Document YbBKqQq6vbODQNGdGwJMRojK
T - 3 *1 1 1
t & - O Z23 \ /'- '
28 Dermal Percutaneous Absorption Study with FC-128
in Albino Rabbits
Experiment No. Conducted At: Dates Conducted: Conducted By:
0979AB0629
Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota
October 25, 1979 to December 17, 1979
t C O S h / Y f o _______ 'V/f/fi7
K. D. O'kalletf, BS
Date
Advanced Toxicologist
Study Director
Reviewed By:
dc: M. T. Case K. L. Ebbens F. D. Griffith W. C. McCormick
A/
K. L. Ebbens, BS
Date
Supervisor, Acute Toxicology
000238
1. Summary
A 28 day percutaneous absorption study with FC-128 was conducted from October 2s, 1979 to December 17, 1979 at Riker Laboratories, Inc., St. Paul, Minnesota using male and female albino rabbits ranging in body weight from 1.95 to 2.90 kg. The test article was administered by dermal application to ten male and ten female rabbits a dosage level of 2,000 m g A g body weight
a for a 24 hour exposure period" No mortalities or untoward behavorial reactions were noted during the 28 day study. Body weight losses were noted in three females at the end of the study. Necropsies were performed on all animals upon termination of the study with no visible lesions noted. Preliminary serum analysis (See Appendix ,W) indicates dermal absorption of FC-128 in albino rabbits, however, due to the limited number of samples analyzed by the sponsor, no concrete conclusion may be drawn.
Introduction The objective of this study-- was to determine the percutaneous absorption
potential of FC-128 in male and female albino rabbits. The study, which was initiated at Riker Laboratories, Inc., St. Paul, iMinnesota on October 25, 1979 and completed on December 17, 1979, was not conducted to support a government submission or marketing permit and is therefore not regulated by the Good Laboratory Practice Regulation of 1978. The raw data generated by the Study Director and the final report are stored in the conducting laboratory's archives.
a a preliminary rangefinder study was conducted to determine the appropriate dosage level to be used in this study.
-- Riker Toxicity Experiment No.: Q979AB0629, Test Method 699
000239
BEST t>uH AVAILABLE
2.
Me thod
Young adult albino rabbits of the New Zealand breed-- were used in this
to-st. AlJ. animal:; wore held under quarantine for several days prior to tcstii
with only animals which appeared to be in good health and suitable as test
animals at the initiation of the study used. The rabbits were housed individ
ually in stainless steel, wire-bottomed cages and maintained on a standard
laboratory ration-- with food and water available ad libitum.
An initial rangefinding study was conducted vising two male and two female
rabbits for each dosage level. The trunk of each animal was clipped free of
hair and the test article placed on the surface of the intact skin which
covered approximately 40si total body surface area. After administration of
the test article, a flexible plastic collar was fitted on each animal a n d
the trunk wrapped with impervious plastic sheeting which will occlude the i
test article. The animals were returned to their cages for a 24 hour period
after which time the test article was removed from the dermal surface of the
animals. The animals were observed for pharmacotoxic reactions both during
the exposure period (immediately post dose administration, one and two hours)
and after removal of the test article (daily for 14 days following dose admin
istration) with all reactions recorded (Table 3). Initial and final body
weights were also recorded (Table 1).
The information derived from the initial rangefinder was used in
determining the dosage level for the 28 day percutaneous study. Preparation
of 10 male and 10 female animals for dosing and application of the test article
were conducted in the same manner as the rangefinder study with the exception
of the collection of blood samples from the orbital sinus plexus prior to
application and again on days 1, 7, 14 and 28 after initiation of the study
for serum which was frozen for sponsor analysis. After the 24 hour exposure
Pel Frees, Inc., Rogers, AR -- Purina Rabbit Chow, Ralston Purina, St. Louis, MO
000240
BEST COPY AVAILABLE 3.
period the test article was removed from the dermal surface of the animals and the animals returned to their cages for the following 28 days. Initial, 7, 14 and 28 day body weights were recorded (Table 2) as were any pharmacotoxic signs noted during the 28 day observation period (Table 4) . A gross nccro>sy was conducted on all animals sacrificed on day 28 and all findings recorded (Table 2). The protocol, principal personnel involved in the study, composition characteristics, and Quality Assurance statement are contained in Appendices I - IV.
000241
TA li I.K L
4
ACUTE DERMAL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS
with FC-- 128 Mortality and Body Weight Data
BEST COPY AVAILABLE
Dose-- (mg/kg)
Sex
Animal Number
Individual Body Weights (kg) Test Day Number 0 14
Number Dead Number Tested
Percent Dead
5000 2000 1000
M 9B2582 M 9B2585 F 9B2629 F 9B2632
M 9B2598 M 9B2601 F 9B2648 F 9B2627
M 9B2604 M 9B2607 F 982630 F 9B2633
2.16 2.34 2.07 2.00
1.18 1.96 1.95 1.94
2.30 2.26 1.98 2.34
2.25 (3 days)
1.97 2.13
2.32 2.41 2.03 2.20
2.19 2.57 1.87 1.99
0/4 0 1/4 25 0/4 0
-- Test article was dosed as a suspension in water
000242
TABLB 2
5
ACUTK PRKCUTANROUS ABSORPTION TOXICITY STUDY - ALBINO RABBITS
With FC-128
Mortality and Body Weight Data
COPYAVAILABLE
Dose--
,,
. . Sex
(mg/kg)
Animal Number
Individual Body Weights (kg) _______ Test Day Number___________ 0 7 14 28
Number Dead Percent Number Tested Dead
2000
M 9B3001 2.52 M 9B3007 2.35 M 9B3013 2,59 M 9B3003 2.50 M 9B3009 2.09 M 9B3015 2.31 M 9B3005 2.13 M 9B3011 2.04 M 9B3074 2.07 M 9B3078 2.06
2.35 2.43 2.26 2.04 2.15 2.37 1.85 1.71 1.98 2.18
2.57 2.66 2.52 2.39 2.26 2.59 2.10 1.87 2.29 2.43
2.88 2.96 2.84 2.77 2.51 2.87 2.46 2.50 2.49 2.75
0/10
0
2000
F 9B2969 1.95 F 9D2975 2.13 F 9B2981 2.21 F 9B2987 2.34 F 9B2971 -^>2.41 F 9B2977 2.13 F 9B2983 ^2.90 F 9B2989 2.21 F 9B2973 2.19 F 9B2979 92.38
1.79 2.18 2.24 2.33 1.87 1.91 1.94 1.97 2.14 1.73
2.05 2.40 2.54 2.44 2.05 2.25 2.13 2.12 2.37 1.57
2.48 2.67 2.82 2.70 2.37 2.35 2.37 2.36 2.50 1.79
0/10
\
0
-- Test article was dosed as a suspension in water Necropsy Necropsies performed upon termination of the study revealed no visible lesions
000243
Dose (mg/kg) 5,000
2,000
1,000
TABLE 3
ACUTE DERMAL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS
with FC-128 Saraary of Reactions
Tire of Onset --
Cessation of Reaction k
Number Affected Following Dose
Following Dose
Tire of Death
Sex Reaction_______ Maraer Dosed ' Administration__________ Arainlstration_________Following Dose
M Hypoactivity Lethargy
F No significant reaction
M No significant reaction
F No significant reaction
M No significant reaction
F No significant reaction
1/2 1/2
Day 9 Day 14
--
--
-- --
Day 14 Until -termination
--
--
------
1 S T COPY AVAILABLE
000244
Time when first animal in the dose group exhibited the reaction -- Time when no animal in the dose group exhibited the reaction
c\
Dose (mg/kg)
TABLE 4
ACUTE PERCUTANEOUS ABSORPTION TOXICITY STUDY - ALBINO RABBITS
with FC-128 Summary of Reactions
Tima of Onset
Cessation of Reaction
Number Affected Following Dose
Following Dose
Time of Death
Sex Reaction_______ Number Dosed ' Administration__________ Administration________ Pollowing Dose
000245
2,000
M No significant reaction
F No significant reaction
Kj.kc.-r ExperimuuL N o .:
APPENDIX I PROTOCOL
8.
TIM": Single Dose 28 Day Percutaneous Absorption Study
SPONSOR: 3M ____ Cerr-nmejrrvr\0 <? k.t>y*\?rftrj______________________________________ _ Division
CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota
TEST ARTICLE:
F C - A ?L.<Z_________________________________________________________ _
CONTROL A R T I C L E : __ p/j}___ ___________________________ ________________________________________
I'KOI`OS ED STAK'D NO/COMPLEViON DATE OF STUDY: n- T<? / I- frO
TEST SYSTEM AND SOURCE: New Zealand White Albino Rabbits
Sex:
-t-fZ
Pel Freez, Inc., Rogers, Arkansas Number: iq -v-ip
Weight Range:
>3 k<Q
o b j e c t i v e -.
The objective of this study will be to determine the percutaneous absorption potential of the test article in albino rabbits. Rabbits were selected as the test system for their historical use in dermal absorption studies, ease of handling and general availability.
method:
The animals, selected from a larger colony by health and body weight, will be randomly housed in standard wire-mesh cages in temperature and humidity con trolled rooms with food-- and water offered ad libitum. Each animal will be assigned a numbered ear tag, which will correspond to a card affixed to the outside of the cage. The trunk of each animal will be clipped free of hair and the test article applied as a single dosage of ,o o o mg/kg to intact skin coverinq approximately 10 total body surface area. A flexible plastic collar-- will be fitted on each animal and the trunk wrapped with impervious plastic sheeting, which will occlude the test article. .The animals will then be returned to their cages for a 24 hour exposure period after which the test article will be removed. Prior to t h e 'application, blood samples will be collected from the orbital sinus plexus and again on days 1, 7, 14, and 28 after initiation of the study for serum which will be frozen for sponsor analysis. A gross necropsy will be conducted on all animals which may dio during the conduct of the study as well as all animals sacrificed on day 28. All gross findings will be recorded and tissue samples of liver, spleen, brain kidney and bone marrow (sternum) will be fixed in 10% buffered formalin for possible future microscopic examination. Initia.1, 7, 14, and 28 day body weights will be recorded as well as any pharmacotoxic signs noted during the conduct of the study. All raw data, other than the blood analysis data which will be the responsibility of the sponsor, and the final report will be stored in the Riker Laboratory's Archives, St. Paul, Minnesota.
Purina Rabbit Chow, Ralston Purina, St. Louis, Missouri -- The collar will be worn for the duration of the study to reduce oral
ingestion of residual test article.
___ .C . Sponsor
l A w u x k /uKiO M /7 M Date
Study Direc
000246
BEST COPY AVAILABLE
Hiker imparimene N o . : < w
Air 'NDIX I ((.'unl. inucil) PROTOCOL
//;/-:/,
v 9.
T E S T : Acute Dermal Toxicity Hanyefipd^-ng Study s\
SPONSOR: 3M f/X /'M'Jlld { . / ? ? / (
f/,,
Divisi
CONDUCTED BY : Safety Evaluation Laboratory, Hiker Laboratories, Inc. St. Paul, Minnesc
TEST ARTICLE: / Q / /j
I'<iNTUi'M . ARTICLE:
jll/i
PROPOSED STARTING/COMPLETION DATE OE STUDY: r r / 7 1 7 -- r / T f T
S ZTEST SYSTEM AND SOURCE: New 'Zealand White Albliinn'o Rabbits Sex:
7J~ r_
Pei -Ereex, Inc., Rogers Arkansas Number
Body Weignt Range 4 Jbs'
OBJECTIVE:
The objective of this study will be to approximate the acute dermal toxicit of the test article in albino rabbits. Rabbits wore scluctod as the tost system for their sensitivity of response, historical data, ease of handling and general availability.
METHOD:
The animals, selected from a larger colony by health and weight, will bo randomly housed in standard wire-mesh cages in temperature and humidity controlled rooms with food-- and water offered ad libitum. Each animal will be assigned a numbered ear tag, which will correspond to a card affixed to the outside of the cage. The trunk of each animal will be clipped free of hair and the test article placed on the surface of the intact skin at singl dosages of fYC ).,P f Y r I , j, Off! mg/kg, however, if these dosage levels d not adequately characterize 'the toxicity of the test article, additional animals will be administered the test article at supplemental dosage levels Any additional dosage levels will be documented and filed with this protoco The test article will be administered to the animals in the form received from the sponsor. After administration of the test article, a flexible plastic collar^- will*be fitted on each animal and the trunk wrapped with impervious plastic sheeting which will occlude the test article. The anim will be returned to their cages for a 24 hour exposure period after which time the test article will be removed from the dermal surface of the animal The animals will be observed for pharmacotoxic reactions both during the ex posuru period (immediately post dose administration, one and two hours) and after removal of the test article (daily for 14 days following dose adminis tration) with all reactions being recorded. Initial and final body weights will also be recorded. The acute median lethal dose (LD50) of the test article will be approximated. All raw data and the final report will be st in the Riker Laboratories Archives, St. Paul, Minnesota.
a -- Purina Rabbit Chow, Ralston Purina, St. Louis, Missouri
-- The collar will be worn for the duration of the study to reduce oral in gestion of residual test article.
A ).
...
Sponsor
__________________________________________________________________________
Date
Study
000247
BEST COPY AVAILABLE
RiJcer Experiment No. ;
DIX I (Concluded) ndnent to Protocol
1. V\,xo /J-ruAv oi^ygc-xcn cxaapO. c c r a g ^ o ^ ^ O TJ
P\,A
A A", ' o f Q ,\Ht >i ( oci)
jMuwAxaA U u A A K o
11ftOf/oi
10.
\ c p t')fy\aISijj':/ Study Director
v/ioh*) Date
2 A \.V `i \-?:>0 m A/v'v/j1 0. I n A j w i J v u v T 'g o ^ v <.P \ < ^ o m v Y u A i L , .s m a .Q u ,c i b r f V v \ / - i
VM - J v x . c a i Q u A c\ u .> ^ ~ i V \
fn,\;iW \ 11 \\y>.
Y 9 > Q < Y \ n O O i . ,/ Study Director J
o/ I i i a A L i b i. 0! - 'I Q W
Vv\ ( v TVTWToTTOf^V, ^/v \(\m.a.a..,q,A
o
UA ( V i c W
Date
4. ,V-KA.'J A'lXrr".
W ' - T - kA\ AV*
*<Tt> I Study Direc
u5 5 Date
'3)hAl-W\.
ew.r Aitili,
c ^ i l . u v - v Aabi
Qilftjuirhof "fo
J1 V \ V ( ^ X \ D Q q l a
Study Director
^ IUr, / I
Date
5.
Study Director
Date
6.
Study Director
Date
7.
Study Director
Date
8.
000248
Study Director
Date
BEST COPY m\\ APPENDIX II lncipal Participating Personnel Involved in the Study
Il
11.
_ Name______ K. L. Ebbcns, BS K. D. O 'Malley, BS
Dr. V . Po thap ray ada G. C. Pecore
Function_______________
Supervisor, Acute Toxicology
Advanced Toxicoligist Study Director
Commercial Chemicals Chemist
Supervisor Animal Laboratory
000249
APPENDIX III Composition Characteristics
12.
This study is not regulated by the Good Laboratory Practice Regulation of 1978 and therefore information pertaining to composition characteristics is not applicable for inclusion in this study.
best copy m u m
000250
APPENDIX IV
13.
BEST COPY AVAILABLE
Quality Assurance Statement
This study is not regulated by the Good Laboratory Practice Regulation of 1978 and therefore a statement signed and prepared by the Quality Assurance group is not applicable. This study was, however, audited by the Quality Assurance group.
in addition to the data audit, different significant phases for studies underway in the Toxicology Laboratory are inspected weekly on a recurring cycle, and the facilities are examined by Laboratory Quality Assurance on a three month schedule.
000251
H H i t n . il t . o ! I f . | >>i i( l i-i i (<
i i : II. U . Kicker k. D. Griffith - 220-21: k. A. UbOi - 22U-21APPENDIX V
K. !.. EBBENS - HIKER SAFETY EVALUATION LAB - 203-1 W. C. McCORMICK - MEDICAL DEPT. - TOXICOLOGY SERVICES - 220-2E SK1N ABSORPTION STUDIES ON FC-143, FC-95, FC-99, FC-134, FC-135, FC-128, FC-129 and FC-98 JUNE 27, 1980
Please consider this an authorization for your laboratory to rolcase tho dermal toxicity/skin absorption studies conducted on the above montioned compounds. It is understood that the studies are being issued in an incomplete form insofar as the fluorochcmical analysis of the serum samples have not been completed and will not be included in the report. Preliminary serum sample analysis indicates absorption of the compounds. The serum data analysis are not sufficient enough to draw any concrete conclusions concerning comparitive toxicity. However, the animal data you have generated addresses this matter in a broader context. It is not certain when the remaining samples will be analyzed and their completion should not hold up your report any longer. Thank you for your patience in this matter.
WCM:k1h
000252
liili iIi.il<.1II<*"(>MIlei1>
I. I . 11__ ..1,--------K. A. I'rok(j|> -- Z'.lO-- 2H
! . . D . W i n t e r - 2 1 0 --2D
XU JC
APPENDIX* V (Concluded)
W ST COPy AVAILABLE
COMMERCIAL CHEMICALS DIVISION ANALYTICAL LAB REPORT ffU 6...
lo Kifxft
Subject
K.*
W. C. MCCORMICK - 220-2E-02 V. POTHAPRACADA AND V. BUNNELLE - 236-3A RIKER SKIN ABSORPTION STUDY June 9, 1980
Reference: Commercial Chemicals Division Analytical Request 015669
For lack of time. only a selected set of serumi samples was analyzed.
Compound FC-129 FC-134 FC-128
TOTAL F PP"_______
Females Day 1 Day 28
Males Day.* Day 28
26.1
69.6
11.4
23.3
0.2 18.1
18.8
23.9
4.4 16.5
1.6 10.5
FC-98 FC--135 FC-95
226.4 6.9 0.9
93.1 20.8 128.0
271.9 2.3
10.3
94.3 7.6
130.2
FC-99
42.5 53.1
111.5 119.8
129.1 72.7
73.5 66.6
Femules
Males
Day 7 _ Day 14 Day 28 Day 7 Day_ 14 Day 28
10.1
12.1
3.5 5.4
6.8 4.6
M i' l i i i x l o f A i i ; i I y it i i : <>xy j'.i/.i iU ii u li/ C C T i - c l u i I i|in* ( . I o n
/nul
D. F. Hagen, Anal. Blochein; 87, 545, 1978).
V. A. Uunnelle VAB/hc
V. Pothapragada
Read and Reviewed by U y Winter
*
000253
