## FINAL REPORT

Study Title



## 14

- DAY RANGE FINDING STUDY WITH

EXP1313100

BY DAILY GAVAGE OR DERMAL EXPOSURE

IN THE RAT

Author

Test Facility

WIL Research Europe B.V.

Hambakenwetering 7

5231 DD ‘s

- Hertogenbosch

The Netherlands

Laboratory Project Identification

Project 505704

Substance 205622/AEXP1313100 Project 50570 4

- Page 2 - 1. CONTENTS

1. CONTENTS

................................................................................................ ...................................... 2

2. STATEMENT OF GLP COM PLIANCE

............................................................................................. 3

3. QUALITY ASSURANCE ST ATEMENT

............................................................................................ 4

4. SUMMARY

................................................................................................ ........................................ 5

5. INTRODUCTION

.............................................................................................................................. 6

5.1. Preface

................................................................................................ ..................................... 6

5.2. Study Plan

................................................................................................ ................................ 6

5.3. Aims of the study

...................................................................................................................... 7

5.4. Guidelines

................................................................................................ ................................ 7

5.5. Storage and retention of records and materials

....................................................................... 7

6. MATERIALS AND METHOD S

.......................................................................................................... 8

6.1. Test substance

......................................................................................................................... 8

6.1.1. Test substance information

............................................................................................. 8

6.1.2. Study specific test substance information

...................................................................... 8

6.1.3. Test Substance formulation

............................................................................................ 8

6.1.4. Chemical Analysis of Dose Preparations

....................................................................... 8

6.2. Test System

............................................................................................................................. 9

6.3. Allocation

................................................................................................ .................................. 9

6.4. Animal Husbandry

.................................................................................................................... 9

6.5. Treatment

............................................................................................................................... 10

6.6. Observations

.......................................................................................................................... 11

6.7. Pathology

............................................................................................................................... 11

6.7.1. Necropsy

....................................................................................................................... 11

6.7.2. Organ Weights

.............................................................................................................. 12

6.8. Electronic data capture

.......................................................................................................... 12

6.9. Interpretation

.......................................................................................................................... 12

6.10. List of deviations

.................................................................................................................... 12

6.10.1. List of protocol deviations

........................................................................................ 12

6.10.2. List of standard operating procedures deviations

.................................................... 13

7. RESULTS

................................................................................................ ....................................... 13

7.1. Observations

.......................................................................................................................... 13

7.1.1. Mortality

........................................................................................................................ 13

7.1.2. Clinical Signs

................................................................................................................ 13

7.1.3. Body Weights

................................................................................................................ 14

7.1.4. Food Consumption

........................................................................................................ 14

7.2. Pathology

............................................................................................................................... 14

7.2.1. Macroscopic Examination

............................................................................................. 14

7.2.2. Organ Weights

.............................................................................................................. 14

8. DISCUSSION AND CONCL USION

................................................................................................ 15

APPENDICES

APPENDIX 1 SUMMARY TABLES

– ORAL EXPOSURE

APPE NDIX 2 SUMMARY TABLES

– DERMAL EXPOSURE

APPENDIX 3 INDIVIDUAL TABLES

– ORAL EXPOSURE

APPENDIX 4 INDIVIDUAL TABLES

– DERMAL EXPOSURE

APPENDIX 5 CERTIFI CATE OF ANALYSISEXP1313100 Project 50570 4

- Page 5 - 4. SUMMARY

Title

14-D ay range finding study with EXP1313100 by daily gavage or dermal exposure in the rat.

Guidelines

The study was based around the following guidelines (the guidelines were not fully applicable as this

study was mainly intended for dose selection):

- EC No 440/2008, B.7 Repeated Dose (28 days) Toxicity (oral), 2008.

- EC No 440/2008, B.9 Repeated Dose (28 days) Toxicity (dermal), 2008.

- OECD 407, Repeated Dose 28

- day O ral Toxicity Study in Rodents, 2008

- OECD 410, Repeated Dose 21/28

- day Dermal Toxicity Study in Rodents, 1981

Rationale for dose levels

The dose levels for this study were selected to be 0, 500 and 1000 mg/kg

, based on the results of an

acute oral toxicity study (project 505697 ) and an ac ute dermal study (project 505698).

Study outline

The test substance, formulated in propylene glycol, was administered daily for 14 days by oral gavage

or dermal exposure to SPF

- bred Wistar rats. For each route of exposure, one control group and t wo

treate d groups were tested, each consisting of 3 males. Males were selected since t his sex has shown

to be more susceptible to treatment with similar test substances according to the sponsor.

Evaluated parameters

The following parameters were evaluated: clinical signs daily, body weight and food consumption

weekly, macroscopy at termination and organ weights on a selection of tissues.

Results and Discussion

Oral exposure :

Body weight s and body weight gain showed an apparent trend towards a slight decrease across the

dose groups. As means at 1000 mg/kg were only slightly lower than the control mean, this change

was considered to be of no toxicological relevance.

No toxicologically relevant clinical signs and macroscopic lesions were noted. Food intake and o rga n

weights were considered to have been unaffected by treatment

.

Dermal exposure:

An increased incidence of erythema (general, maculate or focal), scales and scabs (slight to moderate

degree) was noted on the treated skin area among all animals at 500 and 1000 mg/kg from Day 3

onwards. Scales and scab formation of the treated skin area was confirmed at necropsy for a ll animals

at 500 and 1000 mg/kg. A reversible fissuring of the treated skin area was noted for one animal at

1000 mg/kg between Days 4 and 8

. These local effects were considered to reflect an irritating

potential of the test substance. Hunched posture shown by one animal at 500 mg/kg and all animals at

1000 mg/kg on a few days only was considered to have occurred secondary to the local effects and

not to be indicative of systemic toxicity. Control animals also incidentally showed local effects

consisting of erythema, scabs, and scales, but at clearly lower incidence/severity than test substance

treated animals.

Body weights, food intake and o rgan weights were considered to have been unaffected by treatment.

Conclusion

Oral exposure did not result in toxicologically relevant findings up to a dose of 1000 mg/kg. Dermal

exposure resulted in generally mild local effects on the treated skin area due to irritation. No evidence

of systemic toxicity was noted after dermal exposure.