Document 6Br18R9GJ1nvnKZeegomaVa86
F-xperiment No.: Conducted At: Dates Conducted: Conducted By:
Reviewed By:
Acute Oral Toxicity Screen with T-3421
in Albino Rats
0883A.RO287
Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota
August 2, 1983 to September 7, 1963
'I) ,U4-, . D. M. Markoe, Jr., BS" Toxicologist Study Director
@O/Zi E(ate
K. D. O'Malley, BS Senior Toxicologist Acute Toxicology
Date
i@.@L.-Eb-bent'-, ES
Date
Supervisor, Toxicology Testing
dc: M. T. Case f it:li---Z W. C. M,--Cormick
Summary
The acute oral toxicity screen with T-3421 was conducted from
Aug-ust 2, 1983 to September 7, 1983 at Riker Laboratories, Inc., St. Paul,
Minnesota using male and female albino rats ranging in body weight from 191-258 grams. The test article was administered by gastric intubation at
dosage levels of 5,000, 2,000, 500 and 200 mg/kg body weight with mortalities
of 10/10, 10/10, 10/10 and 2/10 noted respectively from one hour to six days
post dose administration.
The untoward behavioral reactions which occurred
during the 14 day observation period generally consisted of hypoactivity,
lethargy, prostration, diarrhea and unkempt appearance with the onset
occurring from 1-30 minutes to day four post dose adndnistration.
Clonic
convulsions were noted in two animals prior to death, trancient alopecia was
noted in two animals while dyspnea and salivation were noted in one animal
during the study. All reactions subsided by day eleven or death precluded
recovery. Body weight gains were noted in animals which survived the study
period. Necropsies performed at termination of the study revealed no visible
lesions while hyperemic or hemorrhagic lungs and/or hemorrhagic intestinal
tract generally were noted in the animals which died during the conduct of the
study. The acute oral LD50 of T-3421 is greater,than 200 mg/kg and less than
500 mg/kg in male and female albino rats.
Introduction
The objective of this study was to determine the acute oral LD50 of
T-3421 in albino rats. This study was conducted in accordance with the Food
and Drug Administration's 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.
2.
Method and Results ta
Young albino ra s- were used in this test.
All animals were held under
quarantine for several days prior to testing with only animals which appeared
to be in good health and suitable as test animals at the initiation of the
study used. The rats were housed in stock cages in temperature and humidity b
controlled rooms and permitted a standard laboratory diet@ plus water ad
libitum except during the 16 hour period immediately prior to gastric
intubation when food was withheld.
Five male and five female rats were adrlinistered the test material at
preselected dosage levels. The doses were administered at a constant volume
of 10 ml/kg directly into the stomachs of the rats using a hypodermic syringe
eauipped with an intubation needle.
After gastric administration of the test material, the rats were returned to their cages and observed for the following 14 days. Initial, seven day and final body weights, mortalities (Table 1) and adverse reactions (Table 2) were recorded. A necropsy was conducted on all animals that died during the study as well as those euthanatized at the end of the 14 day observation period (Table 1). The protocol, principal personnel involved in the study, composition characteristics and Quality Assurance statement are contained in Appendices I - IV.
a King Labs, Oregon, WI Ralston Purina Laboratory Chow, Ralston Purina, St. Louis, MO
TA.BLF- 1 ACUTE ORAL TOXICITY S7JDY - ALBINO RAFS
with T-3421
Mortality, Necropsy and Body weight Data
E)ose a (,-.g/lkgS)ex
5:)Oo
m
Animal Nt=ber
3P,3553 3R3554 3Tz3555 3R3556 3R3557
5000
3R3573 3R35'14 3P-3575 3R3576 3R3577
zooo
m 3R3556 3R3559 3R3560 3R3561 3R3562
2C)OC
3P,3578 3R3579 3R3560 3R3581 3R3562
Soo
m 3R4070
3R4071
3R4072
3R4073
3R4074
500
F 3R4106
3R4107
3R4106
3R4109
3R4110
individual Body Weights (g)
Test Day Number:
Nu=,ber Dead
0
7
14
Number Tested
208
(Day 6) -
5/5
210
(Day 2) -
197
(Day 6) -
219
(1 Hour) -
214
(Day 6) -
191
(1 Hour) -
5/5
207
(1 Hour) -
207
(1 Hour) -
192
(1 Hour) -
209
(Day 1) -
195 207 209 217 207
199 216 201 205 203
210 212 213 217 216
204 200 205 221 198
(Day 6) (Day 6) (Day 6) (Day 6) (Day 2) -
(Day 6) (1 Hour) (1 Hour) (Day 1) (illiour)-
(Day 3) (Day 4) (Day 6) (Day 5) (Day 4) -
(Day 6) (Day 4) (Day 5) (Day 3) (Day 4) -
5/5 5/5 5/5 5/5
3.
Percent Dead 100 100 100 100 100 100
TA.BL7- 1 (concluded) ACIJTE C)PAL TOXICIN STUDY - ALBII:D PATS
with T-3421 Mortality, Necropsy and Body Weight Data
Dose (,mg/kg) Sex
200
m
Animal *4LLr@be r
3R4075 3R4076 3R4C)77 3R4078 3R4079
200
F 3R4111
3R4112
3R4113
3R4114
3R4115
I.ndividual Body Weights (9)
Test Day Nu=@>er:
N L=.ber Ce ad
0
7
14
'4u--t@>re Te s te d
251
(Day 6) -
1/5
236
274
297
253
303
336
256
302
345
248
249
297
220
230
243
1/5
212
242
242
217
236
236
238
253
257
225
(Day 5) -
4
Percent I>ead 20 20
'@ote Figures in parenthesis indicate time of death
a Test article administered as a suspension in water. The approximate oral IZ50 is greater than 200 mg/kg and less than 500 mg/kg in fasted male and female albino rats.
Necropsy Necropsy of the animals which survived the observation period revealed no visible lesions 'while necropsy of those animals which died during the conduct of the study generally had hyperemic or hemorrhagic lungs. Hemorrhagic small intestine was noted at the 500 mg/kg dose level and one animal from the 200 mg/')..dgose group. One incidence of mottled liver was noted at the 5,000 mg/kg level.
TABLE 2 ACUTE ORAL TOXICITY SCREEN - ALBINO RATS
with T-3421 Summary of Reactions
Reactions
Dose n-q/kq
5000
Sex
m Hypoactivity Lethargy Salivation Dyspnea Diarrhea Unkempt.
Appearance
5000 2000
F Hypoactivity Lethargy Prostration
m flypoactivity Lethargy Prostration Diarrhea Unkempt
Appearance
2000
F ilypoactivity Lethargy Prostration Diarrhea Unkempt
Appearance
Minutes
1-30
60
120
2/5
0/4
2/5
3/5
4/4
1/5
0/5
1/5 0/4
1/5
0/3
4/5
1/3
0/1
2/3
1/1
2/5
2/5
3/5
3/5
1/5
2/5
2/5
1/2
0/2
3/5
1/2 0/2
2/2
Observation Periods Number Affected/Nvmbcr D
-
sed Days
1
2
3
4
5
6
7
9
3/3 3/3 -
-
4/4 0/3
4/4 3/3 3/3 3/3 3/3 -
5/5 4/4 4/4 0/5 0/5 5/5 4/4 4/4 -
4/4 4Z4 -
1/1 1/1 1/1 -
0/1 1/1 1/1 1/1
1/1 1/1
TA13LE 2 (conclude(l) ACUTI'@ ORAT, TOXICITY SCRF,:PN - ALBINO RAT',;
with T-3421 Summary of Reactions
Reactions
Dose Sex
rq/kq
Minutes
-
1-30
60
120
500 500 200 200
m Hypoactivity Cdnvulsions
(clonic)
Hypoactivity Ataxia
m Convulsions
(clonic)
F Alopecia
Observation Periods
-- Number Af fegtgd/Nmmbvx 2gs-Z
-
Days
1
2
3
4
5
6
7
a
9
2/3 1/1 * 1/3 0/1
3/3 2/2 * 1/4 0/3
1/5 0/4
2/4 2/4
Key:
Blank indicates no significant reactions
observations Total Death
inadvertenly missed over weekend
APPENMIX 1
PROTOCOL
Riker Experiment No.:
TEST:
@'C
SPONSOR: 3M
CONDUCTED BY: SafetyEvaluation Laboratory,Riker Laboratories,Inc.,St.Paul,Minnesota
TEST ARTICLE:
CONTROL ARTICLE-.
PROPOSED STARTI NG,,ICOM PLET ION DATE OF TEST:
TEST SYSTEM:
SOURCE:
Sex: Number: Weight Range:
L
7.
Division
OBJECTIVE: METHOD:
The objectiveof thistestwillbe to characteriztehe acute
toxicitoyf the test
articlein albino '-,::F
.-P -
were selectedas a testsystem for reproducibiliotfy
response, historicaulse, ease inhandlingand generalavailability.
The animals willbe housed instainlesssteelsuspended wire mesh cages intemperatureand humidity
controlledrc>omsduringboth the quarantineand testperiods,withfoodq and water offeredad libitumt.
Each animal willbe identifiebdy colorcoding, according to the laboratory'sstandard operatingpro-
cedure,which willcorrespond tothe animal numbers on a card affixedtothe outsideofthecage. A single
dosage of ;
mglkg willbe administeredeach animal,however, itthisdosage leveldoes not
adequately characterizethe toxicitoyf the testarticlea,dditionalanimalswillbe administeredthe test
articleat supplemental dosage levels.Any additionadlosage levelswillbe documented and filedwith
thisprotocolT.he testarticlweillbe administeredtothe animals inthe form receivedfrom the sponsor.
Afteradministratioonf the testarticlet,he animalswillbe returnedtotheircages and observed forany
untoward behavioralreactionsforthe following14 days. Initialnd finalbody weightswillbe recorded.A
gross necropsy which willinclude,but not be limitedto heart,lungs,liverk,idneysand generalgastro-
intestinatlractwillbe conducted on allanimalswhich die duringthe conduct ofthe testas wellas the
animals survivingthetestperiod.Any gross abnormalitieswhich areobserved duringthe conduct ofthe
necropsy willbe recorded with specificmention to the organ and/orsiteobserved.The acute medial
lethaldose (LD.-;o)fthe testarticlweillbe ca)culatedi,fpossible,usinga probitanalysismethod atthe
end of the observationperiod.Allraw data generated by the study directoarnd the finalreportwillbe
storedinthe RikerLaboratoriesA'rchive,St.Paul,Minnesota.
PurinaLaboratoryChow, RalstonPurina,St,Louis,Missouri LA.'-T-H L.L@-F"-r:--
F--jru7@1-l7I!1.V9V3E EDD
JUN 1 1.OJ33
C. -)rl-.ci'@Ll
Sponsor
Date
Study Director
Date
FDm, 1917i-i5-ok-Pwo
Riker Experiment No. : 0883A-TZ0267
APPENDIX Ceviations and/or
I (concluded) A=!endments to protocol
1. Weekena observation for Aucrust 6 ana 7 were ina,-3vertentlv missed ana on SeDteml>er 3rd.
D. M. Markc>e, ljlr. Study Director
10/5/83 Date
2.
Due to a aelav in stuav conduct the propose8 completion aate shoula be &-nended
to 1/64.
D. M. Markoe, Jr. Study Director
12/29/83_ :,at e
3.
Study Direczor
C-a ::e
4.
Study Director
[)at e
S.
Study Director
Uto
9.
APPEN'DRX rr Principal Part.Lcipating per3ornal Tnvolved in =t,.eScud_y
Na= e 0. M. Markoe, jr., 8S K. L. Ebbens, RS -K. 0. O'Ma.Iley, B.S @7,.C. Pecore
Eun c ti on
Toxicologist Sttjdy D-Lrector
Suporvisor TO xi c o 1 c@gy Te s tx ng
Senior Tbxicoloq3.St Acute Toxicology
Supervisor AnL=al Laboratory
APPENDIX III
lo.
Test and/or Control Article Characterization fo
1<
1. The identity strength, uniformity, composition, purity or other pertinent characterizations of the test and/or control substances ?@ave been determined and documented as of
2. The method of synthesis or origin of the test and control substances, including their amount and the method of bioassay (if applicat)le) is
documented.
yes
no
3. The stability of mined or will be
The above cords.
information
the test and/or control substances have been deter-
determined as of ;?--5Tt.,r3
r,@@7@:
and doclnentation are located in the sponsor's re-
"'
Sponsor
93
E)ate
Z-
r V4 9S33
r:jujUi,-Ji-1
C-V Li
APPENDIX IV
QUA@-ITY ASSURANCE
STATEMENT
Acute Toxicology Study No.:
Laboratory
Studies
This short term study was audited by Compliance kudit, and
the The
final re7)ort examined against the raw data on
-7
results of the audit were reoorted to the study director
and
.0 managenent on
In addition'to t-he data audit, different significant phases for studies un,:Ierway in the Acute Toxicologv Laboratcr-v are inspected weeklv on a recurring cycle, and t-he facilities are examined by Comoliance Audit on a three month schedule.
17
i Complia-n ce Audit
Date