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Corning Hazleton Inc. P.O. Box 7545 Madison, WI 53707-7545 Deliveries: 3301 Kinsman Blvd., Madison, WI S3704 608.241.4471 608.241.7227 Fax
ARO2&0321 C O R N IN G Hazleton
Sponsor: 3M
St. Paul, Minnesota
FINAL REPORT
Study Title: Primary Dermal Irritation/Corrosion
Study of T-6684 in Rabbits (OECD Guidelines)
Author: Steven M. Glaza
Study Completion Date: January 10,1997
Performing Laboratory: Coming Hazleton Inc.
3301 Kinsman Boulevard Madison, Wisconsin 53704
Laboratory Project Identification: CHW 61101150
Page 1 of 27
005684
COMPLIANCE STATEMENT
Primary Dermal Irritation/Corrosion Study of T-6684 in Rabbits (OECD Guidelines)
CHW 61101150
This study was conducted in accordance with the Organisation for Economic Cooperation and Development Principles of Good Laboratory Practice, C(81)30(Final).
Acute Studies Coming Hazleton Inc.
VWC1
Date
2 005685
QUALITY ASSURANCE STATEMENT
CHW 61101150
This report has been reviewed by the Quality Assurance Unit of Coming Hazleton Inc,, in accordance with the Organisation for Ecomonic Cooperation and Development (OECD) Principles of Good Laboratory Practice, C(81)30(Final). The following inspections were conducted and findings reported to the Study Director and management.
Inspection Dates
From
___Ifl.
Phase-----------
Date Reported to .study Director
Date Reported to Management
11/25/96 01/08/97
11/25/96 01/08/97
Dose Preparation Data/Report Review
11/25/96 01/08/97
11/25/96 01/08/97
Representative, Quality Assurance Unit
Date
3 00SGS6
STUDY IDENTIFICATION
CHW 61101150
Primary Dermal Irritation/Corrosion Study of T-6684 in Rabbits (OECD Guidelines)
Test Material
T-6684
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 3M Toxicology Service
Medical Department 3M Center, Bldg. 220-2E-02 P.O. Box 33220 St. Paul, MN 55133-3220 (612) 736-7428
Study Director
Study Location
Study Timetable Study Initiation Date Experimental (In-life) Start Date In-life End Date Experimental Termination Date Study Completion Date
Steven M. Glaza Coming Hazleton Inc. P.O. Box 7545 Madison, WI 53707-7545 (608) 241-7292
Coming Hazleton Inc. 3301 Kinsman Boulevard Madison, WI 53704
November 22,1996 November 25,1996 December 9,1996 December 9,1996 January 10,1997
4 005687
Acute Studies
Steven M. Glaza Study Director Manager
Steven R. Sorenson Study Coordinator
Jeffrey B. Hicks In-life Supervisor
Rose M. Bridge Administrative Supervisor
Toxicology Support
Kathy Myers Manager
Calvin L. Horton Supervisor
KEY PERSONNEL
Quality Assurance
Sherry R. W. Petsel Manager
CHW 61101150
Laboratory Animal Medicine
Cindy J. Cary, DYM Diplomate, ACLAM Supervisor
5 5688
CONTENTS
CHW 61101150
COMPLIANCE STATEMENT............................................................................................2
QUALITY ASSURANCE STATEMENT.......................................................................... 3
STUDY IDENTIFICATION................................................................................................4
KEY PERSONNEL..............................................................................................................5
OBJECTIVE......................................................................................................................... 8
TEST MATERIAL...............................................................................................................8 Identification..................................................................................................................... 8 Purity and Stability......... ................................................................................................. 8 Storage and Retention.......................................................................................................8 Safety Precautions.............................................................................................................8
TEST SYSTEM....................................................................................................................9 Test Animal.......................................................................................................................9 Housing............................................................................................................................. 9 Animal Diet.......................................................................................................................9 Animal Selection and Preparation of Exposure A rea...................................................... 9 Justification for Species Selection..................................................................................10
PROCEDURES.................................................................................................................. 10
Preparation of Test Material...........................................................................................10
Treatment........................................................................................................................ 10
Reason for Route of Administration.................
10
Observations................................................................................................................... 10
Termination..................................................................................................................... 11
Statistical Analyses......................................................................................................... 11
Location of Raw Data, Records, and Final Report.........................................................11
RESULTS/DISCUSSION.................................................................................................. 11
SIGNATURE.....................
11
REFERENCES................................................................................................................... 12
6 f w o o S9
CHW 61101150
TABLE 1 Individual Dermal Irritation Scores...........................................................................13 2 Average Primary Dermal Irritation Scores................................................................14 3 Individual Body Weights (g).....................................................................................14
APPENDIX......................................................................................................................... 15
Protocol TP2071...........................................
16
Protocol Amendment No. 1 ........................................................................................... 27
7 005690
OBJECTIVE
CHW 61101150
The objective of this study was to assess the relative level of primary skin irritation/corrosion of a test material on rabbits under semioccluded conditions.1
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 MATERIAL
Identification The test material was identified as T-6684 and described as an off-white liquid.
Purity and Stability The Sponsor assumes responsibility for purity and stability determinations (including under test conditions).
Storage and Retention The test material was stored at room temperature. Any unused test material will be returned to the Sponsor after issuance of the final report according to CHW SOP.
Safety Precautions The test material handling procedures were according to CHW SOPs and policies.
8 005691
TEST SYSTEM
CHW 61101150
Test Animal Adult albino rabbits of the Hra:(NZW)SPF strain were procured from HRP, Inc., Kalamazoo, Michigan on October 30, 1996.
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 stainless steel cages. Environmental controls for the animal room were set to maintain a 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 these conditions existed, they were documented and considered to have had no adverse effect on the study outcome.
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 could be expected to interfere with or affect the results of the study.
Animal Selection and Preparation of Exposure Area Two male and one female healthy, acclimated rabbits, weighing from 2,662 to 2,937 g and approximately 14 to 18 weeks of age, were selected at random and identified by animal number and corresponding ear tag. On the day before treatment, the back and/or flanks of each animal were clipped free of hair to obtain one unblemished skin site. The animals were clipped as needed throughout the study.
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CHW 61101150
Justification for Species Selection Historically, the New Zealand White albino rabbit has been the animal of choice for evaluating the effect of chemicals on the skin.
PROCEDURES
Preparation of Test Material The test material was administered as received. The pH of the test material was not able to be determined.
Treatment The undiluted test material was applied to the intact skin site on each animal's back (approximate exposure area of 6.25 cm2) in the amount of 0.5 mL. The area of application was covered with an 8-ply 2.5-cm x 2.5-cm gauze patch secured with paper tape, loosely overwrapped with Saran Wrap, and secured with Elastoplast to provide a semiocclusive dressing.
At the end of the 4-hour exposure period, the patches were removed and the test sites were washed using tap water and disposable paper towels. The test material was removed from the test sites as thoroughly as possible without irritating the skin.
Reason for Route of Administration Historically, the dermal route has been the route of choice based on the method of Draize.2
Observations Thirty minutes after removal of the test material, the degree of erythema and edema at each test site was read according to the Draize technique (recorded as the 4-hour score). Subsequent examinations were made at 24,48, 72,96 hours and Days 7 and 14. The untreated skin of each animal was used for comparison.
10 C G 5 G 9 3
CHW 61101150
Animals were weighed before test material administration and at weekly intervals throughout the study.
Termination At termination of the in-life phase, all animals were euthanized and discarded.
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.
RESULTS/DISCUSSION
Individual dermal irritation scores are presented in Table 1. Average primary dermal irritation scores and individual body weights are in Tables 2 and 3, respectively.
Application of T-6684 to the skin of rabbits under 4-hour semioccluded conditions resulted in well-defined erythema and slight to moderate edema reactions. Desquamation and Assuring were also observed. All irritation cleared by the Day 14 observation.
SIGNATURE
Study Director Acute Studies
Date
ll
CHW 61101150
REFERENCES 1. "Acute Dermal Irritation/Corrosion," Organisationfor Economic Cooperation and
Development Guidelinesfo r Testing o f Chemicals, Section 4, Health Effects, November 404, Paris Cedex (July 17,1992). 2. Draize, J. H., "Primary Irritation of the Skin," 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. 46-47 (1959).
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Table 1 Individual Dermal Irritation Scores
CHW 61101150
Animal Number 4 24
F61197 F61198 F61199
2 2 2
1 2 2
F61197
3
1
F61198
2
1
F61199 3 2
d Desquamation, f Fissuring.
Hour 48 72
Erythema
11 22 22
Edema
11 11 22
96
2 2 2
2 1 2
Day 7 14
ld 0 2f 0 ld 0
10 10 20
13 ^ - '0 5 0 9 6
Table 2 Average Primary Dermal Irritation Scores
Observation Period
Average Score*
4 Hour 24 Hour 48 Hour 72 Hour 96 Hour Day 7 Day 14
4.7 3.0 3.0 3.0 3.7 2.7 0.0
* The average primary dermal irritation score is the total dermal irritation score for all the animals (erythema and edema) divided by the number of test sites (3) at each observation period.
CHW 61101150
Table 3 Individual Body Weights (g)
Animal Number
F61197 F61198 F61199
Sex
M F M
Predose
2,937 2,662 2,755
Day 7 14
3,036 2,886 2,906
3,137 2,919 2,943
005697
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APPENDIX
Protocol TP2071 Protocol Amendment No. 1
CHW 61101150
15 0 0 5 6 9 8
CHW 61101150
Sample Submittal Form
This form is to be used when submitting samples fo r routine acute testing. Special testing needs can be easily arranged by contacting the Acute Studies Department at (608) 241-7292.
CHW Study No------ D o ' I S T O Enclose with samples and send to: Coming Hazleton Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704
Submitted b y :, C om pany:. Full GLP Compliance:
Yes .F D A (21 C F R 5 8 )
No . EPA (TSCA-- 40 C FR 792)
Date Sample Sent: ________
Number of Reports Required:
. EPA (FIFRA-- 40 CFR 160) _
OECD
--
.M AFF . MOHW
Sample Name:. T - ( o ( o ^ , T - f e U ? r t T '< o i ^ ( o
Physical Description: Special Handling Precaullot^:
O ~ J O V, &__________ ,----------------------------- -----------------------------------------------------------------
~7-
Test material purity and stability information (including under test conditions) on file with Sponsor: / Yes ____ No
Test mixture analysis for concentration/homogeneity/stability to be conducted: ___ Yes* ____ by Sponsor ____ by CHW
Sample Disposal:
Return to Sponsor at following address:
P.
3 I W C D __________ Pta _________
^ r r ^ ^ h y i . s s w */qo
. Dispose of according to C H W SOPs
-- ^ No
Sample Storage Requirements: . L Room temperature
_____ Refrigerated _____ O th er_______________
At additional cost to Sponsor (C H W will contact Sponsor as to these additional charges).
Tests
Acute Oral Toxicity in Rats
-------TP8084 Up and down LD50 procedure ____TP3206 FHSA screen: 5M-5F at 5.0 g/kg
-------Conduct defined study It death occurs at 5 .0 g/kg ____TP3013 EPA screen: 5M-5F at 5.0 g/kg
. -------Conduct defined study If death occurs at 5.0 g/kg J L T P 2 0 6 9 OEC D screen; 5M-5F at 5.0 g/kg
-------Conduct defined study if death occurs at 5 .0 g/kg
Special Instructions:
Acute Dermal Toxicity in Rabbits
-------TP3207 FHSA screen; 5M-5F at 2.0 g/kg ____TP3016 EPA screen: 5M-5F at 2.0 g/kg
-------Conduct defined study If death occurs at 2.0 g/kg -------TP 2070 O EC D screen; 5M-5F at 2.0 g/kg
-------Conduct defined study If death occurs at 2.0 g/kg
p g PecniftuSpecial instructions:.
A-+Jt>
/PrffrpRg b *
I a T -- 4 6 W For CH
---------------
Protocol Issue Date: Study D irector:___
-W.ru.AVp
Primary Skin Irritation
____ TP 3208 FHSA; 6 rabblts-1 abraded. 1 Intact sile/rabbtt __ 7 TP 3014 EPA; 6 rabblts-1 Intact slte/rabblt - K T P 2 0 7 1 O ECD; 3 rabbits-1 intact slte/rabblt ____TP 4206 D O T corrosivity; 6 rabblts-1 Intact sita/rabbit -------TP 7145 Phototoxicity; 6 rabblts-2 intact sltes/rabblt
(one site with UVA exposure) Special instructions:____________________________________
Primary Eye Irritation
____TP 6360 Low-volume procedure; 6 rabbits unwashed ____ TP 3209 FHSA; 6 rabbits unwashed -------TP2012 1978 EPA; 6 rabbits unwashed, 3 washed -------TP 3015 1982 EPA; 6 rabbits unwashed _ ^ jP 2 0 7 2 O ECD; 3 rabbits unwashed
____3 rabbits washed at 4 seconds -------3 rabbits washed at 30 seconds Special Instructions:__________________________________
Guinea Pig Sensitization
____TP2017 EPA Magnusson-KIIgman maximization ____TP6164.EC O EC D /EC Magnussun-KIIgman maximization ____TP200B Buehler sensitization ____TP 6289 Photoallergenic contact dermatitis (Armstrong) Special instructions: _______________________________________
White copy--CHW Yellow copy--Submitter
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CHW 61101150
P OS T OFFI CE BOX 7 54 5 M AD,SON. W ISCONSIN S3707-7545
, C O R N I N G C a l o r y S e r v , Company
Sponsor: 3M
St. Paul, Minnesota
PROTOCOL TP2071
Study Title: Primary Dermal Irrltatlon/Corroslon Study in Rabbits
(OECD Guidelines)
Date: June 1, 1993
Performing Laboratory: Hazleton Wisconsin, Inc.
3301 Kinsman Boulevard Madison, Wisconsin 53704
Laboratory Pro.iect Identification: HWI .noiJSXs
005700
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CHW 61101150
TP2071 Page 2
STUDY IDENTIFICATION
Primary Dermal Irritation/Corroslon Study In Rabbits (OECD Guidelines)
HWI No. Test Material Sponsor
Sponsor's Representative
Study Director
Study Location
Proposed Study Timetable Experimental Start Date Experimental Termination Date Final Report Date
(See sample submittal form)
3M Toxicology Services 220-2E-02 3M Center St. Paul, MN 55144
John L. Butenhoff, PhD 3M Toxicology Services 220-2E-02 3M Center St. Paul, MN 55144 (612) 733-1962
Steven M. Glaza Hazleton Wisconsin, Inc. P.0. Box 7545 Madison, WI 53707-7545 (608) 241-7292
Hazleton Wisconsin, Inc. Building No. 3 3802 Packers Avenue Madison, WI 53704
Week of Week of fA-K-.*, Week of |- a "?- * - 7
18 O S ? O l
CHW 61101150
TP2071 Page 3
1. Study Primary Dermal Irritatlon/Corroslon Study in Rabbits (OECD Guidelines)
2. Purpose To assess the relative level of primary skin irritatlon/corrosion of a test material on rabbits under semi occluded conditions
3. Regulatory Compliance This study will be conducted in accordance with the following Good Laboratory Practice Regulations/Standards/Guidellnes:
[ ] Conduct as a Nonregulated Study [ ] 21 CFR 58 (FDA) [ ] 40 CFR 160 (EPA-FIFRA) [ 1 40 CFR 792 (EPA-TSCA) K j C(81)30 (Final) (OECD) [ ] Notification No. 3850, August 10, 1984 (Japanese MAFF) [ ] Notification No. 313, March 31, 1982, and as amended by
Notification No. 870, October 5, 1988 (Japanese MOHW)
All procedures in this protocol are in compliance with the Animal Welfare Act Regulations. In the opinion of the Sponsor and study director, the study does not unnecessarily duplicate any previous work.
4. Quality Assurance For regulated studies, the protocol, study conduct, and the final report will be audited by the Quality Assurance Unit in accordance with Hazleton Wisconsin (HWI) Standard Operating Procedures (SOPs) and policies.
5- Test Material
A. Identification (See sample submittal form)
B. Physical Description (See sample submittal form)
C. Purity and Stability The Sponsor assumes responsibility for purity and stability determinations (including under test conditions). Samples of test material/vehicle mixture(s) (if applicable) for concentration, solubility, homogeneity, and stability analyses will be taken before administration if requested by the Sponsor. These samples (if taken) will be sent to the Sponsor after experimental termination for possible analysis.
o o s 702
19
CHW 61101150
TP2071 Page 4
D. Storage (See sample submittal form}
E. Beservg_$arnpJe?
Studies of less than 4 weeks In experimental duration will not have reserve samples retained. Reserve sample(s) of each batch/lot of test material will be taken 1f this study 1s more than 4 weeks In experimental duration. The test material reserve sample will be stored at HWI In a freezer set to maintain a temperature of below 0*C for 10 years per HWI SOP. The Sponsor will be contacted after 10 years for disposition In accordance with the appropriate regulatory Good Laboratory Practices. F. Retention Any unused test material will be discarded after Issuance of the final report, unless directed otherwise by the Sponsor. G. Safety Precautions As required by HWI SOPs and policies 6. Experimental Design A. Animals (1) Species
Rabbit (2) Strain/Source
Hra:(NZWJSPF/Hazleton Research Products, Inc. (3) Age at Initiation
Adult (4) Weight at Initiation
2.0 to 3.5 kg (5) Number and Sex
3 of any sex (6) Identification
Individual numbered ear tag.
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CHW 61101150
TP2071 Page 5
(7) Husbandry (a) Housing Individually, in screen'bottom stainless steel cages (heavy gauge). (b) Food A measured amount of High Fiber Rabbit Chow* 15326 (Purina Mills, Inc.). The food 1s routinely analyzed by the manufacturer for nutritional components and environmental contaminants. (c) Vat$r. Ad libitum from an automatic system. Samples of the water are analyzed by HWI for total dissolved solids, hardness, and specified microbiological content and for selected elements, heavy metals, organophosphates, and chlorinated hydrocarbons. (d) Contaminants There are no known contaminants 1n the food or water that would interfere with this study. (e) Environment Environmental controls for the animal room will be set to maintain a temperature of 19 to 23*C, a relative humidity of 50% 20%, and a 12-hour light/12-hour dark cycle. (f) Acclimation At least 7 days
(8) Selection of Test Animals Based on health and body weight according to HWI SOPs. An adequate number of extra animals will be purchased so that no animal in obviously poor health is placed on test.
(9) Justification for Species Selection Historically, the New Zealand White albino rabbit has been the animal of choice for evaluating the effect of chemicals on the skin.
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CHW 61101150
TP2071 Page 6
B. Dose Administration
(1) PcRsrat.tpn-gf-,toP?Mce_&rea
On the day before test material administration, the back and/or flanks of each animal will be clipped free of hair. The treatment sites will be Inspected for Interfering lesions, Irritation, or defects that would preclude the use of any of the animals. The animals will be clipped as needed throughout the study.
(2) Dose Administration Before administration of liquid test materials the pH of the material will be determined (1f possible). The test material will be applied to the intact test area (approximately 6.25 cm*) on each rabbit, 1n the amount of 0.5 mL In the case of liquids and 0.5 g In the case of solids. If a liquid, the test material will be applied undiluted. If a solid, the test material will be moistened with 0.9% saline. Aerosol materials will be discharged Into a beaker and administered as a liquid. The area of application will be covered with a 2.5-cm x 2.5-cm gauze patch secured with oaper tape and overwrapped with Saran Wrap* and Elastoplast tape to provide a semiocclusive dressing. The rabbits will not be collared during the 4-hour application period.
(3) Reason for Route of Administration Historically, the dermal route has been the route of choice based on the method of Draize.
(4) Removal of Test Material After the 4 hours of exposure, the patches and tst material will be removed as thoroughly as possible using water and/or an appropriate solvent without irritating the skin.
C. Observation of Animals
(1) Reading of Dermal Irritation Approximately 30 minutes after removing patches, the degree of erythema and edema will be evaluated according to the Draize technique (Attachment 1) and recorded as th 4-hour score. The intact skin of each animal will serve as its own control. Subsequent readings will be taken at approximately 24, 48, and 72 hours after patch removal. If irritation is present at the 72-hour examination, additional observations will be made at approximately 96 hours and at Days 7, 14, and 21, or until all irritation
70S 22
CHW 61101150
TP2071 Page 7
has cleared. Based on the level of Irritation observed at any of these time points, the study may be terminated at the direction of the study director.
(2) Body Weights Just before test material administration and weekly thereafter (when applicable).
d . P athology Any animals dying during the study will be subjected to an abbreviated gross necropsy examination and all abnormalities will be recorded. After necropsy, the animals will be discarded and no tissues will be saved. At termination of the experimental phase, surviving animals will be designated to be sacrificed and discarded.
E. Statistical Analyses No statistical analyses are required.
7- Report A final report Including those items listed below will be submitted:
Description of the test material Description of the test system Procedures Dates of experimental initiation and termination Tabulation of irritation data Description of any toxic effects other than dermal irritation
8. Location of Raw Data. Records, and Final Report Original data, or copies thereof, will be available at HWI to facilitate auditing the study during its progress and before acceptance of the final report. When the final report is completed, all original paper data, including those items listed below will be retained in the archives of HWI according to HWI SOP.
Protocol and protocol amendments Dose preparation records In-life records
Body weights Dose administration Observations Anatomical pathology records (if applicable) Study correspondence Final report (original signed copy)
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CHW 61101150
TP2071 Page 8 The following supporting records will be retained at HWI but will not be archived with the study data. Animal receipt/acclimation records Water analysis records Animal room temperature and humidity records Refrigerator and freezer temperature records
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CHW 61101150
PROTOCOL APPROVAL
TP2071 Page 9
John L. Butenhoff, PhD
Sponsor's Representative 3M
Steven M. Glaza Study Director Acute Toxicology Hazleton Wisconsin, Inc.
(j
____ --/ t c / a o n Representative Quality Assurance Unit Hazleton Wisconsin, Inc.
(TP2071.3M)
____' f f t Date " 1 Date Date
0S708
25
CHW 61101150
TP2071 Page 10
Attachment 1
Primary Dermal Irritation Scoring Scale (Draize Technique)
(1) Erythema and Eschar Formation
No erythema Very slight erythema (barely perceptible) Well-defined erythema Moderate to severe erythema Severe erythema (beet redness) to slight eschar formation (injuries In depth)
Highest possible erythema score
0 l 2 3
4
(2) Edema Formation
No edema Very slight edema (barely perceptible) Slight edema (edges are well defined by definite raising) Moderate edema (raised approximately 1 mm) Severe edema (raised approximately 1 mm and extending beyond area of exposure)
0 1
2 3
__4_
Highest possible edema score
4
26 0 0 5 7 0 9
CHW 61101150
CHW N o .
PROTOCOL AMENDMENTS
tl io> nS~g>
Amendment No. / Effective NlgaOenggg. 3.SL.
Portion of Protocol Being Modified:
Applicable sections of the protocol.
Reason for Modification: To identify the location where the study will be conducted and to reflect a company name change from Hazleton Wisconsin, Inc. (HWI) to Corning Hazleton Inc. fCHWl. replace wherever applicable the following changes
Modification: _____________Corning Hazleton Inc. fCHWl_____________________________ 3301 Kinsman Boulevard.
__________________________ Madison. WI 53704______________________________________
(G21/01-07-91)
Study Director Approval:
w--vzA\o
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