TS-CKHI02

Attachment #13

Health Effects Data on the New Chemical Substance

Eye Irritation Test in Rabbits

## LAB Research Ltd.

Address: 8200 Veszprém, Szabadságpuszta

Phone: +36 88 545 300

Fax: +36 88 545 301 14

FINAL REPORT

Polymer

ACUTE EYE IRRITATION STUDY

IN RA BBITS

Date of Final Report: 01 September 2011 

### STUDY CODE: 10/339-005N

### STUDY CODE: 10/339-005N Page 5 of 22



## LAB STUDY TITLE : Polymer : Acute Eye Irritation

Study in Rabbits

SPONSOR :

S TUDY PERFORMED BY : LAB Research Ltd.

Address: H-8200 Veszprém, Szabadságpuszta

Hungary

Phone: +36 88 545-300

Fax: +36 88 545-301

STUDY DIRECTOR : Judit Tavaszi, M.Sc. (In life phase)

Vikt ória Zelenák , M.Sc. (Reporting Phase)

ASSISTANT SCIENTIST : István Buda, M.Sc.

VETERINARY CONTROL : István Pásztor , DVM

CENTRAL DISPENSARY : Tamás Mészáros, PhD.

### STUDY CODE: 10/339-005N Page 6 of 22



## LAB CONTENTS

Page

1. SUMMARY 7

2. INTRODUCTION 8

3. MATERIALS AND METHOD S 8

3.1. TEST ITEM 8

3.2. OTHER MATERIALS 9

3.3. EXPERIMEN TAL ANIMALS 9

3.4. HUSBANDRY 10

3.5. FOOD AND FEEDING 10

3.6. WATER SUPPLY AND QUALITY CONTROL OF WATE R 11

3.7. STUDY SCHEDULE 11

3.8. ADMINISTRATION OF TH E TEST ITEM 12

3.8.1. Dosage 12

3.8.2. Application of the Test Item 12

3.8.3. Duration of Exposure 12

3.9. OBSERVATIONS AND SCO RING 12

3.9.1. Clinical Observations 12

3.9.2. Scoring and Assessment of Local Reaction 13

3.9.3. Classification of the Test Items 13

3.9.4. Measurement of Body Weight 14

4. ARCHIVES 14

5. THE PERMISSION OF TH E INSTITUTIONAL IACU C 14

6. DEVIATION TO THE STU DY PLAN 14

7. RESULTS 15

7.1. MORTALITY 15

7.2. BODY WEIGHTS 15

7.3. CLINICAL OBSERVATION 15

7.3.1. General dai ly examination 15

7.3.2. Examination of eye- irritancy 15

8. CONCLUSION 16

INDIVIDUAL SCORES FOR OCULAR IRRITATION 17

MEAN VALUES OF EYE IRRITATION 18

BODY WEIGHT DATA 18

APPENDICES 19

APPENDIX 1: Scoring and Assessment o f Local Reaction 1 – 2 of Appendix 1

APPENDIX 2: Scoring o f Pain Reaction 1 of Appendix 2

APPENDIX 3: Contents o f Purina Base

- Lap Gr. Diet for Rabbits 1 of Appendix 3

APPENDIX 4: Copy o f t he Certificate of Analysis 1 of Appendix 4

APPENDIX 5: Copy o f t he GLP Certificate 1 of Appendix 5

APPENDIX 6: Copy of the Study Plan 1 – 19 of Appendix 6

APPENDIX 7 : Copy of the Amendment 1 to the St udy Plan 1 – 3 of Appendix 7

### STUDY CODE: 10/339-005N Page 7 of 22



## LAB 1. SUMMARY

An acute eye irritation study of the test item Polymer was performed

in New Zealand White rabbits. The irritation effects of the test item were evaluated

according to the Draize method (OECD No.: 405, 2002).

The test item was placed into the conjunctival sac of the left eye of each animal. The

untreated right eye served as control. A volume of 0.1 g of the test item was

administered as a single dose.

The eyes were examined at 1, 24, 48 and 72 hours after the application.

Initial Pain R eaction (IPR) (score 2) was observed in all animal s.

One hour after the application , conjunctival redness (score 1) was observed in one

animal

.

At 24, 48 and 72 hours after treatment there were no clinical signs observed

.

As there were no clinical signs observed, the study was terminated after the 72 hours

observation.

During the study, the control eye of all animals was symptom

- free.

The general stat e and behavior of animals were normal throughout the study period.

There were no notable body weight changes during the study period.

The animal’s individual mean scores (considering readings at 24, 48 and 72 hours

after the treatment) were as follows:

re dness : 0.00, 0.00, 0.00

chemosis : 0.00, 0.00, 0.00

discharge : 0.00, 0.00, 0.00

cornea opacity : 0.00, 0.00, 0.00

iris : 0.00, 0.00, 0.00

The test item Polymer ( Batch No .: , applied

to rabbits’ eye mucosa, caused conjunctiv al redness in one animal at one hour

which were fully reversible within 24 hours.

According to Regulation (EC) No 1272/2008, Polymer does not

require classification as an eye irritant.

### STUDY CODE: 10/339-005N Page 8 of 22



## LAB 2. INTRODUCTION

The objective of the study was to determine the acute eye irritation effect of the test

item Polymer in the New Zealand White Rabbit. The test item was

applied as a single dose to the left eye of treated animals. The degree of irritation was

scored at specified time interval s. Information derived from this test was used to

determine the existence of possible hazards likely to arise from exposure of the eyes

and adjacent mucous membranes to the test item. The duration of the study was

sufficient to evaluate fully the reversibility or irreversibility of the effects observed

.

3. MATERIALS AND METHOD S

Start of Treatment: 29 March 2011

End of Experiment: 01 April 2011

3.1. TEST ITEM

Name: Polymer

Batch/Lot Number:

Description: White solid (wa xy)

Molecular weight: Mw= 130000 Da

Mw< 2000 Da below 0.1%

Purity: 98.6%

Manufacturer: See Sponsor

Manufacture Date: 24 August 2010

Expiry Date: 23 August 2012

Storage conditions: Room temperature (15 -30°C , 40

- 70RH%, in a dark

storeroom without windows)

Safety Precautions: Routine safety precautions (gloves, goggles, face mask,

lab coat) for unknown materials will be applied to

assure personnel health and safety

.

The pH of Test Item was measured as 5.5.

The test item of a suitable chemical purity was pr ovided by the Sponsor. All

precautions required in the handling and disposal of the test item were outlined by the

Sponsor. Identification of the test item was performed in the Central Dispensary Unit

of LAB Research Ltd. on the basis of name, batch number, appearance and colour.

### STUDY CODE: 10/339-005N Page 9 of 22



## LAB 3.2. OTHER MATERIALS

For washing:

Name: Disposable syringe (1 mL)

Batch No.: 12M01

Expiry Date: October 2015

Produced by: Penta Ferte

Name: Natrium Chlorid (0.9%)

Batch No.: 3390210

Expiry Date: February 2013

Produced by: T eva Co.

For euthanasia:

Name: CP -Ketamin 10 %

Batch No.: 10H12 4

Expiry Date: July 2012

Produced by: CP -Pharma, 31303 Burgdorf

Name: CP -Xylazin 2 %

Batch No.: 10G06 2

Expiry Date: June 2013

Produced by: CP -Pharma, 31303 Burgdorf

Name: Euthasol ® 40 %

Lo t No.: 10C25 7

Expiry Date: February 2013

Produced by: AST Beheer B.V. Oudewater Netherlands

3.3. EXPERIMENTAL ANIMALS

Species and strain : New Zealand White rabbits

Source: S&K

- LAP Kft.

2173 Kartal, Császár út 135, Hungary

Justification of strain: The New Zealand White rabbit is one of the standard

strains used for acute irritation toxicity studies.

Animal health: Only animals in acceptable health condition were used

for the test. Both eyes of each animal provisionally

selected for testing were examined approximately one

hour before starting the study. Animals showing eye

irritation, ocular defects or pre

- existing corneal injury

were not used.

Number of animals: 3 animal s

### STUDY CODE: 10/339-005N Page 10 of 22



## LAB Age of animals at treatment : ~ 11 weeks old (young adult)

Sex: M ale

Body weight r ange at the

beginning of the life phase : 2799 – 2904 g

end of the life phase : 2926 – 3010 g

Date of receipt: 23 Ma rch 2011

Acclimatization time: 6 days

Animal identification: The individual identification was by engraved ear tag.

The cages were marked with individual identity cards

with information about study code, sex, dose group,

cage number and individual animal number.

3.4. HUSBANDRY

Number of animal room: 607

Light : 12 hours daily, from 6.00 a.m. to 6.00 p.m.

Temperature: 20 ± 3 °C

Relative humidity: 24 – 56 %

Housing/Enrichment: Rabbits were individually housed in AAAL A C

approved metal wire rabbit cages. Cages were of an

open wire structure and cages were placed together to

allow some social interaction with rabbit(s) in

adjoining cages

Ventilat ion: 15-20 air exchanges/hour

The environmental parameters were recorded twice daily during the study. Minor

v ariations from the target humidity range were observed during the study. These

deviations were considered to have no impact on the animal health , as certified by the

Clinical Veterinarian, or on the outcome of the study and interpretation of the results

due to their low magnitude.

3.5. FOOD AND FEEDING

Animal received PURINA Base

– Lap gr. diet for rabbits produced by AGRIBRANDS

Europe Hungary PLC, H

- 5300 Karcag, Madarasi road, Hungary, ad libitum . Contents

of PURINA Base

- Lap gr. di et for rabbits, which were used during the experimental

phase see in Appendix 3.

### STUDY CODE: 10/339-005N Page 11 of 22



## LAB 3.6. WATER SUPPLY AND QUALITY CONTROL OF WATE R

The animals received municipal t ap water, as for human consumption, ad libitum

, from an automatic system.

The quality control analysis is performed once every three months and microbiological

assessment is performed monthly, by Veszprém County Institute of State Public Health and Medical Officer Service (ÁNTSZ, H

- 8201 Veszprém, József A.u.36.,

Hungary). The quality control results are retained in the archives of LAB Research

Ltd.

3.7. STUDY SCHEDULE

PRE

- EXPERIMENTAL PERIOD

Study Day Absolute date

Animal received Day [ -6] 23 Ma rch 2011

Veterinary c ontrol 23 March 2011

Acclimation Day [ -6] - Day [ -1] 23 March – 28 Ma rch 2011

TREATMENT PERIOD

Day of treatment Day [0 ] 29 Ma rch 2011

Body weight

measurement Day [0 ; terminating day ] 29 Ma rch 2011

01 April 2011

C linical observation Scoring 1, 24, 48

and 72 hours 29 Ma rch 2011

30 March 2011

31 March 2011

01 April 2011

End of in life phase 01 April 2011

### STUDY CODE: 10/339-005N Page 12 of 22



## LAB 3.8. ADMINISTRATION OF TH E TEST ITEM

3.8.1. Dosage

A single dose of 0.1 g of the solid test item Polymer was administered

to each animal.

3.8.2. Application of the Test Item

Three male animals in acceptable health condition were selected for the test. Care was

taken to select only those animals that had a normal eye condition and any with ocular

lesions were rejected.

An initial test was performed using one animal. The test item was instilled into the

conjunctival sac of the left eye. The eyelids were held closed for several seconds to

prevent the loss of the test item. The contralat eral eye served as the control.

Immediately after the administration of the test item, an assessment of the initial pain

reaction was made according to the six point scale shown in Appendix 2.

After consideration of the ocular responses produced in the fi rst animal, two additional

animals were treated.

3.8.3. Duration of Exposure

The eyes of the test animals were washed out at 1 hour after application of test item.

3.9. OBSERVATIONS AND SCO RING

3.9.1. Clinical Observations

The eyes were examined a t 1, 24, 48 and 72 hours after the treatment. The duration of

the observation period was sufficient to identify reversibility or irreversibility of

changes. Any clinical signs of toxicity or signs of ill

- health during the study were

recorded.

At the end of the observation period, each animal was sacrificed by intramuscular

injections of CP

- Ketamin 10% and CP

- Xylazin 2% followed by iv. Euthasol ® 40%

anaesthesia. (see details in 3.2.)

. Death was verified by checking pupil and cornea reflex,

absence of respi ration and pulse.

### STUDY CODE: 10/339-005N Page 13 of 22



## LAB 3.9.2. Scoring and Assessment of Local Reaction

The eye irritation scores were evaluated according to the scoring system by Draize

(1977) and OECD 405 (24 April 2002) shown in Appendix 1.

3.9.3. Classification of the Test Items

I ndividual reactions of the animal were recorded at each observation time. The n ature,

severity and duration of all lesions observed were described. Results were presented

and interpreted according to Regulation (EC) No 1272/2008, as follows:

Irreversible effects on the eye/serious damage to eyes (Category 1)

Substances that have the potential to seriously damage the eyes are classified in

Category 1 (irreversible effects on the eye). These observations include animals with

grade 4 cornea lesions and other severe reactions (e.g., destruction of cornea) observed

at any time during the test, as well as persistent corneal opacity, discoloration of the

cornea by a dye substance, adhesion, pannus, and interference with the function of the

iris or other effects th at impair sight.

Category for irreversible eye effects

If, when applied to the eye of an animal, a substance produces:

— at least in one animal 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

— at least in 2 of 3 tested animals, a positive response of:

o corneal opacity ≥ 3 and/or

o iritis > 1 .5

calculated as the mean scores following grading at 24, 48 and 72 hours after

installation of the test material.

Reversible effects on the eye /irritating to eyes (Category 2)

Substances that have the potential to induce reversible eye irritation are classified in

Category 2 (irritating to eyes).

Category for reversible eye effects

If, when applied to the eye of an animal, a substance produces:

— at least in 2 of 3 tested animals, a positive response of:

o corneal opacity ≥ 1 and/or

o iritis ≥ 1, and/or

o conjunctival redness ≥ 2 and/or

o conjunctival oedema (chemosis) ≥ 2

— calculated as the mean scores following grading at 24, 48 and 72 hours after

installation of the test material, and which fully reverses within an observation

period of 21 days.

### STUDY CODE: 10/339-005N Page 14 of 22



## LAB 3.9.4. Measurement of Body Weight

Individual body weight w as recorded at the beginning and end of the experiment.

(Table 3)

4. ARCHIVES

The study documents:

- study plan and amendment

,

- all raw data,

- sample of the test item,

- study report and any amendment(s),

- correspondence

are stored in the archives of LAB Research Ltd., 8200 Veszprém, Szabadságpuszta,

Hungary according to the Hungarian GLP and applicable SOPs.

After the retention time has elapsed, all the archived materia ls listed above will be

offered to the Sponsor for further storage or disposal.

5. THE PERMISSION OF TH E INSTITUTIONAL IACU C

The Institutional Animal Care and Use Committee (IACUC) of LAB Research Ltd.

reviewed the study plan, amendment and authorised the conduct of the study.

6. DEVIATION TO THE STU DY PLAN

The relative humidity was out of the target range during part of the test (24 – 56 %).

The Draft Report was sent later than indicated in the Study Plan.

Th ese deviation s were considered not to adversely affect the results or integrity of the

study.

### STUDY CODE: 10/339-005N Page 15 of 22



## LAB 7. RESULTS

7.1. MORTALITY

There was no mortality observed during the study.

7.2. BODY WEIGHTS

The body w eight and the body weight change were considered to be normal with no

indication of tr eatment related effect.

7.3. CLINICAL OBSERVATION

7.3.1. General daily examination

There were no clinical signs observed that could be related to treatment.

7.3.2. Examination of eye- irritancy

The eyes were examined at 1, 24, 48 and 72 hours after the application.

Initial Pain Reaction (IPR) (score 2) was observed in all animals.

One hour after the application , conjunctival redness (score 1) was observed in one

animal.

At 24, 48 and 72 hours after treatment there were no clinical signs observed.

As there were no clinical signs observed, the study was terminated after the 72 hours

observation.

During the study, the control eye of all animals was symptom- free.

### STUDY CODE: 10/339-005N Page 16 of 22



## LAB The animal’s individual mean scores (considering readings at 24, 48 and 72 hours

a fter the treatment) were as follows:

redness : 0.00, 0.00, 0.00

chemosis : 0.00, 0.00, 0.00

discharge : 0.00, 0.00, 0.00

cornea opacity : 0.00, 0.00, 0.00

iris : 0.00, 0.00, 0.00

8. CONCLUSION

The test item Polymer ( Batch No .: ) , applied

to rabbits’ eye mucosa, caused conjunctival redness in one animal at one hour

which were fully reversible within 24 hours.

According to Regulation (EC) No 1272/2008, Polymer does not

require classification as an eye irritant.

### STUDY CODE: 10/339-005N Page 17 of 22



## LAB INDIVIDUAL SCORES FOR OCULAR IRRITATION

TABLE 1

Study Code: 10/339-005N Species: NZW Rabbit

Dose: 0.1 g Sex: Male

Start of Exposure: 29 Ma rch 2011 – Day 0 Test Item: Polymer

Time Animal No. Score of irritation

IPR Conjunctivae Opacity of

cornea Iris Control

eye Other

sign

R CH D OD OE R

1 hour 00 051 1 0 0 0 0 0 0

- 2

00088 0 0 0 0 0 0 0

- 2

00085 0 0 0 0 0 0 0

- 2

Time Animal No. Score of irritation

Conjunctivae Opacity of

cornea Iris Control

eye Other

sign R CH D OD OE R

24 hours 00051 0 0 0 0 0 0 0

-

00088 0 0 0 0 0 0 0

-

00085 0 0 0 0 0 0 0

-

Time Animal No. Score of irritation

Conjunctivae Opacity of

cornea Iris Control

eye Other

sign R CH D OD OE R

48 hours 00051 0 0 0 0 0 0 0

-

00088 0 0 0 0 0 0 0

-

00085 0 0 0 0 0 0 0

-

Time Animal No. Score of irritation

Conjunctivae Opacity of

cornea Iris Control

eye Other

sign R CH D OD OE R

72 hours 00051 0 0 0 0 0 0 0

-

00088 0 0 0 0 0 0 0

-

00085 0 0 0 0 0 0 0

-

Abbreviation s:

R = Redness ; OD = Opacity degree of density ; CH = Chemosis ; OE = Extension of opaque area ; D = Discharge ;

IPR = Initial pain reaction ; - = No data

### STUDY CODE: 10/339-005N Page 18 of 22



## LAB MEAN VALUES OF EYE IRRITATION

(24, 48, 72 hour reading)

TABLE 2

Study Code: 10/339-005N Species : NZW Rabbit

Dose: 0.1 g Sex: Male

Start of Exposure: 29 Ma rch 2011 – Day 0 Test Item: Polymer

Animal

Number Sex Cornea

Opacity Iris Conjunctivae

Redness Chemosis Discharge

00051 male 0.00 0.00 0.00 0.00 0.00

00088 male 0.00 0.00 0.00 0.00 0.00

00085 male 0.00 0.00 0.00 0.00 0.00

BODY WEIGHT DATA

TABLE 3

Animal

Number Beginning of study

(g) At the end of study

(g) Body weight gain

(g)

00051 2904 3010 106

00088 2799 2926 127

00085 2904 2991 87

### STUDY CODE: 10/339-005N Page 19 of 22



## LAB 

# APPENDICES

### STUDY CODE: 10/339-005N Page 1 of Appendix 1



## LAB APPENDIX 1:

SCORING AND ASSESSMENT OF LOCAL REACTION

Cornea

a. Opacity

- degree of density (Area most dense taken for reading)

No ulceration or opacity 0

Scattered or diffuse areas of opacity (other than slight

dulling or normal lustre): details of iris clearly visible 1

Easily discernible translucent area: details of iris slightly obscured 2

Nacreous area: no details of iris visible: size of pupil barely discernible 3

Opaque cornea: iris not discernible through the opacity 4

b. Area of cornea involved

One quarter (or less), but not zero 1

Greater than one quarter, but less than half 2

Greater than half, but less than three quarters 3

Greater than three quarters, up to whole area 4

Iris

a. Values

Normal 0

Markedly deepened rugae, congestion, swelling, moderate

circumcorneal hyperaemia: or injection: iris reactive to light

(a sluggish reaction is considered to be an effect) 1

Haemorrhage, gross destruction, or no reaction to light. 2

### STUDY CODE: 10/339-005N Page 2 of Appendix 1



## LAB APPENDIX 1:

SCORING AND ASSESMENT OF LOCAL REACTION

(c ontinued)

Conjunctivae

a. Redness (Palpebral and bulbar)

Normal 0

Some blood vessels hyperaemic (injected) 1

Diffuse, crimson colour, individual vessels not easily discernible 2

Diffuse beefy red 3

b. Chemosis

Normal 0

Some swelling above normal (includes nictating membrane) 1

Obvious swelling with partial eversion of lids 2

Swelling with lids about half closed 3

Swelling with lids more than half closed 4

c. Discharge

No discharge 0

Any amount different from normal (does not include small amounts

observed in inner canthus of normal animals) 1

Discharge with moistening of the lids and hairs just adjacent to lids 2

Discharge with moistening of the lids and hairs, on considerable area

around the eye 3

### STUDY CODE: 10/339-005N Page 1 of Appendix 2



## LAB APPENDIX 2:

SCORING OF PAIN REACTION

Class Reacti on by Animal Descriptive Rating

0 No response No initial pain

1 A few blinks only, normal within one or two minutes Practically no initial pain

2 Rabbit blinks and tries to open eye, but reflex closes it Slight initial pain

3 Rabbit holds eye shut and puts pressure on lids, may rub

eye with paw Moderate initial pain

4 Rabbit holds eye shut vigorously, may squeal Severe initial pain

5 Rabbit holds eye shut vigorously, may squeal, claw at

eye, jump and try to escape Very severe initial pain

The class 0, 1 and class 2 are not anaesthetised.

There is no correlation between the initial pain and the subsequent eye irritation.

### STUDY CODE: 10/339-005N Page 1 of Appendix 3



## LAB APPENDIX 3:

CONTENTS OF PURINA BASE

- LAP GR. DIET FOR RABBITS

Batch number: 0500 019 0510 029

Expiry date: 18 April 2011 03 May 2011

NUTRIENTS

Wet 1 4

. 0 % 1 4

. 0 %

Crude protein 15. 5 % 15. 5 %

Total fat 2

. 7 % 2

. 7 %

Crude fibre 16.0 % 16.0 %

Crude Ash 7.5 % 7.5 %

MINERALS

Calcium 1. 09 % 1. 09 %

Phosphorus 0. 58 % 0. 58 %

Sodium 0. 19 % 0. 19 %

Cu (CuSO 4 * 5H 2 O) 20.00 mg /kg 20.00 mg/kg

AMINO ACIDS

Lysine 0.6 8 % 0.6 8 %

Methionine 0.2 5 % 0.2 5 %

MET + Cystine 0.53% 0.53%

VITAMINS

Vitamin A 1 501 0 IU/kg 1 501 0 IU/kg

Vitamin D 3 1 25 0 IU/kg 1 25 0 IU/kg

Vitamin E 50 mg/kg 50 mg/kg

These data are s tandard and guaranteed values which were provided by the supplier.

### STUDY CODE: 10/339-005N Page 1 of Appendix 4



## LAB APPENDIX 4:

COPY OF THE CERTIFICATE OF ANALYSIS

### STUDY CODE: 10/339-005N Page 1 of Appendix 5



## LAB APPENDIX 5:

COPY OF THE GLP CERTIFICATE

### STUDY CODE: 10/339 -005N Page 1 of Appendix 6



## LAB Research Ltd.

Address: 8200 Veszprém, Szabadságpuszta

Phone: +36 88 545 300

Fax: +36 88 545 301 APPENDIX 6:

COPY OF THE STUDY PLAN



### STUDY PLAN

Polymer

ACUTE EYE IRRITATION STUDY

IN RABBITS

Date of Study Plan: 28 March 2011 

### STUDY CODE: 10/339-005N

### STUDY CODE: 10/339 -005N Page 2 of Appendix 6



## L A B GENERAL INFORMATION

SPONSOR

S TUDY PERFORMED BY : LAB Research Ltd.

Address: H

- 8200 Veszprém, Szabadságpuszta

H ungary

Phone: +36 88 545

- 300

Fax: +36 88 545

- 301

T ITLE OF THE STUDY : Polymer Acute Eye Irritation Study in

Rabbits

### STUDY CODE: 10/339 -005N Page 3 of Appendix 6



## L A B RESPONSIBLE PERSONS * : Istv án Buda M

. Sc

. – Assistant Scientist

István Pásztor DVM/ Peter Maslej DVM, PhD

- veterinary control

Szabolcs Gáty M .Sc.

– Head of QAU

Ani mal House Staff

Central Dispensary Staff

* Other trained, competent personnel may work on the study as required; to be

recorded and reported.

PROPOSED STUDY SCHEDULE i :

START OF EXPERIMENT : 29 March 2011

END OF EXPERIMENT : Not later than 19 April 2011

DRAF T REPORT : Not later than 01 June 2011

FINAL REPORT : Within 90 days from issuance of the draft report,

depending upon receipt of the Sponsor’s comments

and additional documentation (if any required).

BASIS OF STUDY : OECD GUIDELINES FOR TESTING OF

CHEMICALS 405 (24 th April 2002) OECD: Paris,

C OMMISSION REGULATION (EC) No

440/2008, B.5 ( L 142, 30 May 2008 ),

REPORTING FORMAT : Final Report to LAB Research Ltd 's standard

format

REPORT COPIES : Original report to be archived

One PDF copy wil l be sent by email.

One bound and one unbound hard copy will be sent

by courier.

i A det ailed study timing (target) is given in Appendix 3

.

### STUDY CODE: 10/339 -005N Page 4 of Appendix 6



## L A B CONTENTS

1. OBJECTIVE OF THE STU DY 5

2. MATERIALS AND METHOD S 6

2.1. TEST ITEM 6

2.1.1. Identification, Receipt 6

2.1.2. Other Materials 6

2.2. EXPERIMENTAL ANIMALS 6

2.2.1. Husbandry 7

2.2.2. Food and Feeding 7

2.2.3. Water Supply and Quality Control 7

2.2.4. Identification 7

2.3. TESTING PROCEDURE 8

2.4. ADMINISTRATION OF TE ST ITEM 9

2.4.1. Dose Level 9

2.4.2. Application of the Test Item 9

2.4.3. Duration of Exposure 9

2.5. OBSERVATIONS AND SCO RING 9

2.5.1. Clinical Observations and Evaluation of Ocular Irritation 9

2.5.2. Scoring and Assessment of Local Reaction 10

2.5.3. Classifi cation of the Test Item 11

2.5.4. Measurement of Body Weight 12

3. ANIMAL WELFARE 12

4. GOOD LABORATORY PRAC TICE (GLP) AND QUALI TY ASSURANCE 13

5. AMENDMENT AND DEVIAT ION PROCEDURES 13

6. STUDY REPORT 14

7. ARCHIVES 15

8. DISTRIBUTION OF THE STUDY PLAN 15

9. SIGNATURES 15

APPENDICES 16

APPENDIX 1: DETAILS OF MATERIALS TO BE USED FOR EUTHANASIA 17

APPENDIX 2: CONTENTS OF PURINA BASE - LAP GR. DIET FOR RABBITS 18

APPENDIX 3: PROPOSED STUDY SCHEDULE 19

### STUDY CODE: 10/339 -005N Page 5 of Appendix 6



## L A B 1. OBJECTIVE OF THE STU DY

The objective of this study is to determine the degree of ocular irritation resulting from the

test item when administered in a single dose into the conjunctival sac of one eye of up to

3 New Zealand White rabbits. The other eye, which will remain untreated, serves as the

control.

Before testing starts, according to the guideline OECD 405, it is the responsibility of the

Sponsor to ensure that the following considerations have been addressed:

There is not adequate human or animal data to allow regulatory classification of

this test item for eye irritancy.

It is not possible to provide information to make a regulatory classification based

on Structure Activity Relationship (SAR) for eye irritation/corrosion. (a)

There is no evidence that the dose of less than approximately 20 mg of test item

per kg of animal body weight will cause severe systemic toxicity.

The test item is not considered to be corrosive to skin. (b).

It is noted that there is no in vitro eye irritancy assay currently recognised

internationally as a replacement for animal testing for regulatory classification.

Following the above, as part of the initial evaluation, the pH of the test item will be

measured by LAB Research Ltd. (pH target range 2-11.5). Should it fall outside the range

required by the guideline, the test item will be reported as corrosive to eyes, unless the

Sponsor requests and can justify the performance of an animal test.

Notes:

(a) SAR is only applicable to pure test items, not mixtures or materials with any impurities.

(b) Corrosivity data from any previous studies should be considered.

IMPORTANT: If this study is to be used in a REACH submission, it is obligatory

under the EU regulations to first perform an in vitro eye irritation test. Exceptionally,

where there is evidence of a lack of eye irritation then this can be documented as a

justification for non-performance of this assay.

### STUDY CODE: 10/339 -005N Page 6 of Appendix 6



## L A B 2. MATERIALS AND METHODS

2.1. TEST ITEM

Substance Name: Polymer

Batch/Lot Number:

Description: White solid (waxy)

Molecular weight: Mw= 130000 Da

Mw< 2000 Da below 0.1%

Purity: 98.6%

Manufacturer: See Sponsor

Manufacture Date: 24 August 2010

Expiry Date: 23 August 2012

Storage conditions: Room temperature (15

- 30 °C , 40

- 70RH%, in a dark

storeroom without windows)

Safety Precautions : Routine safety precautions (gloves, goggles, face mask,

lab coat) for unknown materials will be ap plied to

assure personnel health and safety.

The pH of the test item will be measured prior to the start of treatment.

2.1.1. Identification, Receipt

The test item of a suitable chemical purity was provided by the Sponsor. All

precautions required in the handling and disposal of the test item were outlined by the

Sponsor. Identification of the test item was performed on the basis of information

provided by the Sponsor in the Central Dispensary of LAB Research Ltd.

2.1.2. Othe r Materials

The details of the materials to be used for euthanasia are given in A ppendix 1

.

2.2. EXPERIMENTAL ANIMALS

Species and strain: New Zealand White rabbit

Source: S&K-LAP Kft.

2173 Kartal, Császár út 135, H ungary

Justification of strain: The New Zealand White rabbit is one of the standard strains

used for acute irritation toxicity studies.

Number of animals: Up to 3 animals

Sex: Male

Age of animals at treatment : Young adult rabbits

Target body weight range: 2 0 00

- 40 00 g at dosing

Acclimation period: At least 5 days

### STUDY CODE: 10/339 -005N Page 7 of Appendix 6



## L A B 2.2.1. Husbandry

Animal health: Only healthy animals will be used for the study, as

certified by the veterinarian.

Housing/Enrichment: Rabbits will be individually housed in AAALAC

approved metal wire rabbit cages. Cages are of an open

wire structure and cages are placed together to allow

some social interaction with rabbit(s) in adjoining

cages.

Light: 12 hours daily, from 6.00 a.m. to 6.00 p.m.

Temperature: 20 ± 3°C

Relative humidity: 30-70 %

Ve ntilation: 15 -20 air exchanges/hour.

The room temperature and relative humidity values will be checked and recorded

twice daily during the study (including acclimatization phase)

.

2.2.2. Food and Feeding

The animals will receive PURINA Base – Lap gr. diet for rabbits produced by

AG RIBRANDS Europe Hungary PLC, H-5300 Karcag, Madarasi út, Hungary, ad

li bitum. For contents of PURINA Base – Lap gr. diet for rabbits: see Appendix 2

.

2.2.3. Water Supply and Quality Control

The animals will receive tap water, as for human consumption, ad libitum , from an

automatic system from the communal water network. The water is considered not to

contain any contaminants that could reasonably be expected to affect the purpose or

integrity of the study. The quality control analysis is performed once every 3 months

and microbiological assessment is performed monthly by Veszprém County Institute of State Public Health and Medical Officer Service (ÁNTSZ, H-8201 Veszprém,

József A.u.36., Hungary). The quality control results are retained in the archives at

LAB Research Ltd.

2.2.4. Identification

The individual animal identification number will be marked with indelible ink on the

ear, or will be on an ear tag. The cages will be marked with individual identity cards

with information about study code, sex, dose group, cage number and the individual

animal number.

### STUDY CODE: 10/339 -005N Page 8 of Appendix 6



## L A B 2.3. TESTING PROCEDURE

The pH of the test item will be determined. If the pH is 2 or less or 11.5 or greater, the

study will not be conducted, unless there is evidence that the test item is not irritating

or corrosive to the eye.

Three male animals in acceptable health condition will be selected for the test. Both

the control eyes and the eyes to be treated will be carefully examined before treatment.

Any animal with ocular lesions will be rejected and not assigned to the study.

For ethical reasons, an initial test will be performed using a single animal. If the

results of this test indicate the test item to be severely irritating or corrosive to the eye,

further testing will not be performed.

Immediately after administration of the test item, an assessment of the initial local

pain reaction (IPR) will be made according to the IPR scale detailed below:

Score Reaction by Animal Descriptive Rating

0 No response No initial pain

1 A few blinks only, normal within one o r two minutes Practically no initial pain

2 Rabbit blinks and tries to open eye, but reflex closes it Slight initial pain

3 Rabbit holds eye shut and puts pressure on lids, may

rub eye with paw Moderate initial pain

4 Rabbit holds eye shut vigorously, m ay squeal Severe initial pain

5 Rabbit holds eye shut vigorously, may squeal, claw at

eye, jump and try to escape Very severe initial pain

Class es 0, 1,2 and 3 will not be anaesthetised as it is considered that usually there is no

correlation between the initial pain and the subsequent eye irritation.

P roviding severe effects are not observed in the first treated animal, two additional

a nimals will subsequently be treated in an identical manner. Both eyes of these

animals may be anaesthetised prior to treatment, at the discretion of the Study

Director.

The test item will be applied in a single dose to the left eye of one or three animals.

The degree of irritation will be observed and scored at specified intervals. Information

derived from this test serves to indicate the existence of possible hazards likely to arise

from exposure of the eyes and associated mucous membranes, to the test item. The

duration of the study will be sufficient to evaluate the reversibility or irreversibility of

the effects. At termination, animals will be sacrificed.

### STUDY CODE: 10/339 -005N Page 9 of Appendix 6



## L A B 2.4. ADMINISTRATION OF TEST ITEM

2.4.1. Dose Level

A single dose of 0.1 g o f the solid test item will be introduced into the eye.

2.4.2. Application of the Test Item

The test item will be administered into the conjunctival sac of the left eye of each

animal. The eye lids will be gently held closed for several seconds to prevent the loss

of the test item.

The untreated contralateral eye will serve as the control.

2.4.3. Duration of Exposure

If the test item has not been removed from the eye of the test animal by physiological

mechanisms at the first observation time point at one hour after treatment, the eye will

be rinsed with physiological saline solution and the report will reflect this.

Animals showing continuing severe pain or distress or any of the following

irreversible changes, will be humanely euthanized without delay: corneal perforation

or significant ulceration of the cornea or conjunctival membrane; blood in the anterior

chamber of the eye; grade 4 corneal opacity which persists for 48 hours; absence of a

light reflex (iridial response grade 2) which persists for 72 hours; necrosis of the

conjunctivae or nictitating membrane; or sloughing.

In the case of corrosive effects, severe irritation, or at 24 hours after instillation,

washing of the eye with physiological saline may be performed at the discretion of the

Study Director.

2.5. OBSERVATIONS AND SCORING

2.5.1. Clinical Observations and Evaluation of Ocular Irritation

Pre-treatment:

Both eyes of each experimental animal(s) provisionally selected for testing will be

examined within 24 hours prior to testing. Animals showing eye irritation, ocular

defects or pre-existing corneal injury will not be used.

Post-treatment:

Evaluations will be made by comparing the treated eye to the control eye. The readings

will be made at 1, 24, 48, and 72 hours, then at 1, 2, and 3 weeks post-treatment.

If there is no evidence of irritation at 72 hours, the study will be terminated.

### STUDY CODE: 10/339 -005N Page 10 of Appendix 6



## L A B If the animal(s) become symptom-free before 21 days, the experiment may be

terminated at that time. As deemed necessary, after recording the observations at

24 hours, the eyes of the rabbit(s) may be further examined with the aid of fluorescein

liquid. Examination will be performed by means of a hand slit-lamp.

Any clinical signs of toxicity or signs of ill-health during the study will be recorded.

At study termination, or in the case of early termination due to eye effects or for moribund

animals, euthanasia will be performed by intramuscular injections of Ketamin (10%) and

Xylazine (2%) followed by i.v. Euthasol® 40% terminal anaesthesia (see Appendix 1 for

details). Death will be verified by checking pupil and cornea reflex, absence of respiration

and pulse.

2.5.2. Scoring and Assessment of Local Reaction

The eye irritation scores will be evaluated according to the scoring system by Draize

(1977) and OECD 405 (24 April 2002) presented in the following table.

1. Conjunctivae

A. Redness (Palpebral and bulbar)

Normal 0

Some blood vessels hyperaemic (injected) 1

Diffuse, crimson colour, individual vessels not easily discernible 2

Diff use beefy red 3

B. Chemosis

Normal 0

Some swelling above normal (includes nictating membrane) 1

Obvious swelling with partial eversion of lids 2

Swelling with lids about half closed 3

Swelling with lids more than half closed 4

C. Discharge

No discharge 0

Any amount different from normal (does not include small amounts

observed in inner canthus of normal animals) 1

Discharge with moistening of the lids and hairs just adjacent to lids 2

Disch arge with moistening of the lids and hairs, on considerable area

around the eye 3

### STUDY CODE: 10/339 -005N Page 11 of Appendix 6



## L A B 2. Iris

D. Values

Normal 0

Markedly deepened rugae, congestion, swelling, moderate

circumcorneal hyperaemia: or injection: iris reactive to light

(a sluggish reaction is considered to be an effect) 1

Haemorrhage, gross destruction, or no reaction to light. 2

3. Cornea

E. Opacity -degree of density (Area most dense taken for reading)

No ulceration or opacity 0

Scattered or diffuse areas of opacity (other than slight

dulling of normal lustre): details of iris clearly visible 1

Easily discernible translucent area: details of iris slightly obscured 2

Na crous area: no details of iris visible: size of pupil barely discernible 3

Opa que cornea: iris not discernible through the opacity 4

F. Area of cornea involved

One quarter (or less), but not zero 1

Greater than one quarter, but less than half 2

Greater than half, but less than three quarters 3

Greater than three quarters, up to whole area 4

2.5.3. Classification of the Test Item

The individual reactions of each animal will be recorded at each observation time. The

n ature, severity and duration of all lesions observed will be described.

Results will be presented and interpreted according to Regulation (EC) No 1272/2008

of the European Parliament and of the Council of 16 December 2008 on classification,

labelling and packaging of substances and mixtures, amending and repealing

Directives 67/548/EEC a nd 1999/45/EC, and amending Regulation (EC)

No 1907/2006 , as follows:

### STUDY CODE: 10/339 -005N Page 12 of Appendix 6



## L A B Irreversible effects on the eye/serious damage to eyes (Category 1)

Substances that have the potential to seriously damage the eyes are classified in

Category 1 (irreversible effects o n the eye). These observations include animals with

grade 4 cornea lesions and other severe reactions (e.g., destruction of cornea) observed

at any time during the test, as well as persistent corneal opacity, discoloration of the

cornea by a dye substanc e, adhesion, pannus, and interference with the function of the

iris or other effects that impair sight.

Category for irreversible eye effects

If, when applied to the eye of an animal, a substance produces:

— at least in one animal 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

— at least in 2 of 3 tested animals, a positive response of:

o corneal opacity ≥ 3 and/or

o iritis > 1.5

calculated as the mean scores following grading at 24, 48 and 72 hours after

installation of the test material.

R eversible effects on the eye/irritating to eyes (Category 2)

Substances that have the potential to induce reversible eye irritation are classified in

Category 2 (irritating to eyes).

Category for reversible eye effects

If, when applied to the eye of an animal, a substance produces:

— at least in 2 of 3 tested animals, a positive response of:

o corneal opacity ≥ 1 and/or

o iritis ≥ 1, and/or

o conjunctival redness ≥ 2 and/or

o conjunctival oedema (chemosis) ≥ 2

— calculated as the mean scores following grading at 24, 48 and 72 hours after

installation of the test material, and which fully reverses within an observation

period of 21 d ays

2.5.4. Measurement of Body Weight

Body weights will be recorded at the beginning and at the end of the experiment.

3. ANIMAL WELFARE

Procedures involving the care and use of animals in this study will be reviewed and

approved by the Institutional Animal Care and Use Committee (IACUC). During the

study, the care and use of animals will be conducted in accordance with the relevant

principles currently used with regard to animal welfare.

### STUDY CODE: 10/339 -005N Page 13 of Appendix 6



## L A B Chemicals likely to be corrosive will not be tested. To ensure a minimum of animal

distress, initially, only a single animal will be exposed to the test chemical. The treated

eye will be examined at 1 hour for signs of serious effects.

In the case of a clear corrosive effect, the animal will be sacrificed and the study

terminated. In the case of a severe irritant effect, less than a clear corrosive effect, no

further animals will be treated and the single animal will be observed as per study

plan. Otherwise, 2 additional rabbits will be used to evaluate the ocular effects of the

test item.

4. GOOD LABORATORY PRACTICE (GLP) AND QUALITY ASSURANCE

In order to enable the results of this study to meet legal requirements including

regulatory submission and/or safety assessment, it will be performed in compliance with

the principles of Good Laboratory Practice Regulations as requested by the Sponsor and

specified in national Hungarian GLP Regulations: 9/2001. (III.30.) EüM-FVM joint

decree of the Minister of Health and the Minister of Agriculture and Regional

Development which corresponds to the OECD GLP, ENV/MC/CHEM (98) 17, which is

consistent to the United States Food and Drug Administration Title 21 Code of Federal

Regulations Part 58, Good Laboratory Practice for Non-clinical studies issued 22

December 1978 Federal Register plus subsequent amendments.

The Quality Assurance Unit will conduct inspections of the study plan, various phases

of the study, certain repetitive operations and the report will be audited according to

our Standard Operating Procedures.

This stu dy will be assessed in compliance with this Study Plan and the LAB Research

Ltd. Standard Operating Procedures. The critical phases of this study as well as the test

facility will be inspected by the Quality Assurance Unit (QAU) and the dates and the

phase s of the inspections will be included into the final report.

The results of all the study audits will be reported to the Study Director. The data

presented in the final report will be audited in comparison to the raw data.

A quality assurance statemen t, signed by the Quality Assurance Unit, will be included in

the Final Report.

The Sponsor’s Study Monitor or authorized designate(s) may inspect this study during

regular working hours for quality assurance purposes and also copy any study

- related

origina l data.

5. AMENDMENT AND DEVIATION PROCEDURES

Planned changes to the study plan can be made at the discretion of the study director

and will be agreed with the Sponsor. Detailed descriptions of all study plan

amendments will be effective at the time of study director's signature. All such

amendments will be sent to the sponsor. The study plan amendment will be distributed

and added to all copies of the study plan.

### STUDY CODE: 10/339 -005N Page 14 of Appendix 6



## L A B Unplanned changes to the study plan will be documented in the raw data and

communicated to the Sponsor. The final report will reflect every study plan deviation,

the reason for the study plan deviation and its anticipated effect on the outcome of the

study.

6. STUDY REPORT

A Report in English in LAB Research Ltd.’s format will be sent to the Sponsor and

will in clude but will not be limited to:

- Name and address of the sponsor, the test facility and the study schedule.

- The names of the study director and other scientists and supervisory personnel

involved in the study.

- The signatures of the study director and the management.

- The signed and dated final reports of each of the individual scientists or other

professionals involved in the study.

- The signature of the Sponsor (if requested by the Sponsor).

- The statement of compliance, signed by the study director.

- The signature and statement of the management.

- The quality assurance statement, signed by the QAU.

- C haracterisation of test item: the identification of the test item, either by name

or code number. The concentration, purity, stability, composition and other

appropriate characteristics of the test item, if the Sponsor provides data.

- A description of the animals: strain, health status, sex, source, identification,

weight at commencement of the study, group size and animal husbandry.

- Details of the administration of the test item.

- I ndividual results of each animal at times of scoring.

- Description of any lesions observed.

- Narrative description of the degree and nature of irritation observed.

- Description of any toxic effects.

- Interpretation of results.

- C onclusions.

- A copy of Study Plan including amendments to and deviations from the

protocol. A list of all deviations to the Study Plan and a statement on their

possible impact on quality and integrity of the study results.

- A copy of the Certificate of Analysis or Test Item Data Sheet.

- A copy of the GLP-Certificate of the test facility.

- Details of archiving - the storage location, list of archived data and samples,

time for archiving.

The draft report will be sent to the Sponsor by e-mail for comment. The final report

will be issued following comments by the Sponsor as a PDF document and a Word

document sent to the Sponsor by e-mail. One bound and one unbound copy will be

sent by courier.

### STUDY CODE: 10/339 -005N Page 15 of Appendix 6



## L A B 7. ARCHIVES

The study documents (study plan and any amendments, all raw data, study report and

any amendments, correspondence) and a sample of the test item will be archived

according to the Hungarian GLP and applicable SOP’s in the archives of LAB

Research Ltd., 8200 Veszprém, Szabadságpuszta, Hungary.

After the retention time agreed with the Sponsor has elapsed, all the archived materials

listed above w ill be offered to the Sponsor or retained for a further period if agreed by

a contract. Otherwise the materials will be discarded.

8. DISTRIBUTION OF THE STUDY PLAN

Sponsor: 1 copy or 1x PDF-file

Study Director: 1 copy

QAU: 1 copy

Archive: 1 original

Central Dispensary: 1 copy

9. SIGNATURES

The Study Director, LAB Research Ltd.'s management, QAU and IACUC will sign the

Study Plan before the start of the study. The signature page with Study Plan will be

sent to the Sponsor after the content of the Study Plan has been agreed. If the Sponsor

does not sign the Study Plan within 5 working days (or as specified in the contract)

then the study may be started with the signature of the Sponsor being made after study

initiation.

### STUDY CODE: 10/339 -005N Page 16 of Appendix 6



## L A B 

## A P P E N D I C E S

### STUDY CODE: 10/339 -005N Page 17 of Appendix 6



## L A B APPENDIX 1:

DETAILS OF MATERIALS TO BE USED FOR EUTHANASIA

Name: CP -Ketamin 10 %

Batch No.: 10B18 3*

Expiry Date: January 2012

Produced by: CP -Pharma, 31303 Burgdorf

Name: CP -Xylazin 2 %

Batch No.: 08E15 9*

Expiry Date: April 2011

Produced by: CP -PHARMA, 31303 Burgdorf

Name: Euthasol ® 40 %

Lot No.: 10C25 7*

Expiry Date: February 2013

Produced by: AST Beheer B.V. Oudewater Netherlands

* Other lots may be used as required; to be documented in the raw data and study

report

### STUDY CODE: 10/339 -005N Page 18 of Appendix 6



## L A B APPENDIX 2:

CONTENTS OF PURINA BASE - LAP GR. DIET FOR RABBITS

NU TRIENTS

Wet 14.00 %

Crude protein 15.50 %

Tota l fat 2.10 %

Crude fibre 16.00 %

Crude Ash 6.80 %

MINERALS

Calcium 0.88 %

Phosphorus 0.55 %

Sodium 0.22 %

Cu (CuSO 4 * 5H 2 O) 20.000 mg /kg

AMINO ACIDS

Lysine 0.66 %

Methionine 0.23 %

Met.+Cyst. 0.50 %

VITAMINS

Vitamin A 15010 IU/kg

Vitamin D 3 1250 IU/kg

Vitamin E 50 mg/kg

These data are guaranteed values provided by the supplier

.

These values can slightly differ in case of changing the Batch of the feed used under

the duration of the study. Should any other Batch will be used, the details will be

documented in draft report, but it will not be considered as a deviation to the Stu dy

Plan.

### STUDY CODE: 10/339 -005N Page 19 of Appendix 6



## L A B APPENDIX 3:

PROPOSED STUDY SCHEDULE

PRE-EXPERIMENTAL PERIOD

Relative date Absolute date

Animal arrival Day [

- 6 ] 23 March 2011

Veterinary control,

acclimatization Within 48 hours of arrival

TREATMENT PERIOD

Day of treatment Day [0] 29 March 2011

Animal ocular examination

and assignment to study Day 0 (pre

- treatment) 29 March 2011

Body weight measurement Day [0, terminating day] 29 March 2011, To be

determined, based upon

the results of observation

Clinical obser

vation Scoring at 1, 24, 48 and 72 hours then at 1, 2 and 3

weeks after treatment if required (see relevant sections

in the study plan)

End of in life phase Not later than Day [21] 19 April 2011

Draft Report Not later than 01 June 2011

### STUDY CODE: 10/339-005N Page 1 of Appendix 7



## LAB Research Ltd.

Address: 8200 Veszprém, Szabadságpuszta

Phone: +36 88 545 300

Fax: +36 88 545 301 APPENDIX 7:

COPY O F THE AMENDMENT 1 TO THE STUDY PLAN



### AMENDMENT 1

TO THE STUDY PLAN

Polymer

ACUTE EYE IRRITATION STUDY

IN RA BBITS



### Date of Amendment 1

to the Study Plan : 2 6 August 2011 STUDY CODE: 1 0/ 339

- 00 5N

### STUDY CODE: 10/339-005N Page 2 of Appendix 7



### AMENDMENT 1 TO THE STUDY PLAN 

## L A B

Changes to the study plan and/or amendment(s) to the study plan as applicable are

detailed below:

Throughout the study plan, as applicable:

Due to departure of the originally appointed Study Director, Judit Tavaszi, M.Sc. (Inlife phase), from LAB Research Ltd., Viktória Zelenák, M.Sc. will be assigned to act

as the Study Director on this study (Draft and Final report phase). In accordance with

OECD ENV/JM/MONO(99)24; OECD Series on Principles of GLP and Compliance

Monitoring Number 8 (Revised) Consensus Document THE ROLE AND

RESPONSIBILITIES OF THE STUDY DIRECTOR IN GLP STUDIES, the new

study director ensures the GLP compliance of the complete study.

Reason for the amendment: To document changes in the study personnel.

Distribution to Study Plan recipients. This change has no impact on the study outcome

or interpretation of the results.

### STUDY CODE: 10/339-005N Page 3 of Appendix 7



### AMENDMENT 1 TO THE STUDY PLAN 

## L A B