Document DGw7kR6GbemK3K6qXpZM6JKGa
FOR DU PONT USE ONLY
AR226-2954
Du Pont HLO 19-91
Study T i t l e Skin S e n s itiz a tio n Test wit
'in Guinea Pigs
Study Completed On March 25, 1991
Contracting Laboratory
Pharmakon Research In t e r n a t io n a l, In c . P.0. Box 313
W averly, Pennsylvania 18471
for
Haskell
E. I . du Pont de Nemours and Company L aboratory f o r Toxicology and In d u s tr ia l
P .0 . Box 5 0 , E lk to n Road Newark, Delaware 19714
__ _ M e d icin e
.
Medical Research No.
Laboratory P ro je c t No. Haskell Laboratory R eport No. 19-91
Page 1 of 74
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uDuu.tP'cont HLO 19-91
PHARMAXON RESEARCH INTERNATIO NAL, INC.
WAVERLY, PENNSYLVANIA 18471
PHONE (717) 586-2411
COMPLIANCE STATEMENT
FAX (717) 586-3450
This study was conducted in compliance with the Principles of Good Laboratory Practices (GLP) as promulgated by the following regulatory agencies:
U.S. Food and Drug Administration, as stated in the Federal Register, 21 CFR Part 58, Friday, September 4, 1987.
U.S. Environmental Protection Agency as stated in the
Federal Register, 40 CFR Part 160, Thursday, August 17,
1989.
.
U.S. Environmental Protection Agency as stated in the Federal Register, 40 CFR Part 792, Thursday, August 17, 1989.
Organization for Economic Co-operation and Development Guidelines for Testing Chemicals (OECD), ISBN 92-64 12221-4, adopted by the council at its 535th meeting on 12th May, 1981.
Study No.: PH 424-DU-007-90
"To the best of my knowledge, this study was conducted in accordance with applicable Good Laboratory Practice regulations; there were no deviations from these regulations that impacted on study conclusions."
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GENERAL INFORMATION
Du Pont HLO 19-91
M aterial Tested: 3 Medical Research N o.: Haskell N o .: Haskell T est Code N o .: Pharmakon Study N o .: Physical Form : P u rity : Composition:
PH 424-D U -007-90 Amber D isp ersio n
Synonyms: Stabil 1 ty:
In the absence o f v is ib le evidence to the c o n tra ry , th e t e s t m a te ria l was assumed to be s ta b le under th e c o n d itio n s o f adm inistration. .
M a te ria l T e s te d :*3 P u rity: Synonyms:
Other Codes:
CAS,Registry N o.: S ta b ility :
P o sitive Control M aterial N -P h en yl-1,4-P h en yle ne d iam i ne
1,4-Benzenediamine p -p h en ylen ed iam ine 8 PPD
.
t A ld ric h Chemical C o ., Lot #05012MK 8 A ld ric h Chemical C o ., C atalog #24139-3
101-54-2
In the absence o f v is ib le evidence to the c o n tra ry , th e t e s t m a te ria l was assumed to be s ta b le under the c o n d itio n s o f admi n is t r a t io n .
-3-
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GENERAL INFORMATION (CONT.)
Du Pont HLO 19-91
Sponsor:
Du Pont Chemicals
.
E. I . du Pont de Nemours and Company
W ilm ington, Delaware
M aterial Tested3 Submitted By:
Du Pont Chemicals E. I . du Pont de Nemours and Company
Jackson Laboratory Deepwater, New Jersey
Pharmakon Notebook N o .: Study In itia te d - Completed:
5 /4 /9 0 - 3/25/91
In - L i f e Phase In itia te d - Completed:
8/11/90 - 9/17/90
There are 74 pages in t h i s r e p o r t.
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DU PONT CENTRAL RESEARCH AND DEVELOPMENT HASKELL LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE
Du Pont HLO 19-91
March 2 5 , 1991
Du Pont Chemicals Jackson Laboratory Deepwater, New Jersey
Skin S e n s itiz a tio n Test w itl
n Guinea Pigs
A ttached is a re p o rt from Pharmakon Research In t e r n a t io n a l, In c . (PH 4 2 4 -D U -0 0 7 -9 0 ). In clu d ed in the r e p o rt are t e s t methods, r e s u lts and
conclusions.
a to p ic a l in d u ctio n c o n c e n tra tio n o f 100% and c h a lle n g e
c o n c en tratio n s' o f 100% and 10% in d i s t i l l e d w a te r, was te s te d on th e shaved in t a c t skin o f 5 male and 5 fem ale guinea p ig s . A p p ro p ria te p o s it iv e , n eg ative and v e h ic le c o n tro l groups were used d u rin g t h is stu d y.
During th e ch a lle n g e phasea,^Tf^ryttiemnaa w__as observed in an.y .t e.s t anim als
tr e a te d w ith e i t h e r 100 o r 10%Lpp^MasB. ^ TM was e--xrp-e--c--t-e--d, a rp o s,iti.v e ^c
f
s e n s it iz a t io n response ( s lig h t T of iSdd/o/orrmmiTild erythem a)` was o'bserved -in r5 o u t or
10 p o s itiv e c o n tro l an im als. In c o n tra s t, no dermal responses were observed in
any o f th e 5 n e g a tiv e or 5 v e h ic le c o n tro l anim als when ch allen g ed w ith the
te s t m a te ria l, p o sitive control m a te ria l, and/or v e h ic le .
Under the conditions o f th is s t u d y M |
h y p e rs e n s itiv ity in guinea p ig s .
t
[iid not produce delayed
m . i=.
k
Dolores E. M alek, Ph.D. Research T o x ic o lo g is t
D E M /alw (H L 09.43)
J
5-
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Amended FPii nnaall DReopnonrrtr
uDu rPtont HLO 19-91
P H A R M A RESEARCH INTERNATIO NAL. INC.
WAVERLY, PENNSYLVANIA 18471
PHONE (717) 586-2411
FAX (717 ) 586-3450
Skin Sensitization Test with H-18,267 in Guinea Pigs
PH 424-DU-007-90
Submitted to
E . I . Du Pont De Nemours Newark, Delaware
Susan E. Armondi, LAT Study Director
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Du Pont HLO 19-91
Skin Sensitization Test with H-18,267 In Guinea Pigs
SUMMARY
Test Article H-18,267 at an induction concentration of 100% and challenge concentrations of 100% and 10% (w/v) in distilled water was tested on the clipped, intact skin of male and female guinea pigs. p-Phenylenediamine (PPD) as a 35% (w/v) suspension in distilled water was used to demonstrate the ability of the test system to detect a skin sensitizer (positive control group). Distilled water served as a vehicle control.
During the primary irritation phase, no dermal irritation was observed in the vehicle control animals. Slight erythema was observed at 24 and 48 hours in the animals receiving the test article at a 100% concentration. No signs of erythema were observed in the test article-treated animals at a 10% concentration. Slight erythema was observed at 24 hours in two positive control animals receiving PPD at a 35% concentration.
During the challenge phase, no to mild erythema was observed in the positive control group treated with p-phenylenediamine at a 35% concentration. No signs of erythema were observed in the test article-treated animals at the 100 or 10% concentration sites. No signs of erythema were observed in the vehicle control animals. No signs of erythema were observed in the negative control animals receiving the positive control at 35% or receiving the vehicle. No signs of erythema were observed in the negative control animals receiving the test article at the 100 or 10% concentrations.
Under the conditions of this study, H-18,267 did not "produce delayed contact hypersensitivity in guinea "
Work by:
Study Director:
Susan E. Armondi, LAT
Reviewed and . Approved for Issue: _/
o. (Ja cmOf]
Susan E. Armondi, LAT Study Director
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Amended Final Report PHARMAKON RESEARCH INTERNATIONAL,
WAVERLY. PENNSYLVANIA 18471
QUALITY ASSURANCE UNIT STATEMENT
Study No.: PH 424-DU-007-90
Du Pont HLO 19-91 INC.
PHONE (717) 586-2411
FAX (717) 586-3450
Study Director: Susan E. Armondi
This study was conducted in compliance with the Good Laboratory Practice Regulations. The Quality Assurance Unit conducted the inspections listed below and reported the results to the study director and to management on the dates indicated.
The following inspections were performed:
Interval
Date
In Life Phase
August 13, 1990
Reporting Phase
September 26. 1990
Date OAU Report Issued
To Study Director September 26, 1990
To Management September 26, 1990
Date
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Du Pont HLO 19-91
INTRODUCTION
The purpose of this study was to evaluate the potential of H-18,267 to produce delayed hypersensitivity or allergic reactions when applied to the skin of guinea pigs. Sensitization was defined as a significant score increase at challenge over the response observed after the primary application of the test material to the test guinea pigs, or the response observed in the negative controls. A significant score increase defined as a 2-or-more step increase (e.g., from 0 to 2, from 1 to 3, etc.) has been used at Haskell Laboratory as the criterion in this study protocol to identify compounds that are sensitizers. The sensitivity of the test system to detect chemical sensitizers was evaluated with p-phenylenediamine. This study was conducted according to Good Laboratory Practice Regulations as stated on page 2 of this report. Areas of noncompliance are documented in the study records. No deviations existed that significantly affected the validity of the study.
MATERIAL AND METHODS
A. Animal Husbandry
Young adult male and female Duncan Hartley albino guinea pigs were
received from BuckberG Lab Animals, Tomkins Cove, New York. The guinea pigs were housed singly in suspended, stainless steel, i" wire-mesh cages.
Each guinea pig was assigned a unique identification card on which the animal number, study number, dose level and sex were recorded and affixed to the cage. Guinea pigs were ear tagged. Purina Certified Guinea Pig
Chow #5026 and water were available ad libitum. Guinea pigs were
acclimated and observed for general health during a period of
approximately five days. Animal rooms were maintained on a
timer-controlled, 12-hour light/12-hour dark cycle. Environmental^
^
conditions of the rooms were targeted for a temperature of 22 3C (66-
77F) and relative humidity of 30 - 70%. Any excursions outside these
ranges were of small magnitude and/or brief duration and did not adversely
affect the validity of the study.
B. Protocol
A copy of the signed original protocol is attached as Appendix A.
Preliminary range-finding tests were conducted to estimate the primary irritation potential of the test material. The results of the range--finding studies were used to select the exposure concentrations for the main study. The main sensitization study consisted of 3 phases: a primary irritation phase, an induction phase and a challenge phase. During each phase, skin responses were scored according to the system presented in Table I. During the study, body weights were recorded weekly.
The topical range-finding test was conducted on 1 female and 2 male guinea pigs ranging in weight from 502 to 628 grams. Aliquots (approximately 0.05 mL) of 12.5%, 25%, 50% and 100% (w/v) suspensions of the test material in distilled water were applied and lightly rubbed onto four separate test sites on the clipped, intact skin on the back of each animal. The intradermal range-finding test was conducted in 1 female and 2 male guinea pigs ranging in weight from 438 to 496 grams. Aliquots (0.1 ml) of 1.0, 10, 50 and 100% (w/v) suspensions of the test material in 0.9%
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Du Pont HLO 19-91
saline were injected intradermally into four separate test sites on the clipped, intact skin on the back of each animal. Irritation responses were scored approximately 24 and 48 hours after treatment.
The primary irritation phase was conducted in 10 guinea pigs (5 males and 5 females) , weighing from 400 to 461 grams , by applying and lightly rubbing in 1 drop (approximately 0.05 ml) of 100% and 10% (w/v) suspensions of the test material in distilled water onto two separate sites of clipped, intact skin of each animal. In addition, 10 positive control guinea pigs (5 males and 5 females), weighing from 409 to 452 grams, were treated by applying and lightly rubbing in 1 drop of a 35% (w/v) suspension of p-phenylenediamine in distilled water onto the clipped, intact left shoulder skin of each animal. Five vehicle control guinea pigs (3 males and 2 females), weighing from 404 to 435 grams, were treated with distilled water in the same manner at one site only. Dermal responses were scored approximately 24 and 48 hours after application of the test material.
Two days after the primary dermal irritation phase, the induction phase of the study was initiated using the same 10 test guinea pigs in which primary irritation had been evaluated. The test article was minimally irritating topically when dosed as received and was also suspendable, not soluble in common vehicles. Therefore, topical route of administration was employed. Induction consisted of a series of 9 topical applications (3 each week) of 0.05 mL of the neat test material. The same induction procedure was followed for the 10 positive control guinea pigs using 0.05 mL of a 35% (w/v) suspension of p-phenylenediamine in distilled
zJ water. The vehicle control animals were similarly treated with 0.05 ml
distilled water. Skin responses were evaluated approximately 24 hours after each induction.
Two weeks after the last induction treatment, the test guinea pigs were challenged for sensitization by applying and lightly rubbing in 1 drop of 100% and 10% (w/v) suspensions of the test material in distilled water onto two separate sites of clipped, intact shoulder skin. The sites used during challenge were the same used on each animal during the primary dermal irritation phase, respectively. The positive control animals were challenged for sensitization by applying and lightly rubbing in 1 drop of a 35% (w/v) suspension of p-phenylenediamine in distilled water onto two separate sites of clipped, intact skin. The vehicle control animals were treated at two sites with distilled water, in the same manner. Also, 2 male and 3 female previously untreated guinea pigs, weighing 408 to 440 grams at study initiation, were treated by applying 1 drop each of 100% and 10% (w/v) suspensions of the test material in distilled water onto two separate sites of clipped, intact skin and served as negative control animals. In addition, these animals received 0.05 ml of distilled water and 0.05 ml of p-phenylenediamine at 35%. These animals also served as negative control animals for the vehicle and positive control materials.
C. Records Retention
All raw data, protocol, correspondence and the final report will be
stored in the archives of Pharmakon Research International, Inc., Waverly,
I PA.
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RESULTS AND CONCLUSIONS
Weekly body weights are presented in Appendix B. A copy of the raw data is presented in Appendix C.
In the intradermal range-finding test, slight to moderate erythema with or without edema was observed. The test article was minimally irritating in the topical dose-range-finding study and as per protocol, the dose concentrations used for the primary irritation phase were 100% and 10%. The dose concentration used for induction was 100%. The dose concentrations chosen for challenge were 100% and 10%.
In the topical range-finding test, slight erythema was observed in one animal at 100%.
During the primary irritation phase, no signs of erythema were observed in the test article-treated animals at the 10% concentration site. Slight erythema was observed in the test article-treated animals at the 100% concentration site. Slight erythema was observed in two positive control animals at 24 hours. No erythema was observed in the vehicle control animals receiving distilled water. Individual animal data are presented in Table II.
During the induction phase, no signs of erythema were observed in the test article-treated animals. Slight erythema was observed in one positive control animal. No erythema was observed in the vehicle control group. Individual animal data from the induction phase are presented in Tabli III.
Dermal responses observed during the challenge phase are summarized in the following table (page 12). Individual animal data are presented in Table IV. ~
AT903
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Responses No erythema Slight erythema Mild erythema
Summary of Skin Responses: Challenge Phase
Positive Control______ PPD
35%a
35%b
24 hr 48 hr 24 hr 48 hr
8/10 8/10 6/10 8/10
2/10 1/10 4/10 1/10
0/10 1/10 0/10 1/10
_______ Test Animals H-18,,267
100%
10%
24 hr 48 hr 24 hr 48 hr
10/10 10/10 10/10 10/10
0/10 0/10 0/10 0/10
0/10 0/10
0/10 0/10
Responses No erythema Slight erythema Mild erythema
Negative Control
H-:L8,267
PPD
100% 10% 35%
24 hr 48 hr 24 hr 48 hr 24 hr 48 hr
5/5 5/5 5/5 5/5 5/5 5/5
0/5 0/5 0/5 0/5 0/5 0/5
0/5 0/5 0/5 0/5 0/5 0/5
Distilled Water
24 hr 48 hr
5/5 5/5
0/5 0/5
0/5 0/5
No erythema
Vehicle Control
24 hr
48 hr
5/5 5/5
aieft shoulder right shoulder
Under the conditions of this study, H-18,267 did not produce delayed contact hypersensitivity in guinea pigs.
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TABLE I SCORING SYSTEM USED TO EVALUATE SKIN RESPONSES
Score 0 1
Skin Reaction
No erythema or Edema
Slight erythema (barely perceptible, usually nonconfluent)
2 Mild erythema (well defined, usually confluent)
3 Moderate erythema
4 Severe erythema (beet redness, with
or without edema, eschar formation or necrosis)
If edema, blanching, necrosis or eschar formation occurred, they were indicated using the following code:
ED = Edema
N = Necrosis
E = Eschar
B = Blanching
SN = Superficial Necrosis
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TABLE I I
PRIMARY IRRITATION PHASE
SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS FOLLOWING TOPICAL EXPOSURE TO H-18,267
GUINEA PIG NUMBER -3440 3441 3442 3443 3470 3445 3446 3447 3448 3449
LEFT FRONT
100%
24 hr
48 hr
01
01
00
01
00
00
11
11
0 1
00
RIGHT FRONT
10%
24 hr
48 hr
00
00
00
00
00
00
00
00
.o 0
0 0
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TABLE II (Cont'd)
PRIMARY IRRITATION PHASE
SKIN RESPONSES OBSERVED IN VEHICLE CONTROL GUINEA PIGS FOLLOWING TOPICAL EXPOSURE TO
DISTILLED WATER
GUINEA PIG NUMBER
3450
3451
3452
3453
3454
LEFT FRONT
Distilled water
24 hr
48 hr
00
00
00
00
00
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TABLE I I (C o n t'd )
PRIMARY IRRITATION PHASE
SKIN RESPONSES OBSERVED IN POSITIVE CONTROL GUINEA PIGS FOLLOWING TOPICAL EXPOSURE TO p-PHENYLENEDIAMINE
GUINEA PIG NUMBER 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469
LEFT FRONT
35%
24 hr
48 hr
00
00
00
10
00
00
10
00
00
00
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TABLE III
INDUCTION PHASE
SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF 100% H-18,267
GUINEA PIG NUMBER 3440 3441 3442 3443 3470 3445 3446 3447 3448 3449
WEEK I SCORES
Dose #1 (LEFT)
Dose #2 (RIGHT)
00
00
00
00
00
00
00
0 .0
00
00
Dose. #3 (LEFT)
0 0 0 0 0 0 0 0 0 0
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TABLE III (continued)
INDUCTION PHASE
SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF DISTILLED WATER
GUINEA PIG NUMBER 3450 3451 3452 3453 3454
WEEK I SCORES
Dose #1 (LEFT)
Dose #2 (RIGHT)
00
00
00
00
00
Dose #3 (LEFT)
0 0 0 0 0
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TABLE III (continued)
INDUCTION PHASE
SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF 35% p-PHENYLENEDIAMINE
GUINEA PIG NUMBER 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469
WEEK I SCORES
Dose #1 (LEFT)
Dose #2 (RIGHT)
00
00
00
00
00
00
00
00
00
00
Dose #3 (LEFT)
0 0 0 0 0 0 0 0 0 0
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TABLE III (continued) INDUCTION PHASE
SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS
.
GUINEA PIG NUMBER 3440 3441 3442 3443 3470 3445 3446 3447 3448 3449
WEEK II SCORES
Dose #4 (LEFT)
0
Dose #5 (RIGHT)
0
00
00
00
00
00
00
00
00
00
Dose #6 (LEFT)
0 0 0 0 0 0 0 0 0 0
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TABLE III (continued)
INDUCTION PHASE
SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FQT.t.QWING t o p i c a l a d m i n i s t r a t i o n o f d i s t i l l e d w a t e r
WEEK II SCORES
GUINEA PIG NUMBER 3450 3451 3452 3453 3454
Dose #4 (LEFT)
0 0 0 0 0
Dose #5 (RIGHT)
0 0 0 0 0
Dose ff (DEFT)
0 0 0 0 0
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TABLE III (continued)
INDUCTION PHASE
SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF 35% p-PHENYLENEDIAMINE
WEEK II SCORES
GUINEA PIG NUMBER 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469
Dose #4 (LEFT)
Dose #5 (RIGHT)
00
00
00
00
00
00
00
0 0
00
00
Dose #6 (LEFT)
0 1 0 0 0 0 0
.0
0 0
22
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TABLE III (continued) INDUCTION PHASE
SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF 100% H-18,267
WEEK III SCORES
GUINEA PIG NUMBER
Dose #7 (LEFT)
Dose #8 (RIGHT)
Dose #9 (LEFT)
3440
00 0
3441
00 0
3442
00 0
3443
00 0
3470
000
3445
00
0
3446
00
0
m
3447
0
0'
0
3448
00
0
3449
00
0
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TABLE III (continued)
INDUCTION PHASE
SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF DISTILLED WATER
WEEK III SCORES
GUINEA PIG NUMBER 3450 3451 3452 3453 3454
Dose #7 (LEFT)
0 0 0 0 0
Dose #8 (RIGHT)
0 0 0 0 0
Dose #9 (LEFT)
0 0 0 0 0
24
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TABLE III (continued)
INDUCTION PHASE
SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF 35% p-PHENYLENEDIAMINE
WEEK III SCORES
GUINEA PIG NUMBER 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469
Dose #7 (LEFT)
0 0 0 0 0 0 0 0 0 0
Dose #8 (RIGHT)
0 0 0 0 0 0 0 0 0 0
Dose #9 (LEFT)
0 0 0 0 0 0 0 0 0 0
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TABLE IV
CHALLENGE PHASE
SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF H-18,267
GUINEA PIG NUMBER 3440 3441 3442 3443 3470 3445 3446 3447 3448 3449
LEFT FRONT
100%
24 hr
48 h r
00
00
00
00
00
00
00
00
00
00
RIGHT FRONT
10%
24 h r
48 h r
00
00
00
00
00
00
00
00
00
00
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TABLE IV (cont'd)
CHALLENGE PHASE
SKIN RESPONSES OBSERVED IN VEHICLE CONTROL GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF DISTILLED WATER
VEHICLE GUINEA PIG NUMBER
3450
3451
3452
3453
3454
LEFT FRONT
Distilled water
24 hr
48 hr
00
00
00
00
00
RIGHT FRONT
Distilled water
24 hr
48 hr
00
00
00
00
00
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TABLE IV (Cont'd)
CHALLENGE PHASE
SKIN RESPONSES OBSERVED IN NEGATIVE CONTROL GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF H-18,267
nTSTTT.T.'Rn WATER AND p-PHENYLENEDIAMINB
GUINEA PIG NUMBER
3455
3456
3457
3458
3459
LEFT FRONT H-18 ,267 100%
24 hr 48 hr
00
00
00
00
00
RIGHT FRONT H-18 ,267 10%
24 hr 48 hr
00
00
00
00
00
LEFT PEAR DISTILLED
WATER 24 hr 48 hr
00
00
00
00
00
RIGHT REAR PPD 35%
24 hr 48 hr
00
00
00
00
00
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TABLE IV (Coni'd)
CHALLENGE PHASE
SKIN RESPONSES OBSERVED IN POSITIVE CONTROL GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF p-PHENYLENEDIAMINE
GUINEA PIG NUMBER 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469
LEFT FRONT
35%
24 hr
48 hr
00
00
00
00
00
00
11
00
1 2
00
RIGHT FRONT
35%
24 hr
48 hr
10
00
00
00
10
00
12
10
o1 00
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Amended Final Report
Du Pont HLO 19-91
APPENDIX A
PROTOCOL AND PROTOCOL AMENDMENT
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PHARMAKON
RESEARCH INTERNATIONAL.
W A V L H O ' . I ' C K I J S V l. V A V I A 1-: J i
Protocol - 424D
INC
Skin Sensitization Test in Guinea Pigs
Du Pont HLO 19-91
CHOME (717) SBG-2411
pax
17)7) 58G -34S0
Sponsor: Testing Facility:
E. I. dupont de Nemours Haskell Laboratory for Toxicology
and Industrial Medicine Newark, DE 19714
Pharmakon Research International, Inc.
Waverly, Pennsylvania 18471
'
Test Facility S-O.P. No.:
PH-424
Study No.:
Purpose of the Study:
To be assigned upon study initiation, f 1+ M 2 . M - 0 U "02'l-- ^0)
This study is designed to evaluate the dermal sensitization potential of the test material in guinea pigs.
Ownership of the Study:
Study Monitor:
The sponsor owns the study. All raw data, analysis, and reports are the property of the sponsor.
Dolores E. Malek, Ph.D., E.I. duPont de Nemours
Study Director:
O.A.U. Responsible
Personnel:
Susan Armondi, LAT, Pharmakon Research
International, Inc.
.
Leslie J. Pinnell, M-S.
Dates of Performance:
Study will begin within one month of the receipt of the test chemical and authorized protocol.
Good Laboratory Practices Statement:
This study will be conducted following the U.S.
Environmental Protection Agency Toxic Substances
. Control Act, Good Laboratory Practice Standards (40 CFR
A\ part lof^er Good Laboratory Practice Standards
*v ' (40 CFR Part 792).
IACUC Statement:
This protocol has been reviewed by the Institutional Animal Care and Use Committee (IACUC) and complies with acceptable standard animal welfare and humane care.
Tentative Date of Submission of
Draft ReportT
. .. Within three weeks following the completion of the
in-life phase of the study. .
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P r o t o c o l - ')l>4nJ
Skill S e n s itiz a tio n Test in G uinea Pics
Du Pont HLO 19-91
Records Maintained:
Raw Data: Record Retention: Analytical Chemistry:
Species: Strain: Supplier: (Source) : Sex:
Weight at Initiation;
All raw data, final reports, documentation and protocoi wxll be maintained in the Pharmakon Central
. Amendments to protocol Feed Lot Number Body weights, initial, weekly and final . Compound preparation Volume administration Observed signs Observed skin reactivity
Maintained in a Standard Pharmakon Notebook
All raw data and completed notebooks.
Analysis and stability of the test article and test article/carner mixture is the responsibility of the sponsor if requested by the sponsor, P h a r m L o n Research International, Inc. will, through its a ^ w ^ ^ T ' COndUGt aPPrPriate analytical analysis and will indicate the additional cost involved following receipt and evaluation of the appropriate
mmeetShoodd 1iCsalnoTt phr0odv'ideIdn, thPeharCmaasekonwhReerseeaarcsha t i s f a c t o r y Intetnatwiu1 , inc. or its subcontractor, at a ditional cost to the sponsor, will develop appropriate methods. If the sponsor elects to analyze the test article/carrier mixtures, Pharmakon Research International, Inc. will collect the sample at appropriate designated intervals during the study and transmit the samples to the sponsor for analysis!
TEST SYSTEM
Guinea pig
Hartley
BuckberG Lab Animals, Tomkins Cove, New York or from any other U.S .D.a acceptable source.
`---- -- WOW Wli.1 tha
the study records and f i n a l report).
Y o u n g ,A d u lt
400 - 650 grams
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Protocol - 424Di ' S k i n S e n s i t i s a t i o n T e s t in G u in e a I' i g s
Du Pont HLO 19-91
No. on Studv:
Method and Justification for Randomization:
Acclimation Period: System of Identification: Research Facility Registration: Animal Rooms:
Housing;
Sanitization: Food:
D o s e - K a n g v - 1i i i c i i n y : 2. Vehicle control: 5 (at the discretion of the Study Monitor, this group may be excluded from the study.) Negative control: 5 (if re-challenge is necessary, a
second set of 5 naive, age-matched negative control animals will be used.) Test article: 10 Positive control: 10 (at the discretion of the Study Director after consultation with the Study Monitor, this group may be excluded from the study.)
Treatment groups will be housed by vertical cage positioning. Any animals showing evidence of clinical signs during acclimation will be eliminated from randomization. Randomization is carried out by use of a computer generated random number table. Before treatment commences, all guinea pigs will be weighed, ranked according to body weight and assigned to treatment groups using a table of random numbers so that each treatment group will have a similar distribution according to body weight. Guinea pigs beyond the extremes of the body weight range will not be assigned to treatment groups. If there is a statistically significant difference in mean body weight between any two groups of the same sex after allocation to the treatment groups, substitution from spare animals will be used to correct the situation.
Minimum: five (5) days
Cages marked with an animal group number, sex and treatment group. Guinea pigs are ear tagged.
HUSBANDRY
U.S.D.A. Registration No. 23-107 under the Animal Welfare Act 74: SC 2131 et seq.
Separate isolation by test system. Light cycle - 12 hours light, 12 hours dark. Temperature/Humidity - Maintained at a temperature of 22#C 3C and a humidity of 30 to 70%.
.. Guinea pigs are housed individually in stainless
steel *j" wire mesh cages. Size in accordance with the
"Guide for the Care and Use of Laboratory Animals" of
the Institute of Laboratory Animal Resources, National
Research Council.
.
Waste material will be removed daily. Cages and feeders will be sanitized every two weeks.
Purina Certified Guinea Pig Chow #5026 or acceptable substitute will be provided ad libitum. Feeders are
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Protocol - '.2411
Skin Sensitization Test in Guinea Pigs
Du Pont HLO 19-91
Food Analysis: Water: Water Analysis:
Rationale for Test System: Rationale for Dose Selection: Justification for Test System: Compound Preparation:
Absorption of the Test Material :
designed to reduce soiling, budging, and scattering. The potential effects of dietary contaminants have been considered, and based on the manufacturer's data, contaminant levels are believed to be within acceptable limits.
There are no contaminants expected to be present in the dietary material known to be capable of interfering with the purpose or conduct of the study.
Availability - fresh tap water, ad libitum. ''
water is monitored for contaminants at periodic inte^gjj according to Standard Operating Procedure
METHODS
This study is intended to provide information on the health hazards likely to arise from exposure to the test material by the dermal route; skin contact is a possible worker and consumer exposure route. -
Based upon the.results of the dose-range finding study and/or at the sponsor's request.
According to EPA Health Effect Test Guidelines EPA 560/6-82-001. The guinea pig has historically been used in the evaluation of chemicals for dermal sensitization.
Liquids Liquids will be applied as received except when specific instructions request dilution or mixing. The use of a vehicle for dilution will be described in the study records and final report.
Solids
The test material will be pulverized if appropriate.
The test material may be moistened with distilled
water or a suitable vehicle to ensure good contact
with the skin. When a vehicle is used, the influence
of the vehicle on penetration of the skin by the test
substance will be considered.
-
Semi-Solids Extremely viscous liquids may be heated to approximately 50C to dosing, with the approval of the Study Monitor. The procedure used will be documented in the study records and included in the final report.
For the purpose of this study, all of the test material applied to the test sites is assumed to be absorbed by the test system. All calculations and the evaluation of effects will be based on the applied dose.
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Protocol - 4.`'4D'1 Fkin Sensitization Test, in Guinea 1'igs
Du Pont HLO 19-91
Vehicle:
The choice oi vehicle varies, depending on the natuie of the test substance. Commonly used vehicles are distilled water, saline, ethanol-.distilled water (00:20, v/v) , dimethyl phthalate, acetone:dimethyl phthalate (1:9, v/v) or propylene glycol. The vehicle . used will be documented in the study records and the final report.
Volume
Administration:
Approximately 0.05 ml/dose
Route of Administration:
The test and control materials will be applied topically and/or injected intradermally, to the clipped, intact shoulder skin.
Rationale for Route of Administration:
Skin contact is a possible worker and consumer exposure route.
No. and Description of Animals per Dose Group:
Method of Study Performance:
Dose-range-finding: 3
Vehicle control: 5 (at the discretion of the Study
Director, this group may be excluded from the
study) .
Negative control: 5 (if re-challenge is necessary, a
second set of 5 naive, age-matched negative control
animals will be used).
Test Article: 10
Positive control: 10 (at the discretion of the Study
Director, after consultation with the Study Monitor,
this group may be excluded from the study).
Dose-range-finding Study
Prior to initiation of the main study, a
dose--range-finding study will be performed. In order
to evaluate the irritation potential of the test
material, 3 animals will be subjected to preliminary
studies as follows:
Animals will be closely clipped over the back and
sides. The test material concentrations will be based
on the solubility of the test compound (solids will be
tested at the maximum soluble concentration and at 2
or 3 lower concentrations). Liquids will be tested at
100% (as received or as prepared per the Sponsor's
instructions) and at 2 or 3 lower concentrations.
Each guinea pig may be dosed with up to 4 different
concentrations at different sites (1 concentration/
site) . In some cases where the solid is not soluble
in a common solvent it will be tested as received by
topical application.
One drop (approximately 0.05 ml) of each
concentration will be applied directly on the
appropriate test site and rubbed gently with the end
of the dosing syringe to cover an area of
approximately 25 mm in diameter.
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Protocol - 424Di
(
S k in Sc-nsi c it a t io n To st in G uinea P ig s
Du Pont HLO 19-91
Obsoi vations for signs of dermal irritation will lie recorded at 24 and 48 hours after application. At each observation, all treated sites will be scored according to Table I.
Primary Irritation Phase For the test guinea pigs there will be 2 sites per animal in the area between the shoulder and the middle of the back. One site will receive the highest concentration which is no more than mildly irritating as determined from the dose-range-finding study. The second site will receive one-tenth of that concentration. Each site will receive 1 drop (approximately 0.05 ml) of the appropriate concentration, rubbed gently into the clipped skin with the end of the dosing syringe to cover an area approximately 25 mm in diameter. The vehicle control guinea pigs, if used, will be treated at 1 site as above using the vehicle only. The positive control guinea pigs will be treated at 1 site with the positive control. The negative control guinea pig will remain untreated until the challenge phase. Observations for signs of dermal irritation will be recorded at 24. and 48 hours after application.
Sensitization Phase (Induction)
'
The first induction application will be made after the
48-hour dermal observation is made for the primary
irritation phase. If the test material is soluble in
appropriate vehicle, e.g., 0.9% saline or dimethyl
phthlate, induction will be performed by intradermal
injection. If the test material is insoluble in the
commonly used vehicles a topical induction procedure
will be used.
The hair at the appropriate application site will be clipped on the day prior to each application or, if a topical induction procedure is employed, at least weekly during induction. After clipping, the area to be treated may be delineated for the convenience of and at the discretion of the study director or the experimenter. The hair will be clipped as needed during the study for evaluation of the dermal
irritation.
A total of 4 intradermal injections will be made, 1 per week at 1 week intervals. A virgin site will be used for each injection. A 0.1 ml aliquot of a 1% solution of the test material in an acceptable solvent (e.g., 0.9% saline, dimethyl phthalate, etc.) will be administered by intradermal injection to the clipped sacral area of each test guinea pig. If distilled water is used as a vehicle in the primary irritation phase, 0.9% saline will be used for the intradermal injections. The vehicle control guinea pigs will be
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Protocol - -42'll)J
Shin Sensi t i u a t i o n `l'e st in Guinea P ig s
Du Pont HLO 19-91
Method Validation/ Positive Control :
Evaluation of Dermal ResDonse:
Heated a s above using the vehicle only. The positive control guinea pigs will be treated as above using the positive control material.
Topical Administration A total of 9 applications will be made to the sacral area, 3 applications per week for 3 weeks. One drop (approximately 0.05 ml) of a minimally irritating concentration of the test material in.- the acceptable solvent (e.g., dimethyl phthalate, 0.9% saline, etc. will be applied directly to the skin and then gently rubbed in with the end of the syringe, to cover an area approximately 25 mm in diameter on each test guinea pig. The vehicle control guihea pigs will receive similar treatments using the vehicle only. The positive control guinea pigs will receive similar treatments using the positive control article.
Challenge Phase
Approximately 14 days after the last induction
treatment, the challenge treatment will be
administered. The test material will be administered
in the same manner as in the primary irritation phase,
treating with the same concentrations at the same
sites. Following the same procedure the negative
control animals will be treated with the same
'
concentrations of the test material, and may be
treated with the vehicle and positive control material
(up to 4 separate test sites). The vehicle control
animals will be treated with the vehicle only. The
positive control animals will receive the positive
control article. If the test results are conclusive
and the test material has either clearly caused
allergic sensitization or is not a sensitizer, the
test is terminated and the guinea pigs are euthanized.
If the reactions are less than conclusive, a second
challenge (rechallenge) may be performed approximately
1 week after the initial challenge using the same test
guinea pigs and additional naive control guinea pigs.
The vehicle and positive control animals may not be
rechallenged.
The procedures and test system will be evaluated with a known dermal sensitizer to confirm the validity of the test. Evaluation of the test system with a known dermal sensitizer may not be conducted concurrently with every study, but testing with a known dermal sensitizer will be performed periodically.
Dermal evaluations will be made between 23-25 hours and/or 47-49 hours following treatment, but the data will be reported as the 24- or 48-hour evaluations.
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P r o t o c o l - 4 24] S l;ir. S e n s it iz j tior. Test in Guinea P ig s
Interpretation Results :
Sensitization Rating:
Intervals a. Primary Irritation Test - Dermal evaluations will
be made approximately 24 and 48 hours after the test material application.
b. Induction - Dermal evaluations will be made approximately 24 hours after each induction treatment.
c. Challenge and Rechallenge (if required) - Dermal evaluations will be made approximately 24 anc 48 hours after the test material applications.
All test sites will be graded on a. scale of 0 to 4 as follows:
TABLE I
Score
Skin Reaction
0 No erythema or edema
1 Slight erythema (barely perceptible, usually nonconfluent)
2 Mild erythema (well defined, usually confluent)
3 Moderate erythema
4 - Severe erythema -(beet redness, with or without edema, eschar formation or necrosis)
If edema, blanching, necrosis, superficial necrosis or eschar formation occur, they will also be indicated using the following code:
ED = Edema N = Necrosis E = Eschar B = Blanching SN = Superficial Necrosis
Sensitization is defined as a 2-or-more step increase
(e.g., from 0 to 2, from 1 to 3, etc.) in dermal
irritation scores in the test animals over those
observed in the negative controls at challenge. When
the test and negative control animals have similar
dermal irritation scores, the test material will not
be considered a sensitizer. The rating of a
sensitizer is as follows:
'
Ratio of Responsers
Degree of Sensitization
1 to 2/10
. Weak Sensitizer
3 to 4/10
38
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S k in S e n s it iz a t io n To st in (ninna P ig
Du Pont HLO 19-91
K a tie ? o l K<.:s;,o n s e r s
Degree- o : .`.' onsi f i x a t i o n
5 to 6/iO
Moderate Senitizer
7 and above
Strong Senitizer
Necroosv:
This rating scale is not fixed rigidly. Scientific evaluation of the data and judgement will be used to decide whether a material will be classified as a weak, mild, etc. sensitizer.
Pathological evaluations of test animals will riot ordinarily be performed. Exceptions will be noted in the study records and final report. '
Euthanasia:
Animals that surive the test period will be euthanized according to the Testing Facility's Euthanasia SOP and incinerated.
Statistical Analysis: Statistical analyses of data will not be performed, unless requested by the sponsor.
Rechallenge:
The sponsor will be notified of animals that are considered sensitized. Verbal instructions for rechallenge will be given by the Sponsor, followed by written confirmation. All test article animals, along with an additional group of four naive guinea pigs, can be rechallenged six (6) days after primary challenge, but not before. The negative and positive control groups will not be rechallenged.
POSITIVE CONTROL ARTICLE
Positive Control Article:
N-Phenyl-1,4 phenylenediamine (PPD)
Supplier (Source):
Aldrich Chemical Company, Milwaukee, Wisconsin
Special Handling Instructions:
Standard precautions
Analysis of Purity:
The purity is the responsibility of the manufacturer.
How Supplied:
100 gm bottle
Rationale for Positive Control Article:
As per sponsor's request.
ATXPL4
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P r o t o c o l - -ln-11)1
jn
S k in S e n s it iz a t io n Te st in Guinea P ig s
Du Pont HLO 19-91
Test Article (Name or Code):
Chemical Abstract No. or Code No.:
Analysis of Purity/Stability:
Carrier Mixtures:
Analysis of the purity and stability of the test article is the responsibility of the sponsor.
Analysis for stability, uniformity .and correctness of concentration of the test article in the carrier is the responsibility of the sponsor.
___ Return Test Article Carrier Mixtures to the Sponsor _Dispose of Test Article Carrier Mixtures Person to whom carrier mixtures should be sent:
Shipping*' Instructions : AMENDMENTS
Date Date ATXPL4
h l c) 0
APPROVAI, OF PROTOCOL
Study Monitor _____ y-z 7--TO ; & ^ . J U r
Study Director h l l 'Y l v J - ( A c m o r b -
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Du Pont HLO 19-91
APPENDIX A
Test Article Information
Identification:
Test Article (Name or Code):
/ f, 2C?
Lot or Sample No:______ ' --
Physical Description:
C G >S /oeA S ro*/
Purity:_____
Expiration Date:_________
Density/Specific Gravity:
Solubility (check one) : Water
Acetone uas< A/0K/V
Ethanol itw c A ro u /t/ Corn Oil
DMSO tS ASKVOtt/V
Other (please specify)_______________ , '
Chemical Classification: Flammable________ Corrosive
Other P H - j -- v1
XI Storage Information:
Material Storage (check one):
Room Temperature
Refrigerator
Freezer _______ ; Other (specify) ____
III Handling Information:
.
Known Hazards:
Precautions: Routine use of protective clothing includes laboratory coats, latex gloves, dust masks, and safety glasses.
Other recommended precautions________________________ -_______ ______
In Case of Emergency Related to this substance, contact:
Go to p e s m a l e k
(person)
of J& p o h t (company/division)
at 3 o Z - i U - S ' 4 ' (phone number)
IV Disposition:
' All materials will be returned to the sponsor three months following submission of the final report to the sponsor. Person and address to
' whom test articles are to be returned.
Name: Address:
A t t /r e . G o o A y * / o S A U p L B A ooa-4
60/P A iK e L L L A M T O A .Y -
& IK TO S S aA A seus/H tK G S
G v/>oa/ j
VI Signature: ATXPL4
Date:
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Protocol Amendment Skin Sensitization Test in Guinea Pigs PH 424-DU-007-90 Test Article: H-18,267
Du Pont H L O 19-91
Method of Study Performance: (page 5 of protocol. Dose-Range-Finding) .
Original Statement Prior to initiation of the main study, a dose-range-finding study will be performed.
Corrected Statement Prior to initiation of the main study, a topical and an interdermal dose-range-finding study will be performed.
Reason for Deviation: <
. In order to determine the route of exposure to
be used in the main study and in discussion with the
sponsor on July 26, 1990
'
M A / X X Q (Ja m i o n
Susan E. Armondi, LAT
Study Director
Pharmakon Research International,
Inc.
l/ltpky 1 ^ 0
Date
AT903
i I
I
42
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Du Pont HLO 19-91
APPENDIX B WEEKLY BODY WEIGHTS (g)
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WEEKLY BODY WEIGHTS (g)
Animal Number
Sex Initial Week II Week III Week IV Week V Week VI Final
Test Group
3440 3441 3442 3443 3470 3445 3446 3447 3448 3449
M M M M M F F F F F
404 432 432 442 400 442 461 413 414 401
423 . 449 459 478 433 474 504 433 426 427
475 514 516 526 490 542 569 477 471 476
525 580 630 673 567 618 683 716 577 650 700 728 585 554 697 746 517 544 582 606 57 9 645 701 732 658 708 794 82 3 515 541 591 585 481 518 574 595 503 550 591 623
>)
44
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Du Pont HLO 19-91
WEEKLY BODY WEIGHTS (g)
Animal Number
. Sex Initial Week II Week III Week IV Week V Week VI__Final
Vehicle Control Group
3450 3451 3452 3453 3454
M 414 445 492 M 431 445 505 M 429 468 541 F 404 428 492 F 435 461 490
552 589 562 630 616 670 527 578 548 566
639 673 676 719 715 753 616 640 634 673
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WEEKLY BODY WEIGHTS (g)
Animal Number
Sex Initial Week II Week III Week IV Week V Week VI Final
Positive Control Group
3460 3461 3462 3463 3464 3465 3466 3467 3468 3469
M 409 M 418 M 429 M 425 M 452 F 422 F 412 F 421 F 439 F 427
438 458 453 459 483 453 447 439 451 452
499 544 594 651 685 526 599 656 722 750 506 529 595 651 696 509 564 620 682 713 535 589 640 698 711 469 503 517 547 573 502 534 592 620 644 490 518 571 620 641 485 513 554 580 594 496 534 567 606 621
m
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Du Pont HLO 19-91
WEEKLY BODY WEIGHTS (g)
Animal Number
Sex Initial Week II Week III Week IV Week V Week VI___Final
Negative Control Group
3455 3456 3457 3458 3559
M 423
454
509
574 624 656 695
M 437
462
513
556 646 699 731
F 440
481
528
606 630 688 728
F 408
452
517
533 598 616 651
F 435
480
482
540 554 639 650
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Du Pont HLO 19-91
APPENDIX C COPY OF RAW DATA
IN
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PHARMAKON Kir.KAKCII INT]'!:NAT IONA!.. INC.
Du Pont HLO 19-91
Sponsor
Skin Sensitization Test in Guinea Piers *D>owsjey-iR\aBinnqjec-rFinduiinq Study
V J' ,r!w_-f m fig MlMM4
PurpoDsSe:7 ^ ' l
f&Pjl J ! A A l & l ) & > x / d / ' s* ;
study No. = f M M - U ' / i n - t i )
/ :
Method :-- lU'i rr
/DtfO*
Date of Initiation: ~7f l J qF)
Date of Termination:
Test Article: // - 7 fl<`7 ________ Amount Receivveedd:: I0 ^ ./
Description: Date Submitted:
y j j/ v s.
s /? /9
Vehicle J J i / h U J T / )
_ Dose Levels : /J ), Q *)'Q / } J ,y/ / ) Q %
Route of Administration: J p A f ^ n ____________________________
Animal P.o. 9 : SPj-nbiym
Speciies: v^Afc/fe/fr, S f i
Food Lot
h f0 3 4 t0 #
Strain: _ Identification
'St
77
No. of Animals on Study: Scale" : f t
1
Sex: Male
Female
Light Cycle Checked:
/
Animals Clipped: j J M
m
Compound Preparation:
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Du Pont HLO 19-91
%
PHARMAKON RESEARCH INTERNATIONAL, INC
Skin Sensitization Test in Guinea Pigs Dose-Range-Finding Study
a u u n s. test.' DOtn sides of the animal are shaved
to a different test site on each g u i ^ pio so as tn COncentratlon. ^ P P ^ e d
response due to dfferent skin locations he f o L a t
.varlatlon ln
test article is described below: nS`
f0rmat f r aPPlicati" the
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Du Pont HLO 19-91
PHARMAKON RESEARCH INTERNATIONAL, INC.
N.D. I! Paqe S
a
Skin Sensitization Test in Guinea Pigs Dose-Ranqe-Findinq Study
= ASponsor ft, du Pcmt rlP PwmouA*4 = ^
rio d/l'CMtmtitf
MUJ(/h#jL> lLLtlu.^ pottTKtuL 1 \ V A jO
Purpose :--
C l 'r b n t . i M , a i n n er* P < cj - ____________ '____________l _______
Study No Mnm-oi-qo 1 '
Method: P)(,'bx1z> Mi!rC(A tjQ'U'y
_____________
i: m h oDate of Initiation
0Date of Termination: 7 /,Q^ ^
Test Article:
Description:
|(P ', \ j
u .
Amount Received:
Date Submitted: r p h
1
Vehicle: 0 . l %
_____________ Dose Levels: h ( j , l ( ' ) . * ^ f ) Q f Y ) X / 1"
Route of Administration: u p f a a d s A i m a l .__________________________________
Animal P.O. #: 6 o ^ - o y m o / ?
______________________________
Species: Food Lot th
3. 0 5 0 1 ^ 0 [A
No. of Animals on Study:
_____ Strain:
j
... . 7 T
ja n m a X
nQ ^
Identification :( f l Q f f j j f ) $
Sex:'Male
Female
/
Scale#:_ m
ima
3P.
.ight Cycle Checked
Animals Clipped
ATABL3 (1)
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PHARMAKON RESEARCH INTERNATIONAL, INC
Skin Sensitization Test in Guinea Piqs Dose-Ranqe-Findinq Studv
N.D.=
mPace
teSt; bth sides of 1:116 aninlal are shaved and exposed to four
c o l l t r S f th teSt material-
different concentrations are applied
to a diff Y
Ur .lfferent test sites. A given concentration is applied
r c s o o n c f r 2^ !! SltG n GaCh 9Uinea Pig 30 as to i * variation in tteesstt aarrttiiccile is dt escribed belowl:ocations- 7116 format for application of the
Figure A
Figure B
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Du Pont HLO 19-91
PHARMAKON RESEARCH INTERNATIONAL, INC. Skin Sensitization Test in Guinea Pigs
N.B.8 Page
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Receipt Date: n l J
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Route of Administration: f l Q A f Y d J t
Animal P.O. #: f H " n n C
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1-2 Primary Irritation and Challenge
3-6 Sensitization Phase (Induction)
Company Sanitized. Does not contain TSCA CBI
Amended Final Report
Du Pont HLO 19-91
N o te b o o k Page
PHARMAKON RESEARCH INTERNATIONAL, IN C .
S k in S e n s itiz a tio n T e st in G uinea P ia s
GENERAL OBSERVATIONS
Study N o .:
l e s t A r t ic le : H - / Y a /,7 uate
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54 Company Sanitized. Does not contain TSCA CBI
Amended Final Report
Du Pont HLO 19-91
%
Notebook
3Page S
PHARMAKON RESEARCH INTERNATIONAL, INC. Skin Sensitization Test in Guinea Ping
Company Sanitized. Does not contain TSCA CBI
Amended Final Report
Du Pont HLO 19-91
PHARMAKON RESEARCH INTERNAIONAL, INC.
N ote book Page S
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Amended Final Report
Du Pont HLO 19-91
Page S PHARMAKON RESEARCH INTERNAIONAL, INC.
3
Skin Sensitization Test in Guinea P i r r c
Body Weights (grams'
Sponsor
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Amended Final Report
Du Pont HLO 19-91
PHARMAKON RESEARCH IN T E R N A T IO N A L , IN C .
S k in S e n s itiz a t io n T e s t in G u in e s P ig s
S tudy N o .: f a
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Amended Final Report
Du Pont HLO 19-91
N.B. a
Page fi PHARMAKON RESEARCH IN T E R N A T IO N A L, IN C .
S k in S e n s itiz a t io n T e s t in G u in e a P ig s
T e s t A r t ic le P re p a ra tio n (C o n tin u e d ) S t u d y N o . : f W M - K - 0 0 7 - 9 0 _____________________________ _______________________
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Du Pont HLO 19-91
Company Sanitized. Does not contain T SC A CBI
PHARMAKON RESEARCH INTERNATIONAL, INC.
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Amended Final Report
Sponsor Test Article-.
PHARMAKON RESEARCn INTERNATIONAL, INC.
Individual Animal Scores During Primary Irritation Phase
P<h 0A A t/rU A ^ -; Study Number;
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Du Pont HLO 19-91
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PHARMAKON RESEARCH INTERNATIONAL, INC. Individual Animal Scores During Induction
Sponsor; ^ - Q -
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Du Pont HLO 19-91
Initials ATABL3
Amended Final Report
Du Pont HLO 19-91
ATABL3
Company Sanitized. Does not contain TSCA CBI
Amended Final Report
Du Pont HLO 19-91
ATABL3
Company Sanitized. Does not contain TSCA CBI
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ATABL3 I
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Amended Final Report
Du pont hlo 19
Company Sanitized. Does not contain T S C A CBI
Amended Final Report
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Company Sanitized. Does not contain TSCA CBI
PHARMAKON RESEARCH INTERNATIONAL, INC. Individual Animal Scores During Induction
T a R T .!
Du Pont HLO 19-91
Amended Final Report
PHARMAKON RESEARCH INTERNATIONAL, INC. Individual Animal Scores During Induction
Sponsor;
/ / / f / f a j U ^ ^ R ^ 'tudy Number;
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Time
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Du Pont HLO 19-91
Initials
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Amended Final Report
PHARMAKON RESEA. .1 INTERNATIONAL, INC. Individual Animal Scores Dring Induction
Sponsor: Test Article: / / --/ ,
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Study iN u m b e r \ P t f
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Du pont HLO 19-91
Initials
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Amended Final Report
Du Pont HLO 19-91
ATABL3
Company Sanitized. Does not contain T SC A CBI
Amended Final Report
Du Pont HL0 19_9l
PHARMAKON RESEARCH INTERNATIONAL, INC. ATADL3
Company Sanitized. Does not contain T SCA CBI
Amended Final Report
Sponsor -. f j . <
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PHARMAKON RESEA.,_H INTERNATIONAL, INC.
Individual Animal Scores after Challenge
^ Study Number:
- s ~ t) "7
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Notebook Page S
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Animal No. Sex
34V<9 f
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PHARMAKON RESEARCH INTERNATIONAL, INC
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Amended Final Report
PHARMAKON RESEAnOH INTERNATIONAL, INC.
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