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# SafePharm Laboratories

EMULGEN B-66: ACUTE DERMAL IRRITATION IN THE RABBIT SPL PROJECTNUMBER: 140/1099

AUTHOR:

TESTFACILITY: A Sanders

Safepharm Laboratories Limited P.O. Box No. 45 Safety & Environmental Research Center 2606 

### , 1 え

kab 組 e 

### , Ichikaimachi DERBY DE12BT Haga TOCHIGI32 ト 3497 JAPAN
140-1099.doclJS U. 

### K. Telephone: (01332) 792896 Facsimile: (01332) 799018「 ー SPL PROJECTNUMBER: 140/1099 PAGE2 QUALITY ASSURANCEREPORT 百せ s study type is classed ぉ short-term. 百 le s岡 d 紅 d test me 也

od for 白 is study type 

### (“ General Study Plan" in OECD terminology) wお お viewed for compliance once only on initial production 

### In

spection of 由 e routine and repetitive procedures 也at constitute the study is carried out as a con 出 uous process designed to encompぉ s 血e major phases at or about the time 也is study was in progress. 

### Thi s report hぉ been audited by Safepharm Quality Assurance U凶 t 

### , and is considered to be an accurate account of 也eda 包 generated and ofthe proced 町 es followed. 

### In each case 

### , the outcome of QA evaluation is repo 巾 d to 也 e Study Director and Management on 也 e day of evaluation. Audits of study documentation

### , and process inspections appropriate to 白 E type and schedule of 也is study were ぉ follows: 13 August 2001 Standard Test Method Compliance Audit 06 February 2002 Test Material Preparation 15 February 2002 

### Anim al Preparation 15 February 2002 Dosing 15 February 2002 Assessment ofResponse**~** 29 March 2002 Draft Report Audit**~** DateofQA S明 a 加 E Final Report Audit**~** Evaluation specific to 也is study 

# 百三 b.1 反応三: DATE:

For Safepharm Quali 匂 TAssurance U凶 t本

•Authorised QA Signatures: Head ofDepa 血 nent JRPateman CBiol MIBiol DipRQAFRQA JMCrow 由er MIScTMRQA 

### 1 9 APR 2002

Deputy Head ofDepar回目立Senior Audit S 阻 ff: JV Johnson BSc MRQA; G Wren ONCMRQA; R Hurst MRQASPL PROJECTNUMBER: 140/1099 PAGE3


### GLPCOMPLIANCE STATEMENT 百 

### le work described w ぉ 

### performed in compliance wi 也 

### UK GLP standards (Schedul 巴 

### 1 

### , Good Laboratory Practice Regulations 1999 (SI 1999β106)). These Regulations 紅 

### 'e in accord 組 

### cewi 吐 1 

### GLP standards published as OECD Principles on Good Laboratory Practice (revised 1997 

### , ENV ぶ

### 1C/CHEM(98) 17); and 紅 

### e in accord 組 

### .ce with , 

### and 凶 

### plement ,出巴 

### requirements of Directives 87/1 

### 8AEC (as amended by Directive 1999/11 厄 

### C) and 88/320 厄 

### EC (ぉ 

### amended by Directive 1999/12A C). 百

### lese international standards 紅 

### e acceptable to the Regulatory agencies of 出 

### e following coun 凶 

### es: Australia 

### , Austri 

### a, Belgium 

### ,

Canad 

### a, the Czech Republic 

### , Denmark

### , Finland

### , France 

### , Germany 

### ,Gr

### eece 

### ,Hungary 

### ,Iceland

### , Ir

### eland

### ,Israel 

### ,Italy 

### , Japan

### ,Republic of Kore 

### a, Luxembourg 

### , Mexico 

### ,百le Netherlands 

### , New Zealand

### , Norway 

### , Poland

### , Portugal 

### , Sloveni 

### a, Sp 出



### n 

### , Sweden

### , Switzerland

### , Turkey 

### , the United 

### Ki ngdom 

### ,

and the United States of Am 

### erica. This report fully and accurately reflects the procedures used and da 匂 

### generated.

# ~...~~. ASanders Study DirectorSPLPROJECT NUMBER: 140/1099 PAGE4


### CONTENTS QUALITYASSURANCEREPORT GLPCOMPLIANCE STATEMENT CONTENTS SUMMARY 1.町

### TRODUCTION TESTMATE 阻 

### AL 2.1 Description

### , Identification and Storage Conditions 2.2 Preparation ofTest Material 2 

### .3 Me 俗 世

### 'ementofpH METHODS 3 .1 

### Anim als and 

### Anim al Husbandry 3.2 Procedure 3 

### .3 

### In terpretation ofResults 4. ARC HlVE

### S 5. RESULTS 6. CONCLUSION 

### 2.

3.



### Table 1 Individual Skin Reactions Appendix 1 Statement of GLP Compliance inAccordance wi 也 

### Directive 88/320

### 1E EC

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唱 EASPLPROJECT NUMBER: 140/1099 PAGE5
EMULGEN B-66: ACUTE DERMAL IRRITATIONIN THE RABBIT 

### SUMMARY 

### Introducnon. 百 le study was performed to 鎚 sess 吐 le 凶 t 組 cy potential of the test material to the skin ofthe New Zealand 

### Whi te rabbit 刀 leme 也od was designed to meet the requirements of the f0

### 1l 0 羽 ng:

• OECD Guidelines for the Testing of Chemicals No. 404 

### “ Acute Dermal IrritationlCoITosion" (adopted 17 July 1992)

• Commission Directive 92/69. 厄 ECMe白 od B4Acute Toxicity (Skin Irritation) 

### Resul ぉ. A single 4-hour 

### , semi-occluded application of the test material to the intact skin of 也氏e rabbits produced no evidence of skin iηitation. 

### Con c[ 

### usion. The test material produced a primary irrita 討

on index of 0.0 祖 d was classified as non-irritant to rabbit skin according to 也e Draize classification scheme. N 0 cOITosive effects werenoted. 刀 le test material did not meet 也 e criteria for classification ぉ註rit 組 t or cOITosive according to 也e EU labe

### 1l ing regulations Commission Directive 93/21 厄 EC.SPLPROJECTNUMBER: 140/1099 PAGE6


### EMULGEN B-66: ACUTEDERMAL IRRITATION IN THE RABBIT 1.悶

### TRODUCTION 百

### le study was performed to assess 也 

### eirri 匂 

### ncy potential of 由 

### e test material following a single 

### , 4 ・



### hour 

### , semi-occluded application to 也

### e intact rabbit skin 刀 

### le method was design 吋 

### to meet the requirements of 仕 

### le following:

• OECD Guidelines for 也 

### eT ,白血

### 19 of Chemicals No. 404 

## “ Acute Dermal IrritationlCoITosion" (adopted 17 J

### u1 y 1992) Commission Directive 92/69 厄 

### EC Method B4Acute Toxicity (Skin 

### Irri tation) 刀 

### le albino rabbit has been shown to be a suitable model for 也

### is type of study and is recommended in也

### etestme 血

### od. 百 le 

### res 

### u1 ts of the study 紅巳 

### believed to be of value in predic 出 

### g 白 

### e likely skin irritancy potential of the test material to man. 百 

### le study was performed between 21 February 2002 and 24 February 2002. 2. TESTMATERIAL 2.1 Description

## , Identification and Storage Conditions Sponsor's identification Description Batchnumber Date received Storage conditions EMULGENB-66 light brown slightly 加 

### rbid viscous liquid 2376 31 December 2001 room temperature in也巴 

### dark Data relating to the identity 

### , purity and stability of 也

### e test material 釘 

### e 白 

### e responsibility of the Sponsor. 2.2 Preparation of Test Material For 也 

### ep 町 

### pose of the study the test material w ぉ 

### used as supplied. τbe absorption of the test material was not deter百lI 

### nedSPLPROJECT NUMBER: 140/1099 PAGE7 2.3 Measurement of pH The pH of a 90% v/v aqueous preparation of the test material was determined prior to commencement ofthe study and found to be approximately 8.5. 3. METHODS 3.1 Animals and An imal Husbandry Three New Zealand 

### Whi te rabbits were supplied by David Percival Ltd

### , Moston

### , Sandbach

### , Cheshire 

### , UK. At the s 匂rt of the study 吐 le animals were 加 the weight range of2.0 to 3 .5 kg 組 d were twelve to sixteen weeks old. 

### Aft er 組 acclimatisation period of at least five days each g 註 mal was given a number unique within the study which was wri 抗告 n wl 仕 1 a black indelible marker-pen on也 e mner s 町 face of 血ee 紅 釦 don也 e cage labe 

### l. 百lear廿 malswere individually housed in suspended metal cages. Free access to IIl抵ns 合i叫cing water and food (Certified 

### Ra bbit Diet (Code 5322) supplied by P

### Ml Nu 凶 tion Intemational , No 口

ingharn

### , UK) w 俗 allowed 耐 oughout 血e study. 百le diet and drinking water were considered not to 

## ∞ nta 凶 any contarninant of a level 白紙 might have affected 也.e purpose or integrity of 也e study. The tempera 旬 re and relative humidity were set to achi 巴 ve limits of 17 to 23 0 C and 30 to 70% respectively. An y occasional deviations 企 'om these targets wer 巴 considered not to have affected 也 e purpose or integrity of the study. The rate of air exchange was at least fifteen changes per hourand 也 e lighting w. ぉ con 甘olled by a tInl e switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness. The animals were provided with environmental enrichment items which were consider巴d not to co 脚 m 組 y cont an1In ant of a level 白紙 might have affected 白 epu 中 ose or integrity of 也 e study. 3 .2 Procedure On the day before the test each of a group of 吐 rree rabbits was clipped free of fur 企om 血e dors al/ flank 訂 'ea using veterinary clippers. Only animals with a healthy intact epidermis by gross observation were selected for the s 知 dy. Onthe day of the test a suitable test site wぉ selected on the back of each rabbit. A quantity of 0.5 ml of 也 e test material w ぉ血仕 oduced under a 2.5 cm x 2.5 cm co 柱。 n gauze patch and placedSPL PROJECTNUMBER: 140/1099 PAGE8 

### in position on the shom skin. 百 1巴 

### patch was secured in position with a strip of s 町 

### gical adhesive tape. To prevent 也 

### ea 由 

### nals interfering wi 由 也

### e patches ,也巴仕阻止 

### of each rabbit was wrapped in 組 

### elasticated corset 釦 

### d 也 

### ea 由

### nals were returned to their cages for the duration of the exposure period. Four hours after application the corset and patches were removed 企 

### omeach anintal and any residual test material removed by gentle swabbing with cottonwool soaked in distilled water Approximately one hour follow 泊

### g the removal of the patches , 

### and 24 , 

### 48 and 72 hours later , 

### the test sites were exanined for evidence of primary irritation and scored according to the following scale: EV ALUATIONOF SKINREAC 

### Tl ONS Erythema and Eschar Formation Value Noe 巧社

### lema ......................,.・ H ・.....・ H ・.....・ H ・..............................・ H ・................・.......・ H ・-・ 

### 0 Veη r 

### slight e 可証

### lema (b 

### arely perceptible) 

## ...- Well-defined e 巧司

### hema..........・ H ・........・ H ・-...............................・ M ・................................. 

### 2 Moderate to severe ery 也

### ema.... ...-.............・ H ・.....................・ H ・......・ H ・....・ H ・....... 

### 3 Severe erythema (beet re的 55) 

### to slight eschar formation 

### 何 回 esin depth)

.............. 4 Oedema Formation Nooedema .........・.......・ H ・.......・ H ・- ...・・・......・ H ・....・ ...・・ ・... .........・ H ・., ........・ H ・.. ... .......... 

### 0 Very slight oedema (b 

### arely perceptible) ...・・ 

### Slight oedema (edges of area well-defmed by defi 凶

### te raising) ............ H ・ M ・....... 

### 2 Moderate oedema (raised approximately 1 millime むの................................-...... 

### 3 Severe oedema (raised more than 1 millimetre and extending beyond 也 E 紅 

### eaof exposure)...... ・ H ・..................・ H ・........・ H ・-........・ H ・.......・ H ・ H ・..・ H ・-......・ H ・.....................・ H ・ 

### 4 An 

### y other skin reactions 

### , if present 

### , were also recorded. 3.3 Interpretation of Results Calculation ofPrimary Irritation Index and Grading oflrritancy Potential Using the Draize Scheme 百 

### le scores for erythema and oedema at 血 

### e 24 and 72-hour readings we ぉ 

### totalled for the 也

### ree test rabbits (12 values) 刷 出 

### s to 凶 

### was divided by six to give the primary irritation index of 批 

### test material. 百

### le te 温



### t material w ぉ 

### classified according to the following scheme devised by「

L SPL PROJECTNUMBER: 14011099 PAGE9 Draize J H (1959) 唱 ermal Toxicity" 

### In: Appraisal of the Safety of Chemicals in Foods 

### , Drugs and Cosmetics. Association ofFood and Drug Officials ofthe United States 

### , Austin

### , Texas 

### , p.4 7: Primary Irritation Index 

# 。 > Ot02 

### >2 to 

### 5 > 5

to 8 Classification of Irritancy Non-irritant Mild 凶 t如 t Moderate irritant Severe irritant If irreversible alteration of 吐 le dermal tissue is noted in 組 y rabbit 

### , as judged by the Study Director 

### , which include ulceration and clear necrosis or signs of sc 紅 tissue 

### , the test material is classified as coπ 'O sive to rabbit skin. Classi 五 cation according to Draize may 

### , therefore 

### , not be applicable. 4. ARCHIVES Unless instructed otherwise by 也 e Sponsor , all original data 副 社le final report will be retained 

## m吐 le Safepharmarchives for five ye 紅 s 

### , after which ir首位uctions will be sought ぉ to お 巾 er retention or disposal.SPL PROJECTNUMBER: 140/1099 PAGE IO


### 5. RESULTS 百

### le individual scores for erythem a/ 

### eschar 組 

### doedem 丸 紅

### 'e given in Table 1. 

### Noevidence of skin訂 

### ritationwas noted during the study. 6. CONCLUSION 百

### le test material produced a prim 紅 

### y irritation index of 0.0 飢 

### d was classified as NON-IRRITANT to rabbit skin according to 也,

### e Draize classification scheme. No corrosive effects were noted. 百 

### le test material did not meet the criteria for classification as i凶 

### tant or corrosive according 

## ω 也 E 

### EU labelling regulations Commission Dir巴 

### ctive 93/21AEC.SPL PROJECT NUMBER: 140/1099 PAGE 11 EMULGEN B-66: ACUTEDERMAL IRRITATIONIN THE RABBIT Table 

### 1 Individual 

### Skin Reactions In

dividual 8cores

- Rabbit Number and 8ex 8kin Reaction Observation Time Total 95 Female 98 Female 103 Female 1

Hour 

# 。 。 。 (0 ) Ery白 em a/E schar 24 Hours 

# 。 。 。 。 Formation 48 Hours 

# 。 。 。 (0 ) 72 Hours 

# 。 。 。 。

1

Hour 

# 。 。 。 (0 ) 24 Hours 

# 。 。 。 。 Oedema Formation 48 Hours 

# 。 。 。 (0) 72 Hours 

# 。 。 。 。 8umof24 叩 d 72-ho 町 Read 皿 gs (8) 

# 。 Primary Irri 阻 lion In dex (8/6) 

# 。 /6 = 0.0 Classification NON-IRRITANT

( ) = Total values not used for calculation ofprimary ir吋阻む onindexSPLPROJECT NUMBER: 140/1099 PAGE 12 

### Appendix 1 Statement of GLPCompliance in 

### Accordance with Directive 88/320

### lE EC

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## r OF HEALTHOF THE GOVERNMENT OF1百

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### GDOM 

### GOOD LABORATORYPRA CfI 

### CE SLUEMENTOF COMPLIANCE lNACCORDANCE 百四百 DB 也CllVEII8f.詔DEEC LABORATORY TESTTYPE SafePh・l'ID Labora 旬詰'" Ltd SIW 咽 ....BIIIID 闘 hrlt Lcm doD lIoad sha 掃 除 w Derb戸hire 

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DATEOF 到 SPE CTl ON 21 Februuy 2 制却 Ag町田"al iDSpectioD for compliance wi 曲 由 e Pri ncipl 問 。 fG 。叫UI!>国軍ory pr ヨ 回 ce W 畠 canied onl at 血e above labo 回抽ry 邑 pan of UK GLP Compli 回目針。 'gramme At 血e 曲目。 f 由 e inspection no devj 副。 ns WI 町 'C found -of 開 館d 回 t 血 agni 阻 de 10 a 宵出 E 曲 ev a1idity of non --cli 刷 白 I sludics penonned at 曲 E 時 facilities 

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### SAFEPHARM LABORATORIES LTD
EMULGEN B-66: ACUTEDERMAL IRRITATIONIN THE RABBIT SPL PROJECTNUMBER: 140/1099



### 1

verif

## シ也at 白 

### is is an exact copy of 吐 

### le origin aI report which is located in the Ar

### chives of Safepharm Laboratories Ltd. 

### , Derby 

### , UK. 

# ¥

A Sanders Study Director 

### DATE: ・......・ 

# 2.2APR 却

## 02 ・ H ・...