus allowing to work together on deliverables and reports. We plan to use the Fraunhofer Service Livelink for this purpose (https://dms-prext.fraunhofer.de).

Two official face to face meetings are foreseen during the project (kick-off LRI RfP Expression of Interest of 17 04/05/2023

meeting, and a final meeting).

Further regular status/discussion meetings are planned between the consortium partners on a monthly basis, to enhance to work progress over the complete project time of 12 months. Because of cost and time restrictions, we plan to have teleconferences and/or online meetings by using the FhG-Netviewer tool. Netviewer allows share and view documents.

Specific milestones, decision points and timing

A clearly defined milestone plan, that identifies all critical decision points during the course of the research programme.

In the following, specific milestones for the individual workpackages are defined.

M1.1: Exchange of example data sheets ITEMM1.2: Define a consistent vocabulary ITEM/ allM1.3: Set up of first explorative database ITEMM1.4: Feedback/ improvement of DB ITEM/ all

M1.5: Import of datasets from WP2/WP3 ITEM/ allM1.6: Development of a LogIn form ITEM

M1.7: Development of a query page ITEM

M2.1: Define criteria for substance selection Bayer, ITEM, BASF

M2.2/3: Import in vivo data into project DB ITEM

M2.4: Selection of substances Bayer, ITEM, BASF

M2.5: Distribution of test substances BASF

M3.1: BCOP BASFM3.2: ICE CiToxLabM3.3: EIT BASFM3.4: HCE BayerM3.5: HetCam BayerM3.6: STE HarlanM3.7: Computational Prediction BASF

M4.1: Submission of data (M3.1-3.7) to ITEM

BASF, Bayer, Harlan, CiToxLab

M4.2: Analysis of the predictivity of theindividual assays ITEM/ all

M4.3: Proposal for testing strategiesITEM, BASF, Bayer

M4.4: Final Report BASF/ all

Kick_off meeting (F2F) allCompound selection (and consultation ofAISE and Cosmetics Europe; webinar) all

Monthly telephone conferences / webinars all

Presentation of results (F2F) all

Feb

15

Meetings and Webinars

WP4: Data Analyis

Sep

15

Oct

15

WP1: Project database (DB) and web application

WP2: Test Substance Selection

WP3: Testing

Mar

15

Apr

15

May

15

Jun

15

Jul 1

5

Aug

15

Partner

Nov

14

Dec

14

Jan

15

Details of similar ongoing or previous research (e.g., list of publications)

BASF SE and BASF Schweiz AG (BASF)

BASF is the world’s leading chemical company: Its portfolio ranges from chemicals, plastics, performance products, agricultural products and fine chemicals to crude oil and natural gas. BASF develops new technologies and uses them to meet the challenges of the future and open up additional market


opportunities. It combines economic success with environmental protection and social responsibility. BASF’s Experimental Toxicology and Ecology offer almost all toxicological and ecological studies for screening and regulatory purposes; additionally labs for toxicological modes of actions and development of alternative methods are available. Internal and publicly funded research projects and constant method development is performed by a staff of 30 scientists and 180 technicians. BASF has substantial experience in EC-, German BMBF-, industry consortia- and CEFIC-funded research and has participated in more than 40 projects. The testing facility provides more than 50 years of experience; tests are generally performed according to international guidelines (e.g. EU, OECD) under Good Laboratory Practice (GLP); animal welfare has been certified by AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care). BASF’s Laboratory for Applied Alternative Methods headed by Dr. Kolle conducts and develops regulatorily accepted and in house validated alternative methods for local tolerance including eye irritation/ corrosion, skin irritation/ corrosion, and skin sensitization. Since the 1990ies the laboratory has participated in several formal validation studies for alternative methods in the local tolerance field. The laboratory conducts approximately 800 regulatory and screening studies including about 300 in vitro eye irritation studies per year.

Dr. Susanne Kolle (biotechnologist) heads the Laboratory for Applied Alternative Methods at BASF SE since 2009. Her previous responsibilities include the Laboratory for the Development of Alternative Methods (2007-2010). In this function she was project manager for the BASF internal project “alternative toxicological methods”. She is BASF representative in the Cefic Alternatives Issue Management Team and was BASF representative in the European partnership for Alternatives to Animal testing (EPAA). Susanne Kolle has been involved and has managed several publically funded projects including the STREP “CellNanoTox”. She is also member of scientific expert groups in the field of local tolerance.

Dr. Wera Teubner (regulatory toxicologist) has supported global chemical registrations since 2005. She has a diploma in biochemistry and has been certified as a toxicologist with EUROTOX since 2005. Her responsibilities include assessment of health hazards by non-animal testing methods, with special attention the legal framework of national chemical legislations and classification and labelling.

Recent publications relevant to the project

Schrage A, Kolle SN, Moreno MC, Norman K, Raabe H, Curren R, van Ravenzwaay B, Landsiedel R. (2011) The bovine corneal opacity and permeability test in routine ocular irritation testing and its improvement within the limits of OECD test guideline 437. Altern Lab Anim. 2011 Mar;39(1):37-53.

Kolle SN, Kandárová H, Wareing B, van Ravenzwaay B, Landsiedel R. (2011) In-house Validation of the EpiOcular(TM) Eye Irritation Test and its Combination with the Bovine Corneal Opacity and Permeability Test for the Assessment of Ocular Irritation. Altern Lab Anim. 2011 Sep;39(4):365-87.

Schrage A, Gamer AO, van Ravenzwaay B, Landsiedel R. (2010) Experience with the HET-CAM method in the routine testing of a broad variety of chemicals and formulations. Altern Lab Anim. 2010 Mar;38(1):39-52.


Teubner W, Mehling A, Schuster PX, Guth K, Worth A, Burton J, van Ravenzwaay B, Landsiedel R. (2013) Computer models versus reality: how well do in silico models currently predict the sensitization potential of a substance. Regul Toxicol Pharmacol. 2013 Dec;67(3):468-85

Teubner W, Urbisch D, Mehling A, Kolle S, Ramirez T, Honarvar N, Guth K, Ravenzwaay B, Landsiedel R (2014) Measuring and Modelling Protein Binding to Predict Skin Sensitization Potentials. Poster presentation at the 16th International Workshop on Quantitative Structure-Activity Relationship in Environmental and Health Sciences Milan, Italy, June 16-20, 2014

Bayer Pharma AG (Bayer)

Bayer is a global enterprise with core competencies in the fields of health care, nutrition and high-tech materials. Our products and services are designed to benefit people and improve their quality of life. Therefore, our research has a focus on finding innovative products in the field of medicine, veterinary medicine and plant protection. Global Early Development at Bayer Pharma AG is providing a broad spectrum of Toxicology services and expertise in toxicological testing and toxicological risk identification. These services include investigations on gene and cell level as well as in tissues and in living organisms to allow Hazard Identification, Risk Assessment and Risk Management based on toxicological studies. The work is done according to GLP rules and regulations and all types of regulatory studies are performed according to internationally accepted guidelines (e.g. OECD, EU, U.S. FDA and EPA). The organization is committed to the development, recognition and use of methods which replace or refine animal studies and therefore is represented on national and international committees and take part in validation studies. Employees of the Investigational Toxicology at Bayer have years of experience and expertise in alternative test methods. This covers especially in vitro systems to determine irritant or corrosive properties of chemicals on skin and/or eyes, where several validation and optimization studies were performed in house as well as in cooperation with others. Both test methods of WP3.4 and 3.5 are routinely performed in the lab since years.

Prof. Hans-Werner Vohr is a trained biologist, whose research interests are in immunology in combination with pharmacology and toxicology. He joined Bayer AG, Wuppertal in 1989 to establish the new field of immunotoxicology in the Institute of Toxicology. In course of the time he gained experiences in this field for all kinds of substances (industrial chemicals, agrochemicals and pharmaceuticals) and was involved in several projects to optimize, establish and validate alternative test methods on this field. Beside skin sensitization irritation and corrosion is one of the major topics in the lab. He is member of several international committees. His position at Bayer Pharma AG is principal expert and head of immunotoxicology.

Dr. Kerstin Tegethoff is a biologist, active in toxicology since 1987. Besides experience in the development of in vitro test systems she has a long history in the field of industrial chemical regulatory toxicology. Her responsibilities include toxicological assessment and C&L of chemicals for REACH and other regulatory purposes (e.g. in the cosmetic area and for medical devices). Increasing emphasis is placed on the development of in vitro testing and assessment strategies for skin and eye irritation.



Heisler, E, Hoffmann, JJ, Peters, P, Ahr, HJ and Vohr HW Discrimination between local irritancy/cytotoxicity vs. immune reactions in vitro: 3D skin models as helpful tools in immunotoxicology. DgfI Meeting, Marburg; Immunobiology Vol. 206 (2002)

Heisler, E, Hoffmann, JJ, Peters, P, Ahr, HJ and Vohr, HW. Advanced Skin Test 2000 (AST-2000) as a potent in vitro tool for the characterization of skin reactions by protein fingerprinting. EUROTOX 2003, Florenz, Toxicology Letters Vol. 144 (2003)

Podola, L and Vohr, HW. 3D-Skin Models as a potent in vitro tool for the characterization of skin reactions by multiplex analysis. DGFI Meeting 2004, Maastricht; Immunobiology 224 (2004)

Vohr, HW and Heisler, E. Three-Dimensional Human Skin/Epidermal Models and Organtypic Human and Mouse Skin Explant System. In: Encyclopedic References of Immunotoxicology, H-W Vohr (Ed.), Springer, 2005

Hoffmann J, Heisler E, Karpinski S, Losse J, Thomas D, Siefken W, Ahr HJ, Vohr HW and Fuchs HW. Epidermal-Skin-Test 1000 (EST-1000) - A New Reconstructed Epidermis for in vitro Skin Corrosivity Testing. In vitro Toxicology 19, 925-9, 2005

K. Tegethoff, H. W. Vohr, G. Stropp: Assessment of in vitro eye irritation – testing strategy, Poster presentation on the 9th World Congress on Alternatives and Animal Use in the Life Sciences, August, 2014, Prague

CiToxLAB – Hungary (CiToxLAB)

CiToxLAB is an international CRO providing a comprehensive range of safety evaluation and specialty services from facilities in France, Canada, Denmark and Hungary, with a combined total in excess of 800 employees. CiToxLAB Hungary performs over 1000 regulatory studies per year for the chemical, agrochemical, personal care and pharmaceutical sectors, including a wide range of short and long term studies in different mammalian and environmental species for international registration in Japan, USA, Europe and other major world markets. The facility in Hungary has over 140 staff and has over 40 years experience in toxicology testing. Tests are generally performed according to international guidelines (e.g. EU, OECD) under Good Laboratory Practice (GLP); animal welfare has been certified by AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care). In vivo testing includes skin and eye irritation testing, with a strong commitment to in vitro testing before live animal testing where possible. In vitro irritation/corrosivity testing in eye and skin has been routine for a number of years. CiToxLAB Hungary is one of the leading world facilities for the Isolated Chicken Eye Test (OECD 438) with experience of testing about 350 materials in the model, working for a wide range of international clients.

David J Esdaile (Scientific Director) manages the scientific aspects of the Laboratory. He has been at this facility for about 10 years. His previous responsibilities working in multinational company toxicology facilities included development and implementation of in vitro and predictive methods. He was


the rapporteur for the first EC collaboration on alternatives for eye irritation in 1990, and has been closely involved with the OECD and ECVAM on the development and validation programmes for a range of skin and eye in vitro methods.

Dr Judit Hargitai (Senior Study Director) is responsible for regulatory studies in genetic toxicology in vitro in bacterial and mammalian cells, and for in vivo genetic toxicology; for LLNA sensitisation testing, immunotoxicology, ELISA analysis, and for in vitro irritation/corrosivity testing for eye and skin. She has about 20 years experience in research.


Heylings JR, Diot S, Esdaile DJ, Fasano WJ, Manning LA, Owen HM (2003)A prevalidation study on the in vitro skin irritation function test (SIFT) for prediction of acute skin irritation in vitro: results and evaluation of ECVAM Phase III. Toxicology in Vitro 17, 123-138.

Balls M; Berg N; Bruner LH; Curren RD; de Silva O; Earl LK; Esdaile DJ; Fentem JH; Liebsch M; Ohno Y; Prinsen MK; Spielmann H; Worth AP. (1999) Eye Irritation Testing: The Way Forward ATLA 27, pp. 72-77.

Whittle E, Basketter D, York M, Kelly I, Hall T, Botham P, Esdaile DJ, Gardner J. (1992) Findings of an inter-laboratory trial of the enucleated eye method as an alternative eye irritation test. Toxicology Methods 2, 30-41.

Capt A, Luzy AP, Esdaile D, Blanck O. (2007) Comparison of the human skin grafted onto nude mouse model with in vivo and in vitro models in the prediction of percutaneous penetration of three lipophilic pesticides. Regul Toxicol Pharmacol. 47, 274-87.

Harlan Laboratories Germany (Harlan)

Harlan Laboratories Germany, is a leading global contract research organization in the field of genotoxicity and in vitro alternative toxicology serving the pharmaceutical, medical device, chemical and agrochemical industries. Since the beginning of 1990 Harlan Laboratories Germany is actively working in the field of in vitro alternatives for toxicological endpoints. During that time Harlan Laboratories Germany actively participated in national and international pre-validation and validation studies (e.g. HET-CAM ring study, phototoxicity, skin corrosion and irritation, cell transformation, HET-micronucleus test). External and publicly funded projects are performed by a staff of 11 scientists and 84 lab technicians. The testing facility has more than 30 years of experience in the field of genotoxicity and cell-based assays. Tests are performed according to Good Laboratory Practice and according to the current EU and OECD guidelines.

Dr. Albrecht Poth is a biologist/toxicologist and deputy director and scientific advisor. He has more than 20 years of experience in the field of toxicology, genetic toxicology and alternative toxicology. He is board member at the In Vitro Testing Industrial Platform (IVTIP).

Dipl. Ing. Andreas Heppenheimer is a biotechnologist and acting as study director for the in vitro alternative toxicity department. He has 10 years of experience in the field of cytotoxicity testing, in vitro skin and eye


corrosion/irritation, phototoxicity and cell transformation.

Recent publications relevant to the project:

Scheel J, Heppenheimer A, Lehringer E, Kreutz J, Poth A, Ammann H, Reisinger K, Banduhn N. (2011) Classification and labeling of industrial products with extreme pH by making use of in vitro methods for the assessment of skin and eye irritation and corrosion in a weight of evidence approach. Toxicol In Vitro. 2011 Oct;25(7):1435-47.

Adler S, Basketter D, Creton S, Pelkonen O, van Benthem J, Zuang V, Andersen KE, Angers-Loustau A, Aptula A, Bal-Price A, Benfenati E, Bernauer U, Bessems J, Bois FY, Boobis A, Brandon E, Bremer S, Broschard T, Casati S, Coecke S, Corvi R, Cronin M, Daston G, Dekant W, Felter S, Grignard E, Gundert-Remy U, Heinonen T, Kimber I, Kleinjans J, Komulainen H, Kreiling R, Kreysa J, Leite SB, Loizou G, Maxwell G, Mazzatorta P, Munn S, Pfuhler S, Phrakonkham P, Piersma A, Poth A, Prieto P, Repetto G, Rogiers V, Schoeters G, Schwarz M, Serafimova R, Tähti H, Testai E, van Delft J, van Loveren H, Vinken M, Worth A, Zaldivar JM. (2011) Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010. Arch Toxicol. 2011 May;85(5):367-485.

Schroeder K, Bremm KD, Alépée N, Bessems JG, Blaauboer B, Boehn SN, Burek C, Coecke S, Gombau L, Hewitt NJ, Heylings J, Huwyler J, Jaeger M, Jagelavicius M, Jarrett N, Ketelslegers H, Kocina I, Koester J, Kreysa J, Note R, Poth A, Radtke M, Rogiers V, Scheel J, Schulz T, Steinkellner H, Toeroek M, Whelan M, Winkler P, Diembeck W. (2011) Report from the EPAA workshop: in vitro ADME in safety testing used by EPAA industry sectors. Toxicol In Vitro. 2011 Apr;25(3):589-604.

Anzai, T., Kaminishi, M. Poth A., Handley J., Satoh T. (2012) Worldwide trend in nanomaterial safety evaluation (2012) Jpn. J. Environ. Toxicol, 15 (2), 17-29

Hothorn LA, Reisinger K, Wolf T, Poth A, Fieblinger D, Liebsch M, Pirow R. (2013) Statistical analysis of the hen's egg test for micronucleus induction (HET-MN assay). Mutat Res. 2013 Sep 18;757(1):68-78.

Ashton R, De Wever B, Fuchs HW, Gaca M, Hill E, Krul C, Poth A, Roggen EL. (2014) State of the art on alternative methods to animal testing from an industrial point of view: ready for regulation? ALTEX. 2014;31(3):357-63.

Fraunhofer Institute of toxicology and experimental medicine – QSAR/databases/information systems (ITEM)

The Fraunhofer ITEM, is part of the Fraunhofer Gesellschaft, the leading non-profit organisation of applied research in Germany. With its expertise Fraunhofer ITEM supports government, national and international organisations and industry in assessing the risk of existing and new products. The group QSAR/databases (department of chemical risk assessment) is part of the department chemical risk assessment and has a long time experience in the development and analyses of toxicological databases. Currently three toxicological databases are under investigation: FeDTeX – a database on mainly 1 and 2 generation reprotoxicty studies, PafTox- a database on particle and fibre toxicity and RepDose – a database on repeated dose


toxicity studies (www.fraunhofer-repdose.de). The RepDose and FeDTeX DB are part of the CEFIC LRI toolbox (http://www.cefic-lri.org/lri-toolbox).These databases contribute to different activities in the improvement of risk assessment methodologies e.g. the development of 1. grouping/category approaches e.g. for the German BUA/ OECD/ the BMBF project Exitox, 2. a new TTC concept for inhalation exposure (Cefic LRI B8), 3. Probabilistic analyses e.g. of extrapolation factors 4. an integrated testing strategy to reduce animal testing for the endpoint repeated dose toxicity (FP6 EU project OSIRIS), and 3. validation of biomarkers for repeated dose toxicity for cosmetics (FP7 EU project Detective). Another example of a comlex database developed and maintained at Fraunhofer ITEM is the RITA database. The RITA (Registry of Industrial Toxicology Animal-data) database is operated since 1988 at Fraunhofer ITEM and the corresponding diagnostic criteria have been made available to toxicologic pathologists worldwide in 2007 when goRENI (www.goreni.org) started to implement a new nomenclature called INHAND. This information system as well as DevTox (www.devtox.org) for developmental anomalies are hosted and improved by Fraunhofer ITEM. Current members of the group Databases and Information Systems have accumulated more than 20 years of experience in this field.

Dr. Sylvia Escher is a chemist/toxicologist and group leader QSAR/ databases in the department of Chemical Risk Assessment. She has more than 7 years of experiences in the development and statistical analysis of the database RepDose to improve risk assessment methodologies.

Dr. Rupert Kellner is biologist/database developer and group leader of databases/information systems in the department of Chemical Risk Assessment. He has a long time experience in biostatistics of toxicological data and the development of databases and web applications.

Mrs. Nelly Simetska is a database developer. She has over 12 years of experience in the development, programming and maintaining of databases such as RepDose, FedTex and PafTox, as well as programming of the web application for study data entry and administration for the RITA project.


Lewin G, Escher SE, van der Burg B, Simetska N, Mangelsdorf I (2014) Structural features of endocrine active chemicals- comparison of in vivo and in vitro data. Reproductive Toxicology, submitted.

Schulz F, Batke M, Mangelsdorf I, Pohlenz-Michel Ch, Simetska N, Lewin G (2014) Sensitivity of different generations and developmental stages in studies on reproductive toxicity. Toxicol Lett. 2014 Apr 21;226(2):245-55.

Vermeire T, Aldenberg T, Buist H, Escher S, Mangelsdorf I, Paune E, Rorije E, Kroese D (2013) OSIRIS, a quest for proof of principle for integrated testing strategies of chemicals for four human health endpoints. Regul Toxicol Pharmacol., 67, 136-45.

Tluczkiewicz I, Batke M, Kroese D, Buist H, Aldenberg T, Pauné E, Grimm H, Kühne R, Schüürmann G, Mangelsdorf I, Escher SE. (2013) The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS). Regul Toxicol Pharmacol. 67, 157–169

Escher SE, Batke M, Hoffmann-Doerr S., Messinger H, Mangelsdorf I (2013)


Interspecies extrapolation based on the RepDose database—A probabilistic approach. Toxicol Lett. 2013 Apr 12;218(2):159-65.

Batke M, Escher S, Hoffmann-Doerr S, Melber C, Messinger H, Mangelsdorf I (2011) Evaluation of time extrapolation factors based on the database RepDose. Toxicol. Lett. 28;205(2)

Batke M, Aldenberg T, Escher S, Mangelsdorf I (2013) Relevance of non-guideline studies for risk assessment: the coverage model based on most frequent targets in repeated dose toxicity studies. Toxicol Lett. 2013 Apr 26;218(3):293-8

Partnering/Co-funding

An indication of additional partners and funding opportunities that can be appropriately leveraged as part of this proposal.

Other groups are working on similar projects (i.e., Cosmetics Europe Eye Irritation Task Force as well as with AISE). To avoid duplication of the in vitro testing, the test substance selection will be discussed with those two groups. Prediscussions have been initiated between those two groups and the VCI.

Fit with LRI objectives/Possible regulatory and policy impact involvements/ Dissemination

Information on the fit of this proposal with LRI objectives and an indication on how and where this research project could play a role in the regulatory and policy areas. Dissemination plans should also be laid down.

The results of this study will provide an insight in the applicability domain of the different test systems used and hence will be relevant for the revisions of adopted and newly drafted OECD TGs.

The results of this study will be submitted for publication in a peer reviewed journal and will be presented at suitable scientific conferences.

Please provide total budget as well as separate budgets for all participating organisations.

Indicative level of funding (€)Summary of Support Requested (€) Year 1 Year 2 Year 3 Year 4 Year 5 Total

Staff 300001.49 300001.49

Travel & Living Expenses

9750.00 9750.00


Consumables 78005.00 78005.00

Sub-Total 387756.49 387756.49

Indirect Costs 141091.01 141091.01

Total 528847.50 528847.50

Return to:Dr Bruno Hubesch Tel: +32 2 676 7492CEFIC-LRI Fax: +32 2 676 7433Ave E. Van Nieuwenhuyse 4 [email protected] BrusselsBelgium

Add Affiliations budget as necessary:

BASFIndicative level of funding (€)Summary of Support Requested (€) Year 1 Year 2 Year 3 Year 4 Year 5 Total

Staff 152853.50 152853.50


2500.00 2500.00

Consumables 33015.00 33015.00

Sub-Total 188368.50 188368.50

Indirect Costs 63965.00 63965.00

Total 252333.50 252333.50

This budget calculation is based on internal cost calculations (for studies performed for internal purposes) and a discount of 17% for this proposal was included.

BayerIndicative level of funding (€)Summary of Support Requested (€) Year 1 Year 2 Year 3 Year 4 Year 5 Total

Staff 72000.00 72000.00


2500.00 2500.00

Consumables 0.00 0.00

Sub-Total 74500.00 74500.00


Total 84000.00 84000.00

CiToxLABIndicative level of funding (€)Summary of Support Requested (€) Year 1 Year 2 Year 3 Year 4 Year 5 Total



Staff 22680.00 22680.00


3000.00 3000.00

Consumables 34020.00 34020.00

Sub-Total 59700.00 59700.00


Total 78600.00 78600.00

HarlanIndicative level of funding (€)Summary of Support Requested (€) Year 1 Year 2 Year 3 Year 4 Year 5 Total

Staff 33248.00 33248.00


1000.00 1000.00

Consumables 10370.00 10370.00

Sub-Total 44618.00 44618.00


Total 69750.00 69750.00

ITEMIndicative level of funding (€)Summary of Support Requested (€) Year 1 Year 2 Year 3 Year 4 Year 5 Total

Staff 19219.99 19219.99Travel & Living Expenses 750.00 750.00

Consumables 0.00 0.00

Sub-Total 19969.99 19969.99


Total 43564.00 43564.00


ANNEX

Literature Cited

Alépée N, Bessou-Touya S, Cotovio J, de Smedt A, de Wever B, Faller C, Jones P, Le Varlet B, Marrec-Fairley M, Pfannenbecker U, Tailhardat M, van Goethem F, McNamee P. (2013) Cosmetic Europe multi-laboratory pre-validation of the SkinEthicTM reconstituted human corneal epithelium test method for the prediction of eye irritation. Toxicology in Vitro 27. 1476-1488

Cooper. J. A.. Saracci. R.. & Cole. P. (1979). Describing the validity of carcinogen screening-tests. British Journal of Cancer. 39. 87-89.

ECETOC Eye Irritation: Reference Chemicals Data Bank (ECETOC TR 48(2). 1998)

ICCVAM Test Method Evaluation Report. Nov. 2006. 2010

Mehmed A, Kuseva C, Stoeva S, Kirilov K, Todorova N, Dimitrov S, Mekenyan O (2014) SAR Models for Predicting Skin and Eye Acute Toxicity Effects Posterpresention at the 16th International Workshop on Quantitative Structure-Activity Relationship in Environmental and Health Sciences Milan. Italy. June 16-20. 2014

OECD (2013a) OECD 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 (2013b) 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 (2014a) Draft Proposal for a New Test Guideline: Reconstructed Human Cornea-like Epithelium (RhCE) Test Method for Identifying Chemicals Not Requiring Classification and Labelling for Eye Irritation or Serious Eye Damage (available at http://www.oecd.org/chemicalsafety/testing/RhCE-Test-Method-for-Identifying-Chemicals-Not-Requiring%20Classification-Labelling-for-Eye-Irritation-Draft-New-TG-2014-07-25.pdf; accessed 04 Aug 2014).

OECD (2014b) Draft Proposal for a New Test Guideline: The Short Time Exposure In Vitro Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage (available at http://www.oecd.org/chemicalsafety/testing/Draft-Test-Guideline-Short-time-Exposure-Test-Method-Review-Comments-June-2014.pdf. accessed 04 Aug 2014)

Prinsen MK, Schipper ME, Wijnands MV. (2011) Histopathology in the isolated chicken eye test and comparison of different stainings of the cornea. Toxicol In Vitro. 2011 Oct;25(7):1475-9.

Rey Moreno MC; Gröters S; Kolle SN; Landsiedel R; van Ravenzwaay B (in preparation) A Semiquantitative Histopathological Method for Evaluating the Eye Irritation Potential of Agrochemical Formulations in the BCOP Assay

Schrage A, Kolle SN, Moreno MC, Norman K, Raabe H, Curren R, van Ravenzwaay B, Landsiedel R. (2011) The bovine corneal opacity and permeability test in routine ocular irritation testing and its improvement within the limits of OECD test guideline 437. Altern Lab Anim. 2011 Mar;39(1):37-53.

Scheel J. et al. (2011) Eye irritation potential: Usefulness of the HET-CAM under the Globally Harmonized System of Classification and Labeling of Chemicals (GHS). Regulatory Toxicology and Pharmacology 59. 471-492


http://www.oecd.org/chemicalsafety/testing/Draft-Test-Guideline-Short-time-Exposure-Test-Method-Review-Comments-June-2014.pdf

http://www.oecd.org/chemicalsafety/testing/Draft-Test-Guideline-Short-time-Exposure-Test-Method-Review-Comments-June-2014.pdf

http://www.oecd.org/chemicalsafety/testing/RhCE-Test-Method-for-Identifying-Chemicals-Not-Requiring%20Classification-Labelling-for-Eye-Irritation-Draft-New-TG-2014-07-25.pdf

http://www.oecd.org/chemicalsafety/testing/RhCE-Test-Method-for-Identifying-Chemicals-Not-Requiring%20Classification-Labelling-for-Eye-Irritation-Draft-New-TG-2014-07-25.pdf

Scott L. Eskes C. Hoffmann S. Adriaens E. Alepée N. Bufo M. Clothier R. Facchini D. Faller C. Guest R. Harbell J. Hartung T. Kamp H. Varlet BL. Meloni M. McNamee P. Osborne R. Pape W. Pfannenbecker U. Prinsen M. Seaman C. Spielmann H. Stokes W. Trouba K. Berghe CV. Goethem FV. Vassallo M. Vinardell P. Zuang V. (2010) A proposed eye irritation testing strategy to reduce and replace in vivo studies using Bottom-Up and Top-Down approaches. Toxicol In Vitro. 2010 Feb;24(1):1-9


cefic-lri expression of interest formmembers.ecetoc.org/.../20140905004640-01-aimt6_prop… ·...

Documents