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 RABBITS

Date of Final Report: 01 September 2011 STUDY CODE: 10/339-005N



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STUDY TITLE : Polymer: Acute Eye Irritation 

Study in Rabbits 

SPONSOR : 

STUDY 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) 

 Viktória Zelenák, M.Sc. (Reporting Phase) 

ASSISTANT SCIENTIST : István Buda, M.Sc. 

VETERINARY CONTROL : István Pásztor, DVM

CENTRAL DISPENSARY : Tamás Mészáros, PhD. 
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CONTENTS

Page

1. SUMMARY 7

2. INTRODUCTION 8

3. MATERIALS AND METHODS 8

3.1. TEST ITEM 8

3.2. OTHER MATERIALS 9

3.3. EXPERIMENTAL ANIMALS 9

3.4. HUSBANDRY 10

3.5. FOOD AND FEEDING 10

3.6. WATER SUPPLY AND QUALITY CONTROL OF WATER 11

3.7. STUDY SCHEDULE 11

3.8. ADMINISTRATION OF THE 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 SCORING 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 THE INSTITUTIONAL IACUC 14

6. DEVIATION TO THE STUDY PLAN 14

7. RESULTS 15

7.1. MORTALITY 15

7.2. BODY WEIGHTS 15

7.3. CLINICAL OBSERVATION 15

7.3.1. General daily 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 of Local Reaction 1 – 2 of Appendix 1 

APPENDIX 2: Scoring of Pain Reaction 1 of Appendix 2 

APPENDIX 3: Contents of Purina Base - Lap Gr. Diet for Rabbits 1 of Appendix 3 

APPENDIX 4: Copy of the Certificate of Analysis 1 of Appendix 4 

APPENDIX 5: Copy of the 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 Study Plan 1 – 3 of Appendix 7 
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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 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. 

The general state 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:

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 

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.
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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 intervals. 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 METHODS 

Start of Treatment: 29 March 2011 

End of Experiment: 01 April 2011 

3.1. TEST ITEM 

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 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 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 in the Central Dispensary Unit 

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

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

Sex: Male

Body weight range at the

beginning of the life phase: 2799 – 2904 g 

end of the life phase: 2926 – 3010 g 

Date of receipt: 23 March 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 AAALAC 

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 

Ventilation: 15-20 air exchanges/hour 

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

variations 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. diet for rabbits, which were used during the experimental 

phase see in Appendix 3. 
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3.6. WATER SUPPLY AND QUALITY CONTROL OF WATER 

The animals received municipal tap 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 March 2011 

Veterinary control 23 March 2011

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

TREATMENT PERIOD

Day of treatment Day [0] 29 March 2011 

Body weight 

measurement 

Day [0; terminating day] 29 March 2011 

01 April 2011 

Clinical observation Scoring 1, 24, 48 

and 72 hours 

29 March 2011 

30 March 2011 

31 March 2011 

01 April 2011 

End of in life phase 01 April 2011 
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3.8. ADMINISTRATION OF THE 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 contralateral 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 first 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 SCORING

3.9.1. Clinical Observations

The eyes were examined at 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 respiration and pulse.
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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

Individual reactions of the animal were recorded at each observation time. The nature, 

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 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.

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. 
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3.9.4. Measurement of Body Weight

Individual body weight was 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 materials listed above will be 

offered to the Sponsor for further storage or disposal. 

5. THE PERMISSION OF THE INSTITUTIONAL IACUC 

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 STUDY 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. 

These deviations were considered not to adversely affect the results or integrity of the 

study. 
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7. RESULTS

7.1. MORTALITY

There was no mortality observed during the study. 

7.2. BODY WEIGHTS

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

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

after 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.
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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 March 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 

00051 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 -

Abbreviations: 

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

IPR = Initial pain reaction; - = No data
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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 March 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 
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APPENDICES
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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 
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APPENDIX 1:

SCORING AND ASSESMENT OF LOCAL REACTION

(continued)

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 
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APPENDIX 2: 

SCORING OF PAIN REACTION

Class Reaction 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. 
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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 14.0% 14.0%

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 (CuSO4*5H2O) 20.00 mg/kg 20.00 mg/kg

AMINO ACIDS

Lysine 0.68% 0.68%

Methionine 0.25% 0.25%

MET + Cystine 0.53% 0.53% 

VITAMINS

Vitamin A 15010 IU/kg 15010 IU/kg

Vitamin D3 1250 IU/kg 1250 IU/kg

Vitamin E 50 mg/kg 50 mg/kg

These data are standard and guaranteed values which were provided by the supplier. 
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APPENDIX 4: 

COPY OF THE CERTIFICATE OF ANALYSIS
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APPENDIX 5: 

COPY OF THE GLP CERTIFICATE
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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 
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L A B 

GENERAL INFORMATION

SPONSOR

STUDY PERFORMED BY : LAB Research Ltd.

Address: H-8200 Veszprém, Szabadságpuszta

Hungary

Phone: +36 88 545 -300

Fax: +36 88 545 -301

TITLE 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* : István Buda M.Sc.– Assistant Scientist 

István Pásztor DVM/ Peter Maslej DVM, PhD -

veterinary control

Szabolcs Gáty M.Sc. – Head of QAU

Animal House Staff

Central Dispensary Staff

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

recorded and reported.

PROPOSED STUDY SCHEDULEi: 

START OF EXPERIMENT : 29 March 2011 

END OF EXPERIMENT : Not later than 19 April 2011 

DRAFT 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 (24th April 2002) OECD: Paris, 

COMMISSION 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 will be sent by email.

One bound and one unbound hard copy will be sent 

by courier.

 

iA detailed study timing (target) is given in Appendix 3.
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L A B 

CONTENTS 

1. OBJECTIVE OF THE STUDY 5

2. MATERIALS AND METHODS 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 TEST 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 SCORING 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. Classification of the Test Item 11

2.5.4. Measurement of Body Weight 12

3. ANIMAL WELFARE 12

4. GOOD LABORATORY PRACTICE (GLP) AND QUALITY ASSURANCE 13

5. AMENDMENT AND DEVIATION 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
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L A B 

1. OBJECTIVE OF THE STUDY

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. 
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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 applied 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. Other Materials 

The details of the materials to be used for euthanasia are given in Appendix 1. 

2.2. EXPERIMENTAL ANIMALS 

Species and strain: New Zealand White rabbit 

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.

Number of animals: Up to 3 animals

Sex: Male 

Age of animals at treatment: Young adult rabbits

Target body weight range: 2000-4000 g at dosing

Acclimation period: At least 5 days
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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 % 

Ventilation: 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 

AGRIBRANDS Europe Hungary PLC, H-5300 Karcag, Madarasi út, Hungary, ad 

libitum. 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. 
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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 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

Classes 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. 

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

animals 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. 
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2.4. ADMINISTRATION OF TEST ITEM 

2.4.1. Dose Level 

A single dose of 0.1 g of 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

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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 

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
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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 

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

Opaque 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 

nature, 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 and 1999/45/EC, and amending Regulation (EC) 

No 1907/2006, as follows:
STUDY CODE: 10/339-005N Page 12 of Appendix 6

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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 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. 

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 

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

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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 study 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 

phases 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 statement, 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 

original 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. 
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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 include 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.

- Characterisation 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. 

- Individual 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. 

- Conclusions. 

- 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

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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 will 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. 
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A P P E N D I C E S 
STUDY CODE: 10/339-005N Page 17 of Appendix 6

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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
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APPENDIX 2: 

CONTENTS OF PURINA BASE - LAP GR. DIET FOR RABBITS 

NUTRIENTS 

Wet 14.00 % 

Crude protein 15.50 % 

Total fat 2.10 % 

Crude fibre 16.00 % 

Crude Ash 6.80 % 

MINERALS 

Calcium 0.88 % 

Phosphorus 0.55 % 

Sodium 0.22 % 

Cu (CuSO4*5H2O) 20.000 mg/kg

AMINO ACIDS

Lysine 0.66 %

Methionine 0.23 %

Met.+Cyst. 0.50 %

VITAMINS

Vitamin A 15010 IU/kg

Vitamin D3 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 Study 

Plan.
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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 observation 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 OF THE AMENDMENT 1 TO THE STUDY PLAN 

AMENDMENT 1 

TO THE STUDY PLAN 

 Polymer

ACUTE EYE IRRITATION STUDY 

IN RABBITS

Date of Amendment 1

to the Study Plan: 26 August 2011 STUDY CODE: 10/339-005N
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