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Table of Contents

1 . Slgn " . " i ps. " .» .N .NNN

"" »»N

.N" . .NNNNN .»»NN " »N " .NNN.N. " N.» " N .NNN

" N " N . .N» . .NNNNNNNNNNN .N . s 

### z. 3~Sry " . " N . .NNNNN.NN" N .NN .NN. " N .NN»NNNNN " NN .N .N .NNNNN»»NN»NN» .6 3. aYN7 .IYa6NYQN .NN"""" NNNN. . .N "" NN

" N " N """""" NNN" N» " » " NNN " N "" N . .N . " NNN

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. .N .»NN .B 

### 4 . IdentilieaHon and R~IW " Y

. . . .f~. .N

.N .N .N " N»NNN" N

" N " N " NN "" .w " N" N " NN. " .NNNN " »NNN

" NN . " ~ 

### 4 .1 Identification ofthe Study . . .. . . .. . . .. . . .. . .. . . .. . . .. . . .. . .. . . . . . .. . . .. . .. . . . . . . . . . .. . . . . . . .. . .. . . . . . . .. . . .. . . . . . . . .. . . . . 9 4 .2 Reaponsibilities . .. . .. . . . .. . . . . . . . . . . . . . . . . . . . .. . .. . . . .. . . . . . .. .. . . . . . . . . . . . .. . . . . .. . .. . . . . . .. . . . . . . .. . . . . . . . .. . .. . . . . . . .. . . . . . .9 S. Ma t erial and Methods" . . " . . " NNNN . " NN»N

.NN " . " N" . .N

. .NNN

" . .NN

. . . . " N

.NN .NN" .NNNNNNN " » .NN. . .10 5 .1 Teat compound . . . . . . . . . . .. . . . . .. . . . . . . . . . . .. . . . . . . .. . . . . . .. . . . . . . . . .. . . . . . . .. . .. . .. . . .. . . .. . . .. . . . . . . . . . . . . . . . . . .. . . .. . . . . . .10 5.2 Formulation ofthe Test Compound . . .. . . . . . . . . . . .. . . . . . .. . .. . . .. . . . . . .. . . . . . . . . . .. . . .. . .. . . .. . . . .. . .. . . . .. . . . . . .11 5.3 Administration ofthe Test Compound. . . . . . . . . .. . . . . . .. . .. . . .. . .. . . .. . .. . . . . . . . . . . .. . .. . . . .. . . . . . .. . . . .. . . . . . . .11 5.4 Analysis ofthe Formulation . . . . . .. . . . . . .. . . . .. . .. . . . .. . . . . . .. .. . . . . . . . . . .. . .. . . . . . . .. . . . . . . . . . . .. . .. . . . . . . . .. . . .. . . . .12 5 .5 Test System(Animals) . . . . . . . . . . . . . . . . . . . . .. . . . . . .. . . . . . . .. . . .. . .. . . . . . . . . .. . . .. . . . . . . . . . . . . . .12 5.6 Housing Conditions. . . .. . . . . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . .. . . . . . .. . . . . . .. . .. . . . . . . . . . .. . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . . . .13 5.7 Number ofAnimals and Dow Levela .. . . . . . .. . . .. . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . .. . . .. . . .. . . . . . . .. . . .. . . . . . . .15 5 .8 Observations . . . . .. . . .. . . . . . . . .. . . .. . . . . . . .. . . . . . . . . . . .. . . .. . . . . . . . . . . . . . . . .. . .. . . .. . .. . . .. . . . . . . .. . .. . . . .. . . . . . . .. . . .. . . . . . . . .15 5.9 Data Collection . . . .. . . . .. . .. . . . . . . . . . . . .. . . .. . . .. . . . . . .. . . . .. . .. . .. . . .. . .. . . .. . .. . . . . . .. . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . .. . . . . .16 5.lOCalculatton of the LD50. .. . . . . . . . .. . . . . . .. . .. . . . .. . . .. . .. . . . . . .. . . . . . .. . .. . . .. . .. . . . . . . . . . . .. . . .. . . . . . . .. . . .. . . . . . . . . . .17 6 " »» .» . " NN "" N " .N " NN " NN .N» " N.N

.NN""" 18 

### 6 .1 DowReaponse Table (LDSO) . .. . . . . . . . . . . . .. . .. . . .. . .. . . .. . .. . .. . . .. . .. . . .. . . .. . . . . . . . . . .. . . . . . . . . . . . .. . .. . . .. . . . . .18 6 .2 Clinical Signs. .. . . . . . . . . . . . . . . . . .. . . . . . . .. . .. . . .. . . .. . . .. . . .. . .. . . .. . .. . . .. . .. . .. . . .. . . . . . . . . . . .. . .. . . .. . . . . . . . . . . . . . . .. . . . . . .18 6.3 Body Weights . . . .. . . . . . . .. . . . . . . . . . . . . .. . .. . . .. . .. . . . . . . .. . . . . . .. . . . . . .. . . .. . .. . . .. . .. . . .. . . .. . . . . . . .. . . .. . . . . . . . . . . .. . . . . . . .18 6 .4 Gross Pathology Findings. .. . . . .. . .. . . .. . . . . . . . . . . . . . .. . .. . . . . . .. . . .. . .. . .. . . .. . . . . . . . . . . .. . . . . . . .. . .. . . . . . . .. . . . . . . . . .19 / " COQ~i " .~" YY " NN"" NN

"" NNNN.N

.» "" .NN

" NNNN

. " NN . "" NNN

" NNN

.»N" . . "" .N» "" NNNNN. .N"" » "" NN "" N "" NN"" NY 

### List of Abbroviations used in the Appendlx . .. . . .. . . . . . . . . . . . . . . . .. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . .. . . 21 Clinical Signs, Oronps . . . . . . . . . . .. . .. . . . . . .. . . . . . . . . . . .. . . .. . .. . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . . . . . . .. . .. . . . . . . .. . . .. . . .. . . .. . . . 22 Clinical Sips, Individual . .. . .. . . . . . . . . .. . .. . . .. . .. . . .. . . . . . . .. . .. . .. . . . . . . .. . . . . . . . . .23 Body Weighta. . . . . . . .. . . . . . . . . . . . .. . . . . . . . .. . . . . . .. . . . .. . .. . . . . . . .. . . . . . .. . . .. . .. . . . . .. . . . . . . .. . . .. . . .. . . . . . .. . . .. . . . . . . . . . . . . . . .. . . .24 Weight Gain . .. . . .. . . .. . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . .. . . . . . . .. . . . . . . .. . . . . . . 25 . . . . .. . . . . .. . . .. . .. . . .. . . .. . . . .. . .. . . .. . . . . . . . . . . .. . . .. . . Macroscopic FindinOs . . . . . . . . . . . . . . . . . . .. . . . . . . . . . .. . .. . . .. . . .. . .. . . . . . .. . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . ... . . .. . .. . . 26 Statement of OLP Compliance . . .. . . . . . .. . . .. . .. . . . . . . . . . . . . . . . . . .. . .. . . .. . .. . . . . . .. . . .. . . . . . . .. . . .. . . . . . . . . . . .. . . . . . . . . . . . 27p. 2



### Study-based inspections were conducted by the Quality Aasurmx on the dates given below . Audit reporta have been submitted in writing to the study director and, if necessary, also to the laboratory management or other pawns affected. Date of Study p6~ Date of report to study dkvdor Inspection inspected and/or msuaxment 

## Sept. 04,2006 STUDY PLAN SGpL 04,2006 oft la, 2006 PRErAlurloNoF FoRMc,rlAoar . la, 2006

nDIwNlSrRAnoN Nov. 21, 2006 - Nov. 21, 2006 FIRST DRAFT Nov. 21,2W6 Nov. 24, 2006 FINAL DRAFT Nov. 24, 2006



### The results ofthe study and the methods used haw been coe+ecNy reported. Date : 

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1 . SipAtnrm

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2 . Summary Thia study was to acu~e oral toxicity to Wider rats of

ty: 9S. The tag compound was adminiabered to the animals by feeding in a single dose for up to 6hours. To make the test compound flavoraoate for the animals, it was carefully mixed with chocolate hazelnut vreed, The results are summarized in the table below . Table 2-1 aPC --I don mpAw t~doaopk~l oocurrrnc . or sipn. um

. oi de.MmortaNty bw . - -- n»uIr tenai . (1sy 2000 0 I 0 1 3 - _ 0 (2nd) 2000- 0 I 0 / 3 - _ 0 " number of anbnals which died spontanaowly andlor wan sacrMad M mor~wnd sbft/ number ofanUnals with Wgns of boddly / IM number of arkwb uwd pr group " or" of three ankrals did not modva the oon vhft dose 

### According to OECDguideline 423 the LDS0cut-off >_ 5000 mg/kg bw

. (Category S / unclasiged ofthe Olobally Katmonized Classification System) . The assessment is made even though only S of six animals received the complete dose of 2000 mg/kg bw

.; but thare ware no signs oftoxic effects in any cases. Adose of 2000 mg/kg body weight was tolerated by female rats without mortalities, clinical signs, effects on weight gain and gross pathological findings.7 

# UBLIC COPY With the deviatlons that ft tat PAM=was not administered by gavage but by feeding in a *We dose for up to 6 bolus and that only S ofsix animals radved do complete don; the method used compiled with the OECD- (luidelimfor Testing of Chemicals No. 423 -"Acute Oral Toxicity - Acute Toxic Class Method" ; adopted: 17th December 2001 ; EECDirective 67/548 Annex V- Method H .l .tria (1967) in its =rent version, and the principles ofthe EPA Haft Effects Test Ouidalines (OPPTS 870

.1100), United States, EPA712-C-98-190 (1998) .

### The studywas Study initiation date : 2006-08-25 (YYYY-MM-DD) Experimental starting date : 2006-09-06 (YYYY-MM-DD) ExpaimeMal completion date : 2006-11-03 (YYYY-MM-DD) Study completion date : see sipature page The study objective was to determine acute oral toxicity. Information derived fiom this test serves to indicate the posa'ble existence ofhazards likely expoauro to arise from short-term

exposne+e by the ocal route ofthe test substance, and - with respect to a proper handlit~ and use - sum to permit classification (labeling) ofa product . lu lan, raw the an retained in the archives specified by OfiiiiN ;=ofa retention sample is in the responsibility ofthe sponsor.

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4 . Idendlication end Responsibilities 

# 4 .1 ideoancaaoo of the S Study No. 4.2 Responsibi8da Study Director

Head of Quality Amudroe Unit Head of Deperbnod Head ofTest Facility Archiving

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s. M .terW sod Methods The "Acute Oral Toaicity - Acute Toxic Cleae Method" described in OECD guideline 423 was ueed forjud~ on the acule toxicity ofthe teat substance. 

### 11 Tat compound Test compound Chemical name Appeerarce : black, powdery to ooarsapdned storap : room tampersture 

### Batch no. A~ Conteot oftest aubwum : 95.8 "~Olt used for calculations) F .xpiry data : 2006-12-09 (YYYY-MM-DD) Confirmation ofthe identity ofthe tog componnd was performed.p. 9



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### 5 .2 Formulation of the Teat Com Due to phyaico-chemical properties starlinS don (2000 ma/kBbw .) suapended in tap watar s EL (2y6) waa tcchnically impoaaible to app1Y bY 6aveee. The animals which received only an unknown S'ctionel amount ofthe starwng dose wm

not considered in this rn

:poR . Trials to fonnuia" the teat compound with other vehicles so did it could be administered by savage also failed because can should be telaLuc .tqalter the test subdanm required amoum

it was offered to the 

### 53 Adinhilstmdon of the TedCompound The individual don for each animal . wee calculated on the ban ofthe body wei& at time of administtntton. To mslo the teat compound flavorsome for the animals, the individual don for each animal was carefally mixed with appe n,rimately 2 ~ chocolate hazelnut spread (Nutellae, Farero, 60624 Froalcfurt, Germany) . For administretion, food was witbheld from the animals for approximately 16 - 24 h before adminiatratton ofthe test compound The animals won food spin approxiwstely 2 h afterthe end ofthe period ofadminiaWtion. For the period of adminiatratton the animals were housed individually. The mixture was offered to the animals in stainless steel containers. Over the period ofadministration in 2of 6cam (animal no. 4 and 7) residuals of the test compound wen mixed with additional chocolabe hazelnut apresd (approximately 18) and were offered to the animals spin. 

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### I* Ovariod lZ

J~ 

### ofadminiatraticn did not exceed 6bours. Residues were documented and Only one animal (animal no . 8) did not consume the complete amount oftest compound within the period ofadministration (Residue: l g ofthe mixtore) . 5 .4 Analyds ofthe Formalation Stability and homogeneity ofthe foimulated teat substance was M confirmed analytically. Tlro tea sabadurce method c6arac~erla~a are not suggestive ofa rapid reaction with the chocolate braelmrt ~ ad The mixture of the chocolate hazelnut spread was prepared froshly prior etatt offeeding al904L Due to the method ofadministration homogeneity was not confirmed analytically. S .S Test 3yste® (Aefnmab) The study was porformed in famate Wlstar rats. The used strain was HsdCpb:Wu (broader: Harlao/Winlcelmam OmbI3,, .~, orGhtar, Germany) . Animals ofthis strain have been use wMdcologlcal stndiee for many yam . Historical data on their physiology and spontaneous atteraotione is available. Tbe state ofhealth ofthe breeding colony is roudnely spot-checked for the mein apeoiSc pathogms. The results ofthen examinations ; an archived. At start ofdo study the animals van nullipermand non-pregnant and five ofall clinical symptoms or diseaser. The ~on time in the animal room was at lad S days. Body weights at start ofstudy: 164g-180g This is according to an age of 10 -12 weeks ap~+oximatoly,

### 13 The animala were assigned to their groups by ran6omi~tion. The random lid was based on evenly distributed chance numbers by a software application. TU animal were identified by labels on the cages stating study number, test compound, animal number, group number, etc. ad by individual animal identification using permanent skin nvwking. 

### 5 .6 Housing Conditions T1Le animal roomhad a standardized climate: Room temperature : 22f2°C 

### Air humidity : SS t5'K Ventilation : approx.10changes per hour Light1 Dark cycle : 12 bows rhythm . OccqAonal deviations from then standards occarred, e.g. during cleaning ofthe animal room

. They did not have any appea+ent influence on the outcome ofthe study. The animal room

was sounded with radio pcogrwt. The animals were group caged conventionally in polycsrbonate cages on low dust wood granulate bedding (J. Rettmmaier 3r 38hne, 73494 Rosearberg, Germany) . The cages ofthe animals were placed on racks. The wood granulate was randomly c6rodrod for contaminants at reQulac intervals and the results have been stored at the apelyaes yielded no evidence of any adverse effects on the aim

ofthe study. The cages ware changed at least once a week. Feed racks and water bottles were not changed All cage material was washed with hot water. In the first stage ofthe washing programan allmline cleaning agentp. 12



### 14 (Neodischer Alka 300; Chemische Fabrik Dr. Weigert CimbH &Co. KCI, conaenj,qtion: 2

.2 g/1) wad used. The animals received the standard diet "Provimi Kliba 3993.0.15 MaualRatte Haltung, Raiaerewgst Switzerland", and tap water ad libitum frompolycarbonate bottles. The nutritive compoaition and the contaminant content ofthe standard diet were checked and analyzed routinely in randomsamples. Nothing untoward was found. The tap water was ofdrinking water quality (according to the Dmkmg Water --\ Decree in the current version) . Tha results of the analyses have been S~Mm MOMWOMMONERM available data yielded no evidence ofany adverse effecb on the aimofthe study. The food was available from racks in the lid of the cage, polycarbonate bottles won used for drinking water. The anima1 room

was cleaned once a week and disinfected at least once a month. A continuous pest control was performed using a cockroach trap without pesticides (e.g. KillgermRoach Trap, Killgam OmbH, 41460Nevse, Germany) . The contact ofthe animala with die tap was avoided in any case.p. 13 

# is 17 Number of Aermd. a.a Dow Lever Three animals are used for each step . The don level to be used as ft starft dose is selected fi+om

one offour fixed levels, S, 50, 300 and 2000 mg/1cQbody weight. The starting dose level should be dud which is most liloly to poducx mortality in some ofdo dosed animals. Absence or presence of compound-=elated mortality of the animals dosed at one atepwill determine the nod step, i .a: " no further testing is needed, " daft ofthree additional animals, with the same dose, dosing ofthree additional atritnds at the next bigber or the next Iowa dose level . T'he subahnce is tested using a stepwise procedure, each step using tbroe animals of a single an (normally females)

. Theprocedure is described in the flow charts of Annex 2, OECDguideline 423. 

# s.e Ob"nunous clinical signs end mortality rates van deoesmined nv=W times on the day of administration end eubseqneatly at low owe daily for an observation period ofat last 14 days. Mortality and in the event ofsymptoms ocxturing, natuc+e, duration and intensity win recorded individuetly. The day ofsdministradon is defined as day 1 . T'~mea after administration eRart until the following day ware recorded either in minutes or in hours, depoWitg on what was apyropride. Mimes were rounded in five-minute-abeps according international ag+eements, e.g. 0' - < 2 .s' to 0', > 2 .5' - < 7.S' to 5' and so on. Hours were rounded to fWl hours. In contrast to this, all further observation intervals are given in days. IIe duration ofthe symptoms and the tima ofdeath am

given relative to the time of administration to the individual animal . T1e real time Points con be taken from the raw data. In general, death will be Wen as a symptomDue m the computer system

used, death is not shown as a clinical symptomin the liab ofthe appendix. If no symptoms are saw until death,

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time ofdeath will be taloen aa the first ocmarence ofa symptouL Em the results section, the findings are summarized without my indication ofintensity. Ttre findings can be found for dogroups end individual animals in the appendix. The weight gain ofthe animals was checked weeldy until the end ofdie Andy. The weights are given in the tables in the appendix a individual and men values. The means and standard deviations were calculated on the ban ofthe rounded individual vahue. The weights are given in grams (g) . Indicated under the heading day 8are e.g. the data obtained on the 7th day after adminlisbation. Animals which died oz were killed in moribund state were weighed (except an day ofadministration) and dissected as won . as possible, and examined macroscopically. The surviving animals were sacrificed by carbon dioxide at do end ofthe study, dissected and examined macroscopically. 

### 5 .9 Data CoUecdoa DnrinQthis study for colleotion, storage and evaluation ofdata a validated LAN-linked computer system was used, which is designed and created in-house. If necessary to data were collected offline. Hardware and opemtinS systems: " HP-1000A (4x, operating systemRTE-A 6 .2) " HP-3000mica 900 (lx, operating system MPFJiX 5 .5) " HP-9000 series 200 (lx, operating systemHP-UX 11 .0) Software: Data was stored on HP-3000 in an HP 'ItirbolmmagdXL Database.17 ) V ,~wj 

### 5 .10 Calcalsden ofthe LDSO The LD50value was estimated 8ccoiding to OECD - Guideline for Testing of Chemicals No

. 423 -"Acute Oral Toxicity - Acute Todc Class Method" ; adopted: December 17, 2001 .

### 6

. Results 6 .1 Dose-Response Table (LDSO) The results ofthe study for acute oral toxicity in dofvted rat including the LD50, are summarized in the tables below . Table " -1 DoeeR~eponee

.

N dose mpncp txtoobpicd o«ciirr.noe of sipns Ims ordeau, mormNty bw . rswlr c9i) 

## (10)2000 0 1 0 1 3 - - 0 (2") 2000- 0 i 0 1 3 - - 0 number of animals which died spontaneously andlor wan sorrillad in moribund atabr I number ofaniniY wMhsigns of io*ty I OM number of animals used per gfouP am of three ankralb did not_rroalw the manivift does LDW ad-W . : a000 epAg bw

. (ONCabEoy d ! undasMed) aooonding to OECDquideline 423 The assessment h made even though only 0of sk animals received the complabdoes of 2000nplkp bw . ; but thwe ware no signs of book aft c-ts in any cases. 

### 6 .2 Clinical Sips No clinical sips wen observed (see appendix page 22 and 23) . 6 .3 Body Weighhtr There were no toxicological effects on body weight or body weight pin. The body weights are given in the appendix es individual and mean values on page 24 . The body weight gain is given on page 29.

### 6

.4 Grow

Pat6oloU Findinp Tbe necropsies pedornned et die end of the study revealed no paRicular Sndings (see appendix, page 26) .

### 7

. Cooclosioa -- Accordingto OECDguideline 423 dre LDSOcut-off >_ 5000mg/kg bw

. (Category S / unclassified ofthe 0 otially Harmonizcd ClaaaiScation System) . Tbe teat compound was administered to the animals by feeding in a single dose for up to 6hours. To make the teat compound flavasome for the animals, it was cm+efully mixed with chocolate hazelnut spread.p. 19



## & Appendix List ofAbbreviatiou Used b the Appndis In addition to the abbreviations for do basic units ofthe Intanational Unit System (SI)_ stipulated by law, and designations for decimal multiples and parts ofwits, the following abbreviations are used:minute % Percent AID . (onto maridiem) = before noon appalc. amoximately bw . body weight C .A . Chemical Abstracts CAS Chemical Abstracts Swvice d day E Mndselction) - final ==M e.8 . (exeMPli giatia) =for example ff following OHS Globally Harmonized Classification System h hour i .e. (id ad) - that is LDSO median lethal dose m mean M moribund sacrifice Max . intens. maximum intensity Lao . no abnormality obeecved no. number p.m (post meridiean) - aft noon p.oJPO (per oa) = oral R4D relative standard deviation SD/a standard deviation T (rod) - death time of d. time ofdeathp. 20 

# 22 clinical sfons; groups Akut/acute clinical siyns t ineidonco ( duration of I rx . I tfos of I sioru intsns . death

. . . . . . . . . . . . . . . .--------------- . . . . . . . . . . . . . . . .----- . . . . . . . . . . . . .------------- . . . . 2000 MO/KO faoslo PO

---- . . . . . .------------------- " - "

-- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .----------- 

### n.a-o. I I I i

. . .--------------------- . . . . . . . . . . .----------------------------------------------- 2000 MO/KO female PO

. . . . . .----- . . . . . . .---------- . . . .------- . . . . . . . . . .----- . . . .-- " -- . . . .--------------- 

### n.s.o. I I I Ip. 21 

# 23 clinical stem

; Individual animal I clinical siora ( duration of I ~ . I tiws of no. I sisns intsns . death

------- .------- . . . . . . . . . . . . . . . .--------------------------- . . . . . . . . .------ " -- " -----

2000 MI/KO famlo PO

. . . . . . . . . . . . . . .----- " --- . . . . . . . . . . . . .------ " -------------------------------------- 4 I n.s .o. S n.s .o. 6 n.s .o. /

. . . . . . . .------- .-- . . . .---- . . . . . . . . . . . . . . . . .------ " ------ . . . . . . . . . .------------ . . . .

2000 MO/KS fonts P0

---------- . . . . . . . . . . . .-- " ---------------- " -- . . . . . . .- " --- "" ---------------- " -- " --- " 7 n.s .o. A ! n.s .s. 9 I n.s .o. 

# I I I PUBLIC COPYTioraowichO / body weights (0) Akut/scuto T *rnr ./ TN / )r nce6ToeT To60s0it cntmi no. 1 a 1S after death tiuo of d.

2000 110/KO woiblich / f~lo P0 4 177 193 118 9 16~ 1 " 2 206 6 I 169 19S 217 176 190 - 214 s 1 6.6 7

.0 6 .6 2000 NAG uoiblich / f~to PO 7 180 204 216 i I 170 191 193 9 171 19S 201 17f 191 -203 s_I 5.5 - 6.7- 11 .4 

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# 25 Oowiehtsontwieklun0 / weight join (0) Akut/aauts fifti Tbrnp.1 .

-, I - Tog / dsy --- ---- ---- soswt'sw .-Entw ./ anisstno - 1 a 1S _- _ _-- total wei ght gain 2000 p0/KO wiblieh / fsnlo PO 4 ! 177 +16 +25 +41 ! I 164 +18 +24 +42 6 169 +26 +22 +48 47V- -2t- -24 -44 s -r 6 .6- ! .3_ 1 .3--- --- --- --- -- - -- - 4.0 2000 MO/KO wibliah / fswslo PO 7 180 +24 +12 +36 i 170 +21 +2 +23 9 ~ 171 +24 +6 +30 174 -23 ? M s 5.9 1 .7 4.7 6.2 

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# 26 Individua l ma croscopia findinoa All findings

------------------- . . .-------------------------------------------- . . . . . .------------------- oniwl tiuo / typo findin0 no. of death

-- . . . . .--t----------I . . . .----- " --- . . . . . . . . . . . . . . .---------- " -------- . . . . . . . .---- . . . . . . . . . . . group 02 2000 MO/KO fomla PO

t 1Sd / E I general observations t I no pethoL"fcal finding 1 I S 1 1Sd / E I General observations I 1 no pathological finding 1 1 6 1 1Sd / E I General observations 1 I no pathological finding group 03 2000 NO/K4 fomlo PO T I 1Sd / E I General observations 1 1 no pathological finding 1 I 8 t 1Sd / L t General observations 1 1 no pathological finding 1 1 9 1 1Sd / E I General observations t t no pathological finding 

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### 27



## fllc Ummlt imd N Landw ;rtachaR urd Varbrauchmwhtft 

# aa I No~-w i~lriiRION~ Owl" AbwiireVh&71 .ILIKI!

Oft I,aborpnxlslOeN Labbntory pnsNss , OLp-WtaMihllwnWitatsmso! of OLP Coiaplianeo lsoaN " IaaeorNiMee f 1fb Abs. I themikelleagessfal Ift OLP m ISOd" Wft d'MwdwW*omdwAmwmWjt=A=jWwft(UMW _ _ft lp " istiom I mum

PMKW

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IweA~U~11~»erilr~tl~wal~r~~w~i~i~~h i~lrilu~~ dw &JL owpftWwI1tlWNlk*lwdMPp. 26Acute Eye Irritation on Rabbits



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boratorv" 

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Study Completion Date: November 9, 2006

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# PUBLIC COPY GLPCompliance Statement The study was conducted in compliance with ft OECDPrinciples of Good



### . . . :~ ~Labo~ttc~~~POrevised in 1997 [ENV/MGCHEM(98)17] and with the revised German Principles of Good Laboratory Practice 

### German Chemicals Act (Bundesgesetablatt Part I, No 2) . . . ,_



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Datep. 29



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1" Signatur es . """"""""""" N "" NNNNNN """ N

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"""""" NNNN """ N

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2 " Su//{nary """"" N """""""""" NNN """""" N " N """""""""""" 6

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### 4 " Identification and Reapoas

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"""""""""" V 4 .1 Identification ofthe Study. . .. . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . 8 4 .2 Responsibilities . . . . .. . . .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . .. . . .. . . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 5 . Material and NN " N """"""""" NN "" N """""""" N

"""""" N

"" N """"""""""""""" / 5.1 Test Compound .. . . . .. . . . . . . . .. . . .. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .10 5.2 Test System

(Atimals) . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . .. . . .. . . .. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . .10 5.3 Housing Conditions . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . . . .. . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . .11 5.4 Exposure Procedure . . . . . . . . . .. . . . . . . . .. . . . .. . . . . . . . . . : : .. . . . . . . .. . .. . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . . . :. . . . . . . . . . . . . . . .12 5 .5 Clinical Observations and Scoring . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13 5.6 Evaluation and Interpretation bf Results . . . . . . . . . . . . . .. . . .. . . . . . .. . . . . . . . .. . . .. . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . . .13

6 " Results " N """""" NN""""" N """"""" . """" N """ . """""" N """"" N

. """""" NN """"""""""""""""" N """ N

""""""""""""" 14

I " Coaclnsion

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"" N "" N """"""""""""""""" N """""" 'Y S " Appendlz N """"""""""""""""""""""""" N "" N """"""""""" N """"" i I Grading ofOcular Lesions. . . . . . . . .. . . . . . . . . . . . . . . . . . .. . .. . . .. . . . . . . . . . . .. . . .. . . . . . . .. . . . . . . . . . . . :. . . . . . . . . 17 . . . . . . . . . . . . . . .. . . . Interpretation of Results. . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . .. . . .. . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . .. . . . . . . . . . . . . . .18 Statement of GLP Compliance . . . . . . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . .. .19p. 30



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Oualitv Assurance Statement Test Item: 

### Study No. : In the relevant laboratory areas the equipment and standard processes used in connection with toxicological short-term studies were audited periodically by the Quality Assurance (process- based inspections) . Audit reports have been submitted in writing to the study director and to the laboratory management . Date of Study phases Date of report to study director Inspection inspected and/or management Sept . 22, 2006 STUDY PLAN Sept . 22, 2006 Nov . 02, 2006 ADMINISTRATION, RAW DATA Nov . 02, 2006 (PROCESS BASED) Nov. 02, 2006 - Nov. 02, 2006 FIRST DRAFT Nov. 02, 2006 Nov. Oa, 2006 FINAL DRAFT Nov. 08, 2006

The results ofthe study and the methods used have been correctly reported. 1 -

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1 . Signatures

Study Director 0 I t 200 9 Date

Management : 

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Date

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2 . Summary This study was performed to assess potential irritant effects o (purity: 95.8° the eye of rabbits. The results are summarized in the table below . Table Z-1 Summery of Irritant Effects (Scorn) Mean Reversible Animal 24 h 48 h 72 h scores Response (days)

omea opacity 0 0 ' 0 0 .0 - no 1 ' IHtis 0 0 0 0 .0 - no Redness conjunctivae 2 1 0 1 .0 - 3 Chemosis con unctlrae 1 0 0 0 .3 - 2 Corneal opacity 0 0 0 .0 - no Irltls 0 , 0 0 0 .0 . - no Redness conjunctivae 0 0 0 0 .0 - 1 "

_ Chemosls con)unctivas 0 0 0 0 .0 - no

. Corneal opacity -0 ~~ 0 . - no bills 0 0 0 0 .0 - no Redness conjunctivae 0 0 0 0 .0 - 1 " - - - Chemosls conjunctivae 0 0 0 _ _ 0 .0 - no response: comeal opacity : mean scores < 2 ~ wide : mean scorn < 1 i con]unctivel redness : mom scores -c 2.5 conJuncdval osdema : mean scorss <2= no : not applicable " : in reaped of the result 1 h post appticadon 

### Conclnsion: .

., it 2<3w+, t3 " ++ Z1<2 .+, .2=++ 22 .5s+ Z2 " + 

### According to classiQcatioe crlte ot Irritating to eyes. There were no systemic Intolerance reactions. The method'used complied with the OECD- Guideline for Testing ofChemicals No. 405 -"Acute Eye IsitationlCorrosion" ; adopted: 24th April 2002; EECDirective 671548 Annex V - Method H .5. (1967) in its current version. .

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PY 3 .

Study initiation date : 2006-09-21 (YYYY-MM-DD) Experimental starting date . : 2006-09-26 (YYYY-MM-DD) Experimental completion date : 2006-09-29 (YYYY-N)M-DD) Study completion date : see $ignature page ~ The study objective was to determine the irritant effects on eyea of albino rabbits. Information derived fromthis test serves to indicate the possible existence of hazards likely to arise fromshort-termexposure of the eye and associated mucous membranes to the test substance, and - with respect to a proper handling and use - serves to permit classiScation (labelling) of a product . T he studyplan, ra

w data and the final report ate retained in the archives specified by

storage ofa retention sample is in the

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4 . Identification and Responsibifitles 41 Identification of theStudv Study No. 4 .2 Responsibilities Studjr Director Head of Test Facility Head of Department Archiving Head ofQuality Assuraace Unit

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5 . Material and Methods The method used complied with the OECD - Guideline for Testing of Chemicalt No . 405 "Acute Eye Irritation/Corrosion" ; adopted: 24th April 2002; EECDirective 67/548 Aunex V - Method B .3 . ( 1967) in its current version For reasons ofanimal welfare a sequential testing strategy was followed in accordance with the current version of the EECDirective 671548 and the OECD Guideline No. 405, irrespective ofthe requirements ofother guidelines for testing for eye irritation/corrosion in rabbits. This testing strategy comprised a stepwise approach including the evaluation of existing human and/or animal data showing effects on the eye or the skin, the ' performance of a SARevaluation for eye and skin corrosion/irritation, measurement -ofpHvalue, the evaluation of data on systemic toxicity via the dermal route, the performance ofa validated in vitro test for sldn corrosion (Human 3DEpidermal Sldn Model) and in vivo testing for slcin irritation/corrosion in rabbits before in vivo testing for eye irritation/corrosion in rabbits. ' 

### The in vitro test for sldn corrosion is archived e test compound is not corrosive to the skin.

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5 .1 Test Compound Test compound

' Chemical name Appearance ' : black, powdery to coarse-grained Storage : room temperature Hatch no. Content oftest substance : 95 .8°ot used for calculations) 

### Expiry date : 2006-12-09 (YYYY-MM-DD) Confirmation ofthe identity ofthe test compound was performed. 5 .2 . Test System(Animals) The study was performed in female albino rabbits (strain Cr1 :KHL(NZW)BR, Charles River, 88353 KiBlegg, Germany) recommended as the preferred species for this type of studies. Healthy adult albino rabbits five of clinical,signs were used. The health of the animals was routinely examined for the main specific pathogens by the breeder: Before the study the rabbits had been vaccinated against pasteurellosis. No treatment with antibiotics was performed priorto receipt ofthe animals, or during the acclimatization phase or study period: In some cases the animals had already been used in earlier studies. This has no influence to the results ofthis study .11 

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ema es were n iparous and not pregnant . The acclimatization time in the test facility was at least S days. 

### Body weights at start ofstudy: 3.0 kg - 3.1 kg Age : young adult animals The animals were identified by labels on the cages stating at least study number, test compound, animal number and by tattooed number assigned by the breeder. 

### 5.3 Housing Condidons ' The animals were housed individually in cage units MetalUNoryl by EBECO . Excrement trays below

the cages contained low

dust wood granulate bedding (J . Rettemnaier 8t S1Shne, 73494Rosenberg, Germany) . The wood granulate was changed at least twice weekly. The animals were regularly transferred to clean cages. 

### The animal roomhad a standardized climate: Room temperature : 20 f3°C Air humidity : SOf25% 

### Light/ Dark cycle : 12 hours rhythm . The humidity and air temperaturewere continuously recorded. Occasionally deviations fromthe standards occurred, e .g. during cleaning of the animal room or effects oftheweather. They did not have any apparent influence on the outcome of the study .12 

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The animals received the standard diet "SsniffK-Z" 4mm (manufacturer: Ssniff Spezialdigten GmbH, 59494 Soest, Germany), approximately 100g per animal per day and tapwater ad libitumfrom polycarbonate bottles. The nutritive composition and the contaminant content ofthe standard diet were checked and analyzed routinely in random samples. Nothing untoward was found . The tap water was ofdrinking water quality (according to the Drinking Water Decree in the current version) and analyzed routinely . The wood granulate was randomly checked for contaminants at regular intervals. 

### The results ofthese analyses have been storeds OWN available data yielded no evidence of any adverse effects on the aim

ot the study

. The animal room

was cleaned at least once aweek and disinfected at least once a month . It was ensured that the diet was not contaminated, and that there was no contact ofthe cleaning or disinfecting solution with the test animals. 

### 5.4 Exposure Procedure On the day before the test, both eyes of each animal were examined including fluoresceip examination. Only animals with healthy intact eyes were used. . 0 .1 gof the pulverized test substance was placed into the conjunctival sac ofone eye ofthe first animal after having gently pulled the lower lid away fromthe dyeball . The lids were gently held together for about one second in order to prevent loss of the test compound. The other eye, which remained untreated, served as control . The eye was not rinsed for at least 24 hours following instillation. If one hour after treatment a severe irritation was not observed, two further rabbits 

### were treated as described.

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5.5 Clinical Observations and Scoring Eye irritations were scored and recorded approximately at 1, 24, 48 and 72 hours post application (in the following p .a.) . If no irritation indices were observed after 72 h, the study was finished. Ifeye irritations were observed, animals were monitored usually on day 7,14and 21 after application until the changes had completely subsided, however for not more than 21 days after application. The degree ofocular lesions was recorded as specified by DRAIZE (see Appendix Table 8-1) and any serious lesions or toxic effects other than ocular lesions were also recorded and fully described. As general criteria the body weight ofeach animal was recorded at the beginning of the study . Ifclinical findings other than eye irritations occur they were recorded daily . 

### 5 .6 Evaluation and Interpretation of Results The interpretation of the results is based on the directive 67/548/EEC and its subsequent amendments (see Appendix Table 8-2) .



### ~~ 7

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6 . Results The individual findings ofthe treated eyes at the various observation times are summarized in the table below . The control eyes did not show any abnormal findings and are not listed in the table. ' Table 6-1 Irritant Efleets on the Eye Animal 1, Body Weight 3.1 kg Observation 1 h ' 24 h 48 h 72 h day 7 day 14 day 21 0 0 0 0 - _ Am of c«nea apacUy 0 0 0 ' 0 - - - Ids ' 0 0 0 0 Rednses °°nMncUvas 2 2 1 0 Che"rod' co4und"as 1 1 0 0 - - Animal 2, Body Weight 3.0 kg _ Observation 1 h '24 h 48 h 72 h day 7 day 14 day 21 Ownof corrwa apulty 0 0 0 0 - . Area of comm

opoft 0 0 0 0 - s 0 . 0 . 0 0 Rsdnas car#xw#m 1 0 ~ 0 0 , . ., . . . .. . .~.,AXr .mu. . . u 0 0 0 - _ : Animal 3, Observation 1 h 24 h 48 h 72 h day 7 dsy 14 day 21 Dprw d °a"w aRdy 0 0 0 0 - ' A'°' of °°mm

opWhr 0 0 0 0 - - iris 0 0 0 0 - R'dn°w c°^Mndhw 2 0 0 0 - Cherri owb aon)unclim 0 0 0 0

- : no further examination Animal 1, 1 h p.a. : test compound adhered to comes and conluncflvva, .

24 h p.a. : test compound adhered b conjunctiva and comes, eye was rinsed with , 0

.996saline solution Animal 2, 1 h p.a. : , test compound adhered to cornea and "Mcli", Animal 3, 1 h p.a. : test compound adhered to comea and conluncdva,

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Table 6-2 Summary of Irritant Ei(eata (Scars) Mean Reversible Animal 24 h 48 h 72 h scores R!=so (days) Corneal 0 . - no 1 Irids 0 0 0 0 .0 - no Redness conjuncdvae 2 1 0 1 .0 - 3 Chemosis con unclivaa 1 0 0 0 .3 - 2 . corneal opadty 0 . - no Iritb 0 0 0 0 .0 - ,no Redness conjune8vae 0 0 0 0 .0 - 1' Chemosle con ncUvae 0 0 0 0.0 - no msa . - na 3 Irflb ~ 0 O 0 0 .0 ' - no Redness conjunctivae 0 0 0 0 .0 - 1' Chemosfe oonLndtvae 0 0 _ 0_ _ _ 0.0 - _ _ - no response: . corneal opacity : mean scores <2= - , ift : mean scores -CIO - , conjunctlval redness : mean acorea < 2 .5 = - , conjunctival oedema : mean scores < 2 = - , no : not applicable ' ; In rasped of the result 1 h post application Z2~3=+, Z1<2=+ ; kZ.5s+ 22=+ t3 ;++

=2~++

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7 . Conclusion The irritant / corrosive effec ere tested on the eye of rabbits. The method used complied with the OECD - Guideline for Testing of Chemicals No

. 405 --Acute Eye Irritation/Corrosion" ; adopted : 241h April 2002; EECDirective 67/548 Annex V- Method B .S. (1967) in its current version. According to classitlcation crf There were no systemic intolerance reactions.

### 8. Appendix Grading of Ocular Lesions

Tabli a-1 Grading o1 Ocular Lesions Comea" Opacity: depres of density (reedinps should be taken *am most ds~nse area) No ulceration or opacity 0 Scattered ordiffuse areas of opadly (othsr than s1pM dulling of normal lustro) ; datalb of kts do*visible I Easily dlscernible translucent am ; details of iris slightly obscured ' 2 Nacrous area; no details of Irfs visible; sin a pupil bany dscemtblN 3 Opaque comes; Iris not dlacsmlbk fhrouph Us opacity ~ Maximum possible: 4 4 ' The arm

dcorneal- o Anwity should be noted Area of Comeal Opacity More than 0

. but Was than %

. 1 Mom thari % ., but less than 'A 2 More than ., but Ins tlhan'Y . 3 More than 4 Maximum

Possible: 4 kli Normal 0 Markody dssperwd nipas, conpestbn, swallinp, modsrats dncauncomsal hypsrssrnia, or injection

; Iris reactive to IIpM(a alupplsh rosctlon Is cornidsred to bean~) i Hsmorfiape, pross dsstrucfton, or no r-acdon f ,*W 2

Maximum

possible : 2 Conjunctivas Redness (rollers lo paipsbral and bulbar ooquncdvas; exdudnp comes and kls) Normal 0 Some blood vssasli hyperasmia pnjeded) 1 DIBua. crimson color; Individual vessels not easily dacwnk)Is 2 DMVse beefy red 3 Chernosis Maximum Possible: 3 3wmNinp (rsftra lo Ilds "or nicEsBnp msmbrrnss) Normal 0 Some walling above normal i Obvious swsllinp, with partial evsrsbn of IWs 2 Swelling, with Iids about half closed 3 SweAMp, with H~ds more than half dosed 4 Maximum Possible: 4p. 44

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Interpretation of Raults



### Table 8-2 Interpretation of Results Serious damage to eyes An eye irritant with risk of serious damage to eyes is a test material that produces: - effects on the cornea, iris or conjunctiva that are not expected to reverse or have not fully reversed within an observation period of normally 21 days and/or - irrdversible colouration of the eyes and/or ' at least in 2 of 3 tested animals, a positive response of . - comeal opacity' t 3 , , and/or - iritis*

_ 2 Irritating to eyes An eye Irritant with risk of significant ocular lesions to eyes is a test material that produces any of the values: at.least in 2 of 3 tested ariimals, with a positive response (fully reversed within an observation period of norrnally 21 days) of: - comeal opacity* t 2 but < 3 and/or - iritis* 21 but < 2 and/or - conjunctival redness* Z 2.5 ' and/or ' - conjuncNval oedema* Z 2

" : calculated as the mean scores at the reading times 24, 48 and 72 hours.p. 45

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Acute Skin Irritation/Corrosion on Rabbits 

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P-+ff" mA

Study Completion Date: November 9, 2006 Page I of 21

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GLP Compliance Statement The study was conducted in compliance with the OECD Principles ofGood Laboratory Practice as rovised in 1997 [ENV1MC10BEM(98yI7} ant with the revised German Principles ofGood Laboratory Practice according to Annex I German Chemicals Act (Hundesgesetzblatt Part l ; No 40, issued June 27, 2002) .



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Table of Contents 1. Signatnres.». . . . . .NNN : . . . .N. . .N. . . . .N. . .»»»»NN . . . . . . . .»N .N»» . .N .NN»». .N . . . .N

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2 " SY"Y/Yary "" N """""""""""""""""""" NN " NN

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V 3 . 1YM N """ . """ N

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"""""""""""""""""" N " . """""""""" . . "" I 4 . Identifleation and ResponsibiUtkaN . . . .». . .». . . . . . . . .NN.NN». . . . . . . . . . .NN»N. . . . . . .N»»NN . . . . . . . . . . . .8 4 .1 Identification ofthe Study. . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . : . . . . . . . . . . . . . .. . . .. . . . . . . . . .. . : . . . . . . . . . . . .. . . . .. . . . . . 8 4 .2 Responsibilities. . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . .8 

### S . Material and Met6ods. . . . .». . . .». .» . .N . . .N» .N». .». . .»NN

.N . . . . . . . . . . . . . . . . .»N». . . . . . . . . . . . . . . . . . . . . . . . . . . . .9 5.1 Test Compound . .. . . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . .. . . .. . . .. . . . . . . . . . . . . . .. . . . . . . . . . . . . . .. . . . . . . .10 5.2 Test System(Animals) . . . . . . . . . . . . . . . . . . . . .. . . . .. . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . .. . . . . . . . . .. . . . .. . . .10 5.3 Housing Conditions . . . . . . . . . . . .. . . . . . . . . . . . .. . . . . . . . .. . . .. . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . .. . . . . . . . . .11 5.4 Exposure Procedure. . . . . .. . . . .. . .. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . .12 . . . . . . . . . . 5.5. Clinical Observations and Scoring . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .. . . . .. . . . . . . . . .. . . . . . . . . .. . . .13 5 .6 Evaluation and Interpretation of Results . . . . . .. . . . . . . .. . . . . . . . . . . . . . . . . . . . : . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .14 6 " Resu l t s """"""""""""""""""""""""""""""" N """ NNN

"" N """ NN

" N """"""" N

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### 8 " Appendi x """""" N "" NN»

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### 18 Grading ofSkin Reactions . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . 18 . . . . . . . . . . . . Interpretation of Results. . : . . . . . :. . . .. . . . . . . . . . . . . . . . .. . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .. . . . . . . . . . . . . . .19 Statement of GLP Compliance . . . . . . . . . . . . .. . . .. . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . : . . .. . . . . . . . . . . . . 20p. 50

Teat Item: Study No . :

Respo In the relevant laboratory areas the equipment and standard processes used in connection with toxicological short-term studies were audited periodically by the Quality Assurance (process- based inspections) . Audit reports have been submitted in writing to the study director and to the laboratory management . . Date of Study phases Date of report to study director Inspection inspected and/or management Sept. 19, 2006 STUDY PLAN Sept . 19, 2006 Nov. 07, 2006 ADMINISTRATION, RAW DATA Nov. 07, 2006 (PROCESS BASED) Oct 30, 2006 - Oct. 30, 2006 FIRST DRAFT Oct. 30, 2006 Nov. 08, 2006 FINAL DRAFT Nov . 08, 2006



### The results ofthe study and the methods used have been correctly reported. 

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