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i - ) 1 .i d ':l| i -i rj '"i ' i t ;VH3 [\7i i Corning Hazleton Inc. P.O. Box 7545 Madison, Wl 53707-7545 ' Deliveries: 330I Kinsman Blvd. Madison, WI S3704 608.241.4471 608.241.7227 Fax ARK-0%1 Sponsor: 3M St. Paul, Minnesota C O R N I N G Hazleton FINAL REPORT Study Title: 5-Daily Dose Dermal Absorption/Toxicity Study of T-6564 in Rabbits Author: F. Bud W. McDonald Study Completion Date: April 28, 1997 Performing Laboratory: Coming Hazleton Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704 Laboratory Project Identification: CHW 6329-185 Page 1 of 50 Corning Pharmaceutical Services QUALITY ASSURANCE STATEMENT CHW 6329-185 This report has been reviewed by the Quality Assurance Unit o f Coming Hazleton Inc., in accordance with the Food and Drug Administration (FDA) Good Laboratory Practice Standards, 21 CFR 58. The following inspections were conducted and findings reported to the Study Director and management. Written status reports of inspections and findings are issued to Coming Hazleton management according to standard operating procedures. Inspection Dates From To Phase Date Reported to Studv Director Date Reported to Management 09/30/96 09/30/96 Protocol Review 10/01/96 10/01/96 12/02/96 12/02/96 Sample Handling 12/02/96 12/02/96 01/03/97 01/03/97 Protocol Amendment 01/03/97 01/03/97 01/13/97 01/14/97 Data/Report Review 01/14/97 01/14/97 ,- ! J Representative, Quality Assurance Unit 2 y--8- 7 7 Date 003977 STUDY IDENTIFICATION CHW 6329-185 5-Daily Dose Dennal Absoxption/Toxicity Study of T-6564 in Rabbits Test Material T-6564 Sponsor 3M Toxicology Service Medical Department 3M Center, Bldg. 220-2E-02 P.O. Box 33220 St. Paul, MN 55133-3220 Sponsor's Representative Roger G. Perkins, PhD, DABT 3M Toxicology Service Medical Department 3M Center, Bldg. 220-2E-02 P.O. Box 33220 St. Paul, MN 55133-3220 (612) 733-3222 Study Director Study Location Study Timetable Study Initiation Date Experimental (In-life) Start Date In-life End Date Experimental Termination Date Study Completion Date F. Bud W. McDonald Coming Hazleton Inc. P.O. Box 7545 Madison, WI 53707-7545 (608)242-7901 Coming Hazleton Inc. 3301 Kinsman Boulevard Madison, WI 53704 October 25, 1996 October 28, 1996 November 25, 1996 April 28, 1997 April 28,1997 3 Acute Studies Steven M. Glaza Manager Francis (Bud) W. McDonald Study Director Jeffrey B. Hicks In-life Supervisor Rose M. Bridge Administrative Supervisor Toxicology Support Kathy Myers Manager Calvin L. Horton Supervisor KEY PERSONNEL CHW 6329-185 Laboratory Animal Medicine Cindy J. Cary, DVM Diplomate, ACLAM Supervisor Anatomical Pathology Thomas E. Palmer, PhD Anatomical Pathologist Deborah L. Pirkel/ Jack Serfort Supervisors Necropsy Quality Assurance Sherry R. W. Petsel Manager 4 002979 CONTENTS CHW 6329-185 QUALITY ASSURANCE STATEMENT..............................................................................2 STUDY IDENTIFICATION................................................................................................... 3 KEY PERSONNEL.................................................................................................................. 4 SUM M A RY ...................................................................................v......... .................................7 OBJECTIVE..............................................................................................................................9 REGULATORY COMPLIANCE........................................................................................... 9 TEST AND CONTROL MATERIALS...................................................................................9 Identification..........................................................................................................................9 Purity and Stability............................................................................................................... 9 Storage and Retention......................................................................................................... 10 Safety Precautions............................................................................................................... 10 TEST SYSTEM............................................... - .................................................................... 10 Test Animal.............. 10 Housing................................................................................................................................ 10 Animal Diet.................. .......................................................................................................11 Selection of Test Animals...................................................................................................11 Study Design............................................................................. i........................................ 11 Justification for Species Selection..................................................................................... 11 PROCEDURES....................................................................................................................... 11 Preparation of Exposure Area.............................................................................................11 Dose Administration........................................................................................................... 12 Reason for Route of Administration.................................................................................. 12 Observations o f Animals.................................................................................................... 13 Blood Sample Collections/Shipment................................................................................. 13 Pathology..............................................................................................................................14 Shipment of Bile and Tissues.............................................................................................14 Statistical Analyses..............................................................................................................14 Location o f Raw Data, Records, and Final Report............................................................14 5 C029S0 CHW 6329-185 RESULTS................................................................................................................................ 15 Body W eights......................................................................................................................15 Clinical Observations.......................................................................................................... 15 Dermal Irritation................................................................................................................. 15 Pathology............................................................................................................................. 15 D IS C U S S IO N .......................................................................................................................... 16 S IG N A T U R E ........................................................................................................................... 16 REFERENCE...........................................................................................................................16 TABLE 1 Individual and Mean Body Weights (g)........................................................................17 2 Individual Clinical Signs.............................................................................................. 18 3 Individual Dermal Irritation Scores Group 1 (Control) - Distilled Water (0.0 mg/kg/day)................................................19 4 Individual Dermal Irritation Scores Group 2 - T-6564 (10.0 mg/kg/day).......................................................................... 20 APPENDIX A .................................................... -................................................................... 21 Individual Animal Pathology Data............... 22 APPENDIX B ......................................................................................................................... 34 Protocol TP6351 ................................................................................................................. 35 Amendment No. 1 to the Protocol............................................ 49 6 002981 SUMMARY CHW 6329-185 This study was done to assess the systemic absoiption/toxicity and relative skin irritancy of T-6564 when applied to the skin o f rabbits for 5 consecutive days. The study was conducted using three male and three female acclimated rabbits of the Hra:(NZW)SPF strain for each treatment group. Group Control/ Dose Level * Number of Animals Test Material (mg/kg/day) Males Females 1 (Control) Distilled water 0.0 J 2 T-6564 10.0 - - a Administered at a dose volume of 0.5 mL/kg of body weight. The back of each rabbit was clipped free of hair and a single dose of the respective control or test material was administered to the skin of the rabbits for 5 consecutive days. The treatment sites remained intact. The area of application was covered with a gauze patch secured with paper tape around all edges and overwrapped with Saran Wrap and Elastoplast tape to provide an occlusive dressing for each approximate 23-hour exposure period. Clinical observations were conducted predose on Day 1 and at approximately 1, 2.5, and 4 hours after each control or test material administration on Days 1 through 5. Mortality checks were conducted twice daily on Days 2 through 29 (a.m. mortality check only on Day 29). Additional clinical observations were conducted daily on Days 6 through 29. Body weights were determined on Day -5 for randomization purposes, before the first control or test material administration (Day 1), and at the scheduled sacrifice interval (Day 29). The initial dermal irritation reading was made before the first control or test material administration (recorded as the Day 1 reading). Subsequent readings o f dermal irritation were made after each patch removal on Days 2 through 6 and on Day 13. A blood sample (approximately 4 mL) was collected from each animal on Days -3, 8, 15, and 22. In addition, at the time of necropsy (Day 29), approximately 20-40 mL of blood was obtained from each control animal and approximately 20 mL of blood was obtained 7 002982 CHW 6329-185 from each Group 2 animal. All samples were centrifuged and separate samples of serum and cellular fractions were obtained and sent frozen on dry ice to the Sponsor. On Day 29, the animals were anesthetized with sodium pentobarbital, bled via the posterior vena cava, exsanguinated and necropsied. The whole liver, bile, an approximate 1-cm x 1-cm section o f the dermal application site, and both kidneys (collected as one sample) were collected from all animals, weighed (volume only determined for bile), and sent frozen to the Sponsor. Application o f T-6564 did not result in any test material-related changes in body weight gain or macroscopic findings at necropsy. All animals appeared normal throughout the study. In the distilled water control animals, no dermal irritation was observed in one animal and slight to severe dermal irritation was observed in the other five animals. In the animals treated with T-6564, slight dermal irritation was seen in three animals, and moderate to severe dermal irritation was seen in the other three animals. The reason for the unexpected dermal irritation in the distilled water control group was not determined. 8 0029S3 OBJECTIVE CHW 6329-185 The objective of this study was to assess the systemic absorption/toxicity and relative skin irritancy o f a test material when applied to the skin of rabbits for 5 consecutive days. REGULATORY COMPLIANCE This study was conducted in accordance with the United States Food and Drug Administration Good Laboratory Practice Regulations for Nonclinical Laboratory Studies, 21 CFR 58, with the exception that analysis of the test material mixtures for concentration, homogeneity/solubility, and stability was not conducted. All procedures used in this study were in compliance with the Animal Welfare Act Regulations. In the opinion of the Sponsor and study director, the study did not unnecessarily duplicate any previous work. All procedural times presented in this report fall within the acceptable ranges as specified in the Wisconsin facility of Coming Hazleton Inc. (CHW) Standard Operating Procedure (SOP). TEST AND CONTROL MATERIALS Identification The test material was identified as T-6564 and was described as. a clear, colorless liquid. The control material was distilled water (Neenah Springs; Expiration May 20, 1997) and was described as a clear, colorless liquid. Purity and Stability The Sponsor assumes responsibility for test material purity and stability determinations (including under test conditions). Analysis of the test material mixtures for concentration, homogeneity/solubility, and stability was not conducted. The purity and stability of the control material were considered to be adequate for the purposes of this study. 9 002984 CHW 6329-185 Storage and Retention ; ' The control and test materials were stored at room temperature. A reserve sample o f the ' - control and test materials was taken and stored in a freezer set to maintain a temperature of -20C 10. The control material reserve sample will be retained at CHW for one year in accordance with CHW SOP. The test material reserve sample was sent to the - Sponsor. Any unused test material was returned to the Sponsor according to CHW SOP. Any remaining control material may be used for other testing and will not be discarded after issuance of the final report. 4 Safety Precautions The control and test material handling procedures were according to CHW SOPs and A policies. **' 1 i TEST SYSTEM Vi Test Animal Adult albino rabbits of the Hra:(NZW)SPF strain were received from HRP, Inc., Kalamazoo, Michigan on October 16, 1996. i S Housing After receipt, the animals were acclimated for a period of at least 7 days. During ' ] acclimation and throughout the study, the animals were individually housed in suspended ' l stainless steel cages. Environmental controls for the animal room were set to maintain a .j temperature of 19 to 23C, a relative humidity of 50% 20%, and a 12-hour light/ 12-hour dark lighting cycle. In cases where variations from the required ; temperature and humidity conditions existed, they were documented and considered to `` have had no adverse effect on the study outcome. .-i 10 `i .i G.029S5 CHW 6329-185 Animal Diet The animals were provided access to water ad libitum and a measured amount of Laboratory Rabbit Diet HF #5326, PMI Feeds, Inc. The feed is routinely analyzed by the manufacturer for nutritional components and environmental contaminants. Samples of the water are periodically analyzed. There were no known contaminants in the feed or water at levels that would be expected to interfere with or affect the results of the study. Selection of Test Animals The animals were identified by animal number and corresponding ear tag and were placed into study groups using a stratified body weight randomization program. The randomization body weights were determined on Day -5. Study Design Animals weighing from 2,038 to 2,270 g and approximately 14 to 18 weeks of age at initiation of treatment were placed into the following study groups: Group Control/ Dose Level Dose Volume Number of Animals Test Material (mg/kg/day) (mL/kg/day) Males Females 1 (Control) Distilled water 2 T-6564 0.0 10.0 0.5 0.5 J> J J*! ~Js Justification for Species Selection Historically, the New Zealand White albino rabbit has been the animal of choice because o f the large amount of background information on this species. PROCEDURES Preparation of Exposure Area On the day before the first control or test material application, the back and, if necessary (to obtain unblemished skin), the flanks of each rabbit was clipped free o f hair with an 11 CHW 6329-185 electric clipper. The clipped area made up approximately 20% of the total body surface area. The test sites (intact skin) were inspected for interfering lesions, irritation, or defects that would preclude the use of any of the animals. The animals were clipped as needed throughout the study (Days 4,13 and 29). Dose Administration All animals received five consecutive days of administration of the respective control or test material. The first day of treatment was designated as Day 1. G roup 1. An individual dose was calculated and measured based on each animal's body weight on the first day of treatment. The control material (distilled water) was applied to the test site at a dose volume of 0.5 mL/kg in a thin and uniform layer. The rate of application was approximately 0.04 mL/cm2. G roup 2. An individual dose of the test material mixture (T-6564 and distilled water) at a concentration of 20 mg/mL was calculated and measured based on each animal's body weight on the first day of treatment. The test material mixture was applied to the test site at a dose volume of 0.5 mL/kg of body weight in a thin and uniform layer. The rate of application was approximately 0.04 mL/cm2. Each area of application in Groups 1 and 2 was covered with a 4-ply 5-cm x 5-cm gauze patch. Each gauze patch was secured with paper tape around all edges and overwrapped with Saran Wrap and Elastoplast tape to provide an occlusive dressing. Collars were used to restrain the animals during each approximate 23-hour exposure period. Approximately 23 hours after each control or test material application, the restraining collars and patches were removed and the application sites were rinsed with tap water and dried with disposable paper towels. Reason for Route of Administration The dermal route is a potential route of exposure in humans. 12 _______________________________________________________CHW 6329-185 Observations of Animals Clinical observations were conducted predose on Day 1 and at approximately 1, 2.5, and 4 hours after each control or test material administration on Days 1 through 5. Mortality checks were conducted twice daily on Days 2 through 29 (a.m. mortality check only on Day 29). Additional clinical observations were conducted daily on Days 6 through 29. Body weights were determined on Day -5 for randomization purposes, before the first control or test material administration (Day 1), and at the scheduled sacrifice interval (Day 29). The initial dermal irritation reading was made before the first control or test material application according to the Draize1technique (recorded as the Day 1 reading). Subsequent readings of dermal irritation were made within 30 to 37 minutes after each patch removal (Days 2 through 6) and on Day 13. Blood Sample Collections/Shipment A blood sample (approximately 4 mL) was collected from a marginal ear vein o f each animal on Days -3, 8,15, and 22. In addition, at the time of necropsy (Day 29), approximately 20 to 40 mL of blood was obtained from each control animal and approximately 20 mL of blood was obtained from each Group 2 animal via the posterior vena cava. All samples were stored at room temperature until centrifuged. After centrifugation, separate samples of serum and cellular fractions were obtained and stored in a freezer set to maintain a temperature of -20C +10C until.shipped to the Sponsor. The serum and cellular fraction samples obtained on Days -3, 8, and 15 were shipped frozen (on dry ice) to the Sponsor (James D. Johnson, 3M E.T. & S, Bldg. 2-3E-09, 935 Bush Avenue, St. Paul, MN, 55106) on Day 17. The serum and cellular fraction samples obtained on Days 22 and 29 were shipped to the Sponsor one week after the experimental (in-life) date of termination in the same manner as the samples obtained prior to Day 22. The Sponsor is responsible for the retention and disposition of the samples. CHW does not accept any responsibility for the analysis of the samples collected in this study nor are these results presented in this report. 13 CHW 6329-185 Pathology At termination o f the in-life experimental phase (Day 29), animals were anesthetized with sodium pentobarbital, bled via the posterior vena cava, exsanguinated, and necropsied in random order. The sites of control or test material application were washed with warm tap water before the necropsy procedure. All animals were subjected to an abbreviated gross necropsy examination and any abnormalities were recorded. The whole liver, bile, an approximate 1-cm x 1-cm section of the dermal application site, and both kidneys (collected as one sample) were collected from all animals, weighed (volume only determined for bile), and immediately placed in a freezer set to maintain a temperature of -20C 10. After necropsy, the animals were discarded. Shipment of Bile and Tissues One week after the date of in-life experimental termination, the tissues (whole livers, dermal application sites, and kidneys) and bile were sent frozen (on dry ice) to the Sponsor (James D. Johnson, 3M E.T. & S, Bldg. 2-3E-09, 935 Bush Avenue, St. Paul, MN, 55106), along with documentation of their corresponding weights or volumes. The Sponsor is responsible for the retention and disposition o f the samples. CHW does not accept any responsibility for the analysis of the samples collected in this study nor are these results presented in this report. Statistical Analyses No statistical analyses were required by the protocol. Location of Raw Data, Records, and Final Report The raw data, records, and an original signed copy of the final report will be retained in the archives of CHW in accordance with CHW SOP. 14 RESULTS CHW 6329-185 Body Weights Individual and mean body weights are in Table 1. All animals, with the exception of Animal No. F60987 (Group 2 male), exhibited a weight loss from randomization to initiation (in-life). This weight loss can be attributed to the acclimation of the animals to restraining collars conducted for 3 days (approximately 23 hours/day) before the initial control and test material administration. All animals gained weight from initiation (Day 1) to termination (Day 29). Clinical Observations Individual clinical signs are in Table 2. All animals appeared normal throughout the study. Dermal Irritation Individual dermal irritation scores are in Tables 3 and 4. The control material (distilled water) did not produce dermal irritation in one animal. Four other control animals exhibited slight to moderate erythema, slight edema and/or slight desquamation reactions. Slight to severe erythema and edema reactions and slight desquamation were observed in the other control animal. No explanation for the unexpected dermal irritation in the distilled water control group was found. The test material, T-6564, produced slight to moderate erythema and edema reactions in five animals. One of these animals also had slight desquamation on the application site. Slight to severe erythema and edema reactions (with subcutaneous hemorrhaging), slight desquamation and coriaceousness, and moderate Assuring were observed in the other animal treated with T-6564. Pathology Individual animal pathology data (tissue weights, bile volumes, and gross pathology observations) are presented in Appendix A. Observed at necropsy on the liver o f one Group 2 female was a single, firm, green, pedunculated mass (0.7 x 0.3 x 0.3 cm) attached to the ventral surface of the right median lobe near the gallbladder. The findings 15 002990 CHW 6329-185 in this animals was not considered to be test material related. No visible lesions were seen in any of the other animals at necropsy. DISCUSSION The acute systemic absorption/toxicity and relative skin irritancy of T-6564 was evaluated in male and female albino rabbits when administered dermally for 5 consecutive days. Application of this material did not result in any test material-related changes in body weight gain or macroscopic findings at necropsy. All animals appeared normal throughout the study. Slight to severe dermal irritation was observed in the distilled water control animals and in the animals treated with T-6564. SIGNATURE F. Bud W. McDonald Study Director Acute Studies Date REFERENCE 1. Draize, J. H., "Acute Dermal Toxicity (Single Exposure)," In: Appraisal o f the Safety o f Chemicals in Foods, Drugs and Cosmetics - Dermal Toxicity, Association of Food and Drug Officials of the U.S., pp. 54-56 (1959). 16 002991 Table 1 Individual and Mean Body Weights (g) CHW 6329-185 Males Animal Random Number -ization Day 1 29 Females Animal Random Day Number -ization 1 29 G roup 1 (Control) - Distilled W ater (0.0 mg/kg/day) F60982 F60983 F60984 2,213 2,203 2,258 2,113 2,764 2,097 2,673 2,102 2,646 F60988 F60989 F60990 2,297 2,246 2,298 2,142 2,714 2,101 2,677 2,114 2,783 Mean 2,225 2,104 2,694 Mean 2,280 2,119 2,725 Group 2 - T-6564 (10.0 mg/kg/day) F60985 F60986 F60987 2,196 2,199 2,263 2,038 2,583 2,086 2,597 2,270 2,823 F60991 F60992 F60993 2,210 2,181 2,269 2,068 2,676 2,047 2509 2,207 2,835 Mean 2,219 2,131 2,668 Mean 2,220 2,107 2,673 17 002992 Table 2 Individual Clinical Signs CHW 6329-185 Animal Number Sex Observation Day I* Hour 1 2.5 4 Day 2 Hour 1 2.5 4 Day 3 Hour 1 2.5 4 Day 4 Hour 1 2.5 4 Day 5 Hour 1 2.5 4 Day(s) 6 7 8-11 12 13-15 16-29 Group 1 (Control) - Distilled Water (0.0 mg/kg/day) F60982 M Appeared normal // // / / F60983 M Appeared normal / / F60984 M Appeared normal / / F60988 F Appeared normal / / F60989 F Appeared normal / / F60990 F Appeared normal / / / / / G roup:! - T-6564 (10.0 mg/ltg/day) F60985 M Appeared normal / / / F60986 M Appeared normal / / / / F60987 M Appeared normal / / / / / / / F60991 F Appeared normal / / / F60992 F Appeared normal S / / F60993 F Appeared normal / . * Each animal appeared normal prior to control or test material administration. / Condition exists. 18 CHW 6329-185 Table 3 Individual Dermal Irritation Scores Group 1 (Control) - Distilled Water (0.0 mg/kg/day) Dermal Reaction Erythema Edema Atonia Desquamation Coriaceousness Fissuring Erythema Edema Atonia Desquamation Coriaceousness Fissuring Erythema Edema Atonia Desquamation Coriaceousness Fissuring Males Study Day 1 2 3 4 5 6 13 Animal No. F60982 0 1 112 2 1 0 111111 0000000 0 0 0000 1 0000000 0 0 00 000 Animal No. F60983 0000000 0 0 00000 0 0 00 000 0000000 0000000 0 0 00 000 Animal No. F60984 0 0 0 122 1 0 0 0 0 110 0000000 0 00000 1 0 000000 0000000 Females Study Day 1 2 3 4 5 6 13 Animal No. F60988 0 1 1 12 2 1 00 11110 0000000 00 0 00 0 0 000 00 0 0 000 00 0 0 Animal No. F60989 0 111 12 1 00 11110 0 00 00 00 0000000 0000000 0000000 Animal No. F60990 0 1 1 12 0 0 1 1 i 1 1 0000000 000000 1 0000000 0000000 I 19 ,'L-J C02994 Table 4 Individual Dermal Irritation Scores Group 2 - T-6564 (10.0 mg/kg/day) CHW 6329-185 Dermal Reaction Males Study Day 1 2 3 4 5 6 13 Animal No. F60985 Erythema Edema Atonia Desquamation Coriaceousness Fissuring 0 0 1 1 110 0 0 00 110 0 000000 0000000 0000000 0000000 Animal No. F60986 Erythema Edema Atonia Desquamation Coriaceousness Fissuring 0 0 0 12 2 1 000022 1 0000000 00 0000 1 0 00 0 000 0 0 0 0 00 0 Animal No. F60987 Erythema Edema Atonia Desquamation Coriaceousness Fissuring 0 0 11 110 0 00 1110 0 0 00 00 0 0 000000 0000000 0 000000 a Subcutaneous hemorrhaging. Females Study Day 1 2 *y 4 5 6 13 Animal No. F60991 00 111l 0 0 0 0 0 0 10 0000000 0000000 0000000 0 00 00 00 Animal No. F60992 0 12 2 y 0 a2 0 1 1 2 y *y 1 0000000 000000 1 0 0 0 0 1 10 0000002 Animal No. F60993 0 12222 1 0 1 11 1 10 0000000 0000000 0000000 0000000 20 002995 APPENDIX A Individual Animal Pathology Data CHW 6329-185 21 002996 Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX A Individual Animal Pathology Data PACE: 1 ANIMAL NUMBER: F60982 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 11/25/96 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: NOT ENTERED DATE AND TIME OF NECROPSY: 11/25/96 14:22 PROSECTOR: DAVID SCHUETTE RECORDER: STEVE VAN ADESTINE POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: STEVE VAN ADESTINE ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE T O B O D Y W E I G H T <%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS D E R M APPL. SI T E (IS) 0.9747 WEIGHT TAKEN K I DN EY <KD) 15.2166 WEIGHT TAKEN L I V E R (LI) 86.3171 WEIGHT TAKEN i BI LE (ML) (BI) 1.6 ......... ......... W E I G H T T A K E N * ORGAN NAME ** GROSS PATHOLOGY OBSERVATIONS *** SEVERITY, K E Y W O R D (S) O R P H R A S E FREE-TEXT COMMENTS AND NOTES G E N E R A L C O M M E N T (GC) KK>) -ABBR N E C PERFORM -NO MACROSCOPIC LESIONS CHW 6329-185 o *0 if >1 .- . A.-'- .. Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX A Individual Animal Pathology Data PAGE: 2 ANIMAL NUMBER: F60963 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 11/25/96 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: NOT ENTERED DATE AND TIME OF NECROPSY: 11/25/96 14:23 PROSECTOR: DEBBIE PIRKEL RECORDER: STEVE VAN ADESTINE POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: STEVE VAN ADESTINE ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE T O B O D Y W E I G H T (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS DERM APPL. SITE K I DN EY (KD) L I VE R (LI) BI LE (ML) (BI) (IS) 1.2753 14.0416 63.7942 0.6 ......... ......... WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN ORGAN NAME * * * GROSS PATHOLOGY OBSERVATIONS *** SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES GENERAL COMMENT (GC) ........................ -ABBR NEC PERFORM -NO MACROSCOPIC LESIONS CHW 6329-185 a Q 'sO 08 Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX A Individual Animal Pathology Data PAGE: 3 ANIMAL NUMBER: F60984 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 11/25/96 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: NOT ENTERED DATE AND TIME OF NECROPSY: 11/25/96 14:34 PROSECTOR: DAVID SCHUETTE RECORDER: STEVE VAN ADESTINE POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: STEVE VAN ADESTINE ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE T O B O D Y W E I G H T (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS DERM APPL. SITE K I D N E Y (KD) L I V E R (LI) BI L E (ML) (BI) (IS) 0.8539 15.5098 86.3868 0.6 ......... ......... WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN ORGAN NAME *** GROSS PATHOLOGY OBSERVATIONS ** SEVERITY, K E Y W O R D (S) O R P H R A S E FREE-TEXT COMMENTS AND NOTES t-Po- G E N E R A L C O M M E N T (GC) ABBR NEC PERFORM NO MACROSCOPIC LESIONS CHW 6329-185 002999 i Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX A Individual Animal Pathology Data PAGE: 4 ANIMAL NUMBER: F6098S SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 11/25/96 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: S TERMINAL BODY WEIGHT: NOT ENTERED DATE AND TIME OF NECROPSY: 11/25/96 14:59 PROSECTOR: DAVID SCHUETTE RECORDER: STEVE VAN ADESTINB POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. T O M PA LM ER WEIGHER; STEVE VAN ADESTINB ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE T O B O D Y W E I G H T <%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS DERM APPL. SITE K I DN EY ((CD) L I V E R (LI) BI L E (ML) (BI) (IS) 0.81B0 13.2012 62.4555 0.8 ......... ......... WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN ORGAN NAME GROSS PATHOLOGY OBSERVATIONS *** SEVERITY, K E Y W O R D (S) O R P H RA SE FREE-TEXT COMMENTS AND NOTES G E N E R A L C O M M E N T (GC) (LOn -ABBR N E C PERFORM -NO MACROSCOPIC LESIONS CHW 6329-185 CQ3000 Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX A Individual Animal Pathology Data PAOEt 5 ANIMAL NUMBER: F609B6 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 11/25/9 STUDV DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: NOT ENTERED DATE AND TIME OF NECROPSY: 11/25/96 15:00 PROSECTOR: DEBBIE PIRKEL RECORDER: STEVE VAN ADESTINE POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: STEVE VAN ADESTINE ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE T O BO DY W E I G H T (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS DERM APPL. SITE K I DN EY <KD) L I VE R (LI) B I L E (ML) (BI) (IS) 1.8205 13.4319 57.2256 O.S ......... ......... WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HEIGHT TAKEN ORGAN NAME *** GROSS PATHOLOGY OBSERVATIONS SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES Ko\) GE NE RA L CO MM EN T (GC) -ABBR NEC PERFORM -NO MACROSCOPIC LESIONS CHW 6329-185 003001 1 Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX A Individual Animal Pathology Data PAGEi E ANIMAL NUMBER: F60987 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 11/25/96 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: NOT ENTERED DATE AND TIME OF NECROPSY: 11/25/9S 15:08 PROSECTOR: DEBBIE PIRKEL RECORDER: STEVE VAN ADESTINB POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: STEVE VAN ADESTINB ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE T O BO D Y W E I G H T (\> ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS DERM APPL. SITE K I DN EY (KD) LI VE R (LI) BI LE (ML) (BI) (IS) 0.7972 15.8230 90.8606 0.2 ......... ......... WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN W E I G H T T A K E N * ORGAN NAME ** GROSS PATHOLOGY OBSERVATIONS SEVERITY, K E Y W O R D (S) O R P H R A S E FREE-TEXT COMMENTS AND NOTES -JIO G E N E R A L C O M M E N T (GC) ABBR NEC PERFORM NO MACROSCOPIC LESIONS Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX A Individual Animal Pathology Data PACE: 7 ANIMAL NUMBER! F609BB SEX: FEMALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 11/25/96 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BODY HEIGHT: NOT ENTERED DATE AND TIME OF NECROPSY: 11/25/96 14:35 PROSECTOR: DEBBIE PIRKEL RECORDER: STEVE VAN ADEST1NE POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: STEVE VAN ADESTINE ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE T O BO DY W E I G H T () ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS DERM APPL. SITE K I DN EY (KD) L I V E R (LI) B I L E (ML) (BI) (IS) 2.0758 16.3783 82.5349 1.6 ......... ......... WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN ORGAN NAME GROSS PATHOLOGY OBSERVATIONS ** SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES GENERAL COMMENT (GC) ........................ -ABBR NEC PERFORM -NO MACROSCOPIC LESIONS CHW 6329-185 C03003 Corning Ha zl et on Inc. Madison, Wisconsin USA APPENDIX A Individual Animal Pathology Data PAGEi S ANIMAL NUMBER: F60989 SEX: FEMALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 11/25/96 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BOOY WEIGHT: NOT ENTERED DATE AND TIME OF NECROPSY: 11/25/96 14:49 PROSECTOR: DEBBIE PIRKEL RECORDER: STEVE VAN ADESTINE POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: STEVE VAN ADESTINE ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE T O BO D Y W E I G H T (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STAT U S DERM APPL. SITE K I DN EY (KD) LI VE R (LI) B I L E (ML) (BI) (IS) 1.1923 16.1(10 77.6005 1.8 WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN ORGAN NAME * * * GROSS PATH OLOGY OBSERVATIONS *** SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES GENERAL COMMENT (GC) ABBR NEC PERFORM -NO MACROSCOPIC LESIONS CHW 6329-185 C03004 Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX A Individual Animal Pathology Data PAGE: 9 ANIMAL NUMBER: F60990 SEX: FEMALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 11/25/96 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: NOT ENTERED DATE AND TIME OF NECROPSY: 11/25/96 14:48 PROSECTOR: DAVID SCHUETTE RECORDER: STEVE VAN ADESTINB POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: STEVE VAN ADESTINE ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE T O B O D Y W E I G H T (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS DERM APPL. SITE K I DN EY (KD) LI VE R (LI) BI LE (ML) (BI) (IS) 0.7232 13.4790 93.1001 1.1 WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN ORGAN NAME * * * GROSS PATH OLOGY OBSERVATIONS *** SEVERITY. KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES GENERAL COMMENT (GC) -ABBR NEC PERFORM -NO MACROSCOPIC LESIONS C03005 Corning Ha zl et on Inc. Madison, Wisconsin USA APPENDIX A Individual Animal Pathology Data PAOE: 10 ANIMAL NUMBER: F60991 SEX: FEMALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 11/25/96 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: NOT ENTERED DATE AND TIME OF NECROPSY: 11/25/96 15:09 PROSECTOR: DAVID SCHUETTE RECORDER: STEVE VAN ADESTINE POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: STEVE VAN ADESTINE ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE T O BO D Y W E I G H T t%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS DERM APPL. SITE K I D N E Y (KD) L I V E R (LI) B I L E (ML) (BI) (IS) 1.0478 13.4087 85.4184 0.2 ......... ......... WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN ORGAN NAME *** G R O S S PATHOLOGY OBSERVATIONS * SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES G E N E R A L C O M M E N T (GC) L I VE R (LI) . . . . -ABBR NEC PERFORM - M A S S (ES) ' J -ATTACHED TO VENTRAL SURFACE OF RIGHT MEDIAN LOBE NEAR GALL BLADDER: SINGLE PEDUNCULATED MASS, 0.7 X 0.3 X 0.3 CM, GREEN, FIRM; SAME ON CUT SURFACE; REGIONAL LN (HEPATIC) NOT IDENTIFIED CHW 6329-185 003006 t- t.. Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX A Individual Animal Pathology Data PACE: 11 ANIMAL NUMBER: F60992 SEX: FEMALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 11/25/96 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: NOT ENTERED DATE AND TIME OF NECROPSY: 11/2S/96 15:25 PROSECTOR: DEBBIE PIRKEL RECORDER: STEVE VAN ADESTINE POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: STEVE VAN ADESTINE ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE T O B O D Y W E I G H T (1) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS DERM APPL. SITE K I DN EY (KD) L I V E R (LI) BI LE (ML) (BI) (IS) 1.3648 13.5655 82.5047 0.5 ......... ......... WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN ORGAN NAME ** G R O S S PATHOLOGY OBSERVATIONS *** SEVERITY, K E Y W O R D (S) O R P H R A S E FREE-TEXT COMMENTS AND NOTES G E N E R A L C O M M E N T (GC) UN>) -ABBR N E C PERFORM -NO MACROSCOPIC LESIONS CHW 6329-185 003007 Jw. Corning Hazleton Inc. Madison, Wisconsin USA APPENDIX A Individual Animal Pathology Data PAGE: 12 ANIMAL NUMBER: F60993 SEX: FEMALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 11/25/96 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: NOT ENTERED DATE AND TIME OF NECROPSY: 11/25/96 15:30 PROSECTOR: DEBBIE PIRKEL RECORDER: STEVE VAN ADESTINE POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: STEVE VAN ADESTINE ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE T O B O D Y W E I G H T (%) ORGAN TO BRAIN WEIGHT RATIO ORGAN STATUS j D E R M APPL. SI T E (IS) 0.9460 WEIGHT TAKEN | K I DN EY (KD) 15.0657 WEIGHT TAKEN LI VE R (LI) 91.6304 WEIGHT TAKEN i BI LE (ML) (BI) 0.4 ......... ......... WEIGHT TAKEN ORGAN NAME * * * GROSS PATHOLOGY OBSERVATIONS *** SEVERITY, KEYWORD(S) OR PHRASE FREE-TEXT COMMENTS AND NOTES OJ U> GENERAL COMMENT (GC) -ABBR NEC PERFORM -NO MACROSCOPIC LESIONS CHW 6329-185 C03008 APPENDIX B Protocol TP6351 Amendment No. 1 to the Protocol CHW 6329-185 34 003009 Corning Hazleton Inc. P.0. Box 7545 Madison V I 53707.7545 Dclii-enes: J JO f Kinsman Bird. Madison. \7 SJ704 60S.34I.447I 60S.241.7227 Fax CHW 6329-185 CORIMING Hazleton Sponsor: St Paul,3MMinnesota PROTOCOL TP6351 Study Title: 5-Daily Dose Dermal Absorption/Toxicity Study of T-6564 in Rabbits Date: October 25, 1996 Performing Laboratory: M3a3Cd0io1smoKnin,ingWsmHisaacnzolneBstooinnuleI5nv3ca.7rd04 Laboratory Project Identification: CHW 6329-185 Corning Pharmaceutical Services 35 03010 CHW 6329-185 CHW 63T2PP9a6-g13e855I2 STUDY IDENTIFICATION 5-Daily Dose Dermal Absotption/Toxicity Study of T-6564 in Rabbits CHW No. Test Material Sponsor Sponsor's Representative Study Director Study Location PrEEDoxxprappofeestrreiiRdmmeSeepnntouttraadtllyDTSTateaitrmermteiDtnaaabttleieon Date 6329-185 T-6564 T33PSMMt.oM.OxP.eiCcdaBoeuicnolloa,txeglMry3D,3NBSe2pel2dar50vgr5ti.mc1e23e23n0-t3-22E20-02 T3(3PSR6MMt.ooM.O1xg2P:ieeC)cadBroeui7coGlnl3o,axt.3eglM-ryP3D3,3eN2BSe2r2kpe2l2diar05nvgr5sti.m,c1e23Pe23nh0-tD3-22,E2D0-0A2BT (FCPM6..oO0amBd8.i)uisBndo2gon4Wx,2H-.W77a5M9zI40le5c1tD5o3no7n0Ian7lcd-.7545 MC33oa0md1iisnKognin,HsWmazIalnet5oB3no7u0Iln4ecv.ard WWWeeeeeekkk ooofff JONacontvuoeabmreyrbe62r,8,21591,997916996 36 003011 CHW 6329-185 CHW 63T2PP9a6-g31e58153 1. S5-tDudayily Dose Dermal Absorption/Toxicity Study in Rabbits 2. TmPouarteaprsoisaselesswthheensaypstpelmieidctaobtshoerpstkioinnoanfdratbobxiitcsitfyoranfidvereclaotnivseecsuktiivneirdraityasncy of a test 3. TPtnReorhseatitgcsbmutiselctaauecttedooRrynrieyadwgluCucimlltolaeitmxdbit:oeupnrlcsieo/asSnntfdcaouenrcdtcaeorddnsci/neGnautrciacdtoeiorlidnna,ensscoewluwibthiitlhitthyte,heehxofcmoelolpogtiweoninnegitthyGa,toaaonnddalLsytasabibsoilroiatfytothrwyeill [[[[(([XJ]]]]]] 442CCN51009o(o8ntCNCCi1dfFF)Foiu3chRRRca0Stti5a71(aoFn896sn02ina(NNFa((oNEEDlo.)PPsoA3.(AnAO)8r3--e5E1FTg03CISuF(DClaRJanaA)tAdep)da)8nS7e0tsued(JyMapAaFnFes)e MOHW) ARunellngeupclraeotscisoeandrsuil.ryesIdnuinpthltiehciaostpepinraoniotyoncpoorlefvathiroeeuisSnpwcooonrmsko.prliaanndcestwudityhdthireecAtonri,mtahleWstuedlfyardeoAesctnot 4. TQAInhsuces.aul(priCatryonHtcoAWecsoU)slu,nSritstaatnuninddceyaarcdccooOnrdpdueacrnatc,teiannwgdiPthtrhoetchefedinWuarleissrce(opSnoOsritPnws)fialaclnibldietypaoouldficiCiteeosd.mbiyngthHeaQzlueatolinty 5. Test Material A. TId-e6n5t6i4fication B. TPohybseicdalocDumesecnritpedtioinn the raw data 37 G03012 CHW 6329-185 CHW 63T2PP9a6-g31e58154 C TtT(ftPeaiohnhurkrmecerecsliniutSeonydnpbasictoeaaniefnomngonsndrptou.erlranSeatdsatidasoe(msbrniuif,itmlneithsatieosytkstmercarnooet)ngisodepwninotieinluolisntniyblbse/e)iss.losistleyuSrnebatfqimoltuiorpteyplste,htueseardinotSydofpttashoetnensadrtsbwoimslritisaataeytbfeitbarleiiynratayletl/hyxvdespeeehetSsericpirwmmloenieilnsmnloatniartxi.loottunrbsee(s) D. SRtooormagteemperature E. sRRtueedsseyerr.vveesSaammpplele(ss) of each batch/lot of test material will be taken for this Tmcohameinpttelaesitntiomanatoteemfritpahleerraeitnsu-erlreivfeeofpsah-2ma0spelCeo(fs)t1hw0eiClsltubudenyt.siltorreetdurantedCHtoWthienSapforneseozrerafsteetr to F. aARllnetyreenulatnituoesdnedin-telisftemteastteinriga.l will be returned to the Sponsor after completion of C. SAasferetyquPirreedcabuytiConHsWSOPs and policies 6. Control Material A. DIdiestnitlliefidcawtiaotner B. CPhleyasri,ccaollDorelesscsriplitqiuoind C. TtPohuberietpyuadraietnyqduaaSntedtafbsotiarlibttihylietypuorfptohsiesscoofmtmhisersctiuadllyy. available material is considered D. SRtooormagteemCpoenrdaittuiroens 38 ' C03013 CHW 6329-185 CHW 63T2PP9a6-g31e58155 E. RReesseerrvveesSaammpplel(ess) of each batch/lot of control material will be taken. Ttohemacionnttarionl amtaetmerpiaelrarteusreervoefs-a2m0pClefs1)0wCil.l be stored at CHW in a freezer set F. AdRinesctyeanrrdetimeodnaianfitnegr icsosnutarnoclemoaftethriealfimnaalyrbepeoursted for other testing and will not be G. ASasferetyquPirreedcabuytiConHsWSOPs and policies Experimental Design A. Animals (1) SRpaebcbiiets (2) SHtrraa:i(nN/ZSWou)rScPeF/HRP, Inc. (3) AAgdeultat Initiation (4) W2.0eitgoh3t.0atkIgnitiation (5) 6Nummalbeesraanndd6Sfeexmales <) IInddeinvtiidfiucaaltinounmbered ear tag (7) Husbandry (a) IHnoduivsiidnugally, in suspended stainless steel cages 39 003014 ii CHW 6329-185 CHW 63T2PP9a6-g31e58156 (b) AFfFoeoremodndesua,tsrIuintriceo.dn).aalmTchooeumnfptoooondfenListasbraoonurdatitnoeernlyvyiRraoannbamblyieztneDtdailebtcyoHnthFtae#mm5i3na2ann6utfs(a.PcMtuIrer (c) AWaccnhodalnaoltltyeriebiznnrietta,dutsemefdolefrhrcoyttoemdtdraolaecnldaerimasbusoeotnnolsvtms.e,adthisecoaslviydysst,memsept.eaclsSi,faioemdrgpalmensiocoprohfbotihsopelhowagtiaectsae,lraanrde (d) TCwhooeunrltedamairnietnenarfonetrksenowwitnh cthoinstasmtudinya.nts in the food or water that (e) mcEE5y0nnac%vivlnieirtr+oaomni2nnm0amy%aeenb,tneteaamtlninpdcteoearnrartt1uruo2prl-etsheodofuofdrru1lt9eihgetChota/tn1ioni2m--2lhia3fol*euCrpro,rodoamacrrekedwluacirtlyilevcsble.ee.hsueTmthitedoidtyarokf (f) AActclleiamstat7iodnays (8) SbanBradoeeanelsepdaqecnloudatimaicmooteiennazdlanhotiuiinenfomtanoTlobtebhspesvtrrutaoioodngAuydfrnasegblmixymrotodrpawuaylopsioatswhnriueinhmsigeinanahligltsntheaawcidcisslatolryprabdsltaeiicfoniepgfedudstrtoocubnhdoCaydtsHeyeisWdntw.itseiSoaTigOthithohPetnast.a.niAmnals will (9) JHothufiisssctthiosfporiiceicccaaeitleilbsoy.e,nctahfuoesreNSoepwfecthZieeesallaSarengldeecWatmiohonituentalobfinboacrkabgbroitunhdasinbfeoernmtahteioanniomnal ot 40 003015 CHW 6329-185 CHW 63T2PP9a6-g31e58157 B. Dose Administration (1) Test Groups J Group TeCstoMntarotelr/ial (Dmogs/ekgL/edvaeyl) MNaulemsber ofFAemniamleasls 1 1(Control) DWistaitlelerd o 3 12 T-6564 10.0- 3 3 3 *** TToobbeeaaddmmiinniisstteerreeddaattaaddoosseevvoolluummeeooff00..501mmL/Lk/gkgofobfobdoydywewiegihgtht (2) ObraTalPearnahrnsebcieieambkoptihntawtaraeslernswi,aal.ddliitt,arlmiclrToyiioentbfhnabneentsetoitefocaisfoctlnniuiertE,pieetsmepxssotaeparha(rdloipeysdnspeftuwi(rarfnteorecoiieelcxttlitoiaosAsmbbklfetrtiathaenhetciaea)asnltltiiwyr'pwuapiwn2nloeld0biudt%lblhecdeamoasonpininsftnrresheetopcheellelededuccmedttstderoeakidttcitaetnhhlrf)crioe,lbaoirltoupuhidpgasneeypehtrpeofo.slrluauifftcenTraarfkthniahtsniyceeogeonsosf,htafuraetdehtvahayceee..hd (3) auArww0baopucpwDoaepd.onapvrnacl0iiiosepslmltmldcpeli1plscllpfellrireaoeihiudplawobbbcnuncmresrlxAeeaemiretietoisseiimatLvtdvnmidtsddedpweor/tealmeliakpfoanatlylisadrthugetslyrciieitelreedto.gsnecoseewdianrnobhnis2dta.wseTaviest3dnaltraiteelwihro-ntoeieTsntarahmheldgeasreidrchtoteecco.dohihadeScuahuooarlvoesrarw'dnpmTdasosiedrtapvraiDeeiahdlaseybtlpuessnetyhtiaaotepimew.yolffmddlWrlamoioiieefayvctTfrp1dbtha4eraa.ooeahbwattd-tehrwpfpicppiemtaToerte*oplahs0iatiynthainpulge.tenai5waleesrehcsnp5ineaerrsaattiie.mcdrclt0mptatremlutroiua-aipnLaoanEnoactbpkatdlni/tltmdiilevoetekisroeael.oenagf(dsncariGlpax.tin.oredooTadptomrxloapln5lmolhGTu/pTiyal.avueenah0torsirDhtehdpnsedoe-espehteocasdiruu*sraiimyaGfprfcaetst1dleirtslalpalrraa1euaomsgdaatipwer1tinunrabmmdideoeeinpudedaolgndaiiglzftnarnsxe.oo22eeyedtisbtter)shseuepetppatvoisa2errwnrcaetoenafsatohtcwhitdltpmctavwluiterlhpiomniimevilid.lndxbllfaieaelieetettrbuomdAebsaeorfrtenleeifltasnhlte 41 G03016 CHW 6329-185 CHW 63T2PP9a6-g31e58158 (4) TRheeasdoenrmfoalr rRoouuteteisoaf Apodtmenitniailstrroautitoenof exposure in humans. (5) tsAbtRhaietppeeemprswperomaooatvxftcoeaihtvmrleeessaopdttrfeaiauolTnnysrddein2tscogct3ooMtwlnhhlatoeaarrutosteterlirswsrmsioaiaulrafllettaeebcnrreoiealarlalpeecampchptrioopotveplniserctidpaaorttaieoroncnscdeoodwtlnuvhtireerleonl.rltbe,mesiifdawtuneaaerslcihaemelsdsaaatpwerpyriil.taihclaTwwthiaoielrnlm, C. Observation of Animals (1) osaDdCBtnnauaeldiliydflynyosy4irco(e1danah-li.co5rmDoeuOncf.raotsbtyoarrsoanre2.clfdr9tlvoei)pnrar..itmcetieOaoa.slc)nbthsssfmieogarradnvtsmmae,rtioiidnoarailntsiastlalryidamtymttiahotiyehnnrirbesooaetufrfatgecetxhiorotnefDntno,radorayelctdl2aain9nwpdipc(harateoe.lnmxsstid.imgmimrnaeastocte,ertlterayaidnalid1ltb,yoyt2wn.t5ihc,ee (2) (wBiSfRrAotreieurittfathtdoaeadiytarnciieconhDh3nmgth0aaeeryonetnfoiait1mndD36i1ia.tn0e)il.a.rglImmnAwcdiaondiillvnudlIittidrertboirsueoliatnamlaoafttrdlaieoedtdrerenemesrtaamacnmlhadalirptrreieairrcttriacioatthlraiodtarineeoddmnmreaoircsnveoiaatsrhdldteris(naDtgDwiasoaiynlywls,ibI2tlhle-re6bem)aeddaaemiinrnnmdatgadaoielnned (3) (FBDooardyyra1nW)d,oeomingihzDtasatiyon2,9,beofroraet dtheeathini(twiahletnesstuorrvicvoanltreoxlcemeadtser1iadlaayp)plication (4) Blood Sample Collections (a) atPFedrrrememdqiionunsieaesnttir(coaayntnioy(ntDimatoyeD2fr9ao)ym1u),potnoDfoauyrsd8a,ys15b,e2f2o,reanthdeaitneitxiaplerdiomseental 42 003017 CHW 6329-185 CHW 63T2PP9a6-g31eS8159 (b) BmDMlaaoeyrtoghd2ion2sda.almoeraprlCevsoel(ilanepcoptifrooanxl/liNmaunamitmelbyaelrs4oamtfLtAh)enwiminiltalelbrsvealcsolplreecdteodsefrtohmrouagh Fwbm2scao0eriaconlxrlommdiibfbimLittecitauoheioonmnedfbep(tdobvaionlfioofsnlrptoDeuoeoddmmrasiysowfeirreb2iopallv9lmeoc.e)hsbn,seeaicaaboopcclnbephatrtvrawoaaoinx,nilliielammadpnbaapielftmrreosoolaaxybmlcitmr2saiaei0fancaitcecrteioedhlfdy)i4c,Ge02ianrd0nomdauomLpnmaLp2oDopofraarifbonbylxibumo2inlmoo9dadola(dttwehleiyll TdwtctciDheneerheraeylnmeeaylturkriiebfclin1raftlea5aeeuorftengottiwfozetoedrieraidnotlrcs.,hlnitanseaibme-aoTnelntSnipdhfdsptsleeoeetoohdsntsnmbeieetsswrtroapafmsuirireoilmnonilpsontzeiaabnatedariiteennoanitotndshtoe-notr2noo.cos0trefeuwedlTrgtdCrluohuyhhmelaewaiDtsc1rSaearea0nefopmyrkdtooaCopsmnc1cl.tst5epeihosotrlTwe.erlinuomhsiiSlrlsealppotrreosobberefnetsarraispatnuisoucon-merrtlnenieiodfswtaeinabnifanstrldfhodetsiezntftreohonroerenndoen The serum and cellular fraction samples will be shipped to: J3B9Sa3Mtl.md5gPeE.Bas.uu2TDls-,.3h.&MEJAo-N0vhS9enns5ou5ne106 JsahmipemseDnt. oJofhtnhseosnamorplheiss. alternate will be notified regarding the 'n CHW 6329-185 CHW 63PT2aP9g6-e31581150 D. Pathology -.1 (1) tAcem(d(fieU1hncrvxoxu-enoeojnocsanreeylrmsailmdclazniucnebtineagmihitcguxnriointeumonetaenisdhinmtIddenaiou-eiotlaacwnnlscatnmlestloesiottydwlddunhalos.yddimnedSnlbeiyidleneatcaemTitbticgooeanishsareorlnratuirdelmanfmgdsbuwiiawaiicinjropnbnsecieihcllanenfcraselaoildtogt)ferblhatrieddeecfmtweenaehomerdltdiaedardiolpv.lvlnebiseDeietearbitnrirmislnueeae,netdsataah))bauc,ty,lewhbirmotlaebabsoielinzoplllrroeeleder(pcdiadsfvblbtaliiiee-lcvmucaw2dainrtar0ameitiedvtiffdhociraetCcohconidgeslomeriaroddsanobvdi1etdstaleieid0eensilulnt.l)yim,aCnaaoanepAna.ncmdcpln,iaanrmeovAbwocianmraeopaptefi,dlotsbtpiasheygbualrirshonandnkerdxndytiibodndieimincntaagraeaolytpes(svyi,a (2) (ea(fSOeabthrvvxbnxoceneioansthaehalamozeDaupnriendmiknmpganriuijyrumaedeaolsitenclenax2ioitdoetlta9iinsiymnotte,leSosn.yswatdah(t,miiwcdeTcelnlraeoaihialnt1ltfibelelhnndi-eerccebitamcmmaesedntmiueiinainsbrdmxlaecesjarceaadag1wocrlsti-sdetrfncieodeomlmawdldenrlpd.iebbtlsee.oleeiraslacbaeraaTttme)nnuivh,oerepnenaaesilenbntewchoodb))re,fhfrowteiobi-tpmvzh2illsleieee0miladdetlbdedeCivwvdeedirieiinamacrgth1t,ortera0lhoballlsyseenioCslacdedvppt.onieelp(umaednalmcAci,lacelrowfaodctpartpeeaidveiosrivenangynainrtthlo,oeaeasbcbidnaatrldeoreb,p)a,isatlyanl,ld (3) TTsTsreehihhsniseeppstpoussfeneaardosmmSizbtppeaolllnmeeetssohpfonea(lelrnipdvdtSerheyrhetrsh,ioierpcbneimeirtleletecino,snottiderttorhdeenersmipanSnoapSldnodeandcipnsitpsiogoplrinowcwsa7eitit.iitiCoghonhi.nn(t4ssoo)ito.fne(rbt,eh)vae.wonelsdTuaemmhkkeiepdaslSfnetewpsey.orisnlcl)soobwlrleeilcilstiboen. ..-'.ii . SNtoatsistatiticsatilcAalnaanlyalsyesses are required. 44' 003019 M CHW 6329-185 CHW 63PT2aP9g6-e31581151 8. ARefpinoarlt report including those items listed belowwill be submitted. .! TTPDDDDGGInraaareeerodbbootssscieuusscccvesssrrrllidaaiiidoppppputtuiitttaafrooaiiiettoooennlhhsnnnxooaoopllnoooooeffifffggrmmmityytamhahnoeleefreayrietnntnattiptteesdloabosissiltxrouttnytideigsacn(yysdnwiiesatdfiwtfetaefraiceteemgioqcibohgntuyntshtes/rtsdsaoseatenlenxbrddmdmyatbaanbestylrdeiemlxrietrdihiaranvoielntoassadetSltiuiotoldmuennodvesyeselDleivreecltor) . *i 9. OtfdsfSmCtLhhioiapngHoreaertioanactgWelsanm,iaitnrsntruiiapigoenaawodteprlcleynrsoiloriladuioflrrdanoadtedtlucdtfihtsaihnar,soe,RiaiagnnfacorfagregiotorwednhdemntiiacoutselaosipDsrpnepnlyropsaeietestretithfpoateoaaseeeorldr,gematr,rffhCgRteweos,ceesHeeloarisllclefinolWlwselooatwterbrnifeoo.ld,ieAddlfnlswbgrc,tIbbmchfheieeRhlseaaltfliichorteogvabehgsewrnefreaeeeoisirdSranrwgava.lfpegvecoeimordalcroTelni.eSeslfahspbnaaeonettebtrmharivloanSeerpecdnecphlfatdeeseoiaotdain(niotomsnaCiss)mofleo,epHndtrarslhaaWeetmleintep(nosrdopafi)trtiaey,honhtFlr.aasaeiefivollanllweOadecarrocieilnCcolltrpliheiHRftogtiabovyrtiWeteinteeepm.hasasoaalerdeWuvorniptaedsaftafphnitCtpttoedehioenHnsreregtWthhoeef ,' I); SlSSDAnPFaht-ruiDoBROmnilnopdisaaatoobfppyeotelndssoliceeednypcmrorroegorevlacwiepmrccdoaprraooeatmeleinarirlizlcsoetdgrdiapoacnpnsh(torttsopiaitidiosnsotorrsthndoinnrgoaetoidltnrnoicaercoaegotcenalcolyorsadrirmgdesncseoenrdddmscoepnyts) 45 "*i 003020 CHW 6329-185 CHW 6329-185 PTaPg6e35112 Tarhcehifvoeldlowwiitnhgtshuepsptourdtyingdarteac.ords will be retained at CHWbut will not be AARIWnennsafiittrmmreiugraamellarenrranoeattolcoyermcsiaaipslntti/ebdramrecafccprtoleieioremrdnzasaetautrinrotedenmamrnpedaceiornhartutedumnsraeindrciteeycorrerecdcosorrddss 46 003021 CHW 6329-185 PROTOCOL APPROVAL CHW 63PT2aP9g6-e31581153 3RSMpoognsoGr'.sPReerpkirness,enPthaDtiv,eDABT ACFS.tocumuBdtuyeindDSgWtiuHrde.aciMzeutlos)ecr-tDononIanlcd. CQoumaliitnygAHsaszulreatnocneIUncn.it (6329-185)HD Date Date 47 003022 CHW 6329-185 Attachment 1 Scoring Scale for Acute Dermal Reactions 203E1r----yNMSStheloioevgndmeheertaerate 023E1d---eNSSMmeloioavgndeheertera((btreaari(esrlaeyidspemderocarepeppttrhiobaxlneimt1oamtewmlye)llIdmefmin)ed by definite raising) 2A031t----oNSMMnlioiaaognrdhkeeterda(ste(ling(oshlteolwiamstpriecatiiutrymrn)etnot onofremlaaslt)icity) 023D1e---sNMMSqluoiaognardhkemeterada(tstie(loipgn(rshoctnaoslecusanlcianengdd)ffllaakkiensg) with denuded areas) 0C231o----rMSMNialocioagnerdhekoeteurda(sdtne(eetcos(rlsueegaahtsheaenirnydptbelrixiattbutlirelei)t)y) 023F1i----ssMNSMuloriaoignrndhkeegterda(dte(ecf(ricanrciaktecskcswraiitcnhkdsbelirenmedeispi)nidge)rmis) CHW 63PT2aP9g6-e31581154 48 C03Q23. p/X-oroo - 137^ (grooccoooi) BEST COPY AV CHW 6329 Coming Hazleton Inc. P.O. Box 7545 M adiwn, 1 55707-7545 Delivfries: 3301 K in tm jn B ird . AItdison, Vt't S3704 M 8.24t.447l 608.241.7227 Fax CO RN IN G Hazleton AMENDMENTNO. 1TOTHE PROTOCOL Protocol No.: TP6351 5-Daily DoseDermal Absorption/ToxicityStudyofT-6564 in Rabbits CHW6329-185 Sponsor T3PS3MM.tMoO.xPe.iCdcaBioeuconlla,oxtlegM3rDy,3NeBS2p2ela5dr0rv5gti1m.c32ee32n-0t3-222E0-02 Sponsor's Representative RogerG. Perkins. PhD, DABT Testing Facility C3M3oa0md1iisKnoginn,HsWmazIalne5tBo3n7o0uI4nlecv.ard Study Director F. Bud W. McDonald This amendment modifies the following portionofthe protocol: EffectiveOctober28, 1996 dotf1eoo.fslstl0eomPw.v0aaiog1tnelegmur:im7La,le/7kc.tgaoE.n0xTn.5pooetmbrbieLme/aakebdgnlm.etaitRlnoeiDasptdeleamsrciegiednnti,ahstBteea.rtadDtbhooleseseteielnAsetvtdhmemilsaotisenferic1isat0tilro.0aanttmioo1gfn0/t.,k0h(ge1m)upgsrT/oiknetgogst.caoiGnldcroworseiuetahpsvseto.htlTehuehmee Corning Pharmaceutical Sonic 49