### February 13, 2009

TSCA Document Control Officer (7407M) Office of Pollution Prevention and Toxics (NewChemicals Program) U.S. Environmental Protection Agency EPA East Building, Room4133 1201 Constitution Ave. Washington, DC 20004-3302 Subject : Premanufacture Notification Submission for TS-M034A0 Dear Sir/Madam

: 

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.1

Enclosed please find a new copy of sanitized pages 14-247 of the Premanufacture Notice TSM034A0. The new

copy of these pages is being sent at the request of Bernice Mudd with EPA and better hide the confidential information. Sincerely,p. 2

9 0 C U.S. ENVIRONMENTAL PROTECTIONAGENCY

i, rnter Me total number of-pAges n the Premanufacture Notice FormApproved. O .M .B. No. 2070-0012. Approval Expires 10-31-96.

t P as _ r 

# a ' GENERAL INSTRUCTIONS TS -

. You must provide all information requested in this formto the extent that it is known to or reasonably ascertaiitable by you. Make reasonable estimates ifyou do not have actual data. Before you complete this form, you should read the "Instructions Manual forPremanufacture Notification" (the Instructions Manual is available fromthe Toxic Substances Control Act (TSCA) Information Service by calling 202-554-1404, or faxing 202-554-5603). Pittsburgh, PA 15251-6399, Attn. TSCA User fee. If a user fee has been remitted forthis notice (40CFR700 .45), indicate in the boxes abovethe TS-user fee identification numberyou have generated. Remember, you user fee ID number must also appear on your corresponding fee remittance, which is sent to EPA, HQAccounting Operations Branch (PM-226), P .O . 360399M, Part I-GENERAL INFORMATION You must provide the currently correct Chemical Abstracts (CA) Name of the new chemical substance, even if you claimthe identity as confidential . You may authorize another person to submit chemical identity information for you, but your submissionwill not be complete and the review will not begin until EPAreceives this information. A letter insupport of your submission should reference your TS user fee identification number . You must submit an original and two copies of this notice including all test data. If you claimed any information as confidential, a single sanitized copy must also be submitted. Part II-HUMAN EXPOSURE AND ENVIRONMENTAL RELEASE If there are several manufacture, processing, or use operations to be described in Part II, sections A and B of this notice, reproduce the sections as needed. Part III-LIST OF ATTACHMENTS Attach additional sheets if there is not enough space to answer a question fully. Label each continuation sheet with the corresponding section heading. In Part III, list these attachments, any test data or other data and any optional information included in the notice. OPTIONAL INFORMATION You may include any information that you want EPA to consider in evaluating the new substance. On page 11 of this form, space has been provided for you to described pollution prevention and recycling information you may have regarding the new substance. So-called "binding" boxes are included throughout this formfor you to indicate your willingness to be bound to certain statements you make in this section, such as use, productionvolume, protective equipment . . This option is intended to reduce delays that routinely accompany the development of consent orders or Significant New Use Rules. Except in the case of exemption applications (such as TMEA, LVE, LOREX) where certain information provided in such notification is binding on the submitter when the Agency approves the exemption application, checking a binding box in this notice does not by itself prohibit the submitter fromlater deviating fromthe information (except chemical identity) reported in the form . CONFIDENTIALITY CLAIMS You may claimany information in this notice as confidential . To assert a claimon the form, mark (X) the confidential box next to the information that you claimas confidential . To assert a claim

in an attachment, circle or bracket the information you claim as confidential . If

you claim

information in the notices as confidential you must also provide a sanitized version of the notice. (including attachments) . For additional instructions on claiming information as confidential, read the Instructions Manual . ® Mark (x) if any information in this notice is claimed as confidential .

EPAFORM

7710-25 (Rev. 5-95) TEST DATA ANDOTHERDATA You are required to submit all test data in your possession or control and to provide a description ofall other data known to or reasonably ascertainable by you, if these data are related to the health and environmental effects on the manufacture, processing, distribution in commerce, use, or disposal of the new chemical substance

. Standard literature citations may be submitted fordata in the open scientific literature. Complete test data (written in English) not summaries ofdata must be submitted if they do not appear in the open literature. You should clearly identify whether test data is on the substance or on an analog. Also, the chemical composition of the tested material should be characterized. Following are examples of test data and other data. Data should be submitted according to the requirements of §720.50 of the Premanufacture Notification Rule (40 CFR Part 720) . Test Data (Check Below any included in this notice) " Environmental fate data El Yes " Other data ® Yes " Health effects data ® Yes Risk assessments " Environmental effects data 0 Yes " Physical/Chemical Properties* ® Yes M 0 L3]

* Aphysical and chemical properties worksheet is located on the last page of this form . TYPE OF NOTICE (Check Only One) ® PMN (Premanufacture Notice)

INTERMEDIATE PMN (submitted in sequence with final product PUN) SNUN (Significant New Use Notice) TMEA (Test Marketing Exemption Application) LVE (Low

Volume Exemption) @ 40 CFR 723 .50(c)(1) LOREX (Low

Release/LowExposure Exemption) @ 40 CFR723.50(c)(2) LVE Modification

on IS THIS ACONSOLIDATED PMN? 1 :1 Yes # of chemicals _ (Prenotice Communication

9 Structure/activity relationships Test data not in the possession or control of the submitter

LOREX Modification

age 3) Replaces previous editions of EPA Form77T0-25.p. 3

Public reporting burden for this collection ofinformation is estimated to average 110hours per response, including time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding the burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to Chief, lnformation Policy Branch, PM-223, U .S. Environmental Protection Agency, 401 M . St., S.W ., Washington, D

.C. 20460 ; and to the Office of Management and Budget, Paperwork ReductionAct (2070-0012), Washington, D .C. 20503 . 

### CERTIFICATION I certify that to the best of my knowledge and belief : 1 . The company named in Part I, section A, subsection 1 a ofthis notice formintends to manufacture or import for a commercial purpose, other than in small quantities solely for research and development, the substance identified in Part I, Section B. 2. All information provided in this notice is complete and truthful as ofthe date of submission. 3 . 1 am submitting with this notice all test data in my possession or control and a description ofall other data known to or reasonably ascertainable by me as required by §720.50 ofthe Premanufacture Notification Rule. Additional Certification Statements: Ifyou are submitting a PMN, Intermediate PMN, Consolidated PMN, or SNUN, check the following user fee certification statement that applies : ® The Company named in Part I, Section Ahas remitted the fee of $2500specified in 40 CFR 700 .45(b), or 0 The Company named in Part I, Section Ahas remitted the fee of $1000for an Intermediate PMN(defined @ 40 CFR 700 .43) in accordance with 40 CFR 700 .45(b), or 0The Company named in Part I Section Ais a small business concern under 40 CFR 700 .43 and has remitted a fee of $100 in accordance with 40 CFR700.45(b) . Ifyou are submitting a low volume exemption (LVE) application in accordance with 40 CFR723.50(c)(1) or a Low release and low

exposure exemption (LoRex) application in accordance with 40 CFR 723.50(c)(2), check the following certification statements: 0The manufacturer submitting this notice intends to manufacture or import the new chemical substance for commercial purposes, other than in small quantities solely for research and development, under the terms of 40 CFR723.50 . F-1 The manufacturer is familiar with the terms ofthis section and will comply with those terms; and F~ The new

chemical substance for which the notice is submitted meets all applicable exemption conditions. F~ If this application is for an LVE in accordance with 40 CFR 723.50(c)(1), the manufacturer intends to commence manufacture ofthe exempted substance for commercial purposes within 1 year of the date ofthe expiration of the 30 day reviewperiod. The accuracy of the statements you make in this notice should reflect your best prediction of the anticipated facts regarding the chemical substance described herein. An knowin g and willful misinterp retation is subject to criminal penal ty pursuant to 18 USC 1001 . Confidential Signature and title ofAuthorized Official (Original Signature Required) Date X Signature of agent -(if applicable) Date

EPA FORM

7710-25 (Rev. 5-95) Page 2Part I -- GENERAL INFORMATION

Section A -- SUBMITTER IDENTI FICATION la. Person Name of authorized official Position Submitting X Notice (in U.S.) Company

Mailing address (number and street) City, State, ZIP Code b. Agent (if Name of authorized official Position applicable) Company

Mailing address (number and street) City, State, ZIP Code Telephone ~ ' Area Code ~ Number

' c. Ifyou are submitting this notice as part of ajoint submission, mark (X) this box. 0 Joint Submitter (if Name of authorized official Position applicable) Company

Mailing address (number and street) City, State, ZIP Code Telephone ~ Area Code ~ Number 2. Technical Name of authorized official Position Contact (in X U .S.) Company

Mailing address (number and street) City, State, ZIP Code Telephone ~ Area Code ~ Number 3. If you have had a prenotice communication (PC) concerning this notice and EPA assigned a PC Number to the notice, enter the number. 10 Mark (X) -01 ® if none 4. If you previously submitted an exemption application for the chemical substance covered by this notice, enter the exemption number assigned by Mark (X) ~-10 ® EPA . Ifyou previously submitted a PMNfor this substance enter the PMN if none number assigned by EPA (i .e. withdrawn or incomplete) . - 5. If you have submitted a notice of Bona fide intent to manufacture or import for the chemical substance covered by this notice, enter the notice number Mark (X) --01 ® assigned by EPA

. ----~ if none 6. Type of Notice - Mark (X) Mark () the "Confidential" box nextto any subsection you claimas confidential

® 0 Import Only Binding Option Mark (X) I Mark (X) 1 . U Manufacture ~ 2.

Only Binding Option ~ 3. F-1 Both Confidential

EPAFORM

7710-25 (Rev

. 5-95) Replaces previous editions of EPAForm7710-25.Part I -- GENERAL INFORMATION-- Continued

Section B-- CHEMICAL IDENTITY INFORMATION : Youmust provide acurrently correct Chemical Abstracts (CA) name of the substance basedon the ninth Collective Index (9C of CA nomenclature rules and conventions . Mark (X the "Confidential" box next to any itemyou claimas confidential Complete either item1 (Class 1 or 2 substances) or 2 (Polymers) as appropriate. Complete all other items. Ifanother person will submit chemical identity information for you (for either Item 1 or2), mark (X) the box at the right. ConfiIdenti the name, company, and address ofthat p erson in a continuation sheet . 10 El dential 1 . Class 1 or 2 chemical substances (for definitions of class 1 and class 2 substances, see the Instructions Manual) a. Class ofsubstance - Mark (X) 1 [ :] Class 1 or 2 [ :] Class 2 X b. Chemical name (Currently correct Chemical Abstracts (CA) Name that is consistent with TSCA Inventory listings for similar substances. For Class 1 substances a CA Index Name must be provided. For Class 2 substances either a CA Index Name or CAPreferred Name must X be provided, which ever is appropriate based on CA 9CI nomenclature rules and conventions) .

c. Please identify which method you used to develop or obtain the specified chemical identity information reported in this notice: (check one) . Method 1 (CAS Inventory Expert Service - a copy ofthe Identification ®Method 2 (Other Source) ]I report obtained fromthe CAS Inventory Expert Services must be submitted as an attachment to this notice) d. Molecular formula and CAS Registry Number (ifa number already exists for the substance) AS# F X e. For a class 1 substance, provide a complete and correct chemical structure diagram . For a class 2 substance - (1) List the immediate precursor substances with their respective CAS Registry Numbers. (2) Describe the nature ofthe reaction or process. (3) Indicate the X range of composition and the typical composition (where appropriate) . (4) Provide a correct representative or partial chemical structure diagram, as complete as can be known, ifone can be reasonably ascertained.

® Mark (X) this box ifyou attach a continuation s h eet . Attachment 2

. EPA FORM

7710-25 (Rev. 5-95) Page 4Part I -- GENERAL INFORMATION-- Continued

Section B-- CHEMICAL IDENTITY INFORMATION-- Continued 2. Polymers (For a definition of polymer, see the Instructions Manual .) Confidential a. Indicate the number-average weight ofthe lowest molecular weight composition ofthe polymer you intend to manufacture. Indicate maximumweight percent of low molecular weight species (not including residual monomers, reactants, or solvents) below500 and below1,000absolute molecular weight ofthat composition. Describe the methods of measurement or the basis for your estimates : GPC ~ Other [] : (Specify) i) lowest number average molecular weight : ii) maximum

weight %

below 500molecular weight: iii) maximum

weight %

below1000 molecular weight: Mark (X) this box ifyou attach a continuation sheet. b . You must make separate confidentiality claims for monomer or other reactant identity, composition information, and residual information. Mark (X) the "Confidential" box next to any itemyou claimas confidential (1) - Provide the specific chemical name and CAS Registry Number (ifa number exists) ofeach monomer or other reactant used in the manufacture of

the polymer . (2) - Mark (X) this column if entry in column (1) is confidential . (3) - Indicate the typical weight percent ofeach monomer or other reactant in the polymer. (4) - Mark (X) the identity column ifyou want a monomer or other reactant used at two weight percent or less to be listed as part ofthe polymer

description on the TSCAChemical Substance Inventory. (5) - Mark (X) this column if entries in columns (3) and (4) are confidential . (6) - Indicate the maximum weight percent of each monomer or other reactant that may be present as a residual in the polymer as manufactured for commercial purposes. (7) - Mark this column ifentry in column (6) is confidential . Monomer or other reactant and CAS Registry Number Confr- Typical Identity Confi- Maximum Confidential composition Mark (X) dential residual dential (1) (2) (3) (4) (5) (6) 7

% % I ~ Mark (X) this box ifyou attach a continuation sheet. c. Please identify which method you used to develop or obtain the specified chemical identity information reported in this notice (check one) .

Method 1 (CAS Inventory Expert Service - a copy ofthe identification report F Method 2 (other source) obtained fromCAS Inventory Expert Service must be submitted as as attachment to this notice) d. The currently correct Chemical Abstracts (CA) name for the polymer that is consistent with TSCA Inventory listings for similar polymers. e . Provide a correct representative or partial chemical structure diagram, as complete as can be known, ifone can be reasonably ascertained. 

## THIS PAGE IS LEFT BLANK INTENTIONALLY.

E]Mark (X) this box ifyou attach a continuation sheet . EPA FORM

7710-25 (Rev. 5-95) Page 5

### Part I -- GENERAL INFORMATION-- Continued

Section B -- CHEMICAL IDENTITY INFORMATION-- Continued ' 3. Impurities (a) - Identify each impurity that may be reasonably anticipated to be present in the chemical substance as manufactured for commercial purpose

the CAS Registry Number if available. Ifthere are unidentified impurities, enter "unidentified ." (b) - Estimate the maximum weight %

ofeach im

puri ty. Ifthere are unidentified impurities, estimate their total weight % . . Provide Impurity and CAS Registry Number

(a) Maximum percent (b) Confidential % % % %

%

% % Mark (X) this box ifyou attach a continuation sheet. 4. Synonyms - Enter any chemical synonyms for the new chemical identified in subsection 1 or 2. Confidential Mark (X) this box ifyou attach a continuation sheet. X 5. Trade identification - Listtrade names for the new chemical substance identified in subsection 1 or 2. Mark (X) this box ifyou attach a continuation sheet. - X

6. Generic chemical name - Ifyou claimchemical identify as confidential, you must provide a generic name for your substance that reveals the specific chemical identity ofthe newchemical substance to the maximum extent possible. Refer to the TSCAChemical Substance Inventory, 1985 Edition, Appendix Bfor guidance on developing generic names. Carbon nanomaterial

Mark (X) this box ifyou attach a continuation sheet . 7. Byproducts - Describe any byproducts resulting fromthe manufacture, processing, use, or disposal of the newchemical substance. Provide the CAS Registry

Number ifavailable. Byproduct (1) CAS Registry Number (2) Confidential None known

Mark (X) this box ifyou attach a continuation sheet . EPAFORM

7710-25 (Rev. 5-95) Page 6

### Part I -- GENERAL INFORMATION-- Continued

Section C-- PRODUCTION, IMPORT, ANDUSE INFORMATION : Mark (X) the "Confidential" box next to any itemy ou claimas confidential . 1 . Production volume -- Estimate the maximumproduction volume during the first 12 months of production. Also estimate the maximum production volume for any consecutive 12-month period during the first three years of production. Estimates should be on 100%newchemical substance basis. For a Low Volume Exemption application, ifyouchoose to have your notice reviewed at a lower production volume than 10,000 kg/yr, specify the volume and mark (x) in the binding box. Ifgranted, you are bound to this volume Maximum

first 12-month production (kg/yr) Maximum12-month production (kg/yr) Confi- Binding (100%new

chemical substance basis) (100%new chemical substance basis) dential Option Mark (x) X 2. Use Information -- You must make separate confidentiality claims for the description ofthe category of use, the percent of production volume devoted to each category, the formulation of the new substance, and other use information. Mark (X) the "Confidential" Box next to any item you claimas confidential . a. (1) -- Describe each intended category of use ofthe newchemical substance by function and application. . (2) -- Mark (X) this column ifentry column (1) is confidential business information (CBI) . (3) -- Indicate your willingness to have the information provided in column (1) binding . (4) -- Estimate the percent oftotal production for the first three years devoted to each category of use. (5) -- Mark (X) this column ifentry in column (4) is confidential business information (CBI) . (6) -- Estimate the percent ofthe new substance as formulated in mixtures, suspensions, emulsions, solutions, or gels as manufactured for commercial purposes at sites under your control associated with each category ofuse . (7) -- Mark (X) this column ifentry in column (6) is confidential business information (CBI) . (8) -- Indicate %

of product volume expected for the listed "use" sectors. Mark more than one box if appropriate. Mark (X) to indicate your willingness to have the use type provided in (8) binding. (9) -- Mark (X) this column if entry(ies) in column (8) is (are) confidential business information (CBI) . Category of use (1) CBI Binding Produc- CBI % in CBI % of substance expected per use CBI Option tion % Form- (8) (by function and application i .e. a dispersive dye Mark (X) ulation Site- Con-* Indus- Com- Binding for finishing p

ol yester fibers (2) (3) (4) (5) (6) (7) limited sumer trial mercial Option (9)

X % X % X X X % X % X X X % X % X X X % X % X X

o, o, % * Ifyou have identified a "consumer" use, please provide on a continuation sheet a detailed description ofthe use(s) ofthis chemical substance in consumer products. In addition include estimates ofthe concentration ofthe newchemical substance as expected in consumer products and describe the chemical reactions by which this substance loses its identity in the consumer product . ~ Mark (X) this box if you attach a continuation sheet. b. Generic Ifyou claimany category of use description in subsection 2a as confidential, enter a generic description of that category. Read the use Instructions Manual for examples ofgeneric use descriptions. description Component of paints, coatings, and industrial composites

~ Mark (X) this box if you attach a continuation sheet. 3 . Hazard Information -- Include in the notice a copy of reasonable facsimile of any hazard warning statement, label, material safety data sheet, or other Binding information which will be provided to any person whois reasonably likely to be exposed to this substance re ardin p y p y y g g protective equipment or practices Option Muk Ixl for the safe handing, transport, use, or disposal ofthe new substance. List in part III hazard information you include. ®Mark (X) this box if you attach hazard information. Attachment 3.

EPA FORM

7710-25 (Rev. 5-95) Page 7

### Part II-- HUMAN EXPOSURE AND ENVIRONMENTAL RELEASE Section A-- INDUSTRIAL SITES CONTROLLED BY THE SUBMITTER Mark (X) the "Confidential" box next to any itemyou claimas confidential Complete section Afor each type of manufacture, processing, or use operation involving the new chemical substance at industrial sites you control . Importers do not have to complete this section for operations outside the U .S. ; however, you may still have reporting requirements if there are further industrial processing or use operations after im port. You must describe these operations. See instructions manual 1 . Operation description Confia. Identi ty -- Enter the identi ty ofthe site at which the op eration will occur. dential Name Site address (number and street) City, County, State, ZIP code If the same operationwill occur at more than one site, enter the number of sites. Identify the additional sites on a continuation sheet, and if any ofthe sites have significantly different production rates or operations, includeall the information requested in this section for those ; sites as attachments. ' Mark (X) this box ifyou attach a continuation sheet. b. Type -- Mark (X) ~ Manufacturing ~ Processing ~ Use c. Amount and Duration -- Com plete I or 2 as a

ppropriate Maximum

kg/batch (iooi new

chemicat ~ Hours/batch ~ Batches/year substance) i i 1 . Batch '

Maximumkg/batch (tooi new chemical , Hours/batch , Batches/year substance) ~

i 2. Continuous d. Process description 1 :1 Mark (X) to indicate your willingness to have your process description binding. (1) Diagram

the major unit operation steps and chemical conversions. Include interimstorage and transport containers (specify- e.g. 5 gallon pails, 55 gallon drum, rail car, tank truck, etc.). (2) Provide the identity, the approximate weight (by kg/day or kg/batch on a 100%new chemical substance basis), and entry point of all starting materials and feedstocks (including reactants, solvents, catalysts, etc.), and ofall products, recycle streams, and wastes. Include cleaning chemicals (note frequency if not used daily or per batch.) . (3) Identify by number the points ofrelease, including small or intermittent releases, to the environment ofthe new chemical substance.

®Mark (X) this box ifyou attach a continuation sheet. Attachment 4 . EPAFORM

7710-25 (Rev. 5-95) Page 8p. 10



### Part II-- HUMANEXPOSURE AND ENVIRONMENTAL RELEASE -- Continued Section A-- INDUSTRIAL SITES CONTROLLED BY THE SUBMITTER- Continued 2 . Occupational Exposure -- You must make separate confidentiality claims for the description of worker activity, physical form ofthe new

chemical substance, number ofworks exposed, and duration of activity. Mark (X) the "Confidential" box next to any itemyou claimas confidential . (1) --Describe the activities (i .e. bag dumping, tote filling, unloading drums, sampling, cleaning, etc.) in which workers may be exposed to the substance. (2) --Mark (X) this column if entry in column (1) is confidential business information (CB1) . (3) --Describe any protective equipment and engineering controls used to protectworkers. (4) and (6) -- Indicate yourwillingness to have the information provided in column (3) or (5) binding. (5) -- Indicate the physical form(s) ofthe new chemical substance (e.g., solid: crystal, granule, powder, or dust) and % newchemical substance (if part of a mixture) at the time of exposure. (7) --Mark (X) this column ifentry in column (5) is confidential business information (CBI) . (8) --Estimate the maximum number ofworkers involved in each activity for all sites combined. (9) --Mark (X) this column ifentry in column (8) is confidential business information (CBI) . (10) and (11) -- Estimate the maximumduration ofthe activity for any worker in hours per day and days per year. (12) -- Mark (X) this column ifentries in columns (10) and (11) are confidential business information (CBl) . Worker activity CBl Protective Equipment/ Binding Physical forms(s) Binding CBI # of CBl Maximum duration ~ CBI (i .e., bag dumping, filling drums)

(1) (z) Engineering Controls (3) Option

Mark (x) (4) and %

new substance (5) Option

Mark (x) (6) (7) Workers

Expose d (9) Hrs/day

(10) Days/yr

(11) (12) (8) 

## THIS PAGE IS LEFT BLANK INTENTIONALLY.

®Mark (X) this box if you attach a continuation sheet. See attachment7. 3 . Environmental Release and Disposal -- You must make separate confidentiality claims for the release number and the amount ofthe new chemical substance released and other release and disposal information. Mark (X) the "Confidential" box next to each itemyou claimas confidential . (1) --Enter the number ofeach release point identified in the process description, part II, section A, subsection ld(3) . (2) -- Estimate the amount ofthe new substance released (a) directly to the environment or (b) into control technology (in kg/day or kg/batch) . (3) --Mark (X) this column ifentries in columns (1) and (2) are confidential business information (CBI) . (4) --Identify the media (stack air, fugitive air (optional-see Instruction Manual), surface water, on-site or off-site land or incineration, POTW, or other (specify)) to which the new

substance will be released from that release point. (5) -- a. Describe control technology, ifany, and control efficiency that will be used to limit the release ofthe new substance to the environment. For releases disposed ofon land, characterize the disposal method and state whether it is approved for disposal of RCRA hazardous waste. On a continuation sheet, for each site describe any additional disposal methods that will be used and whether the waste is subject to secondary or tertiary on-site treatment, b. Estimate the amount released to the environment after control technology (in kg/day) . (6) --Mark (X) this column if entries in columns (4) and (5) are confidential business information (CBI) . (7) --Identify the destination(s) ofreleases to water. Please supply NPDES (National Pollutant Discharge Elimination System) numbers for direct discharges or NPDES numbers of the POTW (Publicly Owned Treatment Works) . Mark ifthe POTW name or NPDES # is confidential business information (CBI) . Release Amount of new substance CBI Media of Control technology and efficiency (you may wish to optionally attach efficiency data) CBI Number released release (1) (2a) (2b) (3 e .g. stackair (4) ~ Binding (5a) 1 Mark (x) (Sb) (6)

. '

(7) Mark (X) the 0 POTW provide name(s) below : CBI ~ Navigable FlOther - Specify provide NPDES# CBI destination(s) of waterway releases to water. 10 Mark (X) this box ifyou attach a continuation sheet. EPAFORM

7710-25 (Rev. 5-95) Page 9p. 11



### Part II-- HUMANEXPOSURE AND ENVIRONMENTAL RELEASE -- Continued Section B-- INDUSTRIAL SITES CONTROLLED BY OTHERS Complete section Bfor typical processing or use operations involving the new chemical substance at sites you do not control . Importers do not haveto complete this section for operations outside the U .S. ; however, you must report any processing or use activities after import. See the Instructions Manual . Complete a separate section B

for each type ofprocessing, or use operation involving the new chemical substance. If the same operation is performed at more than one site describe the typical op eration common to these sites. Identify additional sites on a continuation sheet. 1 . Operation Description -- To claiminformation in this section as confidential, circle or bracket the specific information that you claim as confidential . (1) -- Diagram

the major unit operation steps and chemical conversions, including interimstorage and transport containers (specify - e.g. 5 gallon pails, 55 gallon drums, rail cars, tank trucks, etc) . On the diagram, identify by letter and briefly describe each worker activity. (2) -- Provide the identity, the approximate weight (by kg/day or kg/batch, on an 100%new chemical substance basis), and entry point ofall feedstocks (including reactants, solvents and catalysts, etc) and all products, recycle streams, and wastes. Include cleaning chemicals (note frequency ifnot used daily or per batch) . (3) -- Identify by number the points of release, including small or intermittent releases, to the environment ofthe new chemical substance. (4) Please enter the # ofsites (remember to identify the locations of these sites on a continuation sheet) : # of sites

® Mark (X) this box if you attach a continuation sheet. Attachments 6and 7 2 . Worker Exposure/Environmental Release (1) --From

the diagramabove, provide the letter for each worker activity. Complete 2-8for each worker activity described. (2) --Estimate the number ofworkers exposed for all sites combined. (4) -- Estimate the typical duration of exposure per worker in (a) hours per day and (b) days per year. (6) --Describe physical formofexposure and %new chemical substance (if in mixture), and any protective equipment and engineering controls, ifany, used to protect workers. (7) -- Estimate the percent ofthe newsubstance as formulated when packaged or used as afinal product. (9) -- From

the process diagramabove, enter the number ofeach release point . Complete 9-13 for each release point identified. (10) -- Estimate the amount of the new substance released (a) directly to the environment or (b) into control technology to the environment (in kg/day or kg/batch) . (12) -- Describe media ofrelease i .e. stack air, fugitive air (optional-see Instructions Manual), surface water, on-site or off-site land or incineration, POTW, or other (specify) and control technology, ifany, that will be used to limit the release ofthe new substance to the environment . (14) -- Identify byproducts which may result fromthe operation. (3), (5), (8), (11), (13) and (15) -- Mark (X this column ifany of the proceeding entries are confidential business information (CBl) . Letter # of CBI Duration CBI Protective Equip. / % in CBI Release Amount of CBI Media of Release CBI of Workers of Engineering Controls/ Form- Number New &Control Act- Exposed Exposure Physical Form and % ulation Substance Technology ivity new substance Released (1) (2) (3) (4a) i (4b) (5) (6 (7) (8) (9) (l 0a) , (lOb) (I1) (12) (13) i i i i i (14) -- Byproducts: - (15) None known ®Mark (X) this box ifyou attach a continuation sheet. See attachment 8.

EPA FORM

7710-25 (Rev. 5-95) Page 10p. 12 

## OPTIONAL POLLUTION PREVENTION INFORMATION To claiminformation in this section as confidential circle or bracket the specific information that you claim as confidential . 

### In this section you mayprovide information not reported elsewhere in this formregarding your efforts to reduce or minimize potential risks associated with activities surrounding manufacturing, processing, use and disposal of the PMhT substance. Please include new informationpertinent to pollution prevention, including source reduction, recycling activities and safer processes or products available due to the new chemical substance. Source reduction includes the reduction in the amount or toxicity of chemical wastes by technological modification, process and procedure modification, product reformulation, raw materials substitution, and/or inventory control . Recycling refers to the reclamation of useful chemical components from wastes that would otherwise be treated or released as air emissions or water discharges, or land disposal . Descriptions ofpollution prevention, source reduction and recycling should emphasize potential risk reduction subsequent to compliance with existing regulatory requirements and canbe either quantitative or qualitative. The EPA is interested in the information to assess overall net reductions in toxicity or environmental releases and exposures, not the shifting of risks to other environmental media or non-environmental areas (e.g., occupational or consumer exposure) . In addition, information on the relative cost or performance characteristics ofthe P1V1N substance to potential alternatives may be provided. All information provided in this sectionwill be taken into consideration during the reviewof this substance

. See Instructions Manual and Pollution Prevention Guidance manual for guidance and exam ples. Describe the expected net benefits, such as (1) an overall reduction in risk to human health or the environment ; (2) a reduction in the volume manufactured; (3) a reduction in the generation ofwaste materials through recycling, source reduction or other means; (4) a reduction in potential toxicity or human exposure and/or environmental release ; (5) an increase in product performance, a decrease in the cost of production and/or improved operation efficiency ofthe new chemical substance in comparison to existing chemical substances used in similar application; or (6) the extent to which the new chemical substance may be a substitute for an existing substance that poses a greater overall risk to human health or the environment.

0 Mark (X) this box ifyouattach a continuation sheet .

EPAFORM

7710-25 (Rev. 5-95) Page 11

## Part III -- LIST OF ATTACHMENTS

Attach continuation sheets for sections ofthe form and test data and other data (including physical/chemical properties and structure/activity information), and optional information after this page. Clearly identify the attachment and the section ofthe form to which it relates, if appropriate. Number consecutively the pages ofthe attachments. In the column below, enter the inclusive page numbers ofeach attachment . Mark (X) the "Confidential" box next to any attachment name you claim as confidential . Read the Instructions Manual for guidance on how to claimany information in an attachment as confidential . You must include with the sanitized copy ofthe notice form a sanitized version ofan attachment in which you claiminformation as confidential . Attachment name Attachment page number(s) Confidential 1 . Material Safety Data Sheets for the PMN Substance 14-43 2. Continuation Sheet for Part I, Section B, 1 .e., Chemical Identity Information 44-46 3. Toxicity Review

and Hazard Assessment of the PMN Substance 47-53 X X X X X X X X X X X X

~ Mark (X) this box ifyou attach a continuationsheet. Enter the attachment name and number. EPAFORM

7710-25 (Rev

. 5-95) Page 12p. 14 PHYSICAL ANDCHEMICAL PROPERTIES WORKSHEET To assist EPA's review

ofphysical and chemical properties data, please complete the following worksheet for datayou provide and include it in the notice. Identify the property measured, the page ofthe notice on which the property appears, the value ofthe property, the units in which the property is measured (as necessary), and whether or not the property is claimed as confidential . The physical state ofthe neat substance should be provided. These measured properties should be for the neat (100%pure) chemical substance. Properties that are measured for mixtures or formulations should be so noted (%PMNsubstance in

__ ). You are not required to submit this worksheet; however, EPAstrongly recommends that you do so, as it will simplify review and ensure that confidential information is properly protected. You should submit this worksheet as a supplement to your submission oftest data. This worksheet is not a substitute for submission oftest data. Property Mark (x) if Page Value Measured o coniiprovided number Estimate dential Mark N (a) (b) (e) (M or E) (d) X M Physical state of neat substance X_ (s) -(1) -(g) Vapor pressure Tem p erature °C Torr Density/relative density g/cm3 Solubility Insoluble in water. Not soluble in E @ Temperature oC solvents. The PMNsubstance does form stable suspensions in dimethylformamide Solvent (after high power sonication) but in very limited quantity (about 1-10 mg/L) . Solubility in water @

Temperature °C g/L Melting tem

perature oc Boiling / sublimation temperature@ torr pressure oC Spectra Specific Gravity 2 .0 /cm3 E Particle size distribution X 99.15% particles are > 50 ~tm

. M X 99.15% are < 1 mm

. No particles below 3.6 pm . 0 .10%are < 10 jim

. 0.13% are < 12 pm

. 0.17%are < 15 ~m . X 1 .200 Gp E Young's Modulus X 100-250 m2/g M X Surface area X 5-15 M X Mean Number of Walls X - 15 M X Outer Mean Diameter X - 15 M X Outer Diameter Distribution X - 10 M X Inner Mean Diameter X - 10 M X Inner Diameter Distribution X 0.1-0.4 g/cm3 M X Bulk Density Agglomeration/Aggregation State X Agglomerate rope-like structures M X typically 300-400 m

in diameter . Tensile Stren

gth X 150 GP E Molecular Weight X statistical analysis of a sample of 50 M X kema carbon nanotubes indicate that 90% diameters span from7 to 15 Dm and that 90%

of number of walls spans from5 to 11 walls. Therefore for this sample, molecularweights span from 3.94x106 g/mol to 1 .82 x 109 /mol . ATTACHMENT PAGE 13p. 15 Material Safety Data Sheet

11 . PRODUCT AND COMPANY IDENTIFICATION

_ .~ ;~_ Customer Service Telephone Number: ~ - _ Emergency Information Transportation: CHEMTREC : (800) 424-9300 (24 hrs., 7 days a week) Medical : Rocky Mountain Poison Center: (303) 623-5716 (24 hrs., 7 days a week) Product Information Product name: Synonyms: Molecular formula: Chemical family: Product use: 2 . HAZARDS IDENTIFICATION Emergency Overview Color: black Physical state: solid Form : powder Odor: none coa~ings, composities, and thermoplastic polymers.

WARNINGI MAY FORM

COMBUSTIBLE DUST AIR MIXTURES. MAY CAUSE EYE, SKIN AND RESPIRATORYTRACT IRRITATION. Potential Health Effects Primary routes of exposure: Inhalation and skin contact. Signs and symptoms of acute exposure: Dust: Maycause eye irritation. Maycause irritation of respiratory tract . Prolonged or repeated contact may dry skin and cause irritation.p. 16

r3. COMPOSITION/INFORMATION ON INGREDIENTS Chemical Name CAS-No . Wt/Wt OSHA Hazardous

Thesubstance(s) marked with a "Y" in the Hazard column above, are those identified as hazardous chemicals under the criteria of the OSHA Hazard Communication Standard (29 CFR 1910.1200) . This material is classified as hazardous under Federal OSHA regulation. 4. FI RST AID MEASURES Inhalation: If inhaled, remove victim to fresh air. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical attention. Skin: In case of contact, immediately flush skin with plenty of water. Remove contaminated clothing and shoes. Get medical attention if irritation persists. Wash clothing before reuse. Thoroughly clean shoes before reuse. Eyes: Immediately flush eye(s) with plenty of water . Get medical attention if irritation persists. Ingestion: If swallowed, DO NOT induce vomiting . Get medical attention. Never give anything by mouth to an unconscious person. 5. FIRE-F IGHTING MEASURES Flash point: Not determined Auto-ignition temperature: > 752 °F (> 400 °C) (Method: Standard NF EN 50281-2-1) Lower flammable limit (LFL) : Not determined Upper flammable limit (UFL) : Not determined Extinguishing media (suitable) : Water spray, Carbon dioxide (C02), Dry powder Protective equipment : Fire fighters and others who may be exposed to products of combustion should wear full fire fighting turn out gear (full Bunker Gear) and self-contained breathing apparatus (pressure demand / NIOSH approved or equivalent) . Fire fighting equipment should be thoroughly decontaminated after use .p. 17

Further fireflghting advice: Do not use asolid streamof water. Asolid streamof water can cause a dust explosion. Fire and explosion hazards: Dust clouds generated during handling and/or storage canformexplosive mixtures with air. Dust explosion characteristics vary with the particle size, particle shape, moisture content, contaminants, and other variables. Note: Check that all equipment is properly grounded and installed to satisfy electrical classification requirements. As with any dry material, pouring this material or allowing it to free-fall or to be conveyed through chutes or pipes can accumulate and generate electrostatic sparks, potentially causing ignition of the material itself, or of any flammable materials which may come into contact with the material or its container. 6 . A CCIDE NTAL RELEASE MEASURES In case of spill or leak: Sweep up and shovel into suitable containers for disposal . Use only non-sparking tools. Wet down dust with water sprayjet. Spills should be contained and placed in suitable containers for disposal . Consult a regulatory specialist to determine appropriate state or local reporting requirements, for assistance in waste characterization and/or hazardous waste disposal and other requirements listed in pertinent environmental permits. 7. HANDLING AND STORAGE Handling General information on handling: Keep away from heat, sparks and flames. Avoid contact with the skin, eyes and clothing. Avoid breathing dust . Keep container closed. Avoid creating dust in handling, transfer or clean up. Prevent dust accumulation. Check that all equipment is properly grounded and installed to satisfy electrical classification requirements. Use only with adequate ventilation. Wash thoroughly after handling. Container hazardous when empty. Emptied container retains product residue. Follow label warnings even after container is emptied. RESIDUAL DUSTS MAY EXPLODE ON IGNITION. DO NOT CUT, DRILL, GRIND, OR WELD ON OR NEARTHIS CONTAINER . Improper disposal or reuse of this container may be dangerous and/or illegal . Storage General information on storage conditions: Store in cool, dry, well ventilated area away fromsources of ignition such as flame, sparks and static electricity. Ensure that all storage and handling equipment is properly grounded and installed to satisfy electrical classification requirements. Static electricity may accumulate when transferring material . All storage containers, including drums, cylinders and IBCs, must be bonded and grounded during filling and emptying operations. Version 1 .0 Issued on: 0712512008 Page: 3 1 10p. 18 Material Safety Data Sheet

Storage incompatibility-General : Store separate from

oxidizers. Storage incompatibility-Segregation (specific) : Strong oxidizing agents 8. EXPOSURE CONTROLS/PERSONAL PROTECTION Airborne Exposure Guidelines:p. 19 Material Safety Data Sheet

Only those components with exposure limits are printed in this section. Limits with skin contact designation above have skin contact effect. Air sampling alone is insufficient to accurately quantitate exposure. Measures to prevent significant cutaneous absorption may be required. Limits with a sensitizer designation above mean that exposure to this material may cause allergic reactions. Engineering controls : Investigate engineering techniques to reduce exposures below airborne exposure limits. Provide ventilation if necessary to control exposure levels below airborne exposure limits (see above) . If practical, use local mechanical exhaustventilation at sources of air contamination such as open process equipment. Consult ACGIHventilation manual or NFPA Standard 91 for design of exhaust systems. Respiratory protection : Avoid breathing dust. Where airborne exposure is likely or airborne exposure limits are exceeded (if applicable, see above), use NIOSHapproved respiratory protection equipment appropriate to the material and/or its components (full facepiece recommended) . Consult respirator manufacturer to determineappropriate type equipment for a given application. Observe respirator use limitations specified by NIOSH or the manufacturer . For emergency and other conditions where there may be a potential for significant exposure or where exposure limit may be significantly exceeded, use an approved full face positive-pressure, self-contained breathing apparatus or positive-pressure airline with auxiliary self-contained air supply. Respiratory protection programs must comply with 29 CFR § 1910.134. Skin protection: Wear appropriate chemical resistant protective clothing and chemical resistant gloves to prevent skin contact. Consult glove manufacturer to determine appropriate type glove material for given application. Rinse immediately if skin is contaminated. Wash contaminated clothing and clean protective equipment before reuse. Wash thoroughly after handling. Eye protection: Where eye contact may be likely, wear chemical goggles and have eye flushing equipment available. 9. PHYSICAL AND CHEMICAL PROPERTIES Color : black Physical state: solid Form ; powder Odor: none pH: no data available Density: no data available Specific Gravity (Relative no data available density) : Bulk density

: 100 - 400kg/m3 Vapor pressure: no data available Vapor density: no data availablep. 20

Boiling point/boiling no data available range: Freezing point : no data available Melting point/range: no data available Solubility in water: insoluble 10 . STABILITY AND REACTIVITY Stability: This material is chemically stable under normal and anticipated storage, handling and processing conditions. Materials to avoid: Strong oxidizing agents Conditions I hazards to avoid : To avoid thermal decomposition, do not overheat . Hazardous decomposition products: Thermal decomposition giving toxic products : Carbon oxides 11 . TOXICOLOGI CAL INFOR MATION

Acute toxicity

4

__ Acute toxicity Oral : Slightly toxic. (rat) LD50 = 1,600 mg/kg. Oral : Practically nontoxic. (rat) LD50 > 5,000 mg/kg. Skin Irritation: Non-irritating . (rabbit) Eye Irritation: Non-irritating . (rabbit)

Dermal : No more than slightly toxic . (rabbit) LD50 > 1,000 mg/kg. Carcinocenicitvp. 21 Material Safety Data Sheet °

Chronic inhalation, intratracheal injection administration to rat, mouse, hamster, guinea pig / No in tumor incidence was reported. Carcinoaenicitv Repeated inhalation, intratracheal injection administration to rat / affected organ(s) : lung / signs: fibrosis Human experience Inhalation: Respiratory tract: Epidemiology studies of workers indicate pulmonary function is not affected; no significant increases in cancer.

Oral : No more than slightly toxic. (rat) LD50 > 2,000 mg/kg. Dermal : No more than slightly toxic. (rat) LD50 > 2,000 mg/kg. Skin Irritation: Slightly irritating. (rabbit) Eye Irritation : Moderately irritating. (rabbit) Other routes: Skin Sensitization : Not a skin sensitizer. (mouse) Genoto xicity Assessment in Vitro: No genetic changes were observed in laboratory tests using: bacteria, human cells 12. ECOLOGICAL INFORMATION Chemical Fate and_Pathway No data are available. Ecotoxicolo9v Aquatic toxicity data : Version 1 .0 Issued on: 07125/2008 Page: 7l 10p. 22 Material Safety Data Sheet

Practically nontoxic. Leuciscus idus (Golden orfe) 48 h LCO= 1,000 mg/I Microorganisms: Practically nontoxic. Bacteria ECO= 5,000 mg1I 13. DISPOSAL CONSIDERATIONS Waste disposal : Where possible recycling is preferred to disposal or incineration. If recycling is not an option, incinerate or dispose of in accordance with federal, state, and local regulations. Consult a regulatory specialist to determineappropriate state or local reporting requirements, for assistance in waste characterization and/or hazardous waste disposal and other requirements listed in pertinent environmental permits. Note: Chemical additions to, processing of, or otherwise altering this material may make this waste management information incomplete, inaccurate, or otherwise inappropriate. Furthermore, state and local waste disposal requirements may be more restrictive or otherwise different fromfederal laws and regulations. 14. TRANSPORT INFORMATION US Department of Transportation (DOT) : not regulated International Maritime Dangerous Goods Code (IMDG) : not regulated 15. REGULATORY INFORMATION Chemical Inventorv Status EU. EINECS EINECS Conforms to US. Toxic Substances Control Act TSCA The components ofthis product areall on the TSCA Inventory

. Australia. Industrial Chemical (Notification and AICS Conforms to Assessment) Act Canada. Canadian Environmental Protection Act DSL All components of this product are on the (CEPA) . Domestic Substances List (DSL) . (Can. Gaz. Canadian DSL list . Part 11, Vol . 133) Japan. Kashin-Hou Law List ENCS (JP) Conforms to Korea. Toxic Chemical Control Law (TCCL) List KECI (KR) Conforms to Philippines. The Toxic Substances and Hazardous PICCS (PH) Conforms to and Nuclear Waste Control Act China. Inventory of Existing Chemical Substances INV(CN) Conforms to New Zealand. Inventory of Chemicals (NZIoC), as NZIOC Conforms to published by ERMA New Zealand

Version 1 .0 Issued on: 07I25I2008 Page: 8110p. 23

United States - Federal Reaulations SARA Title III - Section 302Extremely Hazardous Chemicals: SARA 302

: No chemicals in this material are subject to the reporting requirements of SARATitle III, Section 302 . SARA Title III - Section 311/312 Hazard Categories: Acute Health Hazard SARA Title III -Section 313 Toxic Chemicals: Chemical Name CAS-No . De minimis Reportable threshold:

Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) - Reportable Quantity (RQ) : The components in this product are either not CERCLA regulated, regulated but present in negligible concentrations, or regulated with no assigned reportable quantity. OSHA Regulated Carcinogens (NTP, IARC, OSHA Listed) : NTP : No component of this product present at levels greater than or equal to 0 .1 % is identified as a known or anticipated carcinogen by NTP . IARC: No component of this product present at levels greater than or equal to 0 .1 % is identified as probable, possible or confirmed human carcinogen by IARC. OSHA: No component of this product present at levels greater than or equal to 0 .1 % is identified as a carcinogen or potential carcinogen by OSHA . United States - State Reaulations Massachusetts Right to Know Chemical Name

Product code: HES1000 Version 1 .0 Issued on: 0712512008 Page: 9 110Material Safety Data Sheet

New Jersey Right to Know

Pennsylvania Right to Know

Pennsylvania Right to Know - Environmentally Hazardous Substance(s) ifornia Prop. 65 This product does not contain any chemicals known to the State of California to cause cancer, birth defects, or any other reproductive effects. 16. OTHER INFORMATION Latest Revision(s) : Reference number: 000000047038 Date of Revision: 07/25/2008 Date Printed: 09/18/2008p. 25 Material Safety Data Sheet

1 . PRODUCT AND CO

MPANY IDENTIFICATION

Transportation: CHEMTREC: (800) 424-9300 (24 hrs ., 7days a week) Medical : Rocky Mountain Poison Center : (303) 623-5716 (24 hrs., 7 days a week) Product Information Product name: Synonyms: 

# FA Molecular formula: Chemical family: j Product use: in coa mgs, composities, and thermoplastic polymers. 2. HAZARDS IDENTIFICATION Emercaenc

yOverview Color: black Physical state: solid Form : powder Odor : none WARNING! MAY FORM

COMBUSTIBLE DUST AIR MIXTURES. MAY CAUSE EYE, SKIN AND RESPIRATORY TRACT IRRITATION. Potential Health Effects Primary routes ofexposure: Inhalation and skin contact. Signs and symptoms of acute exposure: Dust : May cause eye irritation. May cause irritation of respiratory tract . Prolonged or repeated contact may dry skin and cause irritation.p. 26 Material Safety Data Sheet

3. COMPOSITION/INFORMATION ON INGREDIENTS Chemical Name CAS-No. wtlWt OSHA Hazardous

Thesubstance(s) marked with a "Y" in the Hazard column above, are those identified as hazardous chemicals under the criteria ofthe OSHA Hazard Communication Standard (29 CFR 1910.1200) . This material is classified as hazardous under Federal OSHA regulation. 4 . FIRST AID MEASURES Inhalation: If inhaled, remove victimto fresh air. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical attention. Skin: In case of contact, immediately flush skin with plenty of water. Remove contaminated clothing and shoes. Get medical attention if irritation persists. Wash clothing before reuse. Thoroughly clean shoes before reuse. Eyes: Immediately flush eye(s) with plenty of water . Get medical attention if irritation persists. Ingestion: If swallowed, DO NOT induce vomiting. Get medical attention. Never give anything by mouth to an unconscious person. 5 . FIRE-FIGHTING MEASURES Flash point : no data available Auto-ignition temperature: no data available Lower flammable limit (LFL) : no data available Upper flammable limit (UFL) : no data available Extinguishing media (suitable) : Water spray, Carbon dioxide (C02), Dry powder Protective equipment : Fire fighters and others who may be exposed to products of combustion should wear full fire fighting turn out gear (full Bunker Gear) and self-contained breathing apparatus (pressure demand I NIOSHapproved or equivalent) . Fire fighting equipment should be thoroughly decontaminated after use. Further firefighting advice: Version 1 .1 Issued on: 0712512008 Page: 21 10p. 27 Material Safety Data Sheet

Asolid stream of water can cause a dust explosion. Do not use a solid streamof water. Fire and explosion hazards: Dust clouds generated during handling and/or storage can formexplosive mixtures with air. Dust explosion characteristics vary with the particle size, particle shape, moisture content, contaminants, and other variables. Note: Check that all equipment is properly grounded and installed to satisfy electrical classification requirements. As with any dry material, pouring this material or allowing it to free-fall or to be conveyed through chutes or pipes can accumulate and generate electrostatic sparks, potentially causing ignition ofthe material itself, or of any flammable materials which maycome into contact with the material or its container. 6. ACCIDENTAL RELEASE MEASURES In case of spill or leak: Sweep up and shovel into suitable containers for disposal . Use only non-sparking tools. Wet down dust with water sprayjet . Spills should be contained and placed in suitable containers for disposal . Consult a regulatory specialist to determine appropriate state or local reporting requirements, for assistance in waste characterization and/or hazardous waste disposal and other requirements listed in pertinent environmental permits. 7 . HANDLING AND STORAGE Handling General information on handling : Keep away fromheat, sparks and flames . Avoid contact with the skin, eyes and clothing. Avoid breathing dust . Keep container closed. Avoid creating dust in handling, transfer or clean up. Prevent dust accumulation. Check that all equipment is properly grounded and installed to satisfy electrical classification requirements. Use only with adequate ventilation. Wash thoroughly after handling. Container hazardous when empty . Emptied container retains product residue. Follow label warnings even after container is emptied. RESIDUAL DUSTS MAY EXPLODE ON IGNITION. DO NOT CUT, DRILL, GRIND, OR WELD ON OR NEARTHIS CONTAINER . Improper disposal or reuse ofthis container may be dangerous and/or illegal . Storaae General information on storage conditions: Store in well ventilated area away from heat and sources of ignition such as flame, sparks and static electricity. Ensure that all storage and handling equipment is properly grounded and installed to satisfy electrical classification requirements. Static electricity may accumulate when transferring material . All storage containers, including drums, cylinders and IBCs, must be bonded and grounded during filling and emptying operations. Storage incompatibility - General : Store separate fromoxidizers . Version 1 .1 Issued on: 0712512008 Page: 3110p. 28 Material Safety Data Sheet

Storage incompatibility-Segregation (specific) : Strong oxidizing agents 8. EXPOSURE CONTROLS/PERSONAL PROTECTION

Only those components with exposure limits are printed in this section. Limits with skin contact designation above have skin contact effect . Air sampling alone is insufficient to accurately quantitate exposure. Measures to prevent significant cutaneous absorption may be required. Limits with a sensitizer designation above mean that exposure to this material may cause allergic reactions. Engineering controls: Investigate engineering techniques to reduce exposures below airborne exposure limits. Provideventilation if necessary to control exposure levels below airborne exposure limits (see above) . If practical, use local mechanical exhaust ventilation at sources of air contamination such as open process equipment. Consult ACGIHventilation manual or NFPA Standard 91 for design of exhaust systems. Respiratory protection: Avoid breathing dust. Where airborne exposure is likely or airborne exposure limits are exceeded (if applicable, see above), use NIOSH approved respiratory protection equipment appropriate to the material and/or its components (full facepiece recommended) . Consult respirator manufacturer to determine appropriate type Version 1 .1 Issued on: 07/25/2008 Page: 4 110p. 29 Material Safety Data Sheet

equipment for a given application. Observe respirator use limitations specified by NIOSHor the manufacturer. For emergency and other conditions where there may be a potential for significant exposure or where exposure limit may be significantly exceeded, use an approved full face positive-pressure, self-contained breathing apparatus or positive-pressure airline with auxiliary self-contained air supply. Respiratory protection programs must comply with 29 CFR § 1910.134. Skin protection: Wear appropriate chemical resistant protective clothing and chemical resistant gloves to prevent skin contact. Consult glove manufacturer to determine appropriate type glove material for given application . Rinse immediately if skin is contaminated. Wash contaminated clothing and clean protective equipment before reuse. Wash thoroughly after handling. Eye protection: Where eye contact may be likely, wear chemical goggles and have eye flushing equipment available. 9. PHYSIC

AL AND CHEMICAL PROPERTIES Color: black Physical state: solid Form : powder Odor: none pH: no data available Density: no data available Specific Gravity (Relative no data available density) : Bulk density: 100- 400 kg/m3 Vapor pressure: no data available Vapor density: no data available Boiling pointlboiling no data available range: Freezing point: no data available Melting point/range: no data available Solubility in water: insoluble

4UNNIO-A Version 1 .1 Issued on: 0712512008 Page: 6 ! 10p. 30 Material Safety Data Sheet

10. STABILITY ANDREACTIVITY Stability: This material is chemically stable under normal and anticipated storage, handling and processing conditions. Materials to avoid: Strong oxidizing agents Conditions I hazards to avoid: To avoid thermal decomposition, do not overheat. Hazardous decomposition products: Thermal decomposition giving toxic products : Carbon oxides 11 . TOXICOLOGICAL INFORMATION Data on this material and/or its components are summarized below . 40000MUM~ Acute to

xicity Oral : Slightly toxic. (rat) LD50 = 1,600 mg/kg . 

# EANNImm I Dermal : No more than slightly toxic . (rabbit) LD50 > 1,000mg/kg. Carcinoaenicitv Chronic inhalation, intratracheal injection administration to rat, mouse, hamster, guinea pig / No increase in tumor incidence was reported. Carcinogenicitv Repeated inhalation, intratracheal injection administration to rat / affected organ(s) : lung / signs: fibrosis Human experience Inhalation: Respiratory tract : Epidemiology studies of workers indicate pulmonary function is not affected; no significant increases in cancer. Acute toxicitv Oral : No more than slightly toxic. (rat) LD50 > 2,000 mg/kg. Dermal : No more than slightly toxic. (rat) LD50 > 2,000 mg/kg.p. 31

Skin Irritation: Slightly irritating. (rabbit) Eye Irritation: Moderately irritating. (rabbit) Other routes: Skin Sensitization: Not a skin sensitizer . (mouse) Genotoxicity Assessment in Vitro : No genetic changes were observed in laboratory tests using: bacteria, human cells 12. ECOLOGICAL INFORMATION Chemical Fate and Pathway No data are available. Ecotoxicology Data on this material and/or its components are summarized below . Aquatic toxicity data: Practically nontoxic. Leuciscus idus (Golden orfe) 48 h LCO= 1,000 mg/I Microorganisms : Practically nontoxic. Bacteria ECO= 5,000 mg/I 13. DISPOSAL CONSIDERATIONS Waste disposal : Where possible recycling is preferred to disposal or incineration. If recycling is not an option, incinerate or dispose of in accordance with federal, state, and local regulations. Consult a regulatory specialist to determine appropriate state or local reporting requirements, for assistance in waste characterization and/or hazardous waste disposal and other requirements listed in pertinent environmental permits. Note: Chemical additions to, processing of, or otherwise altering this material may make this waste management information incomplete, inaccurate, or otherwise inappropriate. Furthermore, state and local waste disposal requirements may be more restrictive or otherwise different fromfederal laws and regulations.p. 32

14. TRANSPORT INFORMATION US Department of Transportation (DOT) : not regulated International Maritime Dangerous Goods Code (IMDG) : not regulated 15. REGULATORY INFORMATION Chemical Inventory Status EU. EINECS EINECS Conforms to US. Toxic Substances Control Act TSCA The components of this product are all on the TSCA Inventory. Australia. Industrial Chemical (Notification and AICS Conforms to Assessment) Act Canada. Canadian Environmental Protection Act DSL All components of this product are on the (CEPA) . Domestic Substances List (DSL) . (Can . Gaz . Canadian DSL list . Part II, Vol . 133)

published by ERMA New Zealand United States - Federal Reaulations SARATitle III - Section 302 Extremely Hazardous Chemicals : SARA 302

: No chemicals in this material are subject to the reporting requirements of SARATitle III, Section 302 . SARA Title III - Section 311/312 Hazard Categories : Acute Health Hazard SARA Title 111- Section 313 Toxic Chemicals: SARA 313

: This material does not contain any chemical components with known CAS numbers that exceed the threshold (De Minimis) reporting levels established by SARATitle 111, Section 313 . Comprehensive Environmental Response, Compensation, and LiabilityAct (CERCLA) - Reportable Quantity (RQ) : Japan. Kashin-Hou Law List ENCS (JP) Conforms to Korea. Toxic Chemical Control Law (TCCL) List KECI (KR) Conforms to Philippines. The Toxic Substances and Hazardous PICCS (PH) Conforms to and Nuclear Waste Control Act China. Inventory of Existing Chemical Substances IECSC (CN) Conforms to New Zealand. Inventory of Chemicals (NZIoC), as NZIOC Conforms to

# . _ l] Version 1 .1 Issued on: 0712512008 Page: 8 l 10p. 33 Material Safety Data Sheet

The components in this product are either not CERCLA regulated, regulated but present in negligible concentrations, or regulated with no assigned reportable quantity. OSHA Regulated Carcinogens (NTP, IARC, OSHA Listed) : NTP : No component of this product present at levels greater than or equal to 0 .1% is identified as a known or anticipated carcinogen by NTP . IARC: No component of this product present at levels greater than or equal to 0 .1 % is identified as probable, possible or confirmed human carcinogen by IARC . OSHA: No component of this product present at levels greater than or equal to 0 .1 % is identified as a carcinogen or potential carcinogen by OSHA. United States - State Regulations Massachusetts Right to Know

New Jersey Right to Know Chemical .Name._ _ 

# AN* Pennsylvania Right to Know Chemical Name CAS-NQ ._.-

California Prop. 65 This product does not contain any chemicals known to the State of California to cause cancer, birth defects, or any other reproductive effects. 16. OTHER INFORMATION Latest Revision(s) : Reference number: 000000054675 Date of Revision: 07/25/2008 Date Printed: 07/25/2008p. 35 Material Safety Data Sheet

1 . PRODUCT AND COMPAN Y IDENTIFICATION

Transportation: CHEMTREC: (800) 424-9300 (24 hrs., 7 days a week) Medical : Rocky Mountain Poison Center: (303) 623-5716 (24 hrs., 7 days a week) Product Information Product name: Synonyms: Molecular formula: Chemical family: Product use: 2. HAZARD

S IDENTIFICATION Emergency Overview Color: black Physical state: liquid Odor: slight WARNINGI MAY CAUSE SKIN IRRITATION. MAY CAUSEALLERGIC SKIN REACTION. Potential Health Effects Primary routes of exposure: Inhalation and skin contact. Signs and symptoms of acute exposure: May cause skin irritation. Allergic skin reaction: redness, rash. Skin: Practically nontoxic. Moderately irritating. (based on components) Eyes: Slightly irritating. (based on components)p. 36 Material Safety Data Sheet

Ingestion : Practically nontoxic. (based on components) 3. COMPOSITION/INFORMATION ON INGREDIENTS Chemical Name CAS-No . wtlwt OSHA Hazardous

The substance(s) marked with a "Y" in the Hazard column above, are those identified as hazardous chemicals under the criteria ofthe OSHA Hazard Communication Standard (29 CFR 1910.1200) . This material is classified as hazardous under Federal OSHA regulation . 4. FIRST AID MEASURES Inhalation: If inhaled, remove to fresh air. Skin : In case of contact, immediately flush skin with soap and plenty of water. Remove contaminated clothing and shoes. Get medical attention if symptoms occur. Wash clothing before reuse. Thoroughly clean shoes before reuse. Eyes: Immediately flush eye(s) with plenty of water . Ingestion: If swallowed, DO NOT induce vomiting. Get medical attention. Never give anything by mouth to an unconscious person. 5. FIRE-FIGHTING MEASURES Flash point : > 392 °F (> 200 °C) (closed cup) Auto-ignition temperature: Not determined Lower flammable limit (LFL) : Not determined Upper flammable limit (UFL) : Not determined Extinguishing media (suitable) : Carbon dioxide (C02), Dry powder, Water spray Protective equipment:

Version 1 .1 Issued on: 0712512008 Page: 2 l 10p. 37 Material Safety Data Sheet

Fire fighters and others who may be exposed to products of combustion should wear full fire fighting turn out gear (full Bunker Gear) and self-contained breathing apparatus (pressure demand / NIOSHapproved or equivalent) . Further firefighting advice: Fire fighting equipment should be thoroughly decontaminated after use . Fire and explosion hazards: When burned, the following hazardous products of combustion can occur: Carbon oxides 6. ACCIDENTAL RELEASE MEASURES In case of spill or leak: Spills should be contained and placed in suitable containers for disposal . Consult a regulatory specialist to determine appropriate state or local reporting requirements, for assistance in waste characterization and/or hazardous waste disposal and other requirements listed in pertinent environmental permits. 7. HANDLING ANDSTORAGE Handling General information on handling: Wash thoroughly after handling. Avoid contact with theskin, eyes and clothing . Emptied container retains vapor and product residue. Observe all labeled safeguards until container is cleaned, reconditioned or destroyed. Storaae General information on storage conditions: Keep containers tightly closed in a dry, cool and well-ventilated place. Storagestability - Temperature:- 36 - 104 °F (2 - 40 °C) Storage incompatibility -General : Store separate from strong acids, strong bases, and strong oxidizing agents. 8. EXPOSURE CONTROLS/PERSONAL PROTECTION

Version 1 .1 Issued on: 0712512008 Page: 3I 10p. 38

Only those components with exposure limits are printed in this section. Limits with skin contact designation above have skin contact effect . Air sampling alone is insufficient to accurately quantitate exposure. Measures to prevent significant cutaneous absorption may be required. Limits with a sensitizer designation above mean that exposure to this material may cause allergic reactions. Engineering controls: Investigate engineering techniques to reduce exposures. Provide ventilation if necessary to control exposure levels below

airborne exposure limits (see above) . If practical, use local mechanical exhaust ventilation at sources of air contamination such as open process equipment. Respiratory protection : Avoid breathing vapor or mist . Where airborne exposure is likely or airborne exposure limits are exceeded (if applicable, see above), use NIOSH approved respiratory protection equipment appropriate to the material and/or its components (full facepiece recommended) . Consult respirator manufacturer to determine appropriate type equipment for a given application. Observe respirator use limitations specified by NIOSH or the manufacturer. For emergency and other conditions where there may be a potential for significant exposure or where exposure limit may be significantly exceeded, use an approved full face positive-pressure, self-contained breathing apparatus or positive-pressure airline with auxiliary self-contained air supply. Respiratory protection programs must comply with 29 CFR § 1910.134. Skin protection: . Wear appropriate chemical resistant protective clothing and chemical resistant gloves to prevent skin contact. When handling this material, gloves of the following type(s) should be worn: Neoprene Nitrile rubber Impervious butyl rubber gloves Wear face shield and chemical resistant clothing such as a rubber apronwhen splashing may occur. Rinse immediately if skin is contaminated. Wash contaminated clothing and clean protective equipment before reuse. Wash thoroughly after handling. Eye protection : Use good industrial practice to avoid eye contact. 9. PHYSICAL AND CHEMICAL PROPERTIES Color : black Physical state: liquid Version 1 .1 Issued on: 0712512008 Page: 4 110p. 39 Material Safety Data Sheet

Odor: slight pH: not determined Density: 1,150- 1,200kg/m3 77 °F (25 °C) Vapor pressure: not determined Vapor density: not determined Boiling point/boiling > 392 'F (> 200 *C) range: Melting pointlrange: > 392 °F (> 200 °C) Solubility in water: < 1 mg/I 10 . STABILITY ANDREACTIVITY Stability: This material is chemically stable under normal and anticipated storage, handling and processing conditions. Materials to avoid: Strong oxidizing agents Strong acids strong bases Conditions I hazards to avoid: Keep away from heat and sources of ignition. To avoid thermal decomposition, do not overheat . Hazardous decomposition products : Thermal decomposition giving toxic products : Carbon oxides 11 . TOXIC

OLOGICAL INFORMATION

Oral : Practically nontoxic. (rat) LD50 > 5,000 mg/kg. Dermal : Practically nontoxic. (rabbit) LD50 > 6,000 mg/kg. Skin Irritation: Moderately irritating. (rabbit) Version 1 .1 Issued on: 07/2512008 Page: 6I 10p. 40

Eye Irritation: Slightly irritating. (rabbit) Material Safety Data Sheet

Skin Sensitization: Repeated skin exposure. (laboratory animal) Skin allergy was observed. Genotoxicity Assessment in Vitro: Both positive and negative reponses for genetic changes were observed in laboratory tests using: bacteria Genotoxicitv Assessment in Vivo: No genetic changes were observed in laboratory tests using: animals, rodent Developmental toxicity Exposure during pregnancy. (rat and rabbit) / No birth defects were observed. Human experience Skin contact : ~ Skin: Skin allergy was observed. Carcinoaenicitv Repeated inhalation, intratracheal injection administration to rat / affected organ(s) : lung / signs: fibrosis Human experience Inhalation: Respiratory tract: Epidemiology studies of workers indicate pulmonary function is not affected; no significant increases in cancer. Acute toxicity Oral : No more than slightly toxic . (rat) LD50 >2,000mg/kg. Dermal : No more than slightly toxic . (rat) LD50 > 2,000 mg/kg. Skin Irritation: Slightly irritating. (rabbit) Eye Irritation: Moderately irritating. (rabbit) Other routes:p. 41 Material Safety Data Sheet

Not a skin sensitizer. (mouse) Skin Sensitization: Genotoxicity Assessment in Vitro

: No genetic changes were observed in laboratory tests using: bacteria, human cells 12. ECOLOGICAL INFORMATION Chemical Fate and Pathway Data on this material and/or its components are summarized below . Biodegradation : Not readily biodegradable. (28 d) biodegradation 2 - 3 % Octanol Water Partition Coefficient : log Pow

ca. 3.8 Ecotoxicolopy Data on this material and/or its components are summarized below . Aquatic toxicity data: Practically nontoxic. Oncorhynchus mykiss (rainbow trout) LC50 > 1,000 mg/I 13. DISPOSAL CONSIDERATIONS Waste disposal : Where possible recycling is preferred to disposal or incineration. If recycling is not an option, incinerate or dispose of in accordance with federal, state, and local regulations. Consult a regulatory specialist to determine appropriate state or local reporting requirements, for assistance in wastecharacterization and/or hazardous waste disposal and other requirements listed in pertinent environmental permits. Note : Chemical additions to, processing of, or otherwise altering this material may make this waste management information incomplete, inaccurate, or otherwise inappropriate. Furthermore, state and local waste disposal requirements may be more restrictive or otherwise different from

federal laws and regulations. 14. TRANSPORT INFORMATION US Department of Transportation (DOT) : not regulated International Maritime Dangerous Goods Code (IMDG) UN Number : 3482 Proper shipping name : ENVIRONMENTALLY HAZARDOUS SUBSTANCE, LIQUID, N .O.S.p. 42 Material Safety Data Sheet

Technical name : (EPOXY RESIN) Class : g Packaging group : III Marine pollutant : no Flash point : > 392 °F (> 200 °C) closed cup 15. REGULATORY INFORMATION Chemical Inventory Status EU. EINECS EINECS Conforms to US. Toxic Substances Control Act TSCA The components ofthis product are all on the TSCA Inventory. Australia. Industrial Chemical (Notification and AICS Conforms to Assessment)Act Canada. Canadian Environmental Protection Act DSL All components of this product are on the (CEPA) . Domestic Substances List (DSL) . (Can. Gaz. Canadian DSL list. Part II, Vol . 133) Japan. Kashin-Hou Law List ENCS (JP) Conforms to Korea. Toxic Chemical Control Law (TCCL) List KECI (KR) Conforms to Philippines. The Toxic Substances and Hazardous PICCS (PH) Conforms to and Nuclear Waste Control Act China. Inventory of Existing Chemical Substances IECSC (CN) Conforms to United States - Federal Regulations SARA Title 111- Section 302 Extremely Hazardous Chemicals: SARA 302: No chemicals in this material are subject to the reporting requirements of SARATitle III, Section 302. SARA Title III - Section 311/312 Hazard Categories : Acute Health Hazard SARA Title III - Section 313 Toxic Chemicals: SARA 313

: This material does not contain any chemical components with known CAS numbers that exceed the threshold (De Minimis) reporting levels established by SARATitle 111, Section 313 . Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) - Reportable Quantity (RQ) : The components in this product are either not CERCLAregulated, regulated but present in negligible concentrations, or regulated with no assigned reportable quantity.

Version 1 .1 Issued on: 07/2512008 Page: 8110p. 43 Material Safety Data Sheet --J OSHA Regulated Carcinogens (NTP, IARC, OSHA Listed) : NTP : No component of this product present at levels greaterthan or equal to 0 .1%is identified as a known or anticipated carcinogen by NTP . IARC: No component of this product present at levels greater than or equal to 0.1%is identified as probable, possible or confirmed human carcinogen by IARC. OSHA: No component of this product present at levels greater than or equal to 0 .1 °1o is identified as a carcinogen or potential carcinogen by OSHA. United States - State Regulations Massachusetts Right to Know CAS-No. New Jersey Right to Know No components are subject to the New Jersey Right to Know

Act . Pennsylvania Right to Know

California Prop. 65 This product does not contain any chemicals known to the State of California to cause cancer, birth defects, or any other reproductive effects. 16. OTHER INFORMAT10N Latest Revision(s) : Revised Section(s) : Reference number: Date of Revision: 07/25/2008 Date Printed: 09/18/2008

CANKUNI Version 1 .1 Issued on: 07125/2008 Page: 9110p. 44 Material Safety Data SheetSPONSOR .

STUDYTITLE ACUTE ORAL TOXICITY IN RATS "ACUTE TOXIC CLASS METHOD"

STUDYDIRECTOR Catherine Pelcot

DATE OF ISSUE 

# ,9s r~;~ 2_~'

TESTFACILITY CIT BP 563 - 27005 Evreux - France

IFM Recherche BY 563 27005 Evreux Cedex S.N .C au Copital de 846.092 ¬ T61 : +33 (0)2 32 29 26 26 788 060 465 R.C

.S . Evreux Fax : +33 (0)2 32 67 87 OS VAT : FRI 9 788 060 465 E-mail : CIT@citox.com Agrement Credit Impot Recherche Web site : www .citox .com 

### CONFIDENTIAL

FranceCONTENTS STATEMENT OF THE STUDY DIRECTOR 4 OTHER CIT SCIENTIST INVOLVED IN THE STUDY 5 STATEMENT OF QUALITY ASSURANCE UNIT -~`- < 6 SUMMARY 7 RESUME 1 . INTRODUCTION 2. MATERIALS AND METHODS 2.1 TEST ITEM 2 .1 .1 Identification 2 .1 .2 Vehicle 2 .1 .3 Dosage formpreparation 2 .2 TEST SYSTEM 2.2.1 Animals 2.2.2 Environmental conditions 2.2.3 Food and water 2.3 TREATMENT 2 .3 .1 Fasting of the animals 2 .3 .2 Study design 2.3.3 Administration of the test item 2.4 CLINICAL EXAMINATIONS 2.4.1 Clinical signs and mortality 2.4.2 Body weight 2.5 PATHOLOGY 2.5.1 Sacrifice 2.5.2 Macroscopic necropsy examination 2.5.3 Preservation of tissues 2.6 2.7 2.8 2.9 3. 3.1 3.1 .1 3.1 .2 3.2 4. EVALUATIONAND INTERPRETATIONOF THE RESULTS

ARCHIVING CHRONOLOGY OF THE ST . ULY STUDY PLANADHERENCE RESULTS CLINICAL EXA$IINATIQNS a : Clinical signs and mortality (table 1) Body weight (figure 1, tables 2 and 3) PATHOLOGY (table 4) CONCLUSION 9 11 11 11 11 11 12 12 12 12 12 13 13 13 13 14 14 14 14 14 14 14 14 15 15 15 16 16 16 16 16 16Figure 1 : Mean body weight ofthe treated animals 1 7 Table 1 : Individual clinical signs and mortality 18 Table 2: Individual and mean body weight and weekly body weight change of treated rats

(g) 19 Table 3: Body weight - CIT historical data of control animals dosed by oral route 20 Table 4: Individual macroscopic examinations at necropsy 21 APPENDICES 22 1 . Test article description and analytical certificate 23 2. Diet formula 26 3. CIT GLP certificate 28 and 29STATEMENT O F THE STUDY DIRECTOR The study was performed in compliance with CIT's standard operating procedures and the following principles of Good Laboratory Practice:

. OECD Principles of Good Laboratory Practice (as revised in 1997), ENV/MC/CHEM (98) 17 and all subsequent OECD consensus documents.

. Directive 2004/10/EC of the European Parliament and of the Council of 11 February 2004 on the harmonization of laws, regulations and administrative provisions relating to the application of the Principles of Good Laboratory Practice and the verification of their applications for tests on chemical substances (OJ No. L50 of 20.2.2004) .

. Decret N° 2006-1523 du 04 decembre 2006 concernant les Bonnes Pratiques de Laboratoire (Journal Officiel du 06 decembre 2006), Ministere de 1'Economie, des Finances et de 1'Industrie. However, no chemical analysis of the dosage forms was performed as part of this study. This exception is not considered to impact the overall GLP status ofthe study. The study was also conducted in compliance with the following Animal Protection regulations:

. Council Directive 86/609/EEC of 24th November 1986 on the harmonization of laws, regulations or administrative provisions relating to the protection of animals used for experimental or other scientific purposes .

. Guidance document on the recognition, assessment, and use of clinical signs as humane endpoints for experimental animals used in safety evaluation, OECD Environmental Health and Safety Publications, No. 19. I declare that this report constitutes a true and faithful record of the procedures undertaken and the results obtained during the performance of the study. f ., This study was performed at CIT, BP 563, 27005 Evreux, Franc¢ : Y

Toxicology C . Pelcot Study completion date: ~-1 Apk. L J,a ~ Study Director

### OTHERCIT SCIENTIST INVOLVED IN THE STUDY

Director ofToxicology CIT Management J .J . Legrand Date:

Doctor of Veterinary Medicine

### STATEMENT OF WALITY ASSURANCE UNIT Inspections performed at CIT: The CIT Quality Assurance Unit conducted the inspections detailed below : Dates Type of inspection Inspection Reported to the Reported to Study Director Management p. 50 6

Study plan 27 July 2007 27 July 2007 02 August 2007 Report 12 February 2008 14 February 2008 10 March 2008 In addition, at about the same time, process-based and facility inspections relevant to this study were carried out by the Quality Assurance Unit. The inspections; were performed in compliance with CIT Quality Assurance Unit procedures and the principles of Good Laboratory Practices. The final report is considered to constitute an accurate and complete reflection of the study raw data. 

# _-

. caL7- c

.GCC .~ Date: -2S ~-tt,, ~ C1T Quality Assurance UnitSUMMARY

~_ . ., . guidelines. , 17th December 2001) and EC (2004/73/EC, B.1 tris, 29th Apri12004) The study was conducted in compliance with the principles of Good Laboratory Practice Regulations. Methods The test item was prepared in 0.5% methylcellulose and was administered by oral route (gavage), to groups of three fasted female Sprague-Dawley rats. The study design was as follows : Dose-level Volume Female (mg/kg) (mL/kg) 300 10 3 2000 14.3 3 2000 14.3 3 Clinical signs, mortality and body weight gain were checked for a period of up to 14 days following the single administration of the test item . All animals were subjected to necropsy. Results Dose-level of 300 mg/kg (three females) No deaths and no clinical signs were noted at this dose-level . Dose-level of 2000 mg/kg (three females then confirmation on three other females_) No deaths occurred. Hypoactivity, piloerection and dyspnea were noted in 3/6 animals on day 1 . When compared to CIT historical control animals, a slightly lower body weight gain was noted between day 1 and day 8 in 1/3 females treated at the dose-level of 300 mg/kg, without any relevant consequence at the end of the observation period, and in 1/6 females treated at the dose-level of 2000 mg/kg, between day 8 and day 15. The body weight gain ofthe other animals treated at the dose-level of300 or 2000 mg/kg was not affected by treatment with the test item . At necropsy, no apparent abnormalities were observed in any animal .Conclusion itions of this study, the oral LDo of the test item According to the classification criteria laid down in Council Directive 67/548/EEC (and subsequent adaptations), concerning the potential toxicity by oral route, the test itemshould not be classified.RESUME

~ ignes irec ~ces e CDE (n° 423, 17 decem re e e a EE (2004/73/CEE, B. tris, 29 avril 2004) . L'dtude a ete realisee conform6ment aux regles de Bonnes Pratiques de Laboratoire. Methode Le produit a etd prepar6 clans de la methylcellulose a 0,5 %et administr6 par voie orale (gavage), a des groupes de 3 femelles rats Sprague-Dawley mis a la diete hydrique. Le schema de 1'etude a ete le suivant : Dose Volume Femelle (mg/kg) (mL/kg) 300 10 3 2000 14,3 3 2000 14,3 3 Les signes cliniques, la mortalite et 1'evolution ponderale des animaux ont ete suivis pendant une pgriode de 14jours apres 1'administration unique du produit . Un examen anatomopathologique a ete effectue sur tous les animaux. Resultats Dose de 300 mg/kg (3 femelles) Aucune mortalite et aucun signe clinique ne sont observes a cette dose. Dose de 2000 my/kg (3 femelles puis confirmation sur 3 autres femelles) Aucune mortalite West enregistree. Hypoactivite, pilogrection et dyspnee sont notees chez 3/6 animaux au Jour 1 . En comparaison avec celle des temoins historiques du CIT, 1'evolution ponderale est legerement reduite entre le Jour 1 et le Jour 8 chez 1/3 femelle traitee a la dose de 300 mg/kg, sans aucune consdquence notable a la fin de la p6riode d'observation, et chez 1/6 femelle traitde a la dose de 2000 mg/kg entre le Jour 8 et le Jour 15. L'evolution ponderale des autres animaux traitgs aux doses de 300 ou 2000 mg/kg n'est pas influencde par le traitement avec le produit. L'examen macroscopique des principaux organes realisd chez tous les animaux ne met en evidence aucune anomalie apparente.Conclusion p. 54 10

--- m---conditions ex 6riment l d- cette etude la DL 0 orale du produ'

- - ------- --- Selon les criteres de classification d6crits dans la Directive 67/548/CEE (et ses adaptations), concernant la toxicite aigue par voie orale, le produit ne devrait pas etre classe.l . INTRODUCTION ! is study was to evaluate the toxicity of the test ite ~llowing a single oral administration in rats. p. 55 11

In the assessment ofthe toxic characteristics of a test item, determination of acute oral toxicity is an initial step. It provides information on health hazards likely to arise following a short-term exposure by the oral route in humans and enables the test item to be ranked in different classification systems. The acute toxic class method is a stepwise procedure. The test item is administered orally to one group of animals at one of the defined dose-levels, each step using three animals of one sex. Absence or presence of compound-related mortality of the animals dosed at one step determines the next step, i.e

. :

. no further testing is needed,

. the next step is performed with the same dose-level,

. the next step is performed at the next higher or the next lower dose-level . The study was conducted in compliance with:

. EC Directive 2004/73/EC, B.1 tris, 29th April 2004,

. OECD Guideline No. 423, 17th December 2001 . 2. MATERIALS AND METHODS 2.1 TEST ITEM

e: batch CAS number Description at re"ce'°ip~' container: one plastic flask date of receipt: 29 June 2007 storage conditions: at roomtemperature and protected fromhumidity composition: see analytical certificate expiry date: June 2008. Data relating to the characterization of the test itemare documented in a test article description and an analytical certificate (presented in appendix 1) provided by the Sponsor . 2.1 .2 Vehicle The vehicle used was 0.5% methylcellulose: methylcellulose, batch No. 017K0052 (Sigma, Saint-Quentin-Fallavier, France) in purified water (prepared at CIT by reverse osmosis) .2.1 .3 Dosage formpreparation p. 56 12

The test item was not soluble at the concentration of 100 mg/mL in purified water, 0.5% methylcellulose and corn oil . At the maximal concentration of 70 mg/mL, a suspension was obtained in purified water or in 0 .5% methylcellulose. As the suspension was more homogeneous in 05%methylcellulose, this vehicle was retained. On the day of treatment, the test item was ground to a fine powder using a mortar and pestle, then was prepared at the chosen concentration in the vehicle. The test item preparation was made freshly on the morning of administration by the CIT Pharmacy and any unused material was discarded that same day. 2.2 TEST SYSTEM 2.2 .1 Animals Species, strain and sex: nulliparous and non-pregnant female rat, Sprague-Dawley Rj : SD (IOPS Han) . Reason for this choice: rodent species generally accepted by regulatory authorities for this type of study. Breeder : Janvier, Le Genest-Saint-Isle, France. Number and sex: 3 groups of three females were used. Age/weight : on the day of treatment, the animals were approximately 8 weeks old, and had a mean body weight ::E standard deviation of 189 ± 6 g. Acclimation: at least 5 days before the beginning of the study . Allocation to study: before the beginning ofthe study, on day 1, the required number of animals was selected according to body weight and clinical condition. Identification: individually by earnotches . 2 .2.2 Environmental conditions The conditions in the animal room were set as follows:

. temperature: 22 ± 2°C

. relative humidity : 30 to 70%

. light/dark cycle: 12 h/12 h

. ventilation : approximately 12 cycles/hour offiltered, non-recycled air . The temperature and relative humidity were under continuous control and recording. The records were checked daily and filed. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment are verified and calibrated at regular intervals. The animals were housed in polycarbonate cages with stainless steel lid (48 cmx 27 cm x 20 cm) . Each cage contained one to seven animals during the acclimation period and three rats of the same group during the treatment period. Each cage contained autoclaved sawdust (SICSA, Alfortville, France) . Sawdust is analyzed by the supplier for composition and contaminant levels. 2.2.3 Food and water All the animals had free access to SsniffR/M-H pelleted diet (SSNIFF Spezialdiaten GmbH, Soest, Germany), except as noted in "2 .3 .1 Fasting ofthe animals" . Each batch of food is analyzed by the supplier for composition and contaminant levels. The diet formula is presented in appendix 2. Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum . Bacteriological and chemical analyses of water are performed regularly by external laboratories.p. 57 13, These analyses include the detection of possible contaminants (pesticides, heavy metals and nitrosamines) . No contaminants were known to have been present in the diet, drinking water or bedding material at levels which may be expected to have interfered with or prejudiced the outcome of the study. 2.3 TREATMENT 2.3 .1 Fasting of the animals The animals were fasted for an overnight period of approximately 18 hours before dosing, but had free access to water . Food was given back approximately 4 hours after administration of the test item (dose-level of 300 mg/kg) or after the first administration of the test item (dose-level of 2000 mg/kg) . 2.3 .2 Study design Three females were used for each step. The dose-level used as the starting dose-level was selected fromone of four fixed levels, 5, 50, 300 or 2000 mg/kg body weight . As no information on the toxic potential of the test item was available, for animal welfare reasons, the starting dose-level of 300 mg/kg was chosen . After the first assay, as no deaths occurred, another assay was carried out on three animals at the next higher dose-level, i .e. 2000 mg/kg. After the second assay, as no deaths occurred, the results were then confirmed in three other females at the dose-level of 2000 mg/kg. The study design was as follows : Dose-level Volume Female (mg/kg) (mL/kg) 300 10 3 2000 14.3 3 2000 14

.3 3 2.3 .3 Administration of the test item The dosage form preparations were administered to the animals under a volume of 10 mL/kg (dose-level of 300 mg/kg) or 14.3 mL/kg (dose-level of 2000 mg/kg) . The administration was performed once (dose-level of 300 mg/kg) or twice at a 2-hour interval (dose-level of 2000 mg/kg) by oral route using a metal gavage tube fitted to a 2 or 5 mL plastic syringe (0.1 or 0.2 mL graduations) . The volume administered to each animal was adjusted according to body weight determined on the day of treatment.2.4 CLINICAL EXAMINATIONS p. 58 14

The administration was performed in the morning of day 1 ; it was followed by a 14-day observation period. 2.4.1 Clinical signs and mortality The animals were observed frequently during the hours following administration of the test item, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day. Type, time of onset and duration of clinical signs were recorded for each animal individually. 2.4.2 Body weight The animals were weighed individually just before administration of the test itemon day 1 and then on days 8 and 15. The body weight gain of the treated animals was compared to that of CIT control animals with the same initial body weight. 2.5 PATHOLOGY 2.5 .1 Sacrifice On day 15, all animals were killed by carbon dioxide asphyxiation . 2.5.2 Macroscopic necropsy examination All study animals were subjected to a macroscopic examination as soon as possible after death. After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed. 2.5.3 Preservation of tissues No organ samples were taken. 2.6 EVALUATIONAND INTERPRETATION OF THE RESULTS The interpretation of results was based on the flowcharts of Annex 2 of the OECD Guideline No. 423, 17th December 2001 and of Annex 3 of the Directive 2004/73/EC, B.1 tris, 29th April 2004.2.7 ARCHIVING p. 59 15

The following study materials are archived by CIT, 27005 Evreux, France, for 10years after the end ofthe in vivo phase ofthe study :

. Study plan and possible amendments,

. raw data,

. correspondence,

. final report and possible amendments. On completion of this period, the archived study materials will be returned to the Sponsor, or may be archived at CIT for a further period (at additional cost) . The total duration of archiving (depending on regulations) will be the responsibility ofthe Sponsor . In addition, rawdata not specific to the study including, but not limited to, certificates of analyses for food, water and bedding (if applicable) and records of environmental data and equipment calibration, are also archived by CIT for at least 30years. 2.8 CHRONOLOGY OF THE STUDY The chronology ofthe study was as follows : Procedure Date Experimental starting date (first treatment) Experimental completion date (necropsy of the last animal) 2.9 STUDY PLANADHERENCE The study was performed in accordance with 07 August 2007 11 September 2007

--- -- amendments, with the following deviations fromthe agreed Study plan:

. the temperature and relative humidity recorded in the animal roomwere sometimes the target ranges specified in the Study plan,

. on day l, the body weight of one animal (female No. (177 g),

. the actual administered dose was 2000 mg/kg (instead amendment to the Study plan) . ubsequent outside of 01) was slightly lower than 180 g of 2002 mg/kg as specified in the These minor deviations were not considered to have compromised the validity or integrity of the study.3. RESULTS 3.1 CLINICAL EXAMINATIONS 3.1 .1 Clinical signs and mortality (table 1) Dose-level of 300 mg/kg (three females) No deaths and no clinical signs were noted at this dose-level . Dose-level of 2000 mz/kg (three females then confirmation on three other females) No deaths occurred. Hypoactivity, piloerection and dyspnea were noted in 3/6 animals on day 1 . 3.1 .2 Body weight (figure l, tables 2 and 3) p. 60 

### 16

When compared to CIT historical control animals, a slightly lower body weight gain was noted between day 1 and day 8 in 1/3 females treated at the dose-level of 300 mg/kg, without any relevant consequence at the end of the observation period, and in 1/6 females treated at the dose-level of 2000 mg/kg, between day 8 and day 15. The body weight gain ofthe other animals treated at the dose-level of 300 or 2000 mg/kg was not affected by treatment with the test item . 3.2 PATHOLOGY (table 4) Macroscopic examination of the main organs of the animals revealed no apparent abnormalities. 4. CONCLUSION ~ n_tal__- conditions .of_ .t_-ig _: .,q . 1,ju rhP ,1a.t _ My of the test item

___ ._ .. ._ .. ._. ODD mg/kg in rats. According to the classification criteria laid down in Council Directive 67/548/EEC (and subsequent adaptations), concerning the potential toxicity by oral route, the test itemshould not be classified.Figure 1 : Mean body weight of the treated animals

320 300 280 260 240 220 200 180 160 140 (g)

®

days 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 p. 61 17

--4w- 300 mg/kg -o--2000 ng/kg (first assay) -,A -2000 mg/kg (confirmatory assay)Table 1 : Individual clinical signs and mortality Dose-level Time Females Mortality Clinical signs (mg/kg) 300 30 min

1 h - 2 h - 4 h ~ 01-02-03 No None D2toDl5 J p. 62 18

-------------------------------------------------------------------------------------------------------------------- 2000 15 min - 1 h - 2 h 04-05-06 No None (first assay) 2 h 30 05-06 No Hypoactivity, piloerection, dyspnea 04 No Piloerection, dyspnea 4 h - 6 h 04-05-06 No Hypoactivity, piloerection, dyspnea D 2 to D 5 04-05-06 No None -------------------------------------------------------------------------------------------------------------------- 2000 30 min -1 h (confirmatory 2 h - 2 h 30 - 4 h ~ 07-08-09 No None assay) D 2 to D 15 J min : minutes h : hour D :dayTable 2: Individual and mean body weight and weekly body weight change of treated rats (g) Dose-level Volume Sex Animals Days mg/kg mL/kg 1 (1) 8 (1) 300 10 Female 01 177 02 195 03 192 15 35 212 12 224 37 232 13 245 26 218 18 236 M 188 33 221 14 235 SD 10 6 10 3 11 2000 14.3 Female 04 185 (first assay) 05 193 06 190 50 235 17 252 40 233 15 248 51 241 4 245 M 189 47 236 12 248 SD 4 6 4 7 4 2000 14

.3 Female 07 (confumatory 08 assay) 09 190 41 231 22 253 186 46 232 21 253 197 44 241 9 250 M 191 44 235 17 252 SD 6 3 6 7 2 (1) =body weight gain M =mean SD =standard deviationTable 3: Body weight - CIT historical data of control animals dosed by oral route Check of the body weight (g) of CIT historical control animals Method : Acute oral administration CIT Studies / Experimental : CIT/Study Nos. 27218 RDR/ February 2004 Completion date 29691 RDR/ April 2005 31103 RDR / January 2006 Reference item : Purified water Volume of administration : 10 mL/kg Animals Species, strain : Rat, Sprague-Dawley Rj : SD (IOPS Han) Breeder : Janvier, Le Genest-Saint-Isle, France Age on day 1 : 8 weeks Volume (mL/kg) 1 10 Female M

SD n M:mean (1) : body weight gain SD: standard deviation n : number ofanimals

Sex (1) Days. 8 (1) 15 200 38 240 15 257 8 5 7 6 8 30 30 30 30 30 p. 64 20Table 4: Individual macroscopic examinations at necropsy Dose-level Time Females Macroscopic (mg/kg) abnormalities p. 65 21

300 D 15 01-02-03 No apparent abnormalities -------------------------------------------------------------------------------------------------------------------- 2000 D 15 04-05-06-07-08-09 No apparent abnormalities D : dayAPPENDICES1 . Test article description and analytical certificateTESTARTICLEDESCRIPTION p. 68 24

IDENTITY Test article name Chemical name CAS number EINECS number Origin Batch number Arkema filing number PHYSICAL AND CHEMICAL PROPERTIES Appearance : black powder Part.icule size : 30 gm . (approximately) Specific Gravity : 2,1 kg/m3 at 20°C Autoignition temperature : > 400 °C (standard : NF EN50281-2-1) Solubility : in water : insoluble

TOXICOLOGICAL INFORMATIONS ANDUSE SAFETY See Safety Data Sheet. STORAGE ANDDISPOSAL Storage Expiry date Disposal : Keep hermetically closed in a dry, cool and well-ventiled place . : June 2008 : IncinerationNom du responsable du taboratoirel Laboratory Director : DETERMINATION ! ITEM Reference de la methode RESULTAT l RESULT d'analyse 1 Analysis reference Powder characteristics Ash content °k 7.6% ATG r

~ "'°' 70 .2. Diet formula

# SsniffR/M-H

Complete diet for rats/mice - maintenance Crude proteins Crude fat Crude fiber Crude ash Amino Acids Lysine Methionine Cystine Glycine Leucine Isoleucine Arginine Phenylalanine Tryptophan Histidine Tyrosine Aspartic acid Glutaminic acid Valine Threonine Constituents Calcium 1 .00% Phosphorus 0.70% Sodium 0.25% Magnesium 0.20% Potassium 0.90% 19.00% 3 .30% 4.90% 6.70% 1 .00% 0.30% 0,30% 0.90% 1 .30% 0.70% 1 .20% 0.90% 0.25% 0.50% 0.60% 1 .70% 3 .80% 0.90% 0.70% Vitamins go kg)

A D3 E B1 B2 B6 B12 Biotin Pantothenic acid Choline Folic acid Nicotic acid K3 Inositol Trace elements (je kg) Manganese Copper Zinc Iodine Iron Selenium Cobalt ME (je kg) Itemnumbers V1530 Meal V1531 Micromeal V1534 Pellets 10 mm V1535 Pellets 15 mm 90 mg 12 mg 75 mg 2 mg 220 mg 0.2 mg 2 mg 15,000 IE 1,000 IE 100 mg 10 mg 20 mg 12 mg 80 pg 400 pg 30 mg 1,600 mg 4 mg 60 mg 5 mg 50 mg 12.2 MJ3. CIT GLP certificate!lSertt- " 4eHft - F'40-8f Eiirusr tcWe FraN(;&rse GROUPE INTERMINISTERIEL DES PRODUITS CHIMIQUES Paris, le Objet : Evaluation de la conformite aux Bonnes Pratiques de Laboratoires (BPL) selon les directives 2004/9/CE et 2004/10/CE du 11 f6vrier 2004. Subject : Assessment ofcompliance with Good Laboratory Practices (GLP) under the ECdirectives 2004/9 and 2004/10of II February 2004 . ConsBcutivement ii votre engagement vis-a-vis du GIPC et du COFRAC et en application du d6cret n° 2006- 1523 du 4 decembre 2006 concernant les bonnes pratiques de laboratoires et modifiant le ddcret n° 81-278 du 25 mars 1981 portant creation d'un groupe interministeriel des produits chimiques, je vous confirme que le GIPC, au vu des r6sultats du contr8le exerc8 par le Comite frangais d'accr6ditation (COFRAC) - Section Laboratoires a d8cid8 pour votre installation du statut suivant : Followingyour engagement vis-a-vts the GIPC and COFRACand in application of the decree 11' 2006-1523 of 4 December 2006 relating to the good laboratory practices and modifying the decree n° 81-278 of 25 March 1981 giving birth to an interministerial group of chemical products (GIPC), I confirm to you that the GIPC, given the results of the inspection realised by the French Committee of accreditation (COFRAC) - Laboratory Section has taken thefollowing decision relating to your installation: Respect des principes de BPL Date d'inspection : 7-8 mars 2007 Respect ofthe GLP principles Date of inspection ., 7-8 mars 2007 Domaines de reconnaissance: Inspection de renouvellement (i .r) 1 - essais physico-chimiques Renewal inspection (i .r) 2 - etudes de toxicite 3 - etudes de mutag8nicife Date de decision du GIPC : 29juin 2007 4 - etudes 8cotoxicologiques sur les Date ofGIPCdecision: 29 juin 2007 organismes aquatiques et terrestres 8 - methodes de chimie analytique et Date de prise d'effet : 8 mars 2007 clinique Date of implementation: 8 mars 2007 Areas ofexpertise : Ann6e de premiere conformitd : 1989 1 = Physico-chemical testing Year ofthefirst conformity: 1989 2 = Toxicily studies 3 = Mutagenicity studies Dur6e de validite: 18 mois 4 = Environmental toxicity studies on aquatic or Time ofvalidity: 18 months terrestrial organisms 8 =Analytical and clinicalchemistry

:r_

_ . ._.

CENTRE INTERNATIONAL DE TOXICOLOGIE (CIT) MISEREY - BP 563 27005 EVREUX CEDEX 

## - s JUli . 2007

Pierre CkEYSSEL Conseiller d'Etat h

Secr6tariatgeneral du GIPC - DGE- Simap - 12, rue Villiot - 75572 Paris cedex 12

Telephone : 0153 44 96 10 - T61ecopic : 015344 9172Figure 1 : Mean body weight of treated rats 15 Table 1 : Individual clinical signs and mortality 16 Table 2: Cutaneous reactions 1 7 Table 3: Individual and mean body weight and weekly body weight change (g) 18 Table 4: Body weight - CIT historical data ofcontrol animals dosed by dermal route 19 Table 5: Individual macroscopic examinations at necropsy 20 APPENDICES 21 1 . Test article description and analytical certificate 22 2. Diet formula 25 3. CIT GLP certificate 27 and 28:~s----' Safety& Health

Research Laboratories

STUDY TITLE ACUTE DERMAL TOXICITY

IN RATS

STUDYDIRECTOR Catherine Pelcot

DATE OF ISSUE

TEST FACILITY CIT BP 563 - 27005 Evreux - France

LABORATORY STU

DYNUMBER

IFMRecherche BY 563 27005 Evreux Cedex France S.N .C au Capital de 846

.092 ¬ T6I . : +33 (0)2 32 29 26 26 788 060 465 RC.S. Evreux Fax : +33 (0)2 32 67 87 05 UAT : FR19 788 060 465 E-maif : CfT@citox.com Agrement Crddit fmpdt Recherche Web site : vdww .citox_com p. 75

CONFIDENTIAL

ICONTENTS STATEMENT OF THE STUDY DIRECTOR 4 OTHERCIT SCIENTIST INVOLVED IN THE STUDY 5 STATEMENT OF QUALITY ASSURANCE UNIT 6 SUMMARY 7 RESUME 8 1 . INTRODUCTION 9 2 . MATERIALS ANDMETHODS 9 2 .1 TEST ITEM 9 2 .1 .1 Identification 9 2 .1 .2 Dosage formpreparation 9 2 .1 .3 Other item 9 2.2 TEST SYSTEM 10 2.2.1 Animals 10 2.2.2 Environmental conditions 10 2.2.3 Food and water 10 2.3 TREATMENT 11 2 .3 .1 Study design 11 2 .3 .2 Preparation of the animals 1 1 2 .3.3 Administration ofthe test item 11 2 .4 CLINICAL EXAMINATIONS 11 2 .4.1 Clinical signs and mortality 11 2 .4.2 Body weight 11 2 .5 PATHOLOGY 12 2 .5 .1 Sacrifice 12 2 .5 .2 Macroscopic necropsy examination 12 2.5 .3 Preservation oftissues 12 2.6 DATA EVALUATION 12 2 .7 ARCHIVING 12 2 .8 CHRONOLOGY OF THE STUDY 13 2 .9 STUDY PLAN ADHERENCE 13 3. RESULTS 14 3.1 CLINICAL EXAMINATIONS 14 3.1 .1 Mortality (table 1) 14 3.1 .2 Clinical signs and cutaneous reactions (tables 1 and 2) 14 3.1 .3 Body weight (figure 1, tables 3 and 4) 14 3.2 PATHOLOGY (table 5) 14 4 . CONCLUSION 14

### STATEMENT OF THE STUDY DIRECTOR

The study was performed in compliance with CIT's standard operating procedures and the following principles of Good Laboratory Practice:

. OECD Principles of Good Laboratory Practice (as revised in 1997), ENV/MC/CHEM (98) 17 and all subsequent OECDconsensus documents.

. Directive 2004/10/EC of the European Parliament and of the Council of 11 February 2004 on the harmonization of laws, regulations and administrative provisions relating to the application of the Principles of Good Laboratory Practice and the verification of their applications for tests on chemical substances (OJ No. L50 of20 .2.2004) .

. D6cret N° 2006-1523 du 04 d6cembre 2006 concernant les Bonnes Pratiques de Laboratoire (Journal Officiel du 06 d6cembre 2006), Ministere de 1'Economie, des Finances et de 1'Industrie. The study was also conducted in compliance with the following Animal Protection regulations:

. Council Directive 86/609/EEC of 24th November 1986 on the harmonization of laws, regulations or administrative provisions relating to the protection of animals used for experimental or other scientific purposes.

. Guidance document on the recognition, assessment, and use of clinical signs as humane endpoints for experimental animals used in safety evaluation, OECD Environmental Health and Safety Publications, No. 19. I declare that this report constitutes a true and faithful record of the procedures undertaken and the results obtained during the performance of the study. This study was performed at CIT, BP 563, 27005 Evre ; , France.

Toxicology C . Pelcot Study cor}ipletion date: 31 rj .,rej, Study Director

### OTHERCIT SCIENTIST INVOLVED IN THE STUDY

Director of Toxicology CIT Management J.J . Legrand Date: ~ Z- kt, ,t~,1 too

Doctor of Veterinary Medicine

### STATEMENT OF OU ALITY ASSURANCE UNIT Inspections performed at CIT: The CIT Quality Assurance Unit conducted the inspections detailed below : Dates Type of inspection Inspection Reported to the Reported to Study Director Management Study plan 27 July 2007 27 July 2007 02 August 2007 Report 13 February 2008 14 February 2008 12 March 2008 In addition, at about the same time, process-based and facility inspections relevant to this study were carried out by the Quality Assurance Unit . The inspections were performed in compliance with CIT Quality Assurance Unit procedures and the principles of Good Laboratory Practices. The final report is considered to constitute an accurate and complete reflection of the study raw data.

C'OccC~ Date: -A 5 _70p, s?czs CIT Quality Assurance UnitSUMMARY

- o.402 .,._24t~ _ __. _ _ --m - eruaiy 1987) _and EC (92/69%EEC, B.3, 31st July 1992) gui'delines. The study was conducted in compliance with the principles of Good Laboratory Practice Regulations. . Methods The test itemwas applied to the skin of one group of ten Sprague-Dawley rats (five males and five females) . The application was performed with the test item in its original form at the dose-level of 2000 mg/kg. The test site was then covered by a semi-occlusive dressing for 24 hours. Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single application of the test item . All animals were subjected to necropsy. Results No deaths and no clinical signs were observed during the study. A black coloration ofthe skin was noted in all the animals fromday 2 until day 10 and in all the males and in one female between day 11 and day 15 (end of the observation period) . This coloration masked the evaluation of cutaneous reactions in all the animals from day 2 until day 6. Crusts were observed in 1/5 males and 2/5 females between day 11 and day 15 (end of the observation period) . When compared to CIT historical control animals, the overall body weight gain of the animals was not affected by treatment with the test item . No apparent abnormalities were observed at necropsy in any animal . Conclusion mental - conditions of-this- study, the dermal LDo of According to the classification criteria laid down in Council Directive 67/548/EEC (and subsequent adaptations), concerning the potential toxicity by dermal route, the test itemshould not be classified.RESUME senformement aux lignes direcfrices de "1'OCDE~'402, 24 f6vrier 1987) et -e a CEE (92/69/CEE, B.3, 31 juillet 1992) . L'etude a ete realis6e conformement aux r6gles de Bonnes Pratiques de Laboratoire. Methode Le produit a ete applique sur la peau d'un groupe de 10 rats Sprague-Dawley (5 males et 5 femelles) . L'application a ete effectuee avec le produit tel quel a la dose de 2000 mg/kg. Le site de traitement a ensuite dte recouvert d'un pansement semi-occlusif pendant 24 heures. Les signes cliniques, la mortalite et 1'evolution ponderale des animaux ont ete suivis pendant une periode de 14jours apres 1'application unique du produit . Un examen anatomopathologique a ete effectue sur tous les animaux. Resultats Aucun signe clinique ni aucune mortalite ne sont observds pendant 1'etude. Une coloration noire de la peau est notee chez tous les animaux du Jour 2 au Jour 10 et chez tous les males et 1 femelle entre le Jour 11 et le Jour 15 (fin de la periode d'observation) . Cette coloration a masque l'evaluation des reactions cutanees chez tous les animaux du Jour 2 au Jour 6. Des croutes sont observdes chez 1/5 male et 2/5 femelles entre le Jour 11 et le Jour 15 (fin de la periode d'observation) . Comparee a celle des animaux temoins historiques du CIT, 1'evolution ponderale des animaux West pas influenc6e par le traitement . L'examen macroscopique des principaux organes des animaux ne met en gvidence aucune anomalie apparente. Conclusion cette etude,, . _la -DL 0 dermale du produit Selon les criteres de classification dgcrits dans la Directive 67/548/CEE (et ses adaptations) concernant la toxicite aigue par voie dermale, le produit ne devrait pas etre classe.1 . INTRODUCTION b p. 82 

### 9

' e objective of this study was to evaluate the toxicity of the test item GRAPHISTRENGTH Cl 00 micronised following a single dermal application to rats J . In the assessment of the toxic characteristics of a test item, determination of acute dermal toxicity is an initial step. It provides information on health hazards likely to arise following a short-termexposure by the dermal route in humans. The study was conducted in compliance with:

. OECD guideline No. 402, 24th February 1987,

. EC Directive No. 92/69/EEC, B.3, 31st July 1992. 2. MATERIALS AND METHODS 2.1 TEST ITEM 2.1 .1 Identification suppli name: batch num CAS number: Description at container: one plastic flask date of receipt : 29June 2007 storage conditions : at roomtemperature and protected from composition: see analytical certificate expiry date: June 2008

. humidity Data relating to the characterization of the test itemare documented in a test article and in an analytical certificate (presented in appendix 1) provided by the Sponsor . 2.1 .2 Dosage formpreparation The test itemwas administered in its original form . 2.1 .3 Other item description

Purified water (prepared at CIT by reverse osmosis) was used in order to moisten the test item and ensure a good contact with the skin.2.2 TEST SYSTEM 2.2.1 Animals p. 83 

### 10

Species, strain: rat, Sprague-Dawley Rj : SD (IOPS Han) . Reason for this choice: rodent species generally accepted by regulatory authorities for this type of study. Breeder : Janvier, Le Genest-Saint-Isle, France. Number and sex: one group often animals (five males and five females) . Females were nulliparous and non pregnant . Age/weight : on the day of treatment, the animals were approximately 8 weeks old and had a mean body weight f standard deviation of287 ± 6 g for the males and 214 f 5 g for the females. Acclimation: 4 days before the beginning of the study. Identification: individually by earnotches. 2 .2 .2 Environmental conditions The conditions in the animal room were set as follows:

. temperature: 22 f 2°C

. relative humidity: 30 to 70%

. light/dark cycle: 12 h/12 h

. ventilation: approximately 12 cycles/hour of filtered, non-recycled air. The temperature and relative humidity were under continuous control and recording. The records were checked daily and filed. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment are verified and calibrated at regular intervals . During the acclimation period, one to seven animals of the same sex were housed in polycarbonate cages with stainless steel lid (48 cm x 27 cm x 20 cm) . During the treatment period, the animals were housed individually in polycarbonate cages with stainless steel lid (35.5 cm x 23.5 cmx 19.3 cm) . Each cage contained autoclaved sawdust (SICSA, Alfortville, France) . Sawdust is analyzed by the supplier for composition and contaminant levels. 2 .2.3 Food and water All the animals had free access to SsniffR/M-H pelleted diet (SSNIFF Spezialdiaten GmbH, Soest, Germany) . Each batch of food is analyzed by the supplier for composition and contaminant levels. The diet formula is presented in appendix 2. Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum . Bacteriological and chemical analyses of water are performed regularly by external laboratories. These analyses include the detection of possible contaminants (pesticides, heavy metals and nitrosamines) . No contaminants were known to have been present in the diet, drinking water or bedding material at levels which may be expected to have interfered with or prejudiced the outcome of the study.2 .3 TREATMENT 2.3.1 Study design As the test itemwas anticipated to be non-toxic at the dose-level of 2000 mg/kg, a limit test was performed by application of 2000 mg/kg of the test itemto one group of ten animals (five males and five females) . 2.3.2 Preparation of the animals On the day before treatment, the dorsal area of each animal was clipped (i .e. approximately 5 cm x 7 cmfor males and 5 cmx 6 cmfor females) using an electric clipper. Only animals with healthy intact skin were used for the study. 2.3 .3 Administration of the test item A single dose of 2000 mg/kg of the test item in its original form was placed on a hydrophilic gauze pad (pre-moistened with 2 mL of purified water) and then applied to an area of the skin representing approximately 10% of the total body surface of the animals, calculated according to Meeh's formula (1) (i .e. approximately 5 cmx 7 cm for the males and 5 cm x 6cm for the females) . The test item and the gauze pad were held in contact with the skin for 24 hours by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage. This dressing prevented ingestion ofthe test item by the animal . On removal of the dressing, any residual test item could not be removed using a moistened cotton pad. The dose applied to each animal was adjusted according to the body weight determined on the day of treatment . 2.4 CLINICAL EXAMINATIONS 2.4.1 Clinical signs and mortality The animals were observed frequently during the hours following administration of the test item, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day until day 15. Type, time of onset and duration ofclinical signs were recorded for each animal individually. From day 2, any local cutaneous reaction was recorded. 2.4.2 Body weight The animals were weighed individually just before administration of the test itemon day 1 and then on days 8 and 15. The body weight gain of the treated animals was compared to that of CIT control animals with a similar initial body weight. (1) Meeh's formula 

## S = k3 p2 S = total surface of the animal in dm2 p = weight of the animal in grams k = 0.09 for the rat2.5 PATHOLOGY 2.5.1 Sacrifice On day 15, all animals were killed by carbon dioxide asphyxiation. 2.5.2 Macroscopic necropsy examination p. 85 

### 12

All study animals were subjected to a macroscopic examination as soon as possible after death. After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed. 2.5 .3 Preservation of tissues No organ samples were taken. 2.6 DATA EVALUATION Evaluation of the toxicity of the test item following a single dermal application in rats should include the relationship, if any, between the animals' exposure to the test itemand the incidence and severity of all abnormalities including behavioural and clinical abnormalities, macroscopic lesions, body weight changes, mortality and any other toxic effects. 2.7 ARCHIVING The following study materials are archived by CIT, 27005 Evreux, France, for 10 years after the end ofthe in vivo phase of the study :

. Study plan and possible amendments,

. raw data,

. correspondence,

. final report and possible amendments. On completion of this period, the archived study materials will be returned to the Sponsor, or may be archived at CIT for a further period (at additional cost) . The total duration of archiving (depending on regulations) will be the responsibility of the Sponsor . In addition, raw data not specific to the study including, but not limited to, certificates of analyses for food, water and bedding (if applicable) and records of environmental data and equipment calibration, are also archived by CIT for at least 30 years.2.8 CHRONOLOGY OF THE STUDY The chronology of the study was as follows: Procedure Date Experimental starting date (treatment) 21 August 2007 Experimental completion date (necropsy ofthe last animal) 04 September 2007 2.9 STUDY PLANADHERENCE The study was performed in accordance with Study plat'l~~J!~!~111U~~ subsequent amendments, with the following deviations fromthe agreed Study plan :

. the temperature and relative humidity recorded in the animal roomwere sometimes outside of the target ranges specified in the Study plan,

. the acclimation of the animals was 4 days (instead of at least 5 days) before the beginning of the study. These minor deviations were not considered to have compromised the validity or integrity of the study.3. RESULTS 3.1 CLINICAL EXAMINATIONS 3.1 .1 Mortality (table 1) No deaths occurred during the study. 3.1 .2 Clinical signs and cutaneous reactions (tables 1 and 2) p. 87 

### 14

No clinical signs were observed during the study. A black coloration of the skin was noted in all the animals fromday 2 until day 10 and in all the males and in one female between day 11 and day 15 (end of the observation period) . This coloration masked the evaluation of cutaneous reactions in all the animals from day 2 until day 6. Crusts were observed in 1/5 males and 2/5 females between day 11 and day 15 (end of the observation period) . 3.1 .3 Body weight (figure 1, tables 3 and 4) When compared to CIT historical control animals, the overall body weight gain of the animals was not affected by treatment with the test item . 3.2 PATHOLOGY (table 5) Macroscopic examination of the main organs ofthe animals revealed no apparent abnormalities. 4. CONCLUSION Under the experimental conditions of this study, the dermal LDo of the test item II~~ 000 mg/kg in rats... ~ . --~

. Figure 1 : Mean body weight oftreated rats

400 . 380 360 340 320 300 280 260 240 220 200 (9)

O days 4 5 6 7 8 9 10 11 12 13 14 15 -s- Male -O-Female p. 88 15Table 1 : Individual clinical signs and mortality

Dose-level Time Animals Mortality Clinical signs (mg/kg) Males Females 2000 30 min

2 h - 5 h ~ 01-02-03-04-05 06-07-08-09-10 No None D2toD15J min : minutes h :hour D : dayTable 2: Cutaneous reactions Dose-level Time Animals Cutaneous reactions (mg/kg) Males Females 2000 D 2 to D 6 01-02-03-04-05 06-07-08-09-10 Black coloration of the skin which could have masked a possible erythema D 7 to D 10 01-02-03-04-05 06-07-08-09-10 Black coloration of the skin No cutaneous reactions D 11 06-10 Crusts

01-02-03-04-05 07 Black coloration of the skin No cutaneous reactions 08-09 None D 12 and D 13 03 Crusts, black coloration of the skin 06-10 Crusts 01-02-03-04-05 07 Black coloration of the skin No cutaneous reactions 08-09 None D 14 01-02-03-05 07 Black coloration ofthe skin No cutaneous reactions 06-10 Crusts 04 08-09 None D 15 01-02-03-05 07 Black coloration ofthe skin No cutaneous reactions 06 Crusts 04 08-09-10 None D : dayTable 3: Individual and mean body weight and weekly body weight change (g) Dose-level Days

Sex Animals mg/kg 1 (1) 8 (1) 15 2000 Male 01 295 52 347 53 400 02 280 49 329 44 373 03 287 47 334 53 387 04 288 50 338 49 387 05 284 50 334 51 385 M 287 50 336 50 386 SD 6 2 7 4 10 2000 Female 06 214 17 231 19 250 07 220 16 236 21 257 08 206 19 225 20 245 09 214 15 229 14 243 10 218 19 237 26 263 M 214 17 232 20 252 SD 5 2 5 4 8 (1) = body weight gain M = mean SD = standard deviationTable 4: Body weight - CIT historical data ofcontrol animals dosed by dermal route Check of the body weight (g) of CIT historical control animals Method : Acute dermal administration CIT Studies / Experimental : CIT/Study Nos. 27220 RDR / February 2004 Completion date 29692 RDR/ April 2005 31105 RDR/ January 2006 Reference item : Purified water Volume of administration : 5 mL/kg Animals Species, strain : Rat, Sprague-Dawley Rj : SD (IOPS Han) Breeder : Janvier, Le Genest-Saint-Isle, France Age on day 1 : 8 weeks

Volume (mL/kg) Sex 1 (1) Days 8 (1) 15 5 Male M 333 46 380 48 428

SD 36 14 32 9 34 n 29 29 29 29 29 5 Female M 216 24 241 19 260

SD 9 11 14 9 16 n 29 29 29 29 29 M: mean (1) : body weight gain SD : standard deviation n : number ofanimals p. 92 19

460 440 (420 ' 400 380 360 340 320 300 280 260 240 220 days 200 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 + -Male --A--FemaleTable 5: Individual macroscopic examinations at necropsy Dose-level Time Animals Macroscopic (mg/kg) Males Females abnormalities 2000 D 15 01-02-03-04-05 06-07-08-09-10 No apparent abnormalities D : dayAPPENDICES1 . Test article description and analytical certificateTESTARTICLE DESCRIPTION

PHYSICAL ANDCHEMICAL PROPERTIES Appearance : black powder Particule size : 30jim ( approximately) Specific Gravity : 2,1 kg/m3 at 20°C Autoignition temperature : > 400 °C (standard : NF EN50281-2-1) Solubility : in water : insoluble

TOXICOLOGICAL INFORMATIONS ANDUSE SAFETY I See Safety Data Sheet. I STORAGE AND DISPOSAL Storage : Keep hermetically closed in a dry, cool and well-ventiled place . Expiry date : June 2008 ~ Disposal : Incineration p. 96 23p. 97 24

Reference de la m6thode d'analyse l Analysis reference

Nom du responsable du laboratoirel Laboratory Director :

Signature2. Diet formula

# SsniffRIM-H

Complete diet for rats/mice - maintenance Crude proteins Crude fat Crude fiber Crude ash Amino Acids Lysine Methionine Cystine Glycine Leucine Isoleucine Arginine Phenylalanine Tryptophan Histidine Tyrosine Aspartic acid Glutaminic acid Valine Threonine Trace elements (je Manganese Copper Zinc Iodine Iron Selenium Cobalt 19.00% 3.30% 4.90% 6.70% 1 .00% 0.30% 0.30% 0.90% 1 .30% 0.70% 1 .20% 0.90% 0.25% 0.50% 0.60% 1 .70% 3 .80% 0.90% 0.70% Constituents

Calcium Phosphorus Sodium Magnesium Potassium Vitamins Qe kg) A D3 E B1 B2 B6 B12 Biotin Pantothenic acid Choline Folic acid Nicotic acid K3 Inositol ME (je kg) 1 .00%

0.70% 0 .25% 0.20% 0.90%

kg) 90 mg 12 mg 75 mg 2 mg 220 mg 0.2 mg 2 mg Itemnumbers

V1530 Meal V1531 Micromeal V1534 Pellets 10 mm V1535 Pellets 15 mm 15,000 IE 1,000 IE 100 mg 10 mg 20 mg 12 mg 80 ltg 400 pg 30 mg 1,600 mg 4 mg 60 mg 5 mg 50 mg 12.2 MJ3. CIT GLP certificate"& . u -Auaaa . rMWrAuE Ittiruar1CWe FxamJ~ GROUPE I1VTERIYIINISTERIEL DES PRODUITS CHIMIQUES Paris, le Objet : Evaluation de la conformite aux Bonnes Pratiques de Laboratoires (BPL) selon les directives 2004/9/CE et 2004/10/CE du 11 f&vrier 2004. Subject : Assessment ofcompliance with Good Laboratory Practices (GLP) under the ECdirectives 2004/9 and 2004/10of 11 February 2004 . ConsBcutivement A votre engagement vis-A-vis du GIPC et du COFRAC et en application du d6cret n° 2006- 1523 du 4d6cembre 2006 concernant les bonnes pratiques de laboratoires et modifiant le d6cret n° 81-278 du 25 mars 1981 portant creation d'un groupe interministbriel des produits chimiques, je vous confirme que le GIPC, au vu des rdsultats du controle exere6 par le Comite frangais d'accr6ditation (COFRAC - Section Laboratoires a d8cid6 pour votre installation du statut suivant: Following

your engagement vis-a-vis the GIPC and COFRACand in application of the decree n'2006-1523 of 4 December 2006 relating to the good laboratoiy practices and modifying the decree n° 81-278 of 25 March 1981 giving birth to an interministerial group of chemical products (GIPC), I confirmto you that the GIPC, given the results ofthe inspection realised by the French Committee ofaccreditation (COFRAC - Laboratory Section has taken thefollowing decision relating to your installation: Respect des principes de BPL Date d'inspection : 7-8 mars 2007 Respect ofthe GLPprinciples Date ofinspection : 7-8 mars 2007 Domaines de reconnaissance; Inspection de renouvellement (i .r) 1- essais physico-chimiques Renewal inspection (i.r) 2- 6tudes de toxicit6 3 - 6tudes de mutagbnicite Date de decision du GIPC : 29 juin 2007 4 - 6tudes 6cotoxicologiques sur les Date ofGIPCdecision: 29 juin 2007 organismes aquatiques et terrestres 8- m6thodes de chimie analytique et Date de prise d'effet : 8 mars 2007 clinique Date of implementation: 8 mars 2007 Areas ofexpertise : Annee de premi8re conformitd : 1989 1=Physico-chemical testing Year ofthefirst conformity: 1989 2 = Toxicity studies 3 = Mutagenicity studies Durde de validit6 : 18 mois 4 = Environmental toxicity studies on aquatic or Time ofvalidity: 18 months terrestrial organisms 8 =Analytical andclinicalchemistry

:

CENTRE INTERNATIONAL DETOXICOLOGIE (CIT) MISEREY- BP 563 27005 EVREUX CEDEX 

### - 9 JUIi . 2007

Pierre CkEY'SSEY, Conseiller d'Etat h

Secrbtariat general du GIPC - DGE- Simap - 12, rue Villiot - 75572 Paris cedex 12

Telephone : 0153 44 96 10 -T616copie : 01 53 44 9172p. 102 CONFIDENTIAL

STUDY TITLE ACUTE EYE IRRITATION IN RABBITS STUDYDIRECTOR Catherine Pelcot

DATE O

F ISSUE 

# "Q3,- pcecle TEST FACILITY CIT BP 563 - 27005 Evreux - Prance

IFMRecherche S .N .C au Capita! de 846,092 ¬ 788 060 465 R

.C .S. Evreux VAT ER ! 9 788 060 465 Agremenz Credit Impet Recherche LABO UMBER

B .P 563 27005 Evreux Cedex France T6 . : +33 (0)2 32 29 26 26 Fax : +33 (0)2 32 67 87 05 E-mail : CIT@citox.com Web site : www

.citox .com 

## T6jCONTENTS STATEMENT OF THE STUDY DIRECTOR 3 OTHER CIT SCIENTIST INVOLVED INTHE STUDY 4 STATEMENT OF QUALITYASSURANCE UNIT 5 SUMMARY RESUME 6 7 1 . INTRODUCTION 8 2 . MATERIALS ANDMETHODS 8 2.1 TEST ITEM 8 2.1 .1 Identification 8 2 .1 .2 Dosage formpreparation 8 2 .2 TEST SYSTEM 2.2.1 Animals 2.2.2 Environmental conditions 2 .2.3 Food and water 2.3 TREATMENT 10 2.3 .1 Selection ofthe animals 10 2.3 .2 Administration of the test item 10 2.4 OCULAR EXAMINATIONS 10 2.4.1 Duration of the observation period 10 2.4.2 Description and evaluation of ocular reactions 10 2.5 BODY WEIGHT 11 2.6 INTERPRETATION OF RESULTS 11 2.7 ARCHIVING 12 2.8 CHRONOLOGY OF THE STUDY 12 2.9 STUDY PLANADHERENCE 12 3. RESULTS 13 4. DISCUSSION 13 5. CONCLUSION 13 Table 1 : Individual ocular examinations and mean values of the scores recorded for each

animal (24, 48 and 72 hours) 14 Table 2: Individual body weight (g) 16 APPENDICES 17 1 . Test article description and analytical certificate 18 2 . Diet formula 21 3. CIT GLP certificate 23 and 24

### STATEMENT OF THE STUDY DIRECTOR

The study was performed in compliance with the principles of Good Laboratory Practice as described in:

. OECD Principles of Good Laboratory Practice (as revised in 1997), ENV/MC/CHEM (98) 17 and all subsequent OECDconsensus documents.

. Directive 2004/10/EC ofthe European Parliament and ofthe Council of 11 February 2004 on the harmonization of laws, regulations and administrative provisions relating to the application of the Principles of Good Laboratory Practice and the verification of their applications for tests on chemical substances (OJ No. L50 of 20 .2.2004) .

. Decret N° 2006-1523 du 04 d6cembre 2006 concernant les Bonnes Pratiques de Laboratoire (Journal Officiel du 06 d6cembre 2006), Ministere de 1'Economie, des Finances et de 1'Industrie. The study was also conducted in compliance with the following Animal Protection regulations :

. Council Directive 86/609/EEC of 24th November 1986 on the harmonization of laws, regulations or administrative provisions relating to the protection of animals used for experimental or other scientific purposes.

. Guidance document on the recognition, assessment, and use of clinical signs as humane endpoints for experimental animals used in safety evaluation, OECD Environmental Health and Safety Publications, No. 19. I declare that this report constitutes a true and faithful record of the procedures undertaken and the results obtained during the performance ofthe study. This study was performed at CIT, BP 563, 27005 Evreux, Fran

Toxicology /-

C . Pelcot Study completion/date: J1 [A Fn L j Study Director ,

### OTHER CIT SCIENTIST INVOLVED IN THE STUDY

Director ofToxicology CIT Management J .J. Legrand Date:

Doctor of Veterinary MedicineSTATEMENT OF QUALITYASSURANCE UNIT

Inspections performed at CIT: 

### The CIT QualityAssurance Unit conducted the inspections detailed below : Type of inspection Dates Inspection Reported to the Reported to

Study Director Management Study plan 27 July 2007 27 July 2007 02 August 2007 Report 25 March 2008 27 March 2008 08 April 2008 In addition, at about the same time, process-based and facility inspections relevant to this study were carried out by the Quality Assurance Unit . The inspections were performed in compliance with CIT Quality Assurance Unit procedures and the principles of Good Laboratory Practices. The final report is considered to constitute an accurate and complete reflection of the study raw data.

A . ac- e.e

: c~cc.> Date: .2 3 TIP, 2, :7c-,a CIT QualityAssurance UnitSUMMARY p. 107 

### 6

g 29th April 2004) guidelines. The study was conducted in compliance with the principles of Good Laboratory Practice Regulations. Methods The test item was first administered to a single male New Zealand White rabbit . Since the test itemwas irritant on this first animal, but without persistence until the end ofthe observation period, it was then evaluated sequentially in two other animals. A single dose of the test item in its original form was introduced into the left conjunctival sac. The right eye was not treated and served as control . The eyes were not rinsed after administration of the test item . Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration and then daily until complete reversibility of the ocular reactions (day 9 at the latest) . The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal . Results A slight to marked chemosis was noted in all the animals fromday 1 until day 7 (1/3 animals) or 8 (2/3 animals) . A slight to severe redness of the conjunctiva was observed in all the animals fromday 1 until day 5 (1/3 animals) or 8 (2/3 animals) . A clear discharge was observed in all the animals fromday 1 until day 2, 5 or 6. An iritis was noted in all the animals on day 2; it persisted in one animal until day 4. A slight or moderate corneal opacity was recorded in all the animals on days 2 and 3; it persisted until day 5 in 2/3 animals. This corneal opacity covered the whole area of the cornea of 1/3 animals on day 2. Mean scores calculated for each animal over 24, 48 and 72 hours were 2.7, 2.3 and 2.7 for chemosis, 2.0, 1 .7 and 2.7 for redness ofthe conjunctiva, 0.3, 0.3 and 1 .3 for iris lesions and 2.0, 1 .0 and 2.0 for corneal opacity. Conclusion According to the classification criteria laid down in Council Directive 67/548/EEC (and subsequent adaptations), the test itemshould be considered as irritant to eyes.p. 108 7 RESUME

e Lapin ont ete dva uees se CEE (92/69/CEE, B.5, 31juillet 1992) . L'etude a et6 realisee conformgment aux regles de Bonnes Pratiques de Laboratoire. Methode Le produit a d'abord dte applique sur un seul Lapin male New Zealand White. Le produit ayant montre des proprietgs irritantes sur ce premier animal mais sans persistance jusqu'a la fin de la periode d'observation, il a ensuite ete teste sdquentiellement sur deux autres animaux. Une dose unique de produit tel quel a ete introduite dans le cul-de-sac conjonctival de Neil gauche. L'oeil droit a servi de temoin. Aucun ringage des yeux n'a ete realise apres 1'administration du produit . Les reactions oculaires ont ete observees environ l, 24, 48 et 72 heures apres I'administration puis quotidiennement jusqu'a reversibilite complete des lesions oculaires observees (jour 9 au plus tard) . La moyenne des scores pour le chemosis, la rougeur de la conjonctive, les lesions de 1'iris et l'opacite de la cornee a etd calculde pour chaque animal . Resultats Un chemosis leger A marque est note chez tous les animaux dujour 1 aux jours 7 (1/3 animal) ou 8 (2/3 animaux) . Une rougeur de la conjonctive legere a grave est observee chez tous les animaux du jour 1 aux jours 5 (1/3 animal) ou 8 (2/3 animaux) . Un larmoiement clair est observe chez tous les animaux dujour 1 auxjours 2, 5 ou 6. Une inflammation de 1'iris est notee chez tous les animaux aujour 2 ; elle persiste chez 1 animal jusqu'aujour 4. Une opacite corngenne legere ou moderge est observee chez tous les animaux auxjours 2 et 3 ; elle persistejusqu'aujour 5 chez 2/3 animaux. Cette opacite corneenne a couvert la totalite de la cornee d'1/3 animal aujour 2. La moyenne des scores enregistres pour chaque animal apres 24, 48 et 72 heures est de 2,7 ; 2,3 et 2,7 pour le chemosis, 2,0 ; 1,7 et 2,7 pour la rougeur de la conjonctive, 0,3 ; 0,3 et 1,3 pour les lesions de 1'iris et 2,0; 1,0 et 2,0 pour 1'opacite corneenne. Conclusion

Selon les criteres de classification decrits dans la Directive 67/548/CEE (et ses adaptations), le produit est considere comme irritant pour les yeux.1 . INTRODUCTION

In the assessment of the toxic characteristics of a test item, determination of the irritant effects on the eyes of mammals is an important initial step. Information derived fromthis test serves to indicate the possible hazards likely to arise fromexposure of the eyes, ~and associated mucous membranes, to the test item . This study was conducted in compliance with:

. OECDguideline No. 405, 24th April 2002,

. EC Directive No. 2004/73/EC, part B.5, 29th April 2004. 2. MATERIALS AND METHODS 2.1 TEST ITEM 2 .1 .1 Identification Description at receipt:-blacZ powder container : one plastic flask date of receipt : 29June 2007 storage conditions: at roomtemperature and protected fromhumidity composition : see analytical certificate expiry date: June 2008. Data relating to the characterization of the test itemare documented in a test article description and in an analytical certificate (presented in appendix 1) provided by the Sponsor . 2 .1 .2 Dosage formpreparation The test itemwas used in its original form . The pH of the test item at the concentration of 1% in purified water was not measurable (non soluble and colored test item) .2.2 TEST SYSTEM 2.2.1 Animals p. 110 9

Sex, species, strain: male New Zealand White rabbits. Reason for this choice: species generally accepted by regulatory authorities for this type of study. Breeder : Grimaud freres selection S .A.S., La Corbiere, Roussay, France Number : three animals were used, as recommended by the international guidelines. Age/weight : on the day of treatment, the animals were 2 to 4 months old and had a mean body weight f standard deviation of 2.9 f 0.1 kg. Acclimation: at least 5 days before the beginning ofthe study. Identification: individual metal ear tag. 2.2.2 Environmental conditions The conditions in the animal room were set as follows :

. temperature: 18 ± 3°C

. relative humidity: 30 to 70%

. light/dark cycle: 12 h/12 h

. ventilation : approximately 12 cycles/hour offiltered, non-recycled air. The temperature and relative humidity were under continuous control and recording . The records were checked daily and fled. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment were verified and calibrated at regular intervals. The animals were housed individually in Techniplast (64 cmx 63 cmx 30 cm) or Pajon (50 cm x 57 cm x 75 cm) cages. Each cage was equipped with a food container and a water bottle. 2 .2.3 Food and water During the study, the animals had free access to 110C pelleted diet (SAFE, Villemoisson, Epinay-sur-Orge, France) . Food is analyzed regularly by the supplier for composition and contaminant levels. The diet formula is presented in appendix 2. Drinking water filtered by a FG Millipore membrane (0 .22 micron) was provided ad libitum . Bacteriological and chemical analyses of water are performed regularly by external laboratories. These analyses include the detection of possible contaminants (pesticides, heavy metals and nitrosamines) . No contaminants were known to have been present in the diet or drinking water at levels which may be expected to have interfered with or prejudiced the outcome of the study.2.3 TREATMENT 2.3.1 Selection of the animals p. 111 10

Just before treatment, the eyes of each animal were examined in order to check the absence of any signs of ocular irritation, ocular defects or pre-existing corneal injury. 2.3 .2 Administration ofthe test item The test itemwas first administered to a single animal (No. 474) . Since the test itemwas irritant, but without persistence at the end of the observation period, on this first animal, it was then evaluated sequentially on other animals (No. 483 then No. 484) . A single dose (the maximal quantity of the test item administrable into the eye was approximately 1/3 of the 100 mg required quantity) of the test item in its original form was introduced into the conjunctival sac of the left eye after gently pulling the lower lid away from the eyeball . The lower and upper eyelids were held together for about one second to avoid any loss of test item . The right eye, which remained untreated, served as control . The eyes were not rinsed after administration of the test item . 2.4 OCULAR EXAMINATIONS 2.4.1 Duration of the observation period The eyes were examined approximately 1 hour, 24, 48 and 72 hours after administration of the test item . Since there were persistent ocular reactions at 72 hours, the observation period was extended up to their complete reversibility (day 9 at the latest) . 2.4.2 Description and evaluation of ocular reactions Conjunctival reactions, iritis and corneal opacification were evaluated daily for each animal . For the evaluation of corneal opacification (presence or absence, affected area), the eyes were examined under a UV lamp after instillation of one or two drops of 0.5%sodium fluorescein solution (a clear fluorescence is visible in the areas of opacification) . This evaluation was performed on day 2 and repeated thereafter whenever necessary. Ocular reactions were scored according to the following numerical scale: Coniunctival lesions and discharge Chemosis (lids and/or nictitating membranes)

. no swelling . . . .. . . . . . .. . . .. . . . . . . . .. . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .. . . . . . . . .. . . . . . . . . . . . . .. . . . . .. . . . . . .. . . .. . . . . . . 0

. any swelling above normal (includes nictitating membranes) . .. . .. . . . . . . . .. . . . . .. . . . . . . . . . . . . . ._ . . . . . . . . . . . . . 1

. obvious swelling with partial eversion of lids. . . . . . . . . . . . . . . . . . . . . . . . ., . . . ., ., . ., . . . . ., .,_ . . . . . . .. . . .. . . ., . . . . . . .2

. swelling with lids about half-closed. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . .. . .. . . . . . . . . . . . .. . . . . .. . . . . . .. . .. . . . . . . . . . . . . . . . .. . . .. . . . .3

. swelling with lids more than half-closed . . . . . . . . . . . . . . . . . . .. . ., . . ., . ., . . _ ,. . . . . ., ., . . . . .,_. ._. ., . . . . ., . . . . . . .4 Redness (refers to palpebral and bulbar conjunctivae, cornea and iris)

. blood vessels normal . . .. . .. .. . .. . . . . .. . . . . . . . . . . . . . . . .. . . . . . . . . . .. . .. . . . . . .. . . . . . . . . . . . .. . . . . . . . .. . . . . .. . . . . . .. . .. . . .. . . . . . . . . . .. . . .0

. a number of blood vessels definitely hyperemic (injected) . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . .. . . . . . . . . . . . . 1

. diffuse, crimson colour, individual vessels not easily discernible . . .. . . . . . .. . . . . . . . . . . . .. . .. . . . . . . . . . . . . . .. . 2

. diffuse, beefy red. . . . . . .. . .. . . . . .. .. . .. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . .. . .. . .. . . . . . . . . . . . . . . .. . . . . . .. . . . . .. . . . . . . . . . . . . . . . . . . . . . .3p. 112 11 Discharge

. absence of discharge . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . .. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . .. . . . . . . . . . . . .0

. slight discharge (does not include small amounts normally found in inner canthus) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . . . .1

. discharge with moistening of lids and hairs adjacent to lids . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .. . . .2

. discharge with moistening of lids and hairs on wide area around the eye . . . . . . .. . . . . . . . . . .. . . . . . . . . . . . . 3 Iris lesions

. normal . . .. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . . . . .. . . . . .. . . . . . .. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .0

. markedly deepened rugae, congestion, swelling, moderate circum-corneal hyperemia, or injection, any ofthese or combination of any thereof, iris still reacting to light (sluggish reaction is positive) . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .. . . . . . . . .. . . .1

. no reaction to light, haemorrhage, gross destruction (any or all of these) . . .. . . . . .. . . . . . . . .. . . . . . . . . . . .2 Corneal lesions Degree of opacity (area most dense taken for reading)

. no ulceration or opacity . . . . . .. . . .. . . . . . .. . .. . . . . . . .. . .. . . . . .. . . . . . .. . .. . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . .. . . . . . . . . . .0

. scattered or diffuse areas of opacity (other than slight dulling or normal lustre), details of iris clearly visible . . . . . .. . . . . . . . . . . . . . . . . .. . . . . .. . . . . . . . .. . . . . . .. . . .. . .. . . .. . . . . . .. . . .. . . . . . . . . . . . . .. . . . . . . . . . .. . . . . . . .1

. easily discernible translucent area, details of iris slightly obscured . . .. . . .. . . . . . .. . .. . . . .. . .. . .. . .. . .. . . .2

. nacreous areas, no details of iris visible, size of pupil barely discernible . . . . .. . . . . . . . . . . . . . . . . .. . . . . .. .3

. opaque cornea, iris not discernible through the opacity. . . .. . . .. . . . . . .. . . . . . .. . . . . . . . . . .. . . . . . .. . . . .. . . . . . . . . . . . . .4 Area of opacity

. one quarter (or less) but not zero.. . .. . . . . .. . .. . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . .. . . . . . . . . . . . . . . . .. . .. . . .. .. . . . . . . . .. . . . . . l

. greater than one quarter but less than a half. . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . .. . . . .. . . . . . . . . . . . .. .. . .. . . . . .. . . . . .2

. greater than one half but less than three quarters . . .. . .. . . . . . . . . . . . . . . . . . . . . . ., . . . . . . . . . . . . . . . . . . . . . . ., . . . . . . . . . . . . . . .3

. greater than three quarters up to whole area. . . . . . . . . . . . . . . . .. . . . . . .. . . . . . . . . . .. . . . . . . . . . . . . . . . .. . . . . . .. . . . .. . . . . .. . . . . .4 Any other lesions observed were noted. 2.5 BODY WEIGHT Each animal was weighted at the beginning (day of treatment) and at the end of the observation period. 2.6 INTERPRETATION OF RESULTS The results obtained were evaluated in conjunction with the nature and the reversibility of the scores observed, whilst taking into account all the reactions of the treated animals. Criteria for irritation A substance or a preparation is considered irritant for the eyes if, when applied to the eye of the animal, significant or severe ocular lesions are caused within 72 hours after exposure and which persist for 24 hours or more after treatment with the test item . All the scores at each reading time (24, 48 and 72 hours) and for an effect are used for calculating the respective mean values.2 .7 ARCHIVING The following study materials are archived by CIT, 27005 Evreux, France, for 10 years after the end ofthe in vivo phase of the study:

. Study plan and possible amendments,

. raw data,

. correspondence,

. final report and possible amendments. On completion of this period, the archived study materials will be returned to the Sponsor, or may be archived at CIT for a further period (at additional cost) . The total duration of archiving (depending on regulations) will be the responsibility ofthe Sponsor . In addition, rawdata not specific to the study including, but not limited to, certificates of analyses for food, water and bedding (if applicable) and records of environmental data and equipment calibration, are also archived by CIT for at least 30years. 2 .8 CHRONOLOGY OF THE STUDY The chronology ofthe study is summarized as follows: Procedure Experimental starting date (day oftreatment of the first animal) Experimental completion date (end of the observation period) Date 14 August 2007 07 September 2007 2 .9 STUDY PLANADHERENCE The study was performed in accordance with amendments, with the following deviation fromtrn-~-agreed Study plan:

. the temperature and relative humidity recorded in the animal room were sometimes outside of the target ranges specified in the Study plan. This minor deviation was not considered to have compromised the validity or integrity of the study.3. RESULTS The observations recorded during the study are presented in table 1 . The body weight is presented in table 2. A slight to marked chemosis (grades 1 to 3) was noted in all the animals fromday 1 until day 7 (1/3 animals) or 8 (2/3 animals) . A slight to severe redness of the conjunctiva (grades 1 to 3) was observed in all the animals from day 1 until day 5 (1/3 animals) or 8 (2/3 animals) . A clear discharge was observed in all the animals fromday 1 until day 2, 5 or 6. An iritis of grade 1 was noted in 2/3 the animals on day 2. In the third animal, an iritis of grade 2 was noted on day 2; an iritis of grade 1 persisted until day 4 . A slight or moderate corneal opacity (grade 1 or 2) was recorded in all the animals on day 2; it persisted until day 3 (1/3 animals) or 5 (2/3 animals) . This corneal opacity covered the whole area ofthe cornea of 1/3 animals on day 2. Mean scores calculated for each animal over 24, 48 and 72 hours were 2.7, 2 .3 and 2

.7 for chemosis, 2

.0, 1 .7 and 2.7 for redness of the conjunctiva, 0 .3, 0 .3 and 1 .3 for iris lesions and 2.0, 1 .0 and 2

.0 for corneal opacity. 4. DISCUSSION The grade 2 observed in one animal only on day 2 seems doubtful and not coherent with the grades 1 noted the next days. 5. CONCLUSIONTable 1 : Individual ocular examinations and mean values of the scores recorded for each animal (24, 48 and 72 hours) Rabbit Region Description Scores Mean Interpretation number ofeye ofocular irritation (+) reactions Ih 24h 48h 72h score (1) (-)

D1 D2 D3 D4 474 Conjuncfivae Chemosis 3 3 3 2 2 .7 (+) Redness 2 2 2 2 2 .0 (-) Discharge 1 2 0 0 0.7 Iris 0 1 0 0 0.3 (-) Corneal opacity Intensity 0 2 2 2 2 .0 (+) Area 0 4 3 1 2 .7 Other Su Su Su Su Fluoresoein / U U U 483 Conjunctivae Chemosis 3 3 2 2 2.3 (+) Redness 2 2 2 1 1,7 (_) Discharge 1 2 1 1 1 .3 Iris 0 1 0 0 0 .3 (-) Corneal opacity Intensity 0 2 I 0 1 .0 (-)

Area 0 3 1 0 1 .3 Other Su Su * * Fluorescein / U U U 484 Conjunctivae Chemosis 3 3 3 2 2 .7 (+) Redness 2 3 3 2 2 .7 (+) Discharge 1 1 1 I 1 .0 Iris 0 2 1 1 1 .3 (+) Corneal opacity Intensity 0 2 2 2 2.0 (+)

Area 0 3 3 2 2.7 Other Su Su * * Fluorescein / U U U (1) mean ofscores on days 2, 3 and 4 h=hour D =day (+) = irritant according to E.E .C . criteria (-) =non-irritant according to E.E .C . criteria * = none U = fluorescein batch Nos. L239and L653 / = fluorescein not used Su = residual test itemTable 1 (continued) Rabbit Region Description Scores number ofeye ofocular reactions D5 D6 D7 D8 D9 474 Conjunctivae Chemosis 2 2 1 1 0 Redness 2 2 1 1 0 Discharge 0 0 0 0 0 Iris 0 0 0 0 0 Corneal opacity Intensity 1 0 0 0 0

Area 1 0 0 0 0 Other * * * * Fluorescein U U 483 Conj unctivae Chemosis I I 1 0 - Redness 1 0 0 0 - Discharge 1 1 0 0 Iris 0 0 0 0 Corneal opacity Intensity 0 0 0 0

Area 0 0 0 0 Other * * * * _ Fluorescein 484 Conjunctivae Chemosis 2 2 2 1 0 Redness 1 I 1 l 0 Discharge 1 0 0 0 0 Iris 0 0 0 0 0 Corneal opacity Intensity 1 0 0 0 0

Area 1 0 0 0 0 Other * * * * * Fluorescein U U D=day * = none U = fluorescein batch Nos. L239 and L653 / = fluorescein not used - = ocular examinationnot performedTable 2: Individual body weight (g) Sex Animals Day of End ofthe

treatment observation period Male 474 2778 2993

483 2780 2914 484 3015 3140 M 2858 3016 SD 136 115 M = mean SD= standard deviationp. 118 17

APPENDICES1 . Test article description and analytical certificateT~t article name Chemical narne CAS number UNECS number Qrigill Batch number ftling n

F eci tic C`armFi .ty ASIt!f31gn1ttC3'Ll tei31pelfUt7%2 : black powd2t ; 30p,m( apprnximataly ) : 2,1~ kOjM3 at 2(}'C `%' 400 °C (Standard : 'e``IF E't~ .'r>E}7$1-2-1 ) in wawC : !I?54l1iblo . Solubility

: Keep hermetically closed in e dry, coot and wtil-ventited place . I JUDO IncinerationDETERMINATION I ITEM Reference de la m6thode RESULTAT1 RESULT d'analyse 1 Analysis reference Powder characteristics Ash content % 7.6% ATG 76 WW

ei h-in ._ ., .

Nom du responsable du laboratoirel Laboratory Director :2. Diet formulap. 123 

### 22

Ref 110 COMPLETE DIET RABBIT BREEDING DIET Appearance: 3 mm

diameter granules Conditioning: bags of 20 kgs Daily portion: Rabbits 150 g, water ad libitum . FORMULA % Cereals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . Grain biproducts and leguminous plants .. . . . . . . . . . . . . . . .. . . . Vegetable protein (soya bean meal, yeast) . . . . . .. . . .. . .. . . . . . . . . . . . .. .. . Vitamin and mineral mixture . . . AVERAGE ANALYSIS % Calorific value (Kcal/kg) . . .. . .. .. . Moisture. . . . .. . . . . . .. . . . . . .. . .. . . . . . . . . .. .. . Proteins . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . Lipids . . . . . . . . .. . . .. . .. . . . . .. . . . . . .. . . . . . . . .. . Carbohydrates (N.F.E.) . . . . . . . . . .. . Fibre. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Minerals (ash) . . .. . . . . .. . . . . . .. . . . . . . . . . . AMINOACID VALUES (calculated in mg/kg) Arginine .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . Cystine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . Lysine . . . .. .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . Methionine. . . . . . . . . . . . . . . . .. . . .. . . . . .. . .. . Tryptophan . . . . . . . . . . . . . . . .. . . .. . .. . .. . .. . Glycine . . . . . . . . . . . . . . .. . .. . . .. . . .. . . . . .. . . . . FATTY ACID VALUES (calculated in mg/kg) Palmitic acid . . .. . . .. . .. . . .. . . . . . . . .. .. . . Palmitoleic acid . . . .. . . .. . . . . . .. . . . . . . . . Stearic acid . . . . .. . . . . . .. . . . . . . . . .. . . . . .. . . Oleic acid .. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . Linoleic acid . . . . . . . . . . . .. . . . . . . . . . .. . . . . . Linolenic acid . . . . . . .. . .. . . . . . . . . . . . .. . . . 33.8 48 14 4.2 3100 10 15 2.3 48.2 17 7.5

11300 3400 9300 2800 2400 8700

6400 0 600 6400 12100 2400 MINERALS (calculated in mg/kg) Nat. CMV val . val . Total ----------- ------ P . . . . . . . . . . . . . . . . .. . . . 3600- ------2900 6500 Ca . . . . . . . . . . . . . .. . . . 4200 5800 10000 K . . . . . . . . . . . . . . . .. . . . 12000 0 12000 Na . . .. . . . . . . . . . .. . . . 400 2000 2400 Mg. . .. . .. . . .. . . . . . . . 2500 100 2600 Mn . . . . .. . . .. . . . . . .. 50 40 90 Fe . . . .. . . . . . . . . . . . . .. 150 150 300 Cu . . .. . .. . . . . . . . . . .. Traces 15 15 Zn . . . . . . . . . .. . . .. . .. 30 45 75 Co . . . . . .. . . . . . . . . . .. 0.1 1 .5 1 .6 1 . .. . . . . . .. . . . . . . . . . .. 0.1 0 0.1 Cl . . . . . .. . . . . . . . . . . .. 300 3000 3300

VITAMINS (calculated per kg) Nat. CMV --- val . _------val .----- .-- Total

_.-- Vitamin A Traces 10000 IU 10000 IU Vitamin D3 0 Ii 1000 IU 1000 fu Vitamin Bl 5 mg 0 mg 5 mg Vitamin 132 4 mg 0 mg 4 mg Vitamin 133 20 mg 0 mg 20 mg Vitamin 136 1 mg 1 mg 2 mg Vitamin B12 0 mg 0 mg 0 mg Vitamin E 15 mg 25 mg 40 mg Vitamin K3 0 mg 1 mg 1 mg Vitamin PP 60 mg 5 mg 65 mg Folic acid 0 mg 0 mg 0 mg Biotin 0 mg 0 mg 0 mg Choline 1000 mg 1000 mg 2000 mg

Available under quality "Control Ref . : I 10" SAFE, 7 rue Gallidni, Villemoisson, 91360 Epinay-sur-Orge Tel : 01 .69.04.03 .57 - Fax : 01 .69.04.81 .97 (Ref . Doe. UAR: 2000)3. CIT GLP certificatefdLerM- l3gilPtF - Frmataltd RArusr.eQFte FsAxC~ GROUPE INTERMINISTERIEL DES PRODUI'I'S C$IMIQUES Paris, le 

## - 9 JU1L, 2007 Objet : Evaluation de la conformMaux Bonnes Pratiques de Laboratoires (BPL) selon les directives 2004/9/CE et 2004/10/CE du 11 fevrier 2004. Suhjeet : Assessment ofcompliance with Good Laboratory Practices (GLP) under the ECdirectives 2004/9 and 2004/10 of 11 February 2004 . Cons ¬ cutivement a votre engagement vis-a-vis du GIPC et du COFRAC et en application du d6cret n° 2006- 1523 du 4decembre 2006 concemant les bonnes pratiques de laboratoires et modifiant le decret n° 81-278 du 25 mars 1981 portant cr6ation d'un groupe interminist6riel des produits chimiques, je vous confirme quo le GIPC, au vu des r6sultats du controle exere8 par le Comite franqais d'accr6ditation (COPRAC) - Section Laboratoires a d6cid¬ pour votre installation du statut suivant : Followingyour engagement vis-k-vis the GIPC andCOFRfICandin application ofthe decree n° 2006-1523 of 4 December 2006 relating to the good laboratory practices and modifying the decree n° 81-278 of 25 March 1981 giving birth to an intermlnisterial group ofchemical products (GIPC), I confirm to you that the GIPC, given the results of the inspection realised by the French Committee ofaccreditation (COFR,4C) - Laboratory Section has taken thefollowing decision relating toyour installation; Respect des principes de BPL Date d'inspection : 7-8 mars 2007 Respect ofthe GLP principles Date of inspection : 7-8 mars 2007 Domaines de reconnaissance: Inspection de renouvellement (i .r) 1- essais physico-chimiques Renewal inspection (i .r) 2 - 6tudes de toxicite 3 - 8tudes de mutagenicite Date de d¬cision du GIPC : 29juin 2007 4 - 6tudes ecotoxicologiques sur les Date ofGIPCdecision.- 29 juin 2007 organismes aquatiques et terrestres 8- mbthodes de chimie analytique et Date de prise d'effet : 8 mars 2007 clinique Date of implementation : 8 mars 2007 Areas ofexpertise : AnnBe de premiere conformite : 1989 1=Pltysico-chemicaltesting Year oflhefirst conformity: 1989 2 = Toxicity studies 3 =Mutagenicity studies Durt;e de validit6: 18 mois 4 =Environmental toxicity studies on aquatic or Time ofvalidity: 18 months terrestrial organisms 8 =Analyticaland clinical chemistry 

### I

CENTRE INTERNATIONAL DETOXICOLOGIE (CIT) MISEREY - BP 563 27005 BVREUX CEDEX Pietre CkE-YSSEL. Conseiller d'Etat h

Secr6tariatgeneral du GIPC -DGE- Simap - 12, rue Villiot - 75572 Paris codex 12

Tzfl~,phone : 0153 44 96 10 - Tblecopie : 0153 44 9172p. 126 

### CONFIDENTIAL

STUDY TITLE EVALUATION OF SKIN SENSITIZATION POTENTIAL IN MICE USINGTHE LOCAL LYMPH NODE ASSAY (LLNA)

STUDY DIRECTOR Guillaume Sire

DATE OF ISSUE 

# (D~ ~o-c-)An- ~ TEST FACILITY Crr BP 563 - 27005 Evreux - France

LA.B ~TO ,~IMBER

IFM Recherche S.R 563 27005 Evreux Cedex France SAS au Capital de 846.000 ¬ Te1 : +33 (0)2 32 29 26 26 788 060 465 R

.CS . Evreux Fax : +33 (0)2 32 67 87 05 VAT : FR 19 788 060 465 E-mail : CIT@citox .com Agrememt Credit imp6t Recherche Web site : www .citox .com VyCONTENTS STATEMENT OF THE STUDY DIRECTOR 4 OTHER CIT SCIENTIST INVOLVED INTHE STUDY 5 STATEMENT OF QUALITY ASSURANCE UNIT 6 SUMMARY 7 RESUME 9 1 . INTRODUCTION 11 2. MATERIALS AND METHODS 11 2.1 TEST MATERIALS 11 2.1 .1 Test item 11 2.1 .2 Vehicle 11 2.1 .3 Dosage formpreparation 11 2.1 .4 Other materials 12 2.1 .4.1 Reference item (positive control) 12 2.1 .4.2 Reagent used for the proliferation assay 12 2.2 TEST SYSTEM 12 2.2.1 Animals 12 2.2.2 Environmental conditions 12 2.2.3 Food and water 13 2.3 TREATMENT 13 2.3 .1 Preliminary test 13 2.3.2 Main test 13 2 .3.2.1 Study design 13 2 .3.2.2 Administration of the test materials 14 2.4 CLINICAL EXAMINATIONS 14 2.4.1 Clinical signs, morbidity and mortality 14 2.4.2 Body weight 14 2.4.3 Ear thickness measurements and recording of local reactions 14 2.5 PROLIFERATION ASSAY 15 2.5.1 Intravenous injection of 3H-TdR and sampling ofauricular lymph nodes 15 2.5.2 Preparation of auricular lymph node cell suspensions and determination ofproliferation 15 2.5 .3 Interpretation of results 15 2.6 ARCHIVING 15 2.7 CHRONOLOGY OF THE STUDY 16 2.8 STUDY PLANADHERENCE 163. RESULTS 17 3.1 CHOICE OF THE VEHICLE 17 3.2 PRELIMINARY TEST 17 3.3 MAINTEST 17 3.3 .1 Systemic clinical signs and mortality 17 3.3 .2 Body weight (table 2) 17 3.3 .3 Local irritation (tables 3 and 4) 17 3.3 .4 Proliferation assay 17 4 . CONCLUSION 17 Table 1 : Results ofthe preliminary test (ear thickness measurements) 18 Table 2: Individual body weight and body weight gain (g) 19 Table 3 : Evaluation of cutaneous reactions 21 Table 4: Ear thickness measurements (mm) 22 Table 5: Study results 24 APPENDICES 25 1 . Test article description and analytical certificate 26 2. Diet formula 29 3. Historical data 31 4 . CIT GLP certificate 33 and 34STATEMENT OF THE ST UDY DIRECTOR

The study was performed in compliance with CIT's standard operating procedures and the following principles of Good Laboratory Practice:

. OECD Principles of Good Laboratory Practice (as revised in 1997), ENV/MC/CHEM (98) 17 and all subsequent OECD consensus documents.

. Directive 2004/10/EC of the European Parliament and of the Council of 11 February 2004 on the harmonization of laws, regulations and administrative provisions relating to the application of the Principles of Good Laboratory Practice and the verification of their applications for tests on chemical substances (OJ No. L50 of 20.2.2004) . . Decret N° 2006-1523 du 04 decembre 2006 concernant les Bonnes Pratiques de Laboratoire (Journal Officiel du 06 decembre 2006), Ministere de 1'Economie, des Finances et de 1'Industrie. However, no chemical analysis of the dosage forms was performed as part of this study. This exception is not considered to impact on the overall GLP status ofthe study. The study was also conducted in compliance with the following Animal Protection regulations:

. Council Directive 86/609/EEC of 24th November 1986 on the harmonization of laws, regulations or administrative provisions relating to the protection of animals used for experimental or other scientific purposes.

. Guidance document on the recognition, assessment, and use of clinical signs as humane endpoints for experimental animals used in safety evaluation, OECD Environmental Health and Safety Publications, No. 19. I declare that this report constitutes a true and faithful record of the procedures undertaken and the results obtained during the performance of the study. This study was performed at CIT, BP 563, 27005 Evreux, France.

Toxicology G . Sire Study completion date: U(~ Study Director DESS Cellular Engineering

### OTHERCIT SCIENTIST INVOLVED INTHE STUDY

Director of Toxicology CIT Management J .J. Legrand Date: 0 S

Doctor of Veterinary Medicine

### STATEMENT OF OUALITYASSURANCE UNIT Inspections performed at CIT: The CIT Quality Assurance Unit conducted the inspections detailed below : Dates Type of inspection Inspection Reported to the Reported to Study Director Management Study plan 12 February 2008 12 February 2008 14 February 2008 Report 19 August 2008 19 August 2008 21 August 2008 In addition, at about the same time, process-based and facility inspections relevant to this study were carried out by the Quality Assurance Unit. The inspections were performed in compliance with CIT Quality Assurance Unit procedures and the principles of Good Laboratory Practices . The final report is considered to constitute an accurate and complete reflection of the study raw data.

Marie-Christine Ottini-Bertin Date: 0S ' ~ -P, ~ ~ CIT Quality Assurance UnitT LymphNode Assay (LLNA . Evaluation _ of local irrita_. .,__ . . ~. u, ,u ~ This study was conducted in compliance with the principles of Good Laboratory Practice Regulations. Methods A preliminary test was first performed in order to define the concentrations of test item used in the main test. In the main test, twenty-eight female CBA/J mice were allocated t

ups of four animals receiving the test ite e concentration of 0.1, 0 .25, 0.5, 1 or 2.5%, to be ga~control group of four animals receiving the vehicle (propylene glycol),

. one positive control group of four animals receiving the reference a-hexylcinnamaldehyde (HCA), a moderate sensitizer, at the concentration of 25% . item, During the induction phase, the test item, vehicle or reference itemwas applied over the ears (25 pL per ear) for 3 consecutive days (days 1, 2 and 3) . After 2 days of resting, the proliferation of lymphocytes in the lymph node draining the application site was measured by incorporation of tritiated methyl thymidine (day 6) . The obtained values were used to calculate stimulation indices (SI) . The irritant potential of the test itemwas assessed in parallel by measurement of ear thickness on days 1, 2, 3 and 6. Results The test item was not soluble in the recommended vehicles, consequently, a homogenous suspension, obtained in propylene glycol, was used for the study. The maximum practicable concentration in this vehicle was 2.5% . Therefore, the concentrations selected for the preliminary test were 0.25, 0.5, 1 and 2.5% . Since the test itemwas non-irritant in the preliminary test, the highest concentration retained for the main test was the maximal practicable concentration (2.5%) . Systemic clinical signs and mortality No mortality and no clinical signs were observed during the study. Local irritation A black coloration of the skin of the ears was noted on days 2 and 3 in all animals treated at the concentrations of 1 and 2.5%and on day 6 in 2/4 animals treated at the concentration of 2.5% . No noteworthy increase in ear thickness was observed in the animals ofthe treated groups.p. 133 8 Proliferation assay A significant lymphoproliferation was noted in the positive control group given HCA at 25%, the study was therefore considered valid. No noteworthy lymphoproliferation was noted at any ofthe tested concentrations. The results are presented in the following table: Treatment Concentration Irritation level Stimulation Index (%) (SI) Test item 0.1 non-irritant 1 .13 Test item 0.25 non-irritant 0.72 Test item 0.5 non-irritant 0.84 Test item 1 non-irritant 0.97 Test item 2.5 non-irritant 0.76

------------------- ---------- -----------

---------- -------------------------------- HCA 25 - 8.59 Conclusion ions of this study, the test ite not induce delayed contact hyper'ensiRESUME

e-une~-ny- erseiisibilite e co a-ire - ee 771 77!77 F Lymph Node Assay" (LL°tslA) . L'irritation locale a ete egalement dvaluee en parallele. L'etude a ete rdalisee conformdment aux r6gles de Bonnes Pratiques de Laboratoire. Methode Dans un premier temps, un essai pr6liminaire a ete realisd afin de determiner les concentrations de produit a utiliser dans 1'essai principal . Dans I'essai principal, 28 souris femelles CBA/J ont ete

. 5 groupes traites de 4 animaux recevant le produi la concentration de 0,1 ; 0,25 ; 0,5 ; 1 ou 2,5 %

. 1 groupe t6moin n6gatif de 4 animaux recevant le vehicule (propylene glycol),

. 1 groupe temoin positif de 4 animaux recevant le produit de r6ference, a-hexylcinnamaldehyde (HCA), un sensibilisant modere, d la concentration de 25 % . Pendant la phase d'induction, le produit, le vehicule ou le produit de refdrence a etd appliqud sur les oreilles (25 pL par oreille) pendant 3jours consecutifs (jours 1, 2 et 3) . Apres 2jours de repos, la proliferation lymphocytaire dans le noeud lymphatique drainant le site d'application a ete mesure par incorporation de methyl thymidine tritiee (jour 6) . Les valeurs obtenues ont ete utilisees pour calculer 1'indice de stimulation (IS) . Le potentiel irritant du produit a 6t6 evalue en parall6le en mesurant 1'epaisseur de 1'oreille auxjours 1, 2, 3 et 6

. Resultats Le produit n'a pas ete soluble dans les vehicules recommand6s, par consequent, une suspension homogene, obtenue dans le propylene glycol, a ete utilisee pour 1'6tude. La concentration maximale utilisable dans cc vehicule a ete 2,5 % . Les concentrations retenues pour 1'essai preliminaire ont ete 0,25 ; 0,5 ; 1 et 2,5 % . Le produit n'ayant pas ete irritant lors de 1'essai preliminaire, la concentration maximale retenue pour 1'essai principal a ete la concentration maximale utilisable (2,5 %) . Signes clinigues systemicgues et mortalit6 Aucune mortalite ni aucun signe clinique Wont et6 observ6s pendant 1'etude. Irritation locale Une coloration noire de la peau des oreilles a ete notee auxjours 2 et 3 chez tous les animaux traites aux concentrations 1 et 2,5 % et aujour 6 chez 2/4 animaux traitds a la concentration de 2,5 % . Aucune augmentation notable de 1'epaisseur de 1'oreille n'a et6 notde chez les animaux trait6s avec le produit. Test de proliferation Une lymphoprolifdration significative a ete not6e avec le groupe temoin positif ayant requ le HCA a 25 %, 1'etude est done consid6ree valide. Aucune lymphoproliferation n'a et6 notee aux concentrations testees.Les resultats sont prdsentes dans le tableau suivant : Traitement Concentration Niveau Indice de Stimulation (%) d'irritation (IS) Produit 0,1 non-irritant 1,13 Produit 0,25 non-irritant 0,72 Produit 0,5 non-irritant 0,84 Produit 1 non-irritant 0,97 Produit 2,5 non-irritant 0,76

---- ------------------------- ------ ------- ------- HCA 25 Conclusion 8,59

Dans nos conditions experimentales, le produi induit une hypersensibilite de contact retardee ns Me test du LLNA

.p. 136

1 . INTRODUCTION ll

s study was to evaluate the potential ofthe test ite~~~~ induce delayed contact hypersensitivity, using the murine oca ymp o e ssay (LLNA) . This study was based on the design adopted by ICCVAM (Interagency Coordination Committee on the Validation of Alternative Methods, ICCVAM 1999) and ECETOC (Monograph No. 78 Skin sensitization Testing for the Purpose of Hazard Identification and Risk Assessment, September 2000), with the addition of the evaluation of local irritation. The study has been designed to comply with the following guidelines : OECD Guideline No. 429, 24th April 2002, EC Directive No. 2004/73/EC, part B.42, 29th April 2004. 2. MATERIALS AND METHODS 2.1 TEST MATERIALS 2.1 .1 Test item

description: black powder container : one plastic flask date of receipt : 29 June 2007 storage conditions : at roomtemperature and protected fromhumidity purity/composition: see analytical certificate expiry date: June 2008 . Data relating to the characterization of the test itemare documented in an analytical certificate and a test itemdate sheet (presented in appendix 1) provided by the Sponsor . 2.1 .2 Vehicle The vehicle used was propylene glycol, batch No. S35142-236 (Aldrich, Saint-Quentin-Fallavier, France) . 2.1 .3 Dosage formpreparation The concentrations were expressed in %(w/v) . For the dosage formpreparation at 2.5%, the test item was ground to a fine powder using a mortar and pestle, before to add the vehicle. The lower concentrations were obtained by dilution in the vehicle. All dosage form preparations were made freshly on the morning of administration and any unused material was discarded that same day.p. 137

2.1 .4 Other materials 2.1 .4.1 Reference item(positive control) 

### 12

The reference item (positive control) was a-hexylcinnamaldehyde (RCA), batch No. 04012JE (Aldrich, Saint-Quentin-Fallavier, France), dissolved in a mixture acetone/olive oil (4/1, v/v) at the concentration of 25%(v/v) . The preparation was made freshly on the morning of administration and any unused material was discarded that same day. 2.1 .4.2 Reagent used for the proliferation assay The reagent used for the proliferation assay was batch No. B505 (Amersham, Les Ulis, France) . 

## 13H] methyl-thymidine (3H-TdR), Three days before the injections, the required quantity of 3H-TdR was diluted in 0.9% NaCI (20 pCi in 250 pL of 0.9%NaCl per animal) . The obtained solution was stored at +4°C and protected fromlight before use . 2.2 TEST SYSTEM 2.2.1 Animals Species, strain and sex: Reason for this choice: Age/weight : Number : Breeder : Acclimation: Allocation to groups : Identification: CBA/J mouse, nulliparous and non-pregnant females. species generally accepted by regulatory authorities for this type of study. Females have been chosen since this sex is recommended by regulatory authorities for this type of study. on the first day of the treatment period, the animals of the preliminary test were approximately 10 weeks old and the animals of the main test were approximately 9 weeks old and had a mean body weight ± standard deviation of 21 .2 ± 1 .1 g. 4 females for the preliminary test, 28 females for the main test . Janvier, Le Genest-Saint-Isle, France. at least 5 days before the beginning of the study. animals were assigned to the treatment groups by hand procedure. individually by a number on the tail . 2.2 .2 Environmental conditions The conditions in the animal room were set as follows :

. temperature: 22 f 2°C

. relative humidity: 30 to 70%

. light/dark cycle: 12 h/12 h (7 :00-19:00)

. ventilation: approximately 12 cycles/hour of filtered, non-recycled air. The temperature and relative humidity are under continuous control and recording. The records are checked daily and filed. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment are verified and calibrated at regular intervals. The animals were housed individually in disposable crystal polystyrene cages (22.00 cm

x 8.50 cm

x 8.00 cm) . Each cage contained autoclaved sawdust (SICSA, Alfortville, France) . Sawdust is analyzed by the supplier for composition and contaminant levels.p. 138 

### 13 2.2.3 Food and water All animals had free access to SSNIFF R/M-H pelleted maintenance diet (SSNIFF Spezialdiaten GmbH, Soest, Germany) and tap water (filtered using a 0.22 micron filter) contained in bottles. Each batch ofdiet is analyzed for composition and contaminant level by the supplier. The diet formula is presented in appendix 2. Bacteriological and chemical analyses of water, including the detection of possible contaminants (pesticides, heavy metals and nitrosamines) are performed regularly by external laboratories. The results ofthese analyses are archived at CIT . No contaminants are known to be present in the diet, drinking water or sawdust at levels which may be expected to interfere with or prejudice the outcome of the study . 2.3 TREATMENT 2.3 .1 Preliminary test To assess the irritant potential of the test item (through ear thickness measurement), a preliminary test was performed on a small number of animals, as follows:

. the test itemwas prepared at the concentrations of 2.5, 1, 0.5 and 0.25%,

. for 3 consecutive days, the animals received applications of 25 pL of the dosage form preparations to the external surface of both ears (one concentration per ear),

. measurement of the ear thickness (using a micrometer) was performed each day before treatment and 72 hours after the last application. 2.3 .2 Main test 2.3 .2.1 Study design The concentrations of test item were selected according to the criteria specified in the International Guideline and on the basis of the results of the solubility and preliminary assays. The study design was as follows : Groups Number of animals Treatment Concentration (%) 1 4 females Vehicle 0 2 4 females Test item 0.1 3 4 females Test item 0.25 4 4 females Test item 0.5 5 4 females Test item 1 6 4 females Test item 2.5 7 4 females HCA 25p. 139

2.3.2.2 Administration of the test materials 

### 14

On days 1, 2 and 3, a dose-volume of 25 p,L of the control or dosage formpreparations was applied to the dorsal surface ofboth ears, using an adjustable pipette fitted with a plastic tip. In order to avoid licking and to ensure an optimized application of the test materials, the animals were placed under light isoflurane anesthezia during the administration. No massage was performed but the tip was used to spread the preparation over the application sites. No rinsing was performed between each application. 2.4 CLINICAL EXAMINATIONS 2.4.1 Clinical signs, morbidity and mortality The animals were observed at least once a day during the study for clinical signs, signs of morbidity or mortality . 2.4.2 Body weight The animals were weighed individually on the first day of the study (day 1) and on the day of sacrifice (day 6) . 2.4.3 Ear thickness measurements and recording of local reactions Ear thickness measurements and recording of local reactions were performed in order to assess any possible irritant effect of the test item, as possible irritancy may be involved in false positive lymphoproliferative responses. On days 1, 2 and 3 (before each cutaneous application) and on day 6 (after sacrifice), the thickness of the left ear of each animal of the vehicle control and treated groups was measured using a micrometer . No measurement of ear thickness was performed for the animals of the positive control group. Any irritation reaction (erythema and edema) was recorded in parallel . Any other observation (coloration, presence ofresidual test item, . . .) was noted. The irritation level of the test itemwas determined according to the following table: %increase in ear thickness between day 1 and day 3 or 6 Irritation level Interpretation

< 10% I Non-irritant 10-30% lI Slightly irritant > 30% 111 Irritant2 .5 PROLIFERATION ASSAY 2.5.1 Intravenous injection of 3H-TdR and sampling of auricular lymph nodes p. 140 15

Lymph node cell proliferative responses were measured as described by Kimber and Dearman (1991) . On day 6, all animals of all groups received a single intravenous injection of 250 pL of 0.9% NaCl containing 20 pCi of 3H-TdR (specific activity of 25 Ci/mmol) via the tail vein. Approximately 5 hours later, the animals were killed by cervical dislocation and the auricular lymph nodes were excised. The lymph nodes were pooled for each experimental group. 2.5.2 Preparation ofauricular lymph node cell suspensions and determination of proliferation For each experimental group, a single cell suspension of auricular lymph node cells (ALNC) was prepared by mechanical dissagregation in Petri dishes with the plunger of a syringe. Cell suspensions were washed with 15 mL of 0 .9%NaCl and pellets obtained were re-suspended in 0.9%NaCl for numeration of lymphocytes (cellularity) and determination of their viability by exclusion of trypan blue. Each cell suspension was then centrifuged and pellets were precipitated with 3 mL of 5% (w/v) trichloroacetic acid (TCA) in purified water at +4°C overnight . After a last centrifugation, the pellets were precipitated with 1 mL of 5% TCA . Three mL of Ultima Gold"R scintillation fluid (Packard) were added in order to measure incorporation of 3H-TdR usirng (3-scintillation counting. The results were expressed as disintegration's/mn (dpm) per group and per node. Stimulation Indices (Sl) were calculated according to the following formula:

SI = dpm

oftreated group dpm of control group 2.5.3 Interpretation ofresults The test item was considered as a skin sensitizer when the SI for a dose group is >_ 3. Other relevant criteria such as cellularity, radioactivity levels and ear thickness were also taken into account for the interpretation of results. 2.6 ARCHIVING The following study materials are archived by CIT, 27005 Evreux, the end of the in vivo phase ofthe study :

. Study plan and possible amendments,

. raw data,

. correspondence,

. final report and possible amendments. France, for 10 years after

On completion of this period, the archived study materials will be returned to the Sponsor, or may be archived at CIT for a further period (at additional cost) . The total duration of archiving (depending on regulations) will be the responsibility ofthe Sponsor . In addition, rawdata not specific to the study, including, but, not limited to, certificates of analyses for food, water and bedding (if applicable) and records of environmental data and equipment calibration, are also archived by CIT for at least 30years.p. 141

2.7 CHRONOLOGY OF THE STUDY The chronology ofthe study is summarized as follows : Procedure Date Experimental starting date (solubility assay) 13 March 2008 First day of treatment of the preliminary test 18 March 2008 First day of treatment of the main test 26 March 2008 Day of injection of 3H-TdR and ALNCcollection 31 March 2008 Experimental completion date 04 September 2008 2.8 STUDY PLANADHERENCE 16

The study was performed in accordance with the d subsequent amendments . There were no deviations fromthe agreed Study plan.3. RESULTS 3.1 CHOICE OF THE VEHICLE p. 142 17

The test item was not soluble in the recommended vehicles, consequently, a homogenous suspension, obtained in propylene glycol, was used for the study. The maximum practicable concentration in this vehicle was 2.5% . 3.2 PRELIMINARY TEST The results ofthe preliminary test are presented in table l . A black coloration of the skin of the ears was observed at the concentrations of 1 and 2.5%on days 2 and 3. The test itemwas non-irritant in the preliminary test, whatever the concentrations tested. The highest concentration retained for the main test was therefore the maximal practicable concentration (2.5%) . 3.3 MAINTEST 3.3 .1 Systemic clinical signs and mortality No clinical signs and no mortality were observed during the study. 3.3 .2 Body weight (table 2) The body weight change oftreated animals was similar to that of control animals. 3.3.3 Local irritation (tables 3 and 4) A black coloration of the skin ofthe ears was noted on days 2 and 3 in all animals treated at the concentrations of I and 2.5%and on day 6 in 2/4 animals treated at the concentration of 2.5% . No noteworthy increase in ear thickness was observed in the animals ofthe treated groups. 3.3 .4 Proliferation assay Results of proliferation assay are presented in table 5. The quantity of cells obtained in each group was satisfactory and the cellularity correlated with incorporation of 3H-TdR. The cell viability was higher than 70%in each group. In the positive control group given HCA at the concentration of 25%, a moderate increase in cellularity and a stimulation index exceeding the threshold value of 3 (SI - 8.59) were noted. The study was therefore considered valid. No noteworthy lymphoproliferation was noted with the test item at any of the tested concentrations . 4 . CONCLUSION itions of this study, the test item~~ Local Lymph Node Assay. id not induce delayed contact hypersens~tivity - Fill e murmeTable 1 : Results ofthe preliminary test (ear thickness measurements) p. 143 18

DI D2 D3 D6 Number Concentration Ear Local Ear Local Ear Local Far Local % Animal % Thickness reaction Thickness reaction Thickness reaction Thickness reaction Female 301 2.5 RE 0.24 0 0.25 0/C 0 .26 0/C 0.26 0 8 33 Female 301 1 LE 0.25 0 0 .25 0/C 0.25 0/C 0 .27 0 .

800 Female 302 2

.5 RE 0.24 0 0 .24 0/C 0.24 0/C 0 .24 0 .

0 .00 Female 302 1 LE 0 .24 0 0 .24 0/C 0.24 0/C 0 .23 0 4

.17 Female 303 0

.5 RE 0

.24 0 0 .24 0 0.24 0 0 .25 0 4

.17 Female 303 0

.25 LE 0

.25 0 0.25 0 0 .25 0 0.25 0 0.00 Female 304 0

.5 RE 0

.25 0 0.25 0 0 .25 0 0.25 0 0.00 Female 304 0.25 LE 0 .25 0 0.24 0 0 .25 0 0.26 0 4 .00 RE=tight ear LE=left ear D=day 0=nocutaneous reaction C=black coloration of the ears % = percentage ofearthickness increase compared today ITable 2: Individual body weight and body weight gain (g) Days Groups Animal

No . L 6 (1) 1 01 18.9 19 .4 0

.5 02 21 .3 20 .9 -0.4 03 21 .0 21 .4 0 .4 04 18.8 19.7 0 .9 M 20.0 20 .4 0.3 SD 1 .3 1 .0 0.5 2 05 21 .1 21 .9 0.8

06 20.4 21 .2 0.8 07 22.0 21 .9 -0.1 08 21 .6 22 .0 0

.4 M 21 .3 21 .8 0.5 SD 0.7 0.4 0.4 3 09 22 .6 22

.0 -0

.6 10 19

.4 20

.2 0.8 11 21 .8 21 .5 -0.3 12 20.2 21 .3 1 .1 M 21 .0 21 .3 0 .3 SD 1 .5 0.8 0.8 4 13 21 .4 19 .1 -2

.3 14 20

.6 21 .0 0.4 15 19

.7 19.5 -0.2 16 21 .3 22.3 1 .0 M 20

.8 20

.5 -0

.3 SD 0

.8 1 .5 1 .4 (1) = body weight gain M = mean SD=standard deviationTable 2 (continued) Days Groups Anirrral

No . 1 6 (1) 5 17 20.6 21 .0 0.4

18 20.5 21 .5 1 .0 19 22.1 22.2 0.1 20 21 .5 21 .4 -0.1 M 21 .2 21 .5 0.3 SD 0

.8 0.5 0.5 6 21 21 .7 22 .6 0.9 22 22

.0 22

.3 0

.3 23 23.8 22.5 -1 .3 24 22

.6 21 .2 -1 .4 M 22

.5 22

.2 -0.4 SD 0

.9 0

.6 1 .2 7 25 21 .6 22 .5 0

.9 26 22

.0 22

.9 0

.9 27 22

.1 19

.5 -2.6 28 21 .1 21 .7 0 .6 M 21 .7 21 .7 -0.1 SD 0.5 1 .5 1 .7 (1)=body weight gain M = mean SD = standard deviationTable 3: Evaluation of cutaneous reactions Days Groups Dosage Animal

form No. 1 2 3 6 1 vehicle 01 0 0 0 0 02 0 0 0 0 03 0 0 0 0 04 0 0 0 0 2 test item 05 0 0 0 0

0.1% 06 0 0 0 0

07 0 0 0 0 08 0 0 0 0 3 test item 09, 0 0 0 0

0 .25% 10 0 0 0 0

11 0 0 0 0 12 0 0 0 0 4 test item 13 0 0 0 0

0.5% 14 0 0 0 0

15 0 0 0 0 16 0 0 0 0 5 test item 17 0 0/C 0/C 0

1% 18 0 0/C 0/C 0

19 0 0/C 0/C 0 20 0 0/C 0/C 0 6 test item 21 0 0/C 0/C 0

2.5% 22 0 0/C 0/C 0/C

23 0 0/C 0/C 0/C 24 0 0/C 0/C 0 0=no cutaneous reaction C=black coloration ofthe ears vehicle =propylene glycolTable 4: Ear thickness measurements (mm) Groups Dosage

form 1 vehicle

2 test item

0.1%

3 test item

0 .25% Days

Animal No. 1 2 d 1 3 d2 6 d3 01 0 .26 0 .25 -0.01 0.25 -0

.01 0 .25 -0 .01 02 0 .26 0 .26 0 .00 0.26 0.00 0

.25 -0.01 03 0 .26 0 .27 0 .01 0.26 0.00 0

.25 -0.01 04 0 .25 0.25 0.00 0.24 -0.01 0 .25 0 .00 M 0.26 0.26 0.00 0 .25 -0.01 0.25 -0

.01 SD 0.01 0.01 0.01 0 .01 0 .01 0.00 0.01 % (*) 0

.00 -1 .94 -2 .91 05 0 .25 0 .25 0 .00 0.24 -0.01 0.24 -0.01 06 0.26 0.26 0.00 0.25 -0.01 0.25 -0.01 07 0.26 0.25 -0

.01 0 .25 -0.01 0.25 -0.01 08 0.25 0.24 -0

.01 0 .26 0 .01 0.27 0.02 M 0 .26 0 .25 -0.01 0.25 -0

.01 0 .25 0.00 SD 0 .01 0 .01 0 .01 0.01 0.01 0

.01 0.02 % (*) -1 .96 -1 .96 -0.98 09 0.27 0.26 -0

.01 0 .26 -0.01 0.26 -0.01 10 0 .25 0.24 -0

.01 0 .24 -0.01 0.24 -0

.01 11 0 .26 0 .25 -0 .01 0 .25 -0 .01 0.25 -0

.01 12 0 .26 0 .25 -0.01 0

.26 0 .00 0 .25 -0 .01 M 0 .26 0.25 -0.01 0.25 -0 .01 0 .25 -0.01 SD 0.01 0.01 0

.00 0.01 0.01 0

.01 0.00 % (*) -3.85 -2.88 -3.85 M = mean SD=standard deviation (*)=percentage ofearthickness increase compared to day 1 d 1 =difference ofear thickness between day 2 and day 1 d2=difference ofearthickness between day 3 and day 1 0=difference ofear thickness between day 6 and day 1 vehicle --pro~ylene glycol

---Table 4 (continued) Groups Dosage

form 4 test item

0.5%

5 test item

1%

6 test item

2.5% AnimalNo. 1 13 14 15 16 Days

2 dl 3 d2 6 d3 0.25 0 .24 -0 .01 0.25 0

.00 0 .25 0 .00 0.25 0 .25 0.00 0

.25 0 .00 0 .25 0 .00 0.25 0 .26 0.01 0

.25 0 .00 0 .26 0.01 0.25 0 .25 0 .00 0 .25 0 .00 0 .25 0.00 M 0 .25 0.25 0

.00 0.25 0

.00 0.25 0.00 SD 0.00 0.01 0

.01 0.00 0.00 0.01 0.01 % (*) 0

.00 0.00 1 .00 17 18 19 20 0.25 0

.26 0.01 0

.25 0 .00 0 .26 0 .01 0.26 0 .25 -0 .01 0 .26 0 .00 0 .25 -0.01 0.27 0 .25 -0.02 0

.26 -0.01 0

.26 -0 .01 0.25 0 .25 0 .00 0 .25 0 .00 0 .24 -0 .01 M 0 .26 0.25 -0

.01 0 .26 0 .00 0.25 -0.01 SD 0 .01 0.01 0

.01 0 .01 0 .01 0.01 0.01 % (*) -1 .94 -0 .97 -1 .94 21 22 23 24 0.25 0

.25 0.00 0.26 0.01 0 .26 0 .01 0.25 0 .25 0.00 0

.25 0.00 0

.25 0 .00 0.25 0 .25 0.00 0

.24 -0 .01 0 .24 -0 .01 0 .25 0 .25 0 .00 0 .26 0 .01 0 .26 0.01 M 0 .25 0.25 0

.00 0.25 0.00 0.25 0.00 SD 0 .00 0.00 0

.00 0.01 0.01 0.01 0.01 % (*) 0

.00 1 .00 1 .00 M = mean SD=standard deviation (*) = percentage ofear thickness increase compared to day 1 d I =digerence ofear thickness between day 2 and day 1 d2=difference ofearthickness between day 3 and day 1 d3 =difference ofear thickness between day 6and day 1p. 149

Table 5: Study results

Groups and Cell count Viability Arnomt u -Y d7 Nunub r dpm dpm Stinnulation Incre&sein carthickness oncentrations iable dead fcells x of 0 n des, ergroup, ernode ndex(SI) I/ bct~veen : 7 ev

Fel

-- pergroup 1nd day 6) day -- -- I Vehicle 103 8 92.79 5 .15 ~ i 8 576 .81 72.10 -2.91 i 1 Test rtem - -- - - - 0.1% 183 1 99.46 9 .15 1 .78 8 654.34 81 .79 1 .13 -0.98 1 Test rtem 3 0

.25% 81 3 96 .43 4.05 0.79 8 416.37 52.05 0.72 -3.85 1 Test item 0.5% 82 7 92.13 4 .10 0.80 8 484.86 60,61 0 .84 1 .00 1 Test item I % 69 18 79.31 3.45 0 .67 8 558.54 69 .82 0

.97 -1 .94 1 Test item 2.5% 88 6 93.62 4.40 0.85 8 436.90 54.61 0.76 1 .00 I 1 I HCA ------ 25% 214 18 92.24 21 .40 4.16 8 4956.76 619 .60 8.59 I viable cells

. viability - x100

viable cells +dead cells dpm=disintegrations per ninute HCA =a-hexylcinnamaldehyde amount of cells (x 10° cells) in the treated group I=non-hritant (Bncreasein carthicFaess < loo/)

. cellularity index ECi value =theoretical concentration resulting in aSI value of3 amount of ce0s (x 10° cells) in the vehiclegroup dpm o£treated group

. stinulation index 24

3 value

NA

dpm of control groupAPPENDICES1 . Test article description and analytical certificatePHYSICAL ANDCHEMICAL PROPERTIES Appearance : black powder Particulesize : 30 gm ( approximately) Specific Gravity : 2,1 kg/m3 at 20°C Autoignition temperature : > 400 °C (standard : NF EN 50281-2-1) Solubility : in water : insoluble TOXICOLOGICAL INFY3RiVIATIOiVS ANDUSE SAFETY See Safety Data S

heet. I STORAGE ANDDISPOSAL Storage : Keep hermetically closed in a dry, cool and well-ventiled place . Expiry date : June 2008 Qisposal : Incin eration p. 152 27Date 5 juin 2007



## r Nom du responsable du laboratoirel Laboratory Director :

Signature RWrence de la m6thode

d'analyse / Analysis reference p. 153 282. Diet formula

# SSNIFF RJM-H

Complete diet for rats/mice - maintenance Constituents Crude proteins 19 .00% Calcium 1 .00% Crude fat 3 .30% Phosphorus 0.70% Crude fiber 4.90% Sodium 0.25% Crude ash 6 .70% Magnesium 0.20% Potassium 0.90% Amino Acids Vitamins (je kg) Lysine 1 .00% A 15,000 IE Methionine 0 .30% D3 1,000 IE Cystine 0.30% E 100 mg Glycine 0.90% B1 10 mg Leucine 1 .30% B2 20 mg Isoleucine 0.70% B6 12 mg Arginine 1 .20% B12 80 pg Phenylalanine 0.90.% Biotin 400 fig Tryptophan 0.25% Pantothenic acid 30 mg Histidine 0.50% Choline 1,600 mg Tyrosine 0.60% Folic acid 4 mg Aspartic acid 1 .70% Nicotic acid 60 mg Glutaminic acid 3.80% K3 5 mg Valine 0.90% Inositol 50 mg Threonine 0.70% Trace elements (je kg) ME (je kg) 12 .2 MJ Manganese 90 mg Copper 12 mg Zinc 75 mg Itemnumbers Iodine 2 mg V1530 Meal Iron 220 mg V1531 Micromeal Selenium 0.2 mg V1534 Pellets 10 mm Cobalt 2 mg V1535 Pellets 15 mm3. Historical dataHistorical data Skin sensitization potential in miee (CBA!J straln) using the Local Ly-mph Node Assay (LLhFA) Vehicle . control Propylone Glycol fromDecember 2004 to December 2006 Amount dpm/node increase, in of cells ear thickness x106cel :ls minimum 2.75 33.28 -4.63 maximum 7.90 76 .64 1 .02 Moan 5.03 47.93 -0.98 SD 1 .65 10.60 1 .78 Nb 17 SD - Standard deviation Nb = number of values4. CIT GLP certificateLa-4 " dd.ref -xternue Urosxrqye Pxu+ec-use GROUPE AVTERMINISTERIEL DES PRODUTI'S CHI&IIQUES Paris, le 

### - 9 JUIL 2001 Objet : Evaluation de la conformit6 aux Bonnes Pratiques de Laboratoires (BPL) selon les directives 2004/9/CE et 2004/10/CE du 1l Wrier 2004. Subject : Assessment ofcompliance with Good Laboratory Practices (GLP) under the BCdirectives 200419 and2004110 of 11 February 2004 . Consdcutivement n votre engagement vis-it-vis du GIPC et du COFRAC et en application du ddcret n° 2006- 1523 du 4 d8cembie 2006 concernant les bonnes pratiques de laboratoires et modifiant le dccret n° 81-278 du 25 mars 1981 portant crdation d'un groupe interminist ¬riel des produits chimiques, je vous confurne que le GIPC, au vu des rdsultats du contr6le exerc8 par le ComitB tranpais d'accrdditation (COFRAC) - Section Laboratoires a d8cid6 pour votre installation du statut suivant : Following your engagement vis-d-vis the GIPC and COFRACand in application ofthe decree n° 2006-1523 of 4 December 2006 relating to the good laboratory practices and modifying the decree n° 81-278 of 25 March 1981 giving birth to an interministerial group of chemical products (GIPC), I confirm to you that the GIPC, given the results of the inspection realised by the French Committee of accreditation (COFR .4C) - Laboratory Section has taken the following decision relating toyour installation: Respect des principes de BPL Date d'inspection : 7-8 mars 2007 Respectofthe GLP

principles Date of inspection : 7-8 mars 2007 Domaines de reconnaissance: Inspection de renouvellement (i .r) 1- essais physico-chimiques Renewal inspection (P.r) 2 - 6tudes de toxicitd 3- etudes de mutagsnicite Date de d6cision du GIPC : 29 juin 2007 4- etudes 6cotoxicologiques sur les Date of GIPCdecision: 29juin 2007 organismes aquatiques et terrestres 8- m6thodes de chimie analytique et Date de prise d'effet : 8 mars 2007 clinique Date of implementation : 8 mars 2007 Areas ofexpertise ; Ann6e de premiere conformit8 : 1989 1=Physico-chemical testing Year ofthefirst conformity: 1989 2 = Toxicitystudies 3 =Mutagenicity studies Duree de validite: 18 mois 4= Environmental toxicity studieson aquatic or Time ofvalidity: 18 months terrestrial organisms 8 =Analytical andclinical chemistry

- CENTRE INTERNATIONAL DE TOXICOLOGIE (CIT) MISEREY -BP 563 27005 EVREUX CEDEX Pierre C Conseiller d'Etat h

Secretariat g6ndral du GIPC - uGE- Simap - 12, rue Villiot - 75572 Paris codex 12

Te18phone : 0153 44 96 10 - T ¬ 1ecopie : 01 53 44 91 72STUDY TITLE ACUTE DERMAL IRRITATION

IN RABBITS

STUDYDIRECTOR Catherine Pelcot

DATE OF ISSUE C,qs

# f~Dw q:~s

TEST FACILITY CTT BP 563 - 27005 Evreux - France --_ -~- . " Safety & Health" Research Laboratories

fFMRecherche BY 563 27005 Evreux r dex France e 5 .N .C au Capital de 846.092 ¬ T61 . : +33 (0)2 32 29 26 26 788 060 465 R.C

.S. Evreux Fax : +33 (0)2 32 67 87 05 VAT: FR! 9 788 060 465 E-mail : C(T@citox.com Agremenr Credit Imp6t Recherctie Web site : www .citox .com p. 160

CONFIDENTIAL

1 ~CONTENTS STATEMENT OF THE STUDY DIRECTOR 4 OTHER CIT SCIENTIST INVOLVED IN THE STUDY 5 STATEMENT OF QUALITY ASSURANCE UNIT 6 SUMMARY 7 RESUME 9 1 . INTRODUCTION 11 2. MATERIALS AND METHODS 11 2.1 TEST ITEM 11 2.1 .1 Identification 11 2.1 .2 Dosage formpreparation 11 2.2 TEST SYSTEM 12 2.2 .1 Animals 12 2.2.2 Environmental conditions 12 2.2.3 Food and water 12 2.3 TREATMENT 13 2.3.1 Preparation and selection ofthe animals 13 2.3 .2 Application ofthe test item 13 2.4 CUTANEOUS EXAMINATIONS 13 2.4.1 Duration ofthe observation period 13 2.4 .2 Description and evaluation of cutaneous reactions 13 2.5 BODY WEIGHT 14 2.6 INTERPRETATION OF RESULTS 14 2.6.1 Interpretation of results 14 2.6.1 .1 Criteria for irritation 14 2.6.1 .2 Criteria for corrosion 14 2.7 ARCHIVING 15 2.8 CHRONOLOGY OF THE STUDY 15 2.9 STUDY PLANADHERENCE 15 3. RESULTS 16 4. CONCLUSION 16 Table l : 3-minute exposure - Cutaneous examinations and mean values of the scores recorded for the first animal (24, 48 and 72 hours) 17 Table 2: 1-hour exposure - Cutaneous examinations and mean values of the scores recorded for the first animal (24, 48 and 72 hours) 18 Table 3: 4-hour exposure - Individual cutaneous examinations and mean values of the scores recorded for each animal (24, 48 and 72 hours) 19 Table 4: Individual body weight (g) 21APPENDICES 22 1 . Test article description and analytical certificate 23 2. Diet formula 2( 3. CIT GLP certificate 28 and 29

### STATEMENT OF THE STUDY DIRECTOR

The study was performed in compliance with the principles of Good Laboratory Practice as described in:

. OECD Principles of Good Laboratory Practice (as revised in 1997), ENV/MC/CHEM (98) 17 and all subsequent OECD consensus documents.

. Directive 2004/101EC of the European Parliament and of the Council of 11 February 2004 on the harmonization of laws, regulations and administrative provisions relating to the application of the Principles of Good Laboratory Practice and the verification of their applications for tests on chemical substances (OJ No. L50 of20.2.2004) .

. Ddcret N° 2006-1523 du 04 decembre 2006 concemant les Bonnes Pratiques de Laboratoire (Journal Officiel du 06 decembre 2006), Minist&e de 1'Economie, des Finances et de 1'Industrie. 

### The studywas also conducted in compliance with the following Animal Protection regulations:

. Council Directive 86/609/EEC of 24th November 1986 on the harmonization of laws, regulations or administrative provisions relating to the protection of animals used for experimental or other scientific purposes.

. Guidance document on the recognition, assessment, and use of clinical signs as humane endpoints for experimental animals used in safety evaluation, OECD Environmental Health and Safety Publications, No. 19. I declare that this report constitutes a true and faithful record of the procedures undertaken and the results obtained during the performance of the study. This study was performed at CIT, BP 563, 27005 Evreux, France,( !

Toxicology C . Pelcot Study completion d0e: J1 (A~i ; t a~-? Study Director ,I

### OTHERCIT SCIENTIST INVOLVED INTHE STUDY

Director of Toxicology CIT Management J .J . Legrand Date:

Doctor ofVeterinary Medicine r, 

# fj ~tfGf

### STATEMENT OF QUALITYASSUR ANCE LTNIT Inspections performed at CIT" 

### TheCIT QualityAssurance Unit conducted the inspections detailed below : Type of inspection Dates Inspection Reported to the Reported to

Study Director Management Study plan 27 July 2007 27 July 2007 02 August 2007 Report 21 March 2008 27 March 2008 08 April 2008 In addition, at about the same time, process-based and facility inspections relevant to this study were carried out by the Quality Assurance Unit. The inspections were performed in compliance with CIT Quality Assurance Unit procedures and the principles of Good Laboratory Practices. The final report is considered to constitute an accurate and complete reflection of the study raw data.

a . DC cc~_e~~~> Date: CIT Quality Assurance UnitSUMMARY

r s acc g o OECD (N : , 2 th April 2002) and EC (2004/73/EC B.4; 29th April 2004) guidelines. The study was conducted in compliance with the principles of Good Laboratory Practice Regulations. Methods The test item was first applied for periods of 3 minutes, 1 hour and 4 hours to a single male New Zealand White rabbit . Since the test itemwas neither severely irritant nor corrosive on this first animal, it was then applied simultaneously for 4 hours to two other animals. A single dose of 500 mg of the test itemin its original form was applied to the closely-clipped skin of one flank. The test itemwas held in contact with the skin by means of a semi-occlusive dressing. Cutaneous reactions were observed approximately 1 hour, 24, 48 and 72 hours after removal of the dressing and then daily until reversibility of cutaneous reactions (day 8) . The mean values ofthe scores for edema were calculated for each animal . Results After a 3-minute exposure (one animal) No cutaneous reactions were observed. A grey coloration ofthe skin was noted fromday 1 until day 4. After a 1-hour exposure (one animal) A grey coloration of the skin was noted from day 1 until day 4. This coloration could have masked a possible very slight erythema on day 1 . No cutaneous reactions were observed from day 2 until day 4. After a 4-hour exposure (three animals) A grey coloration of the skin was noted in all the animals all over the observation period. This coloration could have masked a possible very slight or well-defined erythema fromday 1 until day 2, 3 or 4. Avery slight erythema was noted in 1/3 animals on days 4 and 5. A dryness of the skin was noted in 2/3 animals between day 4and day 7. Due to the coloration ofthe skin, the mean scores over 24, 48 and 72 hours for each animal were not calculable for erythema. For edema, the mean scores over 24, 48 and 72 hours for each animal were 0.0, 0.0 and 0.0. However, taking into account the possible erythema masked by the coloration, the maximal mean values over 24, 48 and 72 hours for erythema could be: 0.3, 1 .0 and 1 .3.ible maxi mal mean values for erythema, the test item mg-7o subsequent adaptations), the test itemshould not be classified as irritating to the skin.RESUME

e Lapm se (2004/73/CEE, B.4, 29 avril 2004) . L'etude a ete realisee conformement aux regles de Bonnes Pratiques de Laboratoire. Methode Le produit a d'abord ete applique pendant 3 minutes, 1 heure et 4 heures sur 1 seul Lapin male NewZealand White. Le produit n'ayant pas montre de proprietes severement irritantes ou corrosives sur ce premier animal, il a ensuite ete applique simultanement pendant 4 heures sur 2 autres Lapins. Une dose unique de 500 mg de produit tel quel a ete appliquee sur une surface de peau tondue au niveau d'un des flancs. Le produit a ete maintenu en contact avec la peau au moyen d'un pansement semi-occlusif. Les reactions cutanees ont ete observees environ 1, 24, 48 et 72 heures apres I'enlevement du pansement puis quotidiennementjusqu'a reversibilite complete des reactions cutanees (jour 8) . La moyenne des scores pour 1'oedeme a ete calculee pour chaque animal . Res ultats Apres une exposition de 3 minutes (1 animal) Aucune reaction cutanee n'est observee. Une coloration grise de la peau est notee dujour 1 aujour 4. Apres une exposition de 1 heure (1 animal) Une coloration grise de la peau est notee du jour 1 aujour 4. Cette coloration a pu masquer un eventuel erytheme tres leger au jour 1 . Aucune reaction cutanee n'est observee du jour 2 au jour 4. Apres une exposition de 4 heures (3 animaux) Une coloration grise de la peau est notee chez tous les animaux sur toute la periode d'observation

. Cette coloration a pu masquer un eventuel erytheme tres leger ou bien defini du jour 1 aujour 2, 3 ou 4 . Un erytheme tres leger est note chez 1/3 animal aux jours 4 et 5. Une secheresse cutanee est notee chez 2/3 animaux entre lejour 4 et lejour 7. En raison d'une lecture masquee de 1'erytheme He a la coloration de la peau par le produit, les scores moyens pour chaque animal apres 24, 48 et 72 heures ne sont pas calculables pour 1'erytheme. Pour 1'oedeme, les scores moyens calcules sont de 0,0, 0,0 et 0,0. Cependant, en tenant compte de t'eventuel erytheme masque par la coloration, les scores moyens maximum apres 24, 48 and 72 heures pour 1'erytheme pourraient etre : 0,3, 1,0 et 1,3.Conclusion les conditions experimentales de cette etude par voie cutanee chez le Lapin, le produit -- --- mpechantde c uiresur son potentiel irrita

es criteres de classification decrits dans 1a Directive 67%5 ne devrait pas etre classe comme irritant pour la peau.1 . INTRODUCTION s study was to evaluate the potential of the test ite induce skin irritation following a single topical applicahoin to-ra ~ i s. In the assessment of the toxic characteristics of a test item, determination of the irritant and/or corrosive effects on the skin of mammals is an important initial step. Information derived from this test serves to indicate the possible hazards likely to arise fromexposure of the skin to the test item . This study was conducted in compliance with:

. OECDguideline No. 404, 24th April 2002,

. EC Directive No. 2004/73/EC, B.4, 29th April 2004. 2. MATERIALS AND METHODS 2.1 TEST ITEM 2.1 .1 Identification Description at receipt:~Tack powder container: one plastic flask date of receipt : 29 June 2007 storage conditions : at roomtemperature and protected fromhumidity composition: see analytical certificate expiry date: June 2008. Data relating to the characterization of the test itemare documented in a test article description and in an analytical certificate (presented in appendix 1) provided by the Sponsor . 2.1 .2 Dosage formpreparation The test itemwas used in its original form . Fresh dosage form preparations were made by the CIT Pharmacy on the administration and any unused material was discarded that same day. morning of The pH of the test item at the concentration of 1% in purified water was not measurable (non soluble and colored test item) .2.2 TEST SYSTEM 2.2.1 Animals Sex, species, strain: male New Zealand White rabbits . Reason for this choice: species generally accepted by regulatory authorities for this type of study. Breeder : Grimaud freres selection S.A.S., La Corbi6re, Roussay, France. Number : three animals were used, as recommended by the international guidelines . Age/weight : on the day of treatment, the animals were 2 to 4 months old and had a mean body weight t standard deviation of 2.5 ± 0.1 kg . Acclimation : at least 5 days before the beginning of the study. Identification: individual metal ear tag. 2.2.2 Environmental conditions The conditions in the animal roomwere set as follows:

. temperature: 18 ± 3°C

. relative humidity: 30 to 70%

. light/dark cycle: 12 h/12 h

. ventilation: approximately 12 cycles/hour of filtered, non-recycled air . The temperature and relative humidity were under continuous control and recording. The records were checked daily and filed. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment were verified and calibrated at regular intervals. The animals were housed individually in Techniplast (64 cmx 63 cm x 30 cm) or Pajon (50 cm x 57 cm

x 75 cm) cages. Each cage was equipped with a food container and a water bottle. 2 .2.3 Food and water During the study, the animals had free access to 110C pelleted diet (SAFE, Villemoisson, Epinay-sur-Orge, France) . Food is analyzed regularly by the supplier for composition and contaminant levels. The diet formula is presented in appendix 2. Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum . Bacteriological and chemical analyses of water are performed regularly by external laboratories. These analyses include the detection of possible contaminants (pesticides, heavy metals and nitrosamines) . No contaminants were known to have been present in the diet or drinking water at levels which may be expected to have interfered with or prejudiced the outcome of the study.2.3 TREATMENT 2.3 .1 Preparation and selection of the animals p. 172 13

The day before treatment, both flanks of each animal were clipped using electric clippers and just before treatment, the skin of each animal was examined in order to check the absence of any signs of skin irritation. 2.3 .2 Application of the test item The test item was first evaluated on a single animal (No. 513/474) . The durations of exposure were 3 minutes, 1 hour and 4 hours. Since the test item was neither severely irritant nor corrosive on this first animal, it was then applied simultaneously for 4 hours to two other animals (Nos . 483 and 484) . Doses of 500 mg of the test itemin its original formwere placed on a gauze pad moistened with purified water, which was then applied to an area of approximately 6 cm 2 of the anterior left flank (application for 3 minutes), the anterior right flank (application for 1 hour) or the posterior right flank (application for 4 hours) ofthe animals . The gauze pad was held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage. The untreated skin served as control . After removal ofthe dressing, any residual test itemwas wiped off by means of a dry cotton pad or a cotton pad moistened with acetone then with water . 2.4 CUTANEOUS EXAMINATIONS 2.4.1 Duration ofthe observation period The skin was examined approximately 1 hour, 24, 48 and 72 hours after removal of the dressing. Since there were persistent irritation reactions at 72 hours, the observation period was extended up to their complete reversibility (day 8) . 2.4.2 Description and evaluation of cutaneous reactions Dermal irritation was evaluated for each animal according to the following scoring scale : Erythema and eschar formation :

. no erythema .. . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . .. . . . . . . .. . . .. . .. . . . . . .. . . . . .. . .. . .. . .. . . . 0

. very slight erythema (barely perceptible) .. . .. . . . . .. . .. . .. . . .. . . . . . . .. . . .. . .. . . . . . .. . .. . . . . . . .. . .. . .. 1

. well-defined erythema. . .. . .. . .. . .. . .. . . . . .. . . . . .. . . .. . .. . . . . .. . .. . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 2

. moderate to severe erythema .. . . . . . . . .. . . .. . . . . .. . . . . . . ._. . . . . .. . . .. . .. . . . . . . . . . . . . . .. . . .. . . . . . . . .. . . . . . . . .. . 3

. severe erythema (beet redness) to slight eschar formation (injuries in depth) . . . .. . 4 Edema formation

. no edema . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .. . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .. . . . . . . . :. . . .. . . . . .. . .. . . . . . . . 0

. very slight edema (barely perceptible) . . . .. . . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . .. . . . . . . . . . . . . . . . . 1

. slight edema (edges of area well-defined by definite raising) . . . . . .. . . . . . .. . . . . . . . . . .. . . . . . 2

. moderate edema (raised approximately 1 millimeter) . .. . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .. . . . . . . . 3

. severe edema (raised more than 1 millimeter and extending beyond area of exposure) . . . . . . . . . . . . . . . . .. . . .. .. . .. . . . . .. . . . . . . . . . . . .. . .. . .. . .. . .. . . . . .. . . . . . . . . . . . . . . .. . .. . . .. . . . . . . . . . . . . . .. . .. . . 4 Any other lesions were noted .2 .5 BODY WEIGHT p. 173 14

Each animal was weighted at the beginning (day of treatment) and at the end of the observation period. 2.6 INTERPRETATION OF RESULTS The results obtained were evaluated in conjunction with the nature and the reversibility of the findings observed. 2.6.1 Interpretation of results 2.6.1 .1 Criteria for irritation A substance or a preparation is considered to be irritating to the skin if, when it is applied to healthy intact animal skin for up to 4 hours, significant inflammation is caused and which persists for 24 hours or more after the end of the exposure period. 2.6.1 .2 Criteria for corrosion A substance or a preparation is considered to be corrosive if, when it is applied to healthy intact animal skin, it produces full thickness destruction of skin tissue on at least one animal during the test for skin irritation, or if the result can be predicted (for example: from strongly acid or alkaline reactions) . All scores obtained at each reading time (24, 48 and 72 hours) for an effect are used for calculating the respective mean values.2.7 ARCHIVING p. 174 15

The following study materials are archived by CIT, 27005 Evreux, France, for 10 years after the end ofthe in vivo phase of the study:

. Study plan and possible amendments,

. raw data,

. correspondence,

. final report and possible amendments. On completion of this period, the archived study materials will be returned to the Sponsor, or may be archived at CIT for a further period (at additional cost) . The total duration of archiving (depending on regulations) will be the responsibility of the Sponsor. In addition, raw data not specific to the study including, but not limited to, certificates of analyses for food, water and bedding (if applicable) and records of environmental data and equipment calibration, are also archived by CIT for at least 30years. 2.8 CHRONOLOGY OF THE STUDY The chronology of the study is summarized as follows: Procedure Experimental starting date (day oftreatment of the first animal) Experimental completion date (end of the observation period) 2 .9 STUDY PLANADHERENCE The study was performed in accordance w Date 07 August 2007 16 August 2007

amendments, with the following deviation fro - -agr-7-~y an : nd subsequent

. the temperature and relative humidity recorded in the animal roomwere sometimes outside of the target ranges specified in the Study plan . This minor deviation was not considered to have compromised the validity or integrity of the study.3. RESULTS The observations recorded during the study are presented in tables 1, 2 and 3. The body weight is presented in table 4. After a 3-minute exposure (one animal) No cutaneous reactions were observed. A grey coloration of the skin was noted fromday 1 until day 4. p. 175 16

After a 1-hour exposure (one animal) A grey coloration of the skin was noted from day 1 until day 4. This coloration could have masked a possible very slight erythema (grade 1) on day l . No cutaneous reactions were observed fromday 2 until day 4. After a 4-hour exposure (three animals) A grey coloration of the skin was noted in all the animals all over the observation period. This coloration could have masked a possible very slight or well-defined erythema (grade 1 or 2) fromday 1 until day 2, 3 or 4 . A very slight erythema (grade 1) was noted in 1/3 animals on days 4 and 5. A dryness of the skin was noted in 2/3 animals between day 4 and day 7 . Due to the coloration ofthe skin, the mean scores over 24, 48 and 72 hours for each animal were not calculable for erythema. For edema, the mean scores over 24, 48 and 72 hours for each animal were 0.0, 0.0 and 0.0. However, taking into account the possible erythema masked by the coloration, the maximal mean values over 24, 48 and 72 hours for erythema could be: 0.3, 1 .0 and 1 .3. 4. CONCLUSION

rimental conditions of this study, when applied topicall

IMp. 176 17 Table 1 : 3-minute exposure - Cutaneous examinations and mean values of the scores recorded for the first animal (24, 48 and 72 hours) Rabbit Dermal Scores Mean number Irritation irritation Ih 24h 48h 72h score (1) D1 D2 D3 D4 513/474 Erythema 0 0 0 0 0 .0 Edema 0 0 0 0 0.0 Other C C C C (1) mean of scores on days 2, 3 and 4 h = hour D =day C = grey coloration of the skinp. 177 18 Table 2: 1-hour exposure - Cutaneous examinations and mean values of the scores recorded for the first animal (24, 48 and 72 hours) Rabbit Dermal Scores Mean number Irritation irritation Ih 24h 48h 72h score (1) D1 D2 D3 D4 513/474 Erythema CI 0 0 0 0.0 Edema 0 0 0 0 0 .0 Other * C C C (1) mean ofscores on days 2, 3 and 4 h = hour D =day * = none C = grey coloration of the skin CI = grey coloration ofthe skin which could have masked a possible very slight erythemaTable 3: 4-hour exposure - Individual cutaneous examinations and mean values of the scores recorded for each animal (24, 48 and 72 hours) Rabbit Dermal Scores Mean number Irritation irritation lh 24h 48h 72h score (1) D1 D2 D3 D4 513/474 Erythema C2 C1 0 0 (2) Edema 0 0 0 0 0.0 Other * * C C 483 Erythema C1 C1 C1 C1 (2) Edema 0 0 0 0 0.0 Other * * * 484 Erythema C2 C2 C1 1 (2) Edema 0 0 0 0 0 .0 Other * * * C/S (1) mean of scores on days 2, 3 and 4 (2) = not calculable h =hour D= day (+) = irritant according to E.E.C . criteria (-)=non-irritant according to E.E.C . criteria * =none S=dryness of the skin C=grey coloration ofthe skin C1 =grey coloration ofthe skin which could have masked a possible very slight erythema C2 grey coloration ofthe skin which could have masked a possible well-defined erythemaTable 3 (continued) Rabbit Dermal Scores number Irritation

513/474 Erythema Edema Other 483 Erythema 0 0 0 0 Edema 0 0 0 0 Other C/S C/S C/S C 484 Erythema 1 0 0 0 Edema 0 0 0 0 Other C/S C/S C/S C D= day S = dryness of the skin C = grey coloration of the skin - = cutaneous examination not performedTable 4: Individual body weight (g)

Sex Animals Day of End ofthe treatment observation period Male 513/474 2607 2763

483 2440 2560 484 2351 2557 M 2466 2627 SD 130 118 p. 180 21

M = mean SD = standard deviationp. 181 22

APPENDICES1 . Test article description and analytical certificateWENTITY Test artitle name Cbenimal name CAS numlrcr EINECS number Origin ch nuniber Arkerr.1a filing number ~'STCALANI) CHE.',,Nl'fC-AL PROPERTIES Azrpcananc

.e Partic"Ile. s Specific Gravity Antotgnition temperature Solub-111q, : black powder : 30 gin ( appmx:it.i9trl .y } : 2,1 kgleO at. 2VC : > 400 °C (standard : NT EN 502&1-2-1) : in waier -

. insoluble

: Keep hcrni,etically closed in a dry, coo( avid well-ventiled place . : Jane 2003 IncinerationReference de la m6thode DETERMINATION I ITEM RESULTAT I RESULT d'analyse I Analysis reference Powder characteristics Ash content % 7.6% ATG 70 -

. a,, .~

. w

Nom du responsable du taboratoirel Laboratory Director :

Signature p. 184 252. Diet formulap. 186 27 Ref: 110 COMPLETE DIET RABBIT BREEDING DIET Appearance: 3 mm

diameter granules Conditioning: bags of 20 kgs Daily portion: Rabbits 150 g, water ad libitum . FORMULA % Cereals . . . . .. .. . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . Grain biproducts and leguminous plants . . .. . . . . . .. . . . . . . . . . . Vegetable protein (soya bean meal, yeast) .. . . . . . . . . . . . . .. . . . . . . . . . . . . . . Vitamin and mineral mixture . . . AVERAGE ANALYSIS % Calorific value (Kcal/kg) . . . . . . . . . . Moisture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carbohydrates (N.F .E.) . . . . . . . . . . . . Fibre. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Minerals (ash) . . . . . . . . . . . . . . . . . . . . . . . . . . . AMINOACID VALUES (calculated in mg/kg) Arginine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cystine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lysine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methionine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tryptophan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Glycine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FATTY ACIDVALUES (calculated in mg/kg) Palmitic acid . . . . .. . . . . . . . . .. . . . . . . . . . . . Palmitoleic acid . .. . . . . . . . . . .. . . .. .. . .. Stearic acid . . .. . . .. . .. . . .. . . . . . .. . . .. .. . .. Oleic acid. . . . . .. . . . . . .. . . .. . . . . . .. . . .. .. . .. Linoleic acid .. . . . . . .. . . .. . .. . . . . . . . . .. . .. Linolenic acid . .. . . . . . . . . . .. . . . . . . . . .. . . . 33.8 48 14 4.2 3100 10 15 2.3 48.2 17 7.5

11300 3400 9300 280 .0 2400 8700

6400 0 600 6400 12100 2400 MINERALS (calculated in mg/kg) Nat. CMV val . val . Total P. . . . . . . . . . . . . . . . . . . . . 3600 2900 6500 Ca . . . . . . . . . . . . . . . . . . 4200 5800 10000 K . . . . . . . . . . . . . . . . . . . 12000 0 12000 Na . . . . . . . . . . . . . . . . . 400 2000 2400 Mg . . . . . . . . . . . . . . . . . . 2500 100 2600 Mn . . . . . . . . . . . . . . . . 50 40 90 Fe . . . . . . . . . . . . . . . . . . 150 150 300 Cu . . . . . . . . . . . . . . . . . . Traces 15 15 Zn . . . . . . . . . . . . . . . . . . 30 45 75 Co . . . . . . . . . . . . . . 0 .1 1 .5 1 .6 I . . . . . . . . . . . . . . . . . . . . . 0 .1 0 0 .1 Cl . . . . . . . . . . . . . . . . . . . 300 3000 3300

VITAMINS (calculated per kg) Nat. CMV val . val . Total -------------------------------- Vitamin A Traces 10000 lU 10000 IU Vitamin D3 0 IU 1000 IU 1000 fu Vitamin 131 5 mg 0 mg 5 mg Vitamin 132 4 mg 0 mg 4 mg Vitamin 133 20 mg 0 mg 20 mg Vitamin 136 1 mg 1 mg 2 mg Vitamin B12 0 mg 0 mg 0 mg Vitamin E 15 mg 25 mg 40 mg Vitamin K3 0 mg 1 mg 1 mg Vitamin PP 60 mg 5 mg 65 mg Folic acid 0 mg 0 mg 0 mg Biotin 0 mg 0 mg 0 mg Choline 1000 mg 1000 mg 2000 mg

Available under quality "Control Ref. : 110" SAFE, 7 rue Galli6ni, Villemoisson, 91360 Epinay-sur-Orge Tel : 01 .69.04.03.57 - Fax : 01 .69.04.81 .97 (Ref . Doc. UAR

: 2000)3. CIT GLP certificatei,a. .rlf - Ill~na - rroreraai Wum-eQpe FcaVCP"e GROUPE IIVTEIt1YIINISTERIEL DES PRODUITS CHIMIQUES Paris, le 

# - s JuIL. 2007 OObjet : Evaluation de la conformite aux Bonnes Pratiques de Laboratoires (BPL) selon les directives 200419/CE et 20041101CE du 11 f8vrier 2004. Subject : Assessment ofcompliance with Good LaboratoryPractices (GLP) under the ECdirectives 2004/9 and 2004/10of 11 February 2004 . Cons6cutivement i3 votre engagement vis-6-vis du GIPC et du COFRAC et en application du d8cret n° 2006- 1523 du 4dccembre 2006 concernant les bonnes pratiques de laboratoires et modifiant le d6cret n° 81-278 du 25 mars 1981 portant creation d'un groupe interminist6riel des produits chimiques, je vous confirme quo le GIPC, au vu des rdsultats du contr8le exere6 par le Comite fran~ais d'accr8ditation (COFRAC) - Section Laboratoires a d6cid8 pour votre installation du statut suivant : Followingyour engagement vis-k-vis the GIPC and COFRACand in application of the decree n° 2006-1523 of 4 December 2006 relating to the good laboratory practices and modifying the decree n° 81-278 of 25 March 1981 giving birth to an interministerial group ofchemical products (GIPC, 1 confrrm to you that the GIPC, given the results ofthe inspection realised by the French Committee ofaccreditation (COFRAC) - Laboratory Section has taken thefollowing decision relating 10),01V installation. Respect des principes de BPL Date d'inspection : 7-8 mars 2007 Respectofthe GLPprinciples Date of inspection : 7-8 mars 2007 Domaines de reconnaissance: Inspection de renouvellement (i .r) 1- essais physico-chimiques Renewal inspection (4r) 2 - etudes de toxicit8 3- 8tudes de mutag6nicit6 Date de d¬ cision du GIPC : 29juin 2007 4- rstudes icotoxicologiques sur les Date of GIPCdecision : 29 juin 2007 organismes aquatiques et terrestres 8- m8thodes de chimie analytique et Date de prise d'effet : 8mars 2007 clinique Date of implementation: 8mars 2007 Areas ofexpertise : Annee de premiere conformitd : 1989 1 =Physico-chemicaltesting Year ofthefirst conformity: 1989 2 = Toxicity studies 3=Mutagenicity studies Dur ¬ e de validite: 18 mois 4= Environmental toxicity studies ort aquatic or Time ofvalidity: 18 months terrestrialorganisms 8 =Analytical and clinicalchemistry

CENTRE INTERNATIONAL DE TOXICOLOGIE (CIT) MISEREY - BP 563 27005 EVREUX CEDBX ( IrA\A~ Pierre CPEYSSEL Conseiller d'Etat h

Secr6tariat gdneral du GIPC -DGE- Simap - 12, me Villiot - 75572 Paris codex 12

Telephone : 0153 44 96 10 - Telecopie : 0153 44 9172