Document QaQmQOK9jJ6k6vbKob6aEG8o

AR226-3107 CONFIDENTIAL DPT 430/984441/SE Sponsor * DuPont-Speciality Chemicals Jackson Laboratory Chambers Works Deepwater NJ 08023 USA Research Laboratory Huntingdon Life Sciences Ltd' P.O. Box 2 Huntingdon Cambridgeshire PE 18 6ES ENGLAND Report issued 9 December 1998 Pare i nf n Company Sanitized. Does not contain TSC CB! DPT 430/984441/SE CONTENTS COMPLIANCE WITH GOOD LABORATORY PRACTICE STANDARDS Page 3 QUALITY ASSURANCE STATEMENT............................................. 4 RESPONSIBLE PERSONNEL......................................................................... 5 SUMMARY......................................................................................................... 6 INTRODUCTION............................................................................................... TEST SUBSTANCE........................................................................................... 7 8 EXPERIMENTAL PROCEDURE.................................................................... 9 RESULTS........................................................................................................... CONCLUSION................................................................................................... 12 12 TABLE 1. Dermal reactions............................................................................................ 13 2 ; Company Sanitized Does noi contain T DPT 430/984441/SE COMPLIANCE WITH GOOD LABORATORY PRACTICE STANDARDS The study described in this report was conducted in compliance with the following Good Laboratory Practice standards and I consider the data generated to be valid. The UK Good Laboratory Practice Regulations 1997 (Statutory Instrument No 654). OECD Principles of Good Laboratory Practice (as revised in 1997), ENV/MC/CHEM(98)17. EC Council Directive 87/18/EEC of 18 December 1986 (Official Journal No L 15/29). Brenda I. Parcell, M.I.A.T., Study Director, Huntingdon Life Sciences Ltd. \- \T_ Date : 3 : Company Sanitized. Doss not contain TSCA C QUALITY ASSURANCE STATEMENT DPT 430/984441 /SE The following have been inspected or audited in relation to this study Study Phases Inspected Protocol Review Process Based Inspections Husbandry Housing/Environment Weighing o f animals Test material:Control/Administration Treatment Procedure Scoring Records Audit Training Records Report Date of Inspection 22 September 1998 10 July 1998 10 July 1998 10 July 1998 10 July 1998 10 July 1998 10 July 1998 10 July 1998 10 July 1998 10 July 1998 11 November 1998 Date of Reporting 22 September 1998 13 July 1998 13 July 1998 13 July 1998 13 July 1998 13 July 1998 13 July 1998 13 July 1998 13 July 1998 13 July 1998 11 November 1998 Protocol: An audit of the protocol for this study was conducted and reported to the Study Director and Company Management as indicated above. Process based inspections: At or about the time this study was in progress inspections and audits of routine and repetitive procedures employed on this type of study were carried out. These were conducted and reported to appropriate Company Management as indicated above. Report Audit: This report has been audited by the Quality Assurance Department. This audit was conducted and reported to the Study Director and Company Management as indicated above. The methods, procedures and observations were found to be accurately described and the reported results to reflect the raw data. Kevin P. de-Salis, B.A. (Hons ), C.Biol., M.I.Biol., Dip.R.Q.A., Quality Assurance Unit Head, Department of Quality Assurance, Huntingdon Life Sciences Ltd.' Date :4 : Company Sanitized. Does net contain TSCA CBl RESPONSIBLE PERSONNEL Brenda I. Parcell, M.I.A.T., Study Director, Department of Acute Toxicology. DPT 430/984441/SE : 5 : Company Sanitized. Does not contain TSCA CBf SUMMARY DPT 430/984441/SE A study was performed to assess the skin irritation potential oi followed was that described in: p the rabbit. The method EEC Methods for the determination o f to a e ity r A ^ ^ 92/69/EEC (O Seial Journal No. L383A, 29.12.92), Part B, Method B.4. Acute toxicity (Skin Irritation). OECD Guideline for Testing of Chemicals No. 404 "Acute Dermal Irritation/Corrosion". Adopted 17 July 1992. Three rabbits were each administered a single dermal dose of 0.5 ml of the test substance and observed for 4 days. No dermal irritation was observed following a single semi-occlusive application oi rabbit skin for up to four hours. ito intact B H H R w d l not require labelling with the risk phrase R38, "Irritating to skin", in accordance with "Commission Directive 93/21/EEC. _ /'--"airs TSC-&C&l mpsR Sanitized. Dos nc. c--*- INTRODUCTION DPT 430/984441/SE The study was designed to assess skin irritation potential o f ^ ^ m ^ ^ ^ J Q f o llo w in g a single dermal application to rabbits. The test substance may come into contact with skin during handling or use. The study was conducted in compliance with EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC (Official Journal No. L383A, 29.12.92), Part B, Method B.4. Acute toxicity (Skin Irritation). OECD Guideline for Testing of Chemicals No. 404 "Acute Dermal Irritation/Corrosion". Adopted 17 July 1992. The albino rabbit was chosen as it has been shown to be a suitable model for skin irritation studies and is the animal recommended in the test guidelines. The amount of test substance administered was chosen in compliance with the guidelines. The protocol was approved by Huntingdon Life Sciences Management on 7 July 1998, by the Sponsor on 17 July 1998 and by the Study Director on 11 September 1998. The experimental phase of the study was undertaken between the 15 and 19 September 1998. Company Sanitized. Does not contain TSCA G Identity: Chemical name: Intended use: Appearance: Storage conditions: Lot number: Expiry: Purity: Sample received: TEST SUBSTANCE DPT 430/984441/SE Room temperature [ A Two years from date of receipt 23 June 1998 :8: Comp Sanitised. Does not contain TSU OB EXPERIMENTAL PROCEDURE DPT 430/984441/SE ANIMAL MANAGEMENT Animals for this study were selected from a stock supply of healthy adult rabbits of the New Zealand White strain, obtained from Harlan UK Ltd, Bicester, Oxon, England. They were in the weight range of 2.1 to 2.6 kg and at least 11 weeks of age, prior to treatment (Day 1). All rabbits were acclimatised to the experimental environment for a minimum period of five days prior to the start of the study. The rabbits were selected without conscious bias for the study. They were housed individually in stainless steel cages with perforated floors in Building R14 Room 5. A standard laboratory rabbit diet (Special Diet Services STANRAB (P) SQC pellet) and drinking water were provided ad libitum. The batch of diet used for the study was analysed by the supplier for nutrients, possible contaminants and micro-organisms likely to be present in the diet and which, if in excess of specified amounts, might have an undesirable effect on the test system. The animals were fed hay on arrival and subsequently three times a week. The water supplied to Huntingdon Life Sciences by Anglian Water was potable water for human consumption. Anglian Water takes its guidelines on water quality from the EEC directive relating to water for human consumption (80/778/EEC) and conforms to the United Kingdom Water Act 1989 and subsequent amendments. Results of routine physical and chemical examination o f drinking water at Consumers' taps, as conducted by the supplier, are made available to Huntingdon Life Sciences Ltd as quarterly summaries. . Animal room temperature was maintained at 17 to 20C and relative humidity at 50 - 72 /o. These environmental parameters were recorded daily. Lighting was controlled by means of a time switch to give 1-2-hours of artificial light (0700 - 1900 hours) in each 24 hours period. Each animal was identified by animal stock number and an ear tattoo. This identification will be unique within the Department throughout the duration of the study. Each cage, was identified by a coloured label displaying the study number, animal number and initials of the Study Director and Home Office licensee. TEST SUBSTANCE PREPARATION [I 'as administered as supplied by the Sponsor. The absorption of the test substance was not determined. The homogeneity, stability and purity of the test substance were the responsibility of the Sponsor. : 9 : Company Sanitised. Does not contain TSCA C2i DPT 430/984441/SE TREATMENT PROCEDURE Approximately 24 hours prior to application of the test substance, hair was removed with electric clippers from the dorso-lumbar region of each rabbit exposing an area of skin approximately 100 mm x 100 mm. Approximately 0.5 ml o f the test substance was applied under a 25 mm x 25 mm gauze pad, to intact skin on each animal. To help clarify the irritant potential of the test substance;- initially only one animal was-treated. With-tins animal, the test substance was applied to three treatment sites and the exposure period was varied between treatment sites (ie three minutes, 60 minutes and four hours). L The exposure periods were initiated in a step-wise manner with the 60 minute and four hour exposures only initiated after consideration of results from the earlier exposure periods. r.:. ' . K On the basis of results from this phase of the study, the four hour exposure period was selected for use in ; . the remaining two animals, when the test substance was applied to one intact skin site on each animal. Each treatment site was covered with "Elastoplast" elastic adhesive dressing. Only during the three and 60 minute exposure periods was the initial animal restrained. For the four hour exposure, none of the animals were restrained but were returned to their cages immediately after treatment. At the end of the exposure period(s), the semi-occlusive dressing and gauze pad were removed and the treatment sites washed with warm (33 to 36C) water to remove any residual test substance. The treated area was blotted dry with absorbent paper. mh y OBSERVATIONS k .... Clinical signs I All animals were observed daily for signs of ill health or toxicity. Dermal responses Examination of the treated skin was made on Day 1 (immediately after removal of the patches following 3 minute and 60 minute exposure and approximately 60 minutes after the four hour exposure) and on Days 2, 3 and 4 (equivalent to 24, 48 and 72 hours after exposure). Local dermal irritatiqn was assessed using the prescribed numerical system: Erythema and eschar formation: No erythema . Very slight erythema (barely perceptible) Well-defined erythema Moderate to severe erythema Severe erythema (beet redness) to eschar formation (injuries in depth) preventing erythema reading 0 1 2 3 4 t. t. 10 Uized. Dess not contain TSCACBl Company Sam Oedema formation: No oedema Very slight oedema (barely perceptible) Slight oedema (edges of area well-defined by definite raising) Moderate oedema (raised approximately 1 millimetre) Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure) DPT 430/984441/SE 0 1 2 4 ARCHIVES All raw data and study related documents generated during the course of the study at Huntingdon together with a copy of the final report will be lodged in the Huntingdon Life Sciences Ltd Archive, Huntingdon. Such records will be retained for a minimum period of five years from the date of issue of the final report. At the end o f the five year retention period the client will be contacted and advice sought on the future requirements. Under no circumstances will any item be discarded without the client s knowledge. DEVIATIONS FROM PROTOCOL There were no deviations that were considered to have affected the integrity or validity of the study However, the following were noted: . t $': . Each animal was identified by animal stock number and an ear tattoo. I ^ The higher value recorded for relative humidity was 72%. This exceeded the 30 - 70% range stated in the j protocol. There were no other deviations from the protocol. fe * - : 11 :. Company Sanitized. Does not contain TSCA f:Rl RESULTS DPT 430/984441/SE CLINICAL SIGNS There were no signs of toxicity or ill health in any rabbit during the observation period. DERMAL RESPONSES The numerical values given to the dermal reactions elicited b y ^ | | m | | ^ ^ r e shown in Table 1. No dermal response to treatment was observed following a three minute, 1 hour or 4 hour exposure. CONCLUSION A single semi-occlusive application o; dermal irritation. to intact rabbit skin for up to four hours elicited no : 12 t: Company Sanitized. Does not contain TSCA CBI DPT 430/984441/SE TABLE 1 Dermal reactions observed after application o; Animal No. & Sex 1319 Male* 1320 Male 1321 Male Exposure Time 3 Minutes 1 Hour 4 Hours 4 Hours 4 Hours E=Eiythema Day 0=0edema 1 2 3 4 E 000o -------- QS------1- 4 - --0 ~ --o ~ --G - E 0000 0 0000 E 0000 0 0 0 0 0 E 0000 0 _0. 0 0.. 0 0000 0 00 00 * Screen animal $ r f- t S" ; : 13 : Company Sanitized. Does not contain TSCA CB5