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DETERMINATION OF SKIN IRRITATION POTENTIAL USING THE EPISKIN TM

RECONSTITUTED HUMAN EPIDERMIS MODEL PROJECT NUMBER:

AUTHOR: N Warren

STUDY SPONSOR: TEST FACILITY: Harlan Laboratories Ltd Shardlow Business Park Shardlow Derbyshire DE72 2GD 

## UK Telephone: +44 (0) 1332 792896 Facsimile: +44 (0) 1332 799018PROJECT NUMBER: , PAGE 2


### QUALITY ASSURANCE REPORT This study type is classed as short-term. The standard test method for this study type ("General Study Plan" in OECD terminology) was reviewed for compliance once only on initial production. Inspection of the routine and repetitive procedures that constitute the 

### study is carried out as a continuous process designed to encompass the major phases at or about the time this study was in progress. In additian, inspection of general facilities 

### not specifically related to this study are done monthly or annually in accordance with QA Standard Procedure. This report has been audited by the Quality Assurance Unit, and is considered to be an accurate account of the data generated and of the procedures followed. In each case, the outcome of QA evaluation is reported to the Study Director and 

### Management on the day of evaluation. Audits of study documentation, and process inspections appropriate to the type and schedule of this study were as follows:

19 November 2008 Standard Test Method Compliance Audit 16 April 2009 Test Material Preparation 

### 15 April 2009 Test System Preparation 16 April 2009 Exposure 21 April 2009 Assessment of Response § 26 May 2009 Draft Report Audit § Date of QA Signature Final Report Audit § Evaluation specific to this study



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### DATE: .

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## 09

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## JUN 2009

............. Forthe QualityAssurance Unit'

*Authorised QA S§gnatures: Manager, Quality Assurance: J G Riley BSc (Hons) MRQA 

### Deputy Head of Department: JM Crowther MIScT MRQA Senior Audit Staff: G Wren ONC MRQAPROJECT NUMBER' PAGE 3



### GLP COMPLIANCE STATEMENT The work described was performed in compliance with UK GLP standards (Schedule 1, Good Laboratory Practice Regulations 1999 (SI 1999/3106 as amended by SI 2004/0994)). These Regufations are in accordance with GLP standards published as OECD Principles on Good Laboratory Practice (revised 1997, ENV/MC/CHEM(98)17); and are in accordance with, and implement, the requirements of Directives 200419/EC and 2004/101EC. This report fully and accurately reflects the procedures used and data generated.

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# Z. ........................ ...... .......... DATE:

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# MVJ.&.t /....9......... N Warren MIAT Study Director

This report may be presented in final form as a digital (pdf) document. Such documents are preparetl by scanning the paper originai, and are considered of equivaient integrity and authenticity to versions produced by optical photocopy. However, in all cases the hand-signed paper original, held in secure archives, is the definitive documenLPROJECT NUM6ER: ' PAGE 4



### CONTENTS QUALITY ASSURANCE REPORT 2 GLP COMPL(ANCE STATEMENT 3 CONTENTS 4 SUMMARY 5 1. INTRODUCTION 7 2. TEST MATERIAL 

# a 2.1 Description, Identification and Storage Conditions 8 2.2 Preparation of Test Material 8 3. NEGATIVE AND POSITIVE CONTROL MATERIALS 8 3.1 Preparation of Negative and Positive Control Materials, MTT and Acidified Isopropanol 8 4. EPfSKIN TM

Model Kit 9 5. PROCEDURE 9 5.1 Pre-Test 9 5.2 Main Test 10 6. [NTERPRETATION OF RESULTS 12 6.1 Quantitative MTT Assessment (percentage tissue viability) 12 6.2 Quality Criteria 12 7. ARCHIVES 13 8. RESULTS 14 8.1 Direct MTT Reduction 14 8.2 Test Material, Positive Control Material and Negative Control Material 14 83 Quality Criteria 14 9. CONCLUSION 14 10, REFERENCES 15 Table 1 Mean OD$40 Values and 

### % Viabilities for the Negative Control Material,

Positive Control Material and Test Material 16 Table 2 Qualitative Evaluation of Tissue Viability (MTT uptake visual

evaluation) 17 Appendfx 1 Certificate of Analysis 18 Appendix 2 Statement of GLP Compliance in Accordance with Directive 200419/EC 20PROdECT NUMBER: ' PAGE 5



### DETERMINATION OF SKIN IRRITATION POTENTIAL USING THE EPISKIN TM

RECONSTITUTED HUMAN EPIDERMIS MODEL

SUMMARY 

### Introduction. The purpose of this test was to evaluate the skin irritation potential of the test material using the EPISKIN TM reconstituted human epidermis model after a treatment period of 15 minutes followed by 

## a post-exposure incubation period of 42 hours. The principle of the assay was based on the measurement of cytotoxicity in reconstituted human epidermal cultures following topical exposure to the test material by means of the colourimetric MTT reduction assay. Cell viability is measured by enzymaticreduction of the yellow MTT tetrazolium salt (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) to a blue formazan salt (within the mitochondria of viable cells) in the test material treated tissues relative to the negative controls. The concentration of the inflammatory mediator IL-1a in the culture medium retained following the 42 hour post-exposure incubation period is also determined for test materials which are found to be borderfine non-irritant based upon the MTT reduction endpoint. This complimentary end-point will be used to either confirm a non-irritant result or will be used to override the non-irritant result. Triplicate tissues were treated with the test material for an exposure period of 15 minutes. At the end of the exposure period each tissue was rinsed before incubating for approximately 42 hours. At the end of the post-exposure incubation period each tissue was taken for MTT-loading. The maintenance medium from beneeth each tissue was transferred to pre-labelled micro tubes and stored in a freezer for possible inflammatory mediator determination. After MTT loading a total biopsy of each epidermis was made and placed into micro tubes containing acidified isopropanol for extraction of formazan crystals out of the MTT-loaded tissues. At the end of the formazan extraction period each tube was mixed thoroughly and duplicate 200 pl samples were transferred to the appropriate wells of a pre-labelled 96-well plate. The optical density was measured at 540 nm. Data are presented in the form of % viability (MTT reduction in the test material treated tissues relative to negative control tissues).PROJECT tdUM6ER: ; PAGE 6



### Results: The relative mean viability of the test material treated tissues was 86.6% after a 15-minute exposure. 

### Quality criteria: The quality criteria required for acceptance of results in the test were satisfied.


### Conclusion: The test material was considered to be Non-Irritant.PROJECTNUMBER: PAGE 7



### DETERMINATION OF SKIN IRRITATION POTENTIAL USING 

### THE EPISKIN TM

RECONSTITUTED HUMAN EPIDERMIS MODEL
1. INTRODUCTION 

### The purpose of this test was to evaluate the skin irritation potential of the test material using the EPISKIN TM

reconstituted human epidermis model after a treatment period of 15 minutes followed by a post-exposure incubation period of 42 hours (1, Z. 3, 4) 

### . The principle of the assay is based on the measurement of cytotoxicity in reconstituted human epidermal cultures following topical exposure to the test material by means of the colourimetric MTT reduction assay. Cell viability 

## is measured by enzymatic reduction of the yellow MTT tetrazolium salt (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) to a blue formazan salt (within the mitochondria of viable cells) in the test material treated tissues relative to the negative controls. The concentration of the inflammatory mediator IL-1a in the culture medium retained following the 42 hour post-exposure incubation period is also determined for test materials which are found to be borderline non-irritant based upon the MTT reduction endpoint. This complimentary end-point will be used to either confirm a non-irritant result or will be used to override the non-irritant result.
The EPISKIN TDA model is a three-dimensional reconstituted human epidermis model consisting of adult human-derived epidermal keratinocytes seeded on a dermal substitute consisting of a collagen type I matrix coated with type IV collagen. A highly difPerentiated and stratified epidermis model is obtained after 13 day culture period comprising the main basal, supra basal, spinous and granular layers and a functional stratum corneum. The control group served as a common control with Harlan Laboratories Ltd Project number 2724J0007. The study was performed between 22 April 2009 and 28 April 2009.PROJECT NUMBER: PAGE 8
2. TEST MATERIAL
2.1 Description, Identification and Storage Conditions Sponsor's identification Description ambercoloured liquid Batch number : Date received 11 December 2008 Storage conditions room temperature in the dark The integrity of supplied data relating to the identity, purity and stability of the test materiaf is the responsibility of the Sponsor. A Certificate of Analysis supplied by the Sponsor is given in Appendix 1

2.2 Preparation of Test Material The test material was used as supplied.
3. NEGATIVE AND POSITIVE CONTROL MATERIALS Dulbecco's Phosphate Buffered Saline (PBS) with Ca" and Mg" was used as the negative control. Sodium Dodecyl Sulphate (SDS) was used as the positive control.
3.1 Preparation of Negative and Positive Controi Materials, MTT and Acidified

Isopropanol The negative control material was used as supplied. The positive control material was prepared as a 5% w/v aqueous dilution. A 3 mg/ml MTT stock solution was prepared in PBS. The stock solution was diluted to 0.3 mg/ml with assay medium when required. A 0.04 N concentration of hydrochloric acid in lsopropanol was prepared when required.PROJECT NUMBER: 1 PAGE 9
4. EPISKIN TM Model Kit Date received : 21 April 2009
5. PROCEDURE
5.1 Pre-Test
5.1.1 Assessment of Direct Test Material Reduction of MTT 

### 5.9.1.1 MTT dye metabo/ism, 

### cel8 

### viabffity assay The MTT assay, a colourimetric method of determining cell viabilfty, is based onreduction of the yellow tetrazolium salt (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) to a purpfe formazan dye by mitochondrial succinate dehydrogenase in viable cells.


### 5.9.1.2 Assessment 

### of Direct Test Material Reduction of MTT One limitation of the assay is possible interference of the test substance with M1T. A test substance may directly reduce MTT, thus mimicking dehydrogenase activity of the cellular mitochondria. This property of the test substance is only a problem, if at the time of the MTT test (after rinsing) there is still sufficient amounts of the test substance present on or in the tissues. In this case, the true metabolic MTT reduction and the false direct MTT reduction can be differentiated and quantified by the procedure described below.


### 5.1.9.3 Test 

### for ®frect MTT Reduction As specified, a test substance may interfere with the MTT endpoint, if it is able to directly reduce MTT and at the same time is present on or in the tissues when the MTT viability test is performed. To identify this possible interference, each test substance is checked for the ability to directly reduce MTT according to the following procedure: 10 μl of the test material was added to 2 ml of a 0.3 mg/ml MTT solution freshly prepared in assay medium. The sofution was incubated in the dark at 37°C, 5% CO2 in air for 3 hours. Untreated MTT solution was used as a control.PROJECT NUMBER:' PAGE 10 If the MTT solution containing the test substance turns blue/purple, the test substance is presumed to have reduced the MTT.

5.1.2 Pre-Incubation (Day 0: tissue arrival) 2 ml of maintenance medium, warmed fo approximately 37°C, was pipetted into the first column of 3 welfs of a pre-labelled 12-well plate. Each epidermis unit was transferred into the maintenance medium filled wells (3 units per plate). A different 12-well plate was used for the test material and each control material. The tissues were incubated at 37°C, 5°lo CO z in air for at least 24 hours.

5.2 Main Test
5.2.1 Application of Test Material and Rinsing (Day 1) 2 ml of maintenance medium, warrned to approximately 37°C, was pipetted into the second column of 3 wells of the 12-well plate. Triplicate tissues were treated with the test material for an exposure period of 15 minutes. The test material was applied topically to the corresponding tissues 

### ensuring uniform covering. 10 

## ul of the test material was applied to the epidermis surface. Triplicate tissues, treated with 10 NI of PBS, were used to serve as negative controls. Tripiicate tissues, treated with 10 NI of SDS 5% w/v, were used to serve as positive controls. To ensure satisfactory contact with the positive control material the SDS solution was spread over the entire surface of the epidermis using a pipette tip (taking particular care to cover the centre). After 7 minutes contact time the SDS solution was re-spread with a pipette tip to maintain the distribution of the SDS for the remainder of the contact period. The plate(s) were kept in the biological safety cabinet at room temperature for 15 ± 0.5 minutes. At the end of the exposure period, each tissue was removed from the well using forceps and rinsed using a wash bottle containing PBS with Ca" and Mg'. Rinsing was achieved by filling and emptying each tissue insert for approximately 40 seconds using a constant soft stream of PBS to gently remove any residual test material. The rinsed tissues were transferred to the second column of 3 wells containing 2 ml of maintenance medium in each well. The rinsed tissues were incubated at 37°C, 5% CO2 in air for approximately 42 hours.PROJECT NUMBER: PAGE 11



### 5.2.2 iNTT 

### Loading/Formazan Extracfion (Day 3) Following the 42-hour post-exposure incubation period each 12-well plate was placed onto a plate shaker for 15 ±2 minutes to homogenise the released mediators in the maintenance medium. 1.6 ml of the maintenance medium from beneath each tissue was transferred to pre-labelled micro tubes and store in a freezer at -14 to -30°C for possible inflammatory mediator determination. 2 ml of a 0.3 mg/ml MTT solution, freshly prepared in assay medium, was pipetted into the third column of 3 wells of the 12 well plate(s). The tissues were transferred to the MTT filled wells, being careful to remove any excess maPntenance niedium from the bottom of the tissue insert by blotting on absorbent paper. The tissues were incubated for 3 hours at 37°C, 5% CO 2 in air. At the end of the 3 hour incubation period each tissue was placed onto absorbent paper to dry. The tissues were examined and the degree of MTT staining evaluated (qualitative evaluation of cell viability) using the MTT Visual Scoring scheme. Following qualitative evaluation of tissue viability a total biopsy of the epidermis was made using the EPISKIN TM biopsy punch. The epidermis was carefully separated from the collagen matrix using forceps and both parts (epidermis and collagen matrix) placed into labelled 1.5 ml micro tubes containing 500 pl of acidified isopropanol, ensuring that both the epidermis and collagen matrix were fully immersed. Each tube was plugged to prevent evaporation and mixed thoroughly on a vortex mixer. The tubes were refrigerated at 1 to 10°C until Day 6 of the experiment, allowing the extraction of formazan crystals out of the MTT-loaded tissues.
5.2.3 AbsorbancelOptical Density AAeasurements (Day fi) At the end of the formazan extraction period each tube was mixed thoroughly on a vortex mixer to produce a homogenous coloured solution. For each tissue, duplicate 200 pl samples were transferred to the appropriate wells of a pre-labelled 96-well plate. 200 

## ul of acidified isopropanol alone was added to the two wells designated as 'blanks'. The optical density was measured (quantitative viability analysis) at 540 nm (without a reference filter) using the Anthos 2001 microplate reader.PROJECTNUMBER:_ PAGE 12



### 6. 1NTERPRETATI®N OF RESULTS 6.1 Quantitative MTT Assessment (percentage tissue viability) For the test material the relative mean tissue viabilities obtained after the 15 minute treatment followed by the 42 hour post-exposure incubation period were compared to the mean of the negative control treated tissues (n=3). The relative mean viabilities were calculated in the following way:
% Relative viability = mean OD. of test material x 100

mean OD 540 of negative control Classification of irritation potential is based upon relative tissue viability following the 15 minute exposure period followed by the 42 hour post-exposure incubation period according to the following table:

Criteria for in vitro interpretaGon Classification Mean tissue viabllity is <_50% irritant (I) R38 Mean tissue viability is >50% Non-Irritant (NI). 

### 6.2 Quality Criteria The results of the assay are considered acceptable if the following assay acceptance criterion is achieved:
Positive ControE The assay establishes the acceptance criterion for an acceptable test if the relative mean tissue viability for the positive control treated tissues was s40% relative to the negative control treated tissues, and the Standard Deviation (SD) value of the % viability is 520%.

•= The concentration of the inflammatory mediator IL-1a in the culture medium retained foflowing the 42 hour post-exposure incubation will be determined for test mateda4s which are found to be borderline non-irritant based upon the MTT cell viability endpoint (mean tissue viability 51 - 60%)_ This complimentary end-point will be used to either confirm a non-irritant result or will be used to override the non-irritant resuft.pROJECT NUMBER: ' PAGE 13



### Negative Control The assay establishes the acceptance criterion for an acceptable test if the mean ODeao for the negative controJ treated tissues was ?0.6, and the SD value of the % viability is <_2D%.
7. ARCHIVES 

### Unless instructed otherwise by the Sponsor, all original data and the final report will be retained in the Harlan Laboratories Ltd, Shardlow, UK archives for five years, after which instructions will be sought as to further retention or disposal.PROJECT NUMBER:: PAGE 14



### B. 

### RESULTS 8.1 Direct MTT Reduction The MTT solution containing the test material did not turn blue/purple which indicated that the test material did not directly reduce MTT.
8.2 Test Material, Positive Control Material and Negative Control Material The individual and mean OD 54 o values, standard deviations and tissue viabilities for the test material, negative control material and positive control material are given in TabPe 1. The mean viabilities and standard deviations of the test material and positive controt, relative to the negative control are also given in Table 1. The relative mean viabifity of the test material treated tissues was 86.6% after a 15-minute exposure. The qualitative evaluation of tissue viability is given in Table 2. Following the 15-minute exposure the test material treated tissues appeared blue which was considered indicative of viable tissue.
8.3 Quality Criteria 

### The relative mean tissue viability for the positive control treated tissues was :540% relative to the negative control treated tissues and the Standard Deviation (SD) value of the % viability was _<20%. The positive control acceptance criterion was therefore satisfied.
The mean OD 540 for the negative control treated tissues was ?0.6 and the SD value of the % viability was <-20%. The negative control acceptance criterion was therefore satisfied.
9. C®NCLUSION 

### The test material was considered to be Non-Irritant.PROJECT NUM6ER: PAGE 15
10. REFERENCES 1) Fentem, J.H., Briggs, D., Chesne, C., Elliott, G.R., Harbell, J.W., Heylings, J.R., Portes, P., van de Sandt, J.J.M. and P.A. Botham (2001) A prevalidation study on 

### in vitro tests for acute Skin Irritation: results and evaluation by the Management Team. Toxicology 

### in vitro 15, pp.57-93. 2) Zuang, V., Balls, M., Botham, P.A., Coquette, A., Corsini, E., Curren, R.D., Elliot, G.R., Fentem, J.H., Heylings, J.R., Liebsch, M., Medina, J., Roguet, R., van de Sandt, J.J.M., Wiemann, C. and A.P Worth (2002). Follow-up to the ECVAM prevalidation study on 

### in vitro tests for acute Skin Irritation. ECVAM Skin Irritation Task Force Report 2. ATLA 30, pp. 109-129. 3) Cotovio, J., Grandidier, M-H., Portes, P., Roguet, R. and G. Rubinsteen (2005) 

### The in vitro acute Skin Irritation of chemicals: Optimisation of the EPISKIN Prediction Model within the Framework of the ECVAM Validation Process. ATLA 33, pp.329-349. 

### 4) Hartung. T. (2007) ESAC statement on the validity of in vitro tests for skin irritation. European Commission, Directorate General, Joint Research Centre, Institute for Health and Consumer Protection, European Centre for the Validation of Alternative Methods (ECVAM). Ispra_ Website: hftp://ecvam.jrc.it/index.htm.PROJECT NUMBER: PAGE 16 JETERMINATION OP SKIN IRRITATION POTENTIAL US1NG THE EPISKIN TM

RECONSTITUTED HUMAN EPIDERMIS MODEL 

### Table 1 Mean OD540 Values and % Viabilities for the Negative Control

Material, Positive Control Material and Test Material

Material OD ~ of

tissues Mean OD

~ o

of triplicate tissues } SD of

OD ~ Relative

individual tissue° viabili /° Relative

mean % viability ± SD of °h

viability
0.927 97.5 Negative Control 0.932 0.951 0.04 98.0 100* na Material® 0.995 104.6

0.079 8.3 Positive Control Material ~ 0.042 0.04 4.4 4.1

0.045 4.7 0.001 0.1 0.814 85.6 0.793 83.4 Test Material 0.823 0.04 86.6 3.7

0.863 90.7

*= The mean viability of the negaUve control tissues is set at 100% 

### na = Not applicable ®= Control group shared with Hadan Laboratories Ltd Project number 2724/0007PROJECT NUMBER: ; PAGE 97 : DETERMINATION OF SKIN IRRITATION POTENTIAL USING THE EPISKIN TM RECONSTITUTED HUMAN EPIDERMIS MODEL 

### Table 2 Qualitative Eva[uation of Tissue Viabifity (MTT uptake visual

evaluation)

Material Tissue 1 Tissue 2 Tissue 3
Negative Control Material®

Positive Control Materiali]) ++ ++ ++
~
Test Material

MTT visual scoring scheme

= blue tissue (viable) + = blue/white tissue (semi-viable) ++ = tissue is completely white (dead)

e= Control group shared with Harlan Laboratories Ltd Project number 272410007PROJECT PAGE 18



### Appendix 1 Certificate of AnaBysis

CerEFHcete of Aneh/his

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. . _ ..... AnalyUsai Tast SpaciGcatlon Limit Methar3No. CharacterisRc Lower uppar Valua Unrt Status ABtlendurtl 00 Pa69 Or Fai1 PasS - P G6000652 DPI711BAPPEARANCE YEl.LOW Pas5 - P

(COt<Ol/R) G6000052

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(FOtiM) G8000054 DPt7f3 DLIQUR C1fARACTERISTIC.FREE Paxs - P OFOBJECTIONALODOUR G6000171 IW211BASdi 0.0 2.0 1.3 % P G$00017$ OP14l5 CC3LOUR 0.0 7.0 42 Garrfner P 06000774 Dp6J5 PH 4,5 ' 5.5 54 P G60RD177 DPi738TOTALSOUDS 20_0 2a.p 21,0 4 P GG010176 DC2t2NI7FiOC`EN 2.2 3,4 2F, % P G6020001 DM112S TQ'€AL C' ,OUNT 100 CFU/6 MA7( PasS - P Q&O'C G6020002 DM211 S YfiASTB & 100 CFUIG MAX Pass - P

MOULI7S 0 25°C G60200t1 DM7611SGRAM ABSENT Pass - P

Pepe 1.1 2PROJECT NUMBER: r ~ ~ . PAGE 19



### Appendix 1(continued) Certificate of Analysis

C®r[ificate of Analyui& r
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No_ n0. C7neYmty. OAO11 QIi Cont®cK. Pax No.

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9G I t ie t 4 commended that this prOtlrrEt be used wekhln 6 montfls af deiivery Batc3i ^ atPfus: Pass Condinned ny

Stephen Hughes

PagL20f 2PROJECT NUMBER:.. _ PAGE 20



### Appendix 2 Statetnent of GLP Compliance in Accordance with Directive

2004J9fEC 

# (D~ Department



# ~ of Health



### THW DEPA;IZTMFNT OF IIFALTR OF THE GQVERNMEIyT

OFTFIE UNITED KINGDOM GOOIi LABORiiTORY PRACCICE
- STATEMENTOFCOb4PIdANCE

.

.. IN ACCORDANCE WITH DD2ECTIVE 200491EC

18STFACI1ITY _ .. . TESTTYYE
IIarlan T,aboratories Ltd: AnalyticaVClinical Chemistry Shardlow Business Park Environmental Fate

. London Road Environmental Taxiculogy Shardlovv - Mutagen(city Dcrby

. - PhyslChem - DE722GD Toxicology -

JfAT60FII.'SPECFION 19thAugust 20DS A general inspecfion for compfiance with the Principles of Good Laboratory Practice was camed out at the above test facility as pattofthe UK GLP Compliance Programme. A[ the time of inspection no deviations were found of sufficient magnitude to affect the vaiidity of non-clinical studies perfottned at these facilitics,