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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""»N».NNNNN»N..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 of the Study . . .. . . .. . . .. . . .. . .. . . .. . . .. . . .. . .. . . . . . .. . . .. . .. . . . . . . . . . .. . . . . . . .. . .. . . ... . .. . . .. . . . . . .. .. . ... 9 4.2 Reaponsibilities . .. . .. . . . .. . .... . ... . . . . . ... . . .. . .. . . . .. . . .. . .. .. .. . . . . . . . . . .. . . . . .. . .. . . . . . .. . . . . . . .. . . . . . . . .. . .. . . ... . .. . . . . . .9 

S. Material and Methods ".." .."NNNN. " NN»N.NN" . "N"..N..NNN". .NN...."N.NN.NN".NNNNNNN"».NN...10 

5.1 Teat compound . . ... . ... . .. . . . . .. . ... . . . . . . .. . . . . . . .. . ... . .. . ... . ... .. . ... . . .. . .. . .. . . .. . . .. . . .. . . . . . . . . . . . . . ... . .. . . .. . . . . . .10 

5.2 Formulation of the Test Compound . . .. .. . . . . . . . . .. . . . . . .. . .. . . .. . . .. . .. . . . . . . . . . .. . . .. . .. . . .. . . . .. . .. . . . .. . . . . . .11 5.3 Administration of the Test Compound. . . . . . . . . .. . ... . .. . .. . . .. . .. . . .. . .. . . . . . . . .. . .. . .. . . . .. . . . . . .. . . . .. . . . . . . .11 5.4 Analysis of the Formulation . ... . .. . . . . . .. . . . .. . .. . . . .. . . . . . .. .. . . ... . . . . .. . .. . . ... . .. . . . . . ... . . .. . .. . . . . . . . .. . . .. . . ..12 5.5 Test System (Animals) .. . . . . . . ... . ... . . . . . .. . . . . . .. . . ... . .. . . .. . .. . ... . . . . .. . . .. . . . . . ... . . . . . .12 5.6 Housing Conditions. . . .. . . . . . . . .. .. . . . . . . . . . . . . .. . . . . . ... . .. . . . . . .. . . . . . .. . .. . . . . . . .. . .. . . . . . . . . . ... . . .. . . .. . ... . . . . . . .. . .13 5.7 Number of Animals 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 . . .. . . . . . .. . . .. . .. . . . . . . ... . . . . ... . .. . .. . . .. . .. . . . . . .. . . .. . . ... . .. . . .. . . . . . ... . . .. . . . . . . . . . . . 27 
p. 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 PRErAlurloN oF 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 of the study and the methods used haw been coe+ecNy reported. 

Date : 

197 
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1. SipAtnrm 
, PUBLIC COPY 

2. Summary 

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

t y: 9S. 

The tag compound was adminiabered to the animals by feeding in a single dose for 

up to 6 hours. 

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 of anUnals with Wgns of boddly / IM number of arkwb uwd pr 

group 

" or" of three ankrals did not modva the oonvhft dose 

According to OECD guideline 423 the LDS0 cut-off 

>_ 5000 mg/kg bw. (Category S / unclasiged of the 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 of toxic effects in any cases . 

A dose 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 of six animals radved do 

complete don; the method used compiled with the OECD - (luidelim for Testing of 

Chemicals No. 423 -"Acute Oral Toxicity - Acute Toxic Class Method"; adopted: 

17th December 2001; EEC Directive 67/548 Annex V - Method H.l .tria (1967) in 

its =rent version, and the principles of the EPA Haft Effects Test Ouidalines 

(OPPTS 870.1100), United States, EPA 712-C-98-190 (1998). 
The study was 

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 of hazards likely expoauro to arise 

from short-term exposne+e by the ocal route of the test substance, and - with respect 

to a proper handlit~ and use - sum to permit classification (labeling) of a product. 

lu lan, raw the an retained in the archives specified by 

OfiiiiN;= 

of a retention sample is in the 

responsibility of the sponsor. 
, PUBLIC CO 

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 of Test Facility 

Archiving 
 PUBLIC COPY 

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 of the teat substance. 

11 Tat compound 

Test compound 

Chemical name 

Appeerarce : black, powdery to ooarsapdned 

storap : room tampersture 

Batch no. 

A~ 

Conteot of test aubwum : 95.8 

"~Olt 

used for calculations) 

F.xpiry data : 2006-12-09 (YYYY-MM-DD) 

Confirmation of the identity of the tog componnd was performed. 
p. 9 

jAd0O 0I18 

11 

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 

of the 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 Ted Compound 

The individual don for each animal. wee calculated on the ban of the 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 of the test compound The animals won food spin 

approxiwstely 2 h after the end of the period of adminiaWtion. 

For the period of adminiatratton the animals were housed individually. The mixture 

was offered to the animals in stainless steel containers. 

Over the period of administration in 2 of 6 cam (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~ 

of adminiatraticn did not exceed 6 bours. Residues were documented and 

Only one animal (animal no. 8) did not consume the complete amount of test 

compound within the period of administration (Residue: l g of the mixtore). 

5.4 Analyds of the Formalation 

Stability and homogeneity of the foimulated teat substance was M confirmed 

analytically. Tlro tea sabadurce method c6arac~erla~a are not suggestive of a rapid 

reaction with the chocolate braelmrt ~ ad 

The mixture of the chocolate hazelnut spread was 

prepared froshly prior etatt of feeding al904L 

Due to the method of administration 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 of this 

strain have been use wMdcologlcal stndiee for many 

yam. Historical data on their physiology and spontaneous atteraotione is available . 

Tbe state of health of the breeding colony is roudnely spot-checked for the mein 

apeoiSc pathogms. The results of then examinations ; an archived. 

At start of do study the animals van nulliperm and non-pregnant and five of all 

clinical symptoms or diseaser. The ~on time in the animal room was at 

lad S days. 

Body weights at start of study: 

164g-180g 

This is according to an age of 10 -12 weeks ap~+oximatoly, 
13 

The animal a 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 room had a standardized climate: 

Room temperature : 22 f2°C 

Air humidity : SS t5'K 

Ventilation : approx.10 changes per hour 

Light1 Dark cycle : 12 bows rhythm. 

OccqAonal deviations from then standards occarred, e.g. during cleaning of the 

animal room. They did not have any appea+ent influence on the outcome of the 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 of the 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 of the 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 of the washing program an allmline cleaning agent 
p. 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 from polycarbonate 

bottles. 

The nutritive compoaition and the contaminant content of the standard diet were 

checked and analyzed routinely in random samples. Nothing untoward was found. 

The tap water was of drinking 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 of any adverse effecb on the aim of the 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 . Killgerm Roach Trap, Killgam OmbH, 41460 Nevse, Germany). The contact 

of the 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 of four fixed levels, S, 50, 300 and 2000 mg/1cQ body weight. 

The starting dose level should be dud which is most liloly to poducx mortality in 

some of do dosed animals. Absence or presence of compound-=elated mortality of 

the animals dosed at one atep will determine the nod step, i.a: 

" no further testing is needed, 

" daft of three additional animals, with the same dose, 

dosing of three 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) . The procedure is described in the flow charts of 

Annex 2, OECD guideline 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 of at 

last 14 days. Mortality and in the event of symptoms ocxturing, natuc+e, duration 

and intensity win recorded individuetly. The day of sdministradon 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 of the symptoms and 

the tima of death 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 symptom Due m the computer system used, death is not shown as a 

clinical symptom in the liab of the appendix. If no symptoms are saw until death, 
16 COPY 

time of death will be taloen aa the first ocmarence of a symptouL Em the results 

section, the findings are summarized without my indication of intensity. Ttre 

findings can be found for do groups end individual animals in the appendix. 

The weight gain of the animals was checked weeldy until the end of die 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 of the rounded individual 

vahue. The weights are given in grams (g). Indicated under the heading day 8 are 

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 

of administration) and dissected as won. as possible, and examined macroscopically. 

The surviving animals were sacrificed by carbon dioxide at do end of the study, 

dissected and examined macroscopically. 

5.9 Data CoUecdoa 

DnrinQ this study for colleotion, storage and evaluation of data 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-1000 A (4x, operating system RTE-A 6.2) 

" HP-3000 mica 900 (lx, operating system MPFJiX 5.5) 

" HP-9000 series 200 (lx, operating system HP-UX 11 .0) 

Software: Data was stored on HP-3000 in an HP 'ItirbolmmagdXL Database. 
17 

) 

V ,~wj 

5.10 Calcalsden of the LDSO 

The LD50 value 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 of the study for acute oral toxicity in do fvted rat including the LD50, 

are summarized in the tables below. 

Table "-1 DoeeR~eponee 

. 

N 

dose mpncp txtoobpicd o«ciirr.noe of sipns Ims or deau, 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 of aniniY wMh signs 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. (ON CabEoy d ! undasMed) 

aooonding to OECD quideline 423 

The assessment h made even though only 0 of sk animals received the 

complab does of 2000 nplkp 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 --

According to OECD guideline 423 dre LDSO cut-off 

>_ 5000 mg/kg bw. (Category S / unclassified of the 0 otially Harmonizcd 

ClaaaiScation System). 

Tbe teat compound was administered to the animals by feeding in a single dose for 

up to 6 hours. 

To make the teat compound flavasome for the animals, it was cm+efully mixed with 

chocolate hazelnut spread. 
p. 19 

& Appendix 

List of Abbreviatiou Used b the Appndis 

In addition to the abbreviations for do basic units of the Intanational Unit System 

(SI)_ stipulated by law, and designations for decimal multiples and parts of wits, the 

following abbreviations are used: 

minute 

% Percent 

AID. (onto maridiem) = before noon 

appal c. 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 of death 
p. 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 I 
p. 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 

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TioraowichO / body weights (0) Akut/scuto 

T *rnr ./ TN / )r nce6 ToeT To60s0it 

cntmino. 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 

24 

PUD"LIC COFY 
25 

Oowiehtsontwieklun0 / weight join (0) Akut/aauts 

fifti 

Tbrnp.1 . 

-, 

I - Tog / dsy --- ---- ---- soswt'sw.-Entw./ 

anisstno - 1 a 1S _- _ _-- total weight 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 m a 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 

PUBLIC Cop ~ 
27 

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Acute Eye Irritation on Rabbits 

PUBLIC COPY 

boratorv" 

Nor, 

Study Completion Date: November 9, 2006 

, . Page 1 of 20 
PUBLIC COPY 

GLP Compliance Statement 

The study was conducted in compliance with ft OECD Principles of Good 

. . . :~ ~ Labo~ttc~~~PO revised in 1997 [ENV/MGCHEM(98)17] and with the 

revised German Principles of Good Laboratory Practice 

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

Oc t. _Js, 2 oO 6 

Date 
p. 29 

PUBLIC COPY 

Table of Contents 

1" Signatures. """""""""""N""NNNNNN"""N"""NNNN"""N"""""" NNNN"""N""N"""NNNN"""""" NN"""N""""N""""NN""""""""" S 

2" Su//{nary"""""N

"""""""""" NNN"""""" N "N"""""""""""" 6 

V" 

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

4" Identification and Reapoas"Y"YYe."NNN"""N"NNNNN""".NN""""NN"""""N"""""""N""""N"""" NNN"""""""""" V 4.1 Identification of the 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"""N""N"""""" N"N""""""N"N"""""""NN"" NN""NN"" N"" N"""""""""""""""""N"""""" 'Y 

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

, PUBLIC COPY 

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 of the study and the methods used have been correctly reported. 

1 

- 
gN©v,ZOb. 6 

1. Signatures 

Study Director 0 I t 2009 

Date 

Management: 

, PUBLIC COPY 

Date 
, PUBLIC COPY 

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 resu lt 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 of Chemicals 

No. 405 -"Acute Eye IsitationlCorrosion"; adopted: 24th April 2002; EEC Directive 

671548 Annex V - Method H.5 . (1967) in its current version. . 
'= ~ 7 PUBLIC COPY 

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 from this test serves to indicate the possible existence of 

hazards likely to arise from short-term exposure 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. 

The study plan, raw data and the final report ate retained in the archives specified by 

storage of a retention sample is in the 
. PUBLIC COPY 

4. Identification and Responsibifitles 

41 Identification of the Studv 

Study No. 

4.2 Responsibilities 

Studjr Director 

Head of Test Facility 

Head of Department 

Archiving 

Head of Quality Assuraace Unit 
, PUBLIC COPY 

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; EEC Directive 

67/548 Aunex V - Method B.3. (1967) in its current version 

For reasons of animal welfare a sequential testing strategy was followed in 

accordance with the current version of the EEC Directive 671548 and the OECD 

Guideline No. 405, irrespective of the requirements of other 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 SAR evaluation for eye and skin corrosion/irritation, measurement 

-of pH value, the evaluation of data on systemic toxicity via the dermal route, the 

performance of a validated in vitro test for sldn corrosion (Human 3D Epidermal 

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. 
 PUBLIC COPY 

5.1 Test Compound 

Test compound 

' Chemical name 

Appearance ' : black, powdery to coarse-grained 

Storage : room temperature 

Hatch no. 

Content of test substance : 95.8°ot used for calculations) 

Expiry date : 2006-12-09 (YYYY-MM-DD) 

Confirmation of the identity of the 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 prior to receipt of the 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 of this study. 
11 PU LIC 

ema es were n iparous and not pregnant. The acclimatization time in the test 

facility was at least S days. 

Body weights at start of study: 

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, 73494 Rosenberg, Germany). The wood granulate was 

changed at least twice weekly. The animals were regularly transferred to clean 

cages. 

The animal room had a standardized climate: 

Room temperature : 20 f3°C 

Air humidity : SO f25% 

Light/ Dark cycle : 12 hours rhythm. 

The humidity and air temperature were continuously recorded. Occasionally 

deviations from the standards occurred, e.g. during cleaning of the animal room or 

effects of the weather. They did not have any apparent influence on the outcome of 

the study. 
12 PUBLIC Cop 

The animals received the standard diet "SsniffK-Z" 4mm (manufacturer: Ssniff 

Spezialdigten GmbH, 59494 Soest, Germany), approximately 100 g per animal per 

day and tap water ad libitum from polycarbonate bottles. 

The nutritive composition and the contaminant content of the standard diet were 

checked and analyzed routinely in random samples. Nothing untoward was found. 

The tap water was of drinking 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 of these 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 a week and disinfected at least once a 

month. It was ensured that the diet was not contaminated, and that there was no 

contact of the 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 g of the pulverized test substance was placed into the conjunctival sac of one eye 

of the first animal after having gently pulled the lower lid away from the 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. 
 PUBLIC C 

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 . If eye irritations were observed, animals were 

monitored usually on day 7,14 and 21 after application until the changes had 

completely subsided, however for not more than 21 days after application. 

The degree of ocular 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 of each animal was recorded at the beginning of 

the study. If clinical 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 
 PUBLIC COPY 

6. Results 

The individual findings of the 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 Own of 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 

, 0.996 saline 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, 
 PUBLIC COPY 

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~++ 
 PUBLIC COPY 

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; 

EEC Directive 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 or diffuse 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 d corneal- 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: 4 
p. 44 

 PUBLIC COPY 

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 

 PUBLIC COPY 

8!r Umwelt und Natursch Landwirtschaft und 

Verbiraucherschutz 

des LandEs Noidrhein-W ienPaalrmchiL 4019D DbmWmf Abammie5m Y1,7~ 31 .1 1Ai.oi 

Outi Laborproxisigood Laboratory Practice 

GLP-YsschdniouaOlitatsmsnt of GLIP Compliance 

(gsmittlaccotdinll to f 1!b Abu. 1 ChsaibalisnOsests) 

Elm OCPRdnWeMlqe sur OOwwooMr» der EplmliMMIW Aswwat ofoa1 ait1 wIY OL! ~oawd)i~ 1~ 

3LP~ 9wni~ Ch~~~ bew~ ~ CA~w~wIr~4 aI Di~diw s~ll0+®C ~ 

eAl3QtYE0 ww d~ dnrchalOht Jn: 

® PrOfeinrIchtunplTest fai_ciltty [jPa4kWdarUTest site 

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Praunpm nsch KategorlPn " ArM of Expertise, 

WMra ChwnvwvsuP nr. axroscc Vd& . .l c~y awwwwmp w &3=00 pates" 

Katspoes Z . c+w0WZ 

Prohrq.e sar eatbnnweq dw toidlwlophehen Wr wid" 

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PrOfunpse sur ssatnnxmo der ad~vsri+dsndin nwtspsnidty'tudtn 

Elprnt.clwltan (in vlao uea in vko) . 

Icahgwis o ad@ar o 

~ Tc~ eAcalopis; Kurtssllkarmwo0anssr big .-snl~aal laiaaloYr shat ltms canoaopsnidy; 

I1mnYl10l01dk0100w. 

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Detun der Inapektlon Dab of Inspection 

Irw.is~r.iM I+~r.a.nwri.rl 

30. August bis 03. SepEerrlbef 2004 on 30 August unUl 3 SopesrnbeK 2004 
Pr011UWohQmY OdrWdab Ye 11 rlo TAeabwi uwrI wd lel adOp b Ydad" IN IUf nd8aw1 

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DOwIiaA,10.12.2004 

Im AWlnp 

p. 46 
~.r----~ 

Acute Skin Irritation/Corrosion on Rabbits 

PUBLIC COPY 

P-+ff" mA 

Study Completion Date: November 9, 2006 

Page I of 21 
, PUBLIC COPY 

GLP Compliance Statement 

The study was conducted in compliance with the OECD Principles of Good 

Laboratory Practice as rovised in 1997 [ENV1MC10BEM(98yI7} ant with the 

revised German Principles of Good Laboratory Practice according to Annex I 

German Chemicals Act (Hundesgesetzblatt Part l; No 40, issued June 27, 2002). 

Oc ~.- .!~ , 2©0~ 

Date 
p. 49 

, PUBLIC C 

Table of Contents 

1. Signatnres.». ... . .NNN:.. . .N . ..N .... .N . ..»»»»NN........»N.N»»..N.NN»»..N....N...........""".....N......... S 

2" SY"Y/Yary"" N""""""""""""""""""""NN"NN"""""""""NNN"N"""""".""""."""""""""""""""""NN"""""N""""""""" N"" .""""". V 

3. 1YM N"""."""N""""""""N""""""""""""""""""N"."""""""""".."" I 

4. Identifleation and ResponsibiUtkaN....»...». .... ....NN.NN».. . ... . ....NN»N.......N»»NN.. .. . .... ...8 

4.1 Identification of the 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" Results """""""""""""""""""""""""""""""N"""NNN""N"""NN"N"""""""N"" N"N"""""""N""""""""""NN"""""""""""N""NNN"""""""" is 

7" 

1 / 

8" Appendix """""" N"" NN»"""" NNN"""NNNN"""""""" 18 Grading of Skin Reactions . . . . . . . . . ... . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . .. . . . . . . . . . . . . ... . . . . . . . 18 Interpretation of Results. . : . . . . . :. . . .. . . . . . . . . . . ... . . .. . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .. . . . . . . . ... . . . .19 Statement of GLP Compliance . . . . . . . . . . . . .. . . .. . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . :. . .. . . . . . . . . . . . . 20 
p. 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 of the study and the methods used have been correctly reported. 

AlAts" 

, PUBLIC CO