Document NN0yw8eMo5Np27GNY9JXOEaR
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35 H
493
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Report on the results of 28-day repeated administration toxicity study using a mammal
1. General items
Name of novel chemical substance
(IUPAC nomenclature) Other name
Structural formula or rational formula (if neither is known, outline of preparation method)
Described in page 2.
Purity of the novel chemical substance used in the test Name of impurity and concentration Lot No.
[Notes]
HB
State at a room
temperature
Stability
Melting point
u Boiling point
2Cu" Vapor pressure
o
o Partition coefficient os Dissolution
'33 Water
S'
DMSO
=3 CoO Acetone
Other (ethanol)
Brown viscous solid Unknown
Oil soluble and water soluble *2 *3
*4
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2. Acute toxicity test
Test Kind of test Animal No. and term species
1 14-day repeated
administration test
Rat
No. of animals per group
Male 3 head Female 3 head
Administration path
Dose (mg/kg)
LD50 or NOEL* Experi-
(mg/kg)
ment
site
Oral administration
(mg/kg/day) 1,000 500 250
Abnormal Abnormal Abnormal
snr 3 o L
50 # control
Normal Normal
NOEL 50 mg/kg/day (observation items: bodyweight, general
condition, hem atological test, hem atobiochem ical test, organ weight,
dissection, histopathological
cpf 3o Cn>O0 >os--ri
p
I P po-rPctr o
test)
* NOEL: No-Observed-Effect Level # Purified water @ Test carried out on the kidney of the male medium-control group, 50 mg/kg group and 1000 mg/kg group.
General condition
(Male)
250 mg/kg group: soft stool (2/3)
500 mg/kg group: soft stool (2/3)
1.000 mg/kg group: soft stool (3/3)
(Female)
500 mg/kg group: soft stool (3/3)
1.000 mg/kg group: soft stool (3/3)
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3. 28-Day repeated administration toxicity test
Test substance administration term From July 30, Heisei 15 (2003) to August 26, Heisei 15 (2003)
Animal species and lineage
Rat, Crj: CD (SD) IGS
No. of animals per group
Administration path
Purity of
test
o
o
mg/kg
IP IBodyweight (adninistratioii day 12
term )'
I| day 17-day 28 Bodyweigh (reaivery term) day 1
Forced oral administration (purified water)
Male: 6 head Female: 6 head
QMtrol sroup
0
e?
Lo>v-dose Sroup 10
$
Medium-doss Medium-dos2 High-dose 0) group (2) group S>roup 40 >00.\ 1 000
& C? $ C? $
Recoverygroup
0 c? *oT
1,000 $
-- -- -- -- -- -- T .--
------ -- -- -- i --
..T - --
day5^ day 10
V--
day 14
IJeed intake (administr ation term)
i Feed intake (recovery term) day 8
1 ------ ---------- __
T-- --A
General condition soft stool
----
-- -- -- 6/6 2/6 12/12 12/12 -- -- 6/6 5/6
Hematological Activated partial test thromboplastin time
-- -- -- -- T -- -- --
----
! Hematobicachemical Alkali
test Dhosf)hatase
1
----
-- -- .-- -- -- .
A|
----
131ooc1glucose
iUburnin
Jrinary test Amount of urine Organ weight (absolute weight)
------ -- -------- -- ---- -- --V -- -- * -- -- -- -- -- --.
--- -- -- --------
1 V-- (
---- A --`
----
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-- l----
5
Purity of
test 40>0
substance
O
O
mg/kg
Organ weight (relative weight)
Liv er Testicles
Btain
Con trol . gro up
(
Low -dose
gn>up 10
j i - _ _ J L . -Or'
Mediuin-dose Mediuin-dose
(l)group
(2) g coup
40 2 (10
c? T0 _ i L
77
--
7/
----
High- dose . group
1,000
Recover, group
() 1,000 & 7 7 0.
A
7
-- --.
----- ~J A
/
A--
Dissection Kidney Pyelectasia
1/6 -- -- -- 1/6 -- -- -- -- -- -- -- -- --
Spleen Node
White section
Centrilobular hepatic cell h/pertrophy SmaIIgranuloma (+)
---- -- ---- --
--*
-- -- -- -- -- -- -- -- -- 1/6 -- -- -- -- 1/6 -- -- -- -- -- -- --
4* 4= * -- * 3/6 --. -- * -- 4=
Single ce!! necrosis (+), __ 4--
Kidney (+)
----
Pyelectasia
Localization of medulla 1/6
(+) Seminal vesicle
vacuole {+)
--
-- 1/6
*
* *
Spleen Local necrosis (++)
-- --. *
* 4c * * ** 4= 1/1 * * . 0/1 *
* *. *
1/6 * -- -- 1/6 4c -- * -- 4/6 -- -- * -- * * * -- -- 4: 4= 4= 4= * 4= -- -- * * 4: 4s
1/1 * -- -- * * 0/1 *
Follicle hypertrophy -- (++}
NOEL (mgdcg) Changes based on NOEL . estimation
_ * * )C * 0/1 * -- -- 4 4 1/1 40 mg/kg/day
Soft stool observed in males and females of 200 mg/kg or higher dose
*
-'---i-SBacaa-- . -- '. . ....-- .n-- Pathohistological Liver test
Sompany
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no abnormality i or T: tendency V orA : risk factor (P) <0.05 orA : risk factor (P) <0.01 *: not tested
4. Other
Repeated administration Name Chemical Evaluation & Research Institute, Hita Lab.
toxicity
Address 3-822 Ishi-cho, Hita City, Ohita Prefecture, Telephone 0973(24)7211
Test implementation
facility
Test manager
Name Keiji Shiraishi
Seal
Implementation date
From July 16, Heisei 15 (2003) to December 5, Heisei 15 (2003)
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Title:
Work assignment table 28-Day repeated oral administration toxicity test o f ^ ^ H H H H f H j i n rats
Name
Work content
Test manager:
to carry out work such as test planning, test work management, overall
Keiji Shiraishi
analysis and evaluation of the results, report preparation, etc., and have
general responsibilities for all work carried out for the test
Person in charge of to carry out quarantine inspection as well as conditioning and rearing
testing:
management of animals, test substance preparation, administration, general
Naomi Kawazu
condition observation, bodyweight measurement, feed intake measurement,
etc., and have responsibilities for animal experiment work.
Person in charge of to carry out work such as dissection, tissue collection, organ weight
pathological testing: measurement, histopathological test, etc., and have responsibilities for
Kazutoshi Shinoda pathological and morphological work.
Person in charge of to carry out work such as hematological tests, hematobiochemical tests, urine
clinical testing:
tests, etc., and have responsibilities for work related to biochemical analyses
Keiji Shiraishi
of biological samples
^ Person in charge of to carry out work such as test substance stability determination, confirmation
analysis:
of stability and uniformity of test substance solutions prepared, etc., and have
Takaharu Hara
responsibilities for work related to analyses.
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Statement Chemical Evaluation & Research Institute, Hita Laboratory
Test requestor: DuPont K.K.
Title: 28-Day repeated oral administration toxicity test of
in rats
This final report (copy) is an accurate transcription of the final report of the above titled test.
December 5,2003 Operation Manager: Shigeharu Yamasaki
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Final Report 28-Day repeated oral administration toxicity test o^
m rats
December 2003 Chemical Evaluation & Research Institute, Hita Laboratory [Seal]
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Statement
Chemical Evaluation & Research Institute, Hita Laboratory
Test requestor: DuPont K.K.
Title: 28-Day repeated oral administration toxicity test
in rats
The test described above was carried out according to `Testing facilities specified in Ministry Ordinance Article 4 stipulating items, etc., of test related to novel chemical substances and evaluation of toxicity related to designated chemical substance" (GLP) [Environmental Protection Notification 39, Notification No. 229 of Pharmaceutical Affairs Bureau and MOT Basic Industry Bureau Notification No. 85 dated March 31, Showa 59 (1984), amended on March 1, Heisei 12 (2000)] and "OECD Principles of Good Laboratory Practice (November 26, 1997).
In addition, this final report has been confirmed to reflect the raw data accurately, and the test data obtained are confirmed to be effective.
December 5,2003 Test Manager: Keiji Shiraishi
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Quality Assurance Certificate Chemical Evaluation & Research Institute, Hita Lab.
Test requestor: DuPont K.K. Title: 28-Day repeated oral administration toxicity test of
in rats
The auditing and inspection of this test were carried out by the QA department of Chemical Evaluation & Research Institute, Hita Lab. The date of auditing or inspection and date of the results reported to the person in charge of study or operation manager are as follows
Auditing or inspection item
Date of auditing or inspection
Study protocol
July 18, 2003
Study protocol change
July 23, 2003
Record of receiving animals
July 28, 2003
Test substance preparation
July 29,2003
Study protocol change (No. 2)
July 30, 2003
Animal grouping record
July 30, 2003
Substance administration
July 31, 2003
Study protocol change (No. 3)
August 11, 2003
Dissection
August 27, 2003
Profile
September 2,2003
Study protocol change (No. 4)
October 31,2003
Study protocol change (No. 5)
October 31, 2003
Clinical test results
November 19, 2003
Pathological test results
November 25, 2003
Animal experiment results
November 27,2003
Physicochemical test report draft
November 27, 2003
Clinical test result, 2ndtime
November 28,2003
Test substance and rearing conditions records November 28,2003
Final report draft
November 28, 2003
Physicochemical test report draft rvaluation - December 3,2003
Final report draft rvaluation
December 5,2003
Final report
December 5, 2003
Date of auditing or inspection result
reported July 22,2003 July 23, 2003 July 28,2003 July 30, 2003 July 30,2003 July 30, 2003 July 31,2003 August 11, 2003 August 27,2003 September 2, 2003 November 4, 2003 November 4, 2003 November 19, 2003 November 25, 2003 November 27,2003 November 28, 2003 November 28,2003 November 28, 2003 November 28, 2003 December 3, 2003 December 5, 2003 December 5,2003
This report describes the method and procedures used in the test accurately, and the results reported reflect the raw data accurately.
December 5, 2003 Person in charge of quality assurance: Keiji Shiraishi
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Test substance code No.: HR5158
Title: 28-Day repeated oral administration toxicity test of
in rats
Test requestor: DuPont K.K. 1-8-1 Shimomeguro, Meguro-ku, Tokyo, 153-0064
Test facility: Chemical Evaluation & Research Institute, Hita Lab. 3-822 Ishii-cho, Hita City, Ohita Prefecture, 877-0061
Object: the object is to elucidate variety, extent and reversibility of toxic signs developed and to determine no-observed effect level (NOEL) by observing changes in the function and morphology of animal body in the case of 28-day repeated oral administration of the test substance.
Testing method: the method according to "28-day repeated administration toxicity test to use mammals" specified in the "Partial amendment, etc., of "Novel chemical substance testing method" (Environmental Protection Notification No. 700, Notification No. 1039 of Pharmaceutical Affairs Bureau and MITI-Basic Industry Bureau Notification No. 1014 dated December 5,1986" and "407, Repeated dose oral toxicity - rodent: 28-day or 14-day study" specified in "OECD guideline for testing of chemicals" (May 12, 1981) was carried out.
GLP applied: "Testing facilities specified in Ministry Ordinance Article 4 stipulating items, etc., of test related to novel chemical substances and evaluation of toxicity related to designated chemical substance" (GLP) [Environmental Protection Notification 39, Notification No. 229 of Pharmaceutical Affairs B.ureau and M1T1 Basic Industry Bureau Notification No.. 85 dated March 31,1984, amended on March 31, 2000] and "OECD Principles of Good Laboratory Practice (November 26, 1997) was used.
Test schedule Start of study Experimental animal received Start of experiment (start of substance administration) Dissection at the end of administration term
July 16, 2003 July 22, 2003 July 30, 2003 August 27, 2003
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Start of recovery test Dissection at the end of recovery term End of experiment (end of hematological test) End of study
August 27, 2003 September 10, 2003 October 31,2003 December 5, 2003
Document storage site and storage term The raw data, study protocol, test request, test substance brochure, final report, QA
inspection documents, other records or documents and specimens are to be stored at the document storage room of the Hita Laboratory of the Institution, and the test substance samples by lot were stored in the test substance storage room for 10 years from receiving a notification of the Chemical Substance Control Law, Article 4, Clause 1, No. 1,2 or 3 being applicable. The date receiving the notification is to be contacted to the Hita Laboratory of the Institution by the test requester. The handling after the storage term requires approval from the test requester. In the case of specimens, test substances, etc., the qualities of which are liable to be changed during the storage, the storage term is for the duration of the qualities being able to be evaluated, and the disposal requires approval from the test requester.
Storage of original documents The original of the study protocol and amendments is to be stored at the Hita Laboratory
of the Institution. Furthermore, its copy is to be stored by the test requester. The original final report is to be stored at the Hita Laboratory of the Institution.
Furthermore, its copy is to be stored by the test requester together with a statement (certificate of the content being not different from the original) issued by the operation manager of Hita Laboratory of the Institution attached.
Study manager and other persons involved in the study and their work assignments
Study manager:
Keiji Shiraishi
(Carrying out work such as test planning, test work management, overall analysis and
evaluation of the results, report preparation, etc., and having general responsibilities for all works
carried out for the test)
Person in charge of testing: Naomi Kawazu (Carrying out quarantine inspection as well as conditioning and rearing management of
animals, test substance preparation, administration, general condition observation, bodyweight measurement, feed intake measurement, etc., and having responsibilities for animal experiment work)
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f Person in charge of pathological testing: Kazutoshi Shinoda (Carrying out work such as dissection, tissue collection, organ weight measurement,
histopathological test, etc., and having responsibilities for pathological and morphological work)
Person in charge of clinical testing: Keiji Shiraishi (Carrying out work such as hematological tests, hematobiochemical tests, urine tests, etc.,
and having responsibilities for work related to biochemical analyses of biological samples)
Person in charge of analysis: Takaharu Hara (Carrying out work such as test substance stability determination, confirmation of
stability and uniformity of test substance solutions prepared, etc., and having responsibilities for work related to analyses)
Approval by final report author Study manager:
December 5, 2003 Keiji Shiraishi [signature] Affiliation: Hita Laboratory, 2ndDepartment for Testing
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Table of Contents
Abstract
Material and method 1. Test substance 2. Experimental animal 3. Rearing environment 4. Group configuration 5. Stability of test substance 6. Test substance preparation 7. Substance administration 8. Observation and test 9. Statistical method
Factors affecting the study
Results 1. 2. 3. 4. 5. 6. 7. 8. 9.
General condition Body weight Feed intake Hematological test Hematobiochemical test Urinary test Organ weight Dissection Histopathological test
Discussion
Page
15
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Figures 1 Body weights 2 Food intakes
............................................................. ............ ................................................
1 3
Tables 1 Summary of clinical signs ............................................................. 2 Summary of body weights .......... ................................................ . 3 Summary of food intakes ........................................................... 4 Summary of hematological examinations ......... 5 Summary of blood chemical examinations .............. 6 Summary of urinalyses ..................................
7 Summary of absolute organ weights ...................................
8 Summary ofrelative organ weights .................. - ..............J 9 Summary ofmacroscopic examinations ; ................................. .1 0 Summary of histopathological examinations ..............................
1 2 4 6 8 10 11 12 13 14
Photos
1,2
..............................................; ........ - ................... 1
Addenda 1 Clinical signs of individual animals .............................................. 1 2 Body weights of individual animals .............................................. 6 3 ' Food intakes of individual animals ................................... 9 4 Hematological data o f individual animals ..................................... 12 5 Blood chemical data o f individual animals .................................. 16 6 Urinalytic data o f individual animals .............................. ......... 20
7 Absolute organ weights of individual animals ...... ...................... 22
8 Relative organ weights o f individual animals .............................. 24 9 Pathological foldings o f individual animals ................................ 26
Attached documents
Physicochemical test report
16
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Abstract
, 28-day repeated oral administration toxicity test and 14-day
recovery test were carried out by using 6 head per grup of Crj: CD (SD) IGS male and female
rats of 5 weeks old. The doses used were 4 levels from 1,000 mg/kg/day as the maximum dose
followed by 200,40, and 10 mg/kg/day. Incidentally, the 1,000 mg/kg/day group and medium
control group were allowed to have recovery groups.
In the present study, there was no fatal case considered to be attributable to the test
substance administration. Moreover, there were no toxicological effects of the test substance
administration observed during the whole administration term with respect to the results of
hematological tests, hematobiochemical tests, urinary tests and dissection carried out after the
administration term.
With respect to the general condition, those males and females with a dose of 200 mg/kg
or higher showed soft stool, and this finding was considered to be the effect of the test substance
administration. In addition, the males in the 1,000 mg/kg group showed body weight increase
inhibition from day 12 to day 28.
In the case of organ weight measurements, the relative weight of the liver in the females
of the 1,000 mg/kg group was found to be increased.
As a result of histopathological examination, centrilobular hepatic cell hypertrophy and
single cell necrosis in the liver were observed in males of the 1,000 mg/kg group.
In the recovery test, all changes observed during the administration term and at the end of
the administration terms showed recovery.
The results as described above suggested mainly soft stool, bodyweight increase
inhibition and changes in the liver as an effect of the administration
and
from all of those changes, it was considered to be recoverable. Incidentally, the NOEL of
y ^ ^ ^ H B f p u n d e r the conditions used in the present study was estimated to be 40
mg/kg/day because of soft stool observed in males and females of groups with a dose of 200
mg/kg/day or more.
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Materials and Methods 1. Test substance (information provided by the test requester) 1.1 Name
1.3 Source DuPont K.K.
1.4 Structural formula
18
1.6 Name and concentration ofImpurity
1.7 Physicochemical property State at a room temperature: brown viscous solid
Stability: unknown Melting point: Boiling point: Vapor pressure: Partition coefficient: __ Hydrolysis: unknown
r iTzed. Doss no! contain TSCl
'3:
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Dissolution: oil soluble and water soluble
Solubility:
Water
Less than 50 mg/mL (measured at the institution)
DMSO
Less than 50 mg/mL (measured at the institution)
Acetone
-
Other
Ethanol
Soluble (unknown solubility)
1.8 Storage conditions
The storage was at a room temperature (experimental storage, cabinet 6).
1.9 Handling precaution
Protective gloves, mask, cap and white lab coat were worn.
2. Experimental animals Cij: CD (SD) IGS rats (SPF) were purchased from Nippon Charles River K.K. (Hino
Shiiku Center, 735 Komatuki, Hino-cho, Gamou-gun, Shiga Prefecture 529-1633). After quarantine inspection and conditioning, the random extraction method by weight was used to select animals of normal growth and good general condition, and the animals were grouped so that the mean bodyweight was approximately same in each group. The age of the animals at the time of the start of substance administration was 5 weeks old, the male body weight was in the range of 141.7-159.9 g, and the female bodyweight was in the range of 115.5-132.9 g. The animal identification was with ear tags.
3. Rearing environment Throughout the whole rearing term including the quarantine inspection and conditioning
period, the animals were kept in a barrier system rearing room set at a temperature in the range of 21-25C, relative humidity in the range of 40-70%, number of ventilation in the range of 1015 times/hr and light-dark cycle with 12 hr interval (light turned on 7th hour and off on 19thhour of day). The actually measured results of the temperature and relative humidity were 21.9-23.9C and 54.6-71.8%, respectively.
On the day 2 of the recovery term, the function of the air-conditioner was suspended for 8 min due to being hit by lightning causing the humidity to rise (the maximum humidity of 71.8%). As a result of the subsequent observation of the general condition of the animals, no abnormality was observed, and the incident was considered not to affect the results of the study.
Prior to grouping, the animals were kept 5 head/cage in stainless steel and metal mesh floor cages (260Wx380Dxl80H mm, Tokiwa Kagaku Kikai K.K.), and after grouping the animals were individually kept in stainless steel and metal mesh cages (165Wx300Dxl50H mm,
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Tokiwa Kagaku Kikai K.K.). The bottom trays were exchanged once a week before grouping and 2 times a week after grouping. Incidentally, because of soft stool observed in the medium dose group and high dose group as well as high dose recovery group, the trays were exchanged every day from day 2 of the administration term to day 3 of the recovery term for those groups and 2 times a week from day 4 of the recovery term. The feeders, cages and racks were exchanged once each at the time of grouping and end of the administration term (recovery groups only). Incidentally, the racks and cages were tagged for identification.
The feed used was a solid feed (MF, Lot No. 030510, Oriental Yeast Industry K.K.), and the drinking water was tap water of Hita City (chlorine added) allowed to be taken freely from an automated water feeder. The feed and rearing equipment and tools were autoclave-sterilized (121C for 30 min) before using. For the feed, the analytical data determined by Japan Food Research Laboratories were obtained from the manufacturer, and the items were confirmed to be within the standard values of the US Environmental Protection Agency Regulations. In addition, the miscellaneous inclusions of drinking water were tested twice a year by the Kurume Laboratory of the Institution, in one of those tests, the entire 46 items of water quality described in the Ministry of Welfare and Health Ordinance No. 69 (becoming effective on December 1, 1993 were tested, in the second test, 32 items among them were tested, and the results were confirmed to be within the standard values.
Throughout the whole rearing term including the quarantine inspection and conditioning period, those rearing environmental factors showed no variations considered to affect the results of the study.
4. Group configuration
The group configuration used was as in the following table.
Test group
Dose (mg/kg/day)
Dose volume (mL/kg)
Dose concentration
(w/v%)
No. of animal Male (animal No.) Female (animal No.)
Medium control group
0 10
0
6(1-6)
6(43-48)
Medium control recovery group
0
10
0
6(7-12)
6 (49 - 54)
Low dose group
10 10
0.1
6(13-18)
6 (55 - 60)
Medium dose (1) group
40 10 0.4
6(19-24)
6 (61 - 66)
Medium dose (2) group
200 10
2.0
6 (25 - 30)
6 (67 - 72)
High dose group
1,000
10
10.0
6(31-36)
6 (73 - 78)
High dose recovery group
1,000
10
10.0
6(37-42)
6(79 - 84)
Reasons for doses used: a 14-day repeated oral administration toxicity test was carried out with 4 doses of 50, 250, 500 and 1,000 mg/kg/day. As a result, there were changes in the general condition observed in the 250 mg/kg group and suspected to be attributable to the test substance. Therefore, in the present study, the high dose was set at 1,000 mg/kg/day followed by 200,40
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and 10 mg/kg/day, that is, the total of 4 doses being used. Incidentally, the recovery groups were set for 1,000 mg/kg/day and medium control.
5. Stability of test substance The stability of the test substance during the administration term was confirmed at the
Hita Laboratory of the Institution. The stability of the test substance was confirmed by measuring its infrared absorption
spectrum before the start and after the end of the administration term. The infrared absorption spectrum measurements were carried out by using a Fourier
transform infrared spectrophotometer (Model FTS 135, Nippon Bio-Rad Laboratories K.K.) in the range of 4,000 cm*1- 400 cm'1.
Before the start of the administration, the identification was carried out by comparing with a spectrum provided by the test requester, and in the measurement carried out after completing the administration term, the spectrum before the administration was used to compare to find any change.
6. Test substance preparation 6.1 Medium
The state of suspension in pure water was found to be good, and thus, the medium selected was pure water (Lot No. A168, Takasugi Seiyaku K.K.).
6.2 Preparation method The test substance was accurately weighed and suspended in pure water by adding a
small amount of pure water at a time into an agate mortar to prepare 0.1,0.4, 2.0 and 10.0 w/v% solutions. Incidentally, the test substance preparation was carried out once a week.
6.3 Homogeneity test and stability test For those test substance solutions prepared by the preparation method described above,
stability and uniformity tests were carried out at the Hita Laboratory of the Institution. As a result, the 10.0 and 0.05 w/v% solutions prepared were confirmed to be stable in a cool and dark place for 7 days. Furthermore, the homogeneity was found to be good.
For the homogeneity of the test substance solutions prepared, the 10.0 w/v% and 0.05 w/v% solutions immediately after their preparations were sampled at top, middle and bottom layers with n = 3 for each layer, the samples were diluted with methanol, the test substance concentration was measured by using high performance liquid chromatography (HPLC), and the homogeneity was confirmed from the relative standard deviation of the test substance
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concentrations at respective sampling sites. For the stability confirmation, the 10.0 w/v% and 0.05 w/v% solutions were stored in a cool and dark place, sampled from the middle layer with n = 3 after 3 days and 7 days, the samples were diluted with methanol, the test substance concentration was measured by using high performance liquid chromatography (HPLC), and the stability was confirmed by finding any change from the concentrations immediately after preparation (results of homogeneity test).
HPLC analysis conditions (1) Instrument used (HPLC1)
Interface: Model D-7000IF (Hitachi, Ltd.) Pump: Model L-7100 (Hitachi, Ltd.) Autosampler: Model L-7200 (Hitachi, Ltd.) RI detector: Model L-7490 (Hitachi, Ltd.) Column oven: Model L-5020 (Hitachi, Ltd.) Date processor: Model D-7000 HPLC System Manager (Hitachi, Ltd.) (2) Measurement conditions Column: Shodex Asahipak GF-310HQ 7.6 mm I.D. x 300 mm Column temperature: 40C Mobile phase: methanol Flow rate: 1 mL/min Amount injected: 50 xL
7. Administration A syringe (Terumo Corp.) with a Nelaton catheter (Terumo Corp.) connected was used
to carry out forced oral administration everyday in the morning repeatedly for 28 days. Subsequently, a recovery term of 14 days was set.
8. Observations and tests The day and week calculation system is as follows. The day to start substance
administration was set as day 1, the day before the day to start substance administration was set as day -1, and the week when the administration was started was set as week 1. Furthermore, the next day of the final day of substance administration was set as day 1 (recovery), and the week of starting the recovery term was set as week 1 (recovery).
8.1 General condition
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The general condition was observed 3 times a day before substance administration (in the morning), during and after substance administration and in the afternoon everyday from day 1 to day 28. During the recovery term, the observation was carried out once a day in the morning every day from day 1 (recovery) to day 14 (recovery).
Incidentally, the symptoms observed were summarized every week, the animal No. of animal showing a symptom was recorded in an individual table (Addendum). Furthermore, the symptoms observed were classified as those observed during the administration term and those in the recovery term, and the number of cases observed in each group was recorded in a group table (Table). 8.2 Bodyweight measurement
The measurement was carried out on day-2 (at the time of grouping) before substance administration, day 1, 3, 8,12,17,21, 26 and 28 during the administration term and day 1 (recovery), 5,10, and 14 during the recovery term.
Incidentally, to calculate relative weight of organs, the bodyweight measurement was carried out at the end of the administration term and end of the recovery term. 8.3 Feed intake measurement
The measurement was carried out once before substance administration, on day 3, 8,15, 22, and 28 during the administration term and day 4 (recovery), 8 and 14 during the recovery term.
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8.4 Hematological test
The measurements of the following items were carried out on blood or plasma samples
collected from the abdominal aorta under ether anesthesia after overnight fasting(16-20 hr) at the
end of administration term (excluding the recovery groups) and at the end of the recovery term.
As an anti-coagulant, a 3.2% aqueous solution of sodium citrate was used in the case of
measurements of prothrombin time, and activated partial thromboplastin time, and EDTA-2K
was used for other measurements.
Item 1) Red blood cell count (RBC) 2) White blood cell count (WBC) 3) Hemoglobin concentration (Hb)
4) Hematocrit (Ht)
(x lO'VuL) (X lO'VuL) (g/dL)
(%)
Method Electric resistance method Electric resistance method Non-cyanohemoglobin method
RBC X MCV
5) Mean corpuscular volume (MCV) 6) Mean corpuscular hemoglobin content (MCH)
(fL) (Pg)
7) Mean corpuscular hemoglobin concentration (MCHC) (g/dL)
8) Platelet count (Platelet)
9) Reticulocyte proportion (Reticulo) 10) Prothrombin time (PT) 11) Activated partial thromboplastin time (APTT) 12) Leukocyte proportion (Differentiation of leukocyte)
Band neutrophils (N-Band) Segmented neutrophils (N-Seg) Eosinophils (Eosino) Basophils (Baso) Lymphocytes (Lymph) Monocyte (Mono)
(X 107mL)
(%)
(sec) (sec)
(%)
103
Electric resistance method
m xlO3 RBC
xl0= Ht
Electric resistance method RNA staining Magnetic sensor system Magnetic sensor system Wright staining
Instrument used 1-8) Automated general hematological analyzer (Model CELL-DYN 3500, ABOTT
LABORATORIES) 9) General hematological testing device (Model ADVIA 120, Bayer Medical)' 10,11) Automated blood coagulation meter (Model KC-10A, AMELUNG) 12) Microscope (Model VANOX, OLYMPUS)
8.5 Hematobiochemical test From the blood collected at the same time as in the section 8.4, the serum was isolated,
and the measurements of the following items were carried out for serum samples prepared.
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25
Item 1) GOT 2) GPT 3) Alkaline phosphatase (ALP) 4) Cholinesterase (ChE)
5 )y-GTP 6) Total cholesterol (T-Cho) 7) Triglyceride (TG) 8) Blood glucose (glucose) 9) Total protein (T-Protein) 10) Albumin (Albumin) 11) A/G ratio (A/G ratio) 12) Urea nitrogen (BUN) 13) Creatinine (Creatinine) 14) Total bilirubin (T-Bil) 15) Calcium (Ca) 16) Inorganic phosphorus (IP) 17) Sodium (Na) 18) Potassium (K) 19) Chlorine (Cl)
(IU/L) (IU/L) (IU/L) (IU/L) (IU/L) (mg/dL) (mg/dL) (mg/dL) (g/dL) (g/dL)
(mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mEq/L) (mEq/L) (mEq/L)
Method UV method (JSCC-based formula) UV method (JSCC-based formula) p-Nitrophenyl phosphate method Butyrylthiocholine iodide method
L-Y-glutamyl-3-carboxy-4-nitroanilide method CODADPS method GPOADPS glycerol erasure method Hexokinase-G-6-PDH method Biuret method Bromocresol Green method Albumin/(T-Protein - Albumin) (calculated value) Urease-GIDH method Creatinase-F-DAOS method Azobilirubin method OCPC method Fiske-Subbarow method _ Crown-Ether membrane electrode method Crown-Ether membrane electrode method Coulometric titration method
Instrument used 1-3), 6-8), 12), 13), 15), 16)
4), 5), 9), 10), 14)
17-19)
Automated biochemical analyzer (Hitachi Model 7170 Automatic Analyzer) Automated biochemical analyzer (Hitachi Model 7150 Automatic Analyzer) Electrolyte analyzer (Model PVA-ain, A&T)
8.6 Urine test The measurement was carried out once (day 28) during the administration term
(excluding recovery groups) and once (day 14 (recovery)) during the recovery term. For a urine sample (about 16 hr accumulation) collected in an individual metabolic cage
(150Wx200Dx263H mm), the amount and coloration were measured, and the measurements of pH, protein, ketone body, bilirubin, occult blood, glucose and urobilinogen were carried out by using test paper (N-Multistix Bayer Medical).
8.7 Pathological test 1) Dissection
All cases were observed in detail.
2) Organ weight measurement
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26
For all cases, the weight measurements of the following organs were carried out. Furthermore, relative weights were calculated based on the bodyweight measured at the end.
Liver, kidney, testicles, ovaries, brain, spleen and adrenal gland
3) Histopathological examination (1) For all cases, the following organs and tissues were collected.
Classification
Organ or tissue
Respiratory system
Trachea, lung
Digestive system
Incisors, esophagus, stomach, intestines (duodenum, rectum), pancreas, liver
Cardiovascular system
Heart
Urinary system
kidney, bladder
Reproductive system
testicle, epididymis, prostate gland, seminal vesicle (including
Nervous system
coagulating gland), ovary, uterus and vagina Brain (cerebrum and cerebellum)
Hematopoietic system
bone marrow (femur), mesenterium lymphatic nodes, spleen,
Endocrine system
thymus gland pituitary gland, thyroid gland (including parathyroid gland),
adrenal gland
Sensory organ
eyeball
The organs and tissues collected were fixed in a 10% neutrally buffered formalin solution. Incidentally, the testicle and epididymis were fixed with Bouin's solution.
(2) For the following organs and tissues, paraffin-embedded section specimens were prepared, stained with hematoxylin-eosin staining and observed under an optical microscope.
Study group Medium control group
Medium control recovery group 200 mg/kg group 1,000 mg/kg group
______ Organ or tissue_______________________________ Stomach (anterior stomach and glandular stomach), intestine (duodenum, jejunum, ileum, cecum, colon and rectum), liver, heart, kidney, spleen and adrenal gland Liver (male only)
Liver (male only) Stomach (anterior stomach and glandular stomach), intestine
Ssm pm gSm$fke*,!ms not eonta TSGACBf
/"n /""'n.
27
(duodenum, jejunum, ileum, cecum, colon and rectum), liver, heart, kidney, spleen and adrenal gland 1,000 mg/kg recovery group Liver (male only)
(3) Following organs and tissues examined as naked eye-observed morbid portions
Study group (animal no.)
Organ or tissue
40 mg/kg group (No. 22)
Kidney
200 mg/kg group (No. 30)
Spleen
1,000 mg/kg recovery group (No. 42)
Spleen
9. Statistical method The results on bodyweight (except at the time of body removal), feed intake.
Hematological tests, hematobiochemical tests, amount of urine and organ weights were tested for equality of variance by the Bartlett method, and if there was equal variance observed at a 5% significance level, a one-way analysis of variance was carried out. If the results of analysis of variance showed a significant difference, a test by the Dunnett method was carried out between the medium control group and respective administration groups.
If no equal variance was observed, a Kruskai-Wallis test was carried out, and if there was a significant difference observed, a test was carried out between the medium control group and respective administration groups by using the non-parametric Dunnett method.
Factors affecting study 1. Unpredictable incident suspected to affect the reliability of the test results
In the hematobiochemical test of one case (No. 2) in the medium control group, the blood glucose showed an abnormally high value. The result was far higher than the background value of the Laboratory. The result was considered as a reference value because of a risk of affecting statistical processing and excluded from the statistical analysis. Incidentally, this was noliMsofficei] considered to show any effect on the result of evaluation in the study.
The function of the air-conditioner was temporarily suspended for 8 min due to a lighting strike on day 2 of the recovery term causing the humidity elevation (maximum humidity of 71.8%) in the rearing room. As a result of the observation of the general condition carried out subsequently, no abnormal finding was found, and the incident was considered to have no effect on the results of the study.
2. Violation of the study protocol
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28
According to the study protocol, the bottom tray exchange was to be carried out twice a week, but in the medium and high dose groups as well as high dose recovery group, soft stool was observed, and the tray exchange was carried out every day from day 2 of the administration term to day 3 of the recovery term. This incident was not[Msoffice2] considered to cause any effects on the results of evaluation in the study.
3. No environmental factor considered to affect the reliability of the results of the study was observed
Test results 1. General condition (Table 1, Addendum 1) 1.1 During the administration term Male: soft stool (6/6) in the 200 mg/kg group and soft stool (12/12) in the 1,000 mg/kg groups <State of appearance of soft stool>
In the 200 mg/kg group, sporadically or continuously observed from day 15 to day 28. In the 1,000 mg/kg groups, sporadically or continuously observed from day 2 to day 28. Female: soft stool (2/6) in the 200 mg/kg group and soft stool (12/12) in the 1,000 mg/kg groups <State of appearance of soft stool> In the 200 mg/kg group, sporadically observed from day 16 to day 28. In the 1,000 mg/kg groups, sporadically or continuously observed from day 2 to day 28.
1.2 During the recovery term Male: soft stool (6/6) in the 1,000 mg/kg group <State of appearance of soft stool>
In the 1,000 mg/kg group, observed from day 1 to day 3 Female: soft stool (5/6) in the 1,000 mg/kg group <State of appearance of soft stool>
In the 1,000 mg/kg group, observed from day 1 to day 3
2. Bodyweight (Figure 1, Table 2, Addendum 2) 2.1 During the administration term
Male: in the 1,000 mg/kg group, low value observed on day 12 and low value tendency observed from day 17 to day 28
Female: no abnormality observed
2.2 During the recovery term
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Male: in 1,000 mg/kg, low value observed from day 1 to day 14 Female: no abnormality observed
3. Feed intake (Figure 2, Table 3, Addendum 3) 3.1 During the administration term
Both males and females showed no abnormalities.
3.2 During the recovery terms Male: no abnormality observed Female: in the 1,000 mg/kg group, high value observed on day 8
4. Hematological tests (Table 4, Addendum 4) 4.1 At the end of the administration term
Male: in the 200 mg/kg group, shortened activated partial thromboplastin time observed Female: no abnormality observed
4.2 At the end of the recovery term Both males and females showed no abnormalities.
5. Hematobiochemical tests (Table 5, Addendum 5) .5.1 At the end of the administration term
Male: in the groups of 200 mg/kg or higher dose, reduced albumin observed. In addition, in the 40 mg/kg group, increased alkaline phosphatase observed.
Female: no abnormality observed.
5.2 At the end of the recovery term Male: in the 1,000 mg/kg group, reduced blood glucose level observed Female: no abnormality observed
6. Urine tests (Table 6, Addendum 6) 6.1 At the end of the administration term
Both males and females showed no abnormalities
6.2 At the end of the recovery term Male: in the 1,000 mg/kg group, increased amount of urine observed Female: no abnormality observed
gpoepan SanizedL Doeano*
30
7. Organ weight (Tables 7 and 8, Addendums 7 and 8) 7.1 At the end of the administration term
Male: no abnormality observed Female: in the 1,000 mg/kg group, increased relative weight of the liver observed
7.2 At the end of the recovery term Male: in the 1,000 mg/kg group, increased relative weights of testicle and brain observed Female: no abnormality observed
8. Dissection (Table 9, Addendum 9) 8.1 At the end of the administration term
Male: in the medium control group, pyelectasia (1/6) of the kidney; in the 40 mg/kg group, pyelectasia (1/6) of the kidney; and in the 200 mg/kg group, whitened section (1/6) of the spleen observed
Female: no abnormality observed
8.2 At the end of the recovery term Male: in the 1,000 mg/kg group, node in the spleen (1/6) observed Female: no abnormality observed
9. Histopathological examination (Table 10, Addendum 9) 9.1 At the end of the administration term
Male: in the 1,000 mg/kg group, centrilobular hepatic cell hypertrophy (+, 3/6) and single cell necrosis (+, 4/6) in the liver observed. In addition, in the medium control group, pyelectasia of the kidney (+, 1/6); in the 40 mg/kg group, pyelectasia of the kidney (+, 1/1); and in 200 mg/kg group, small granuloma (+, 1/6) in the liver and local necrosis (++, 1/1) in the spleen was observed
Female: single-occurrence cyst (+, 1/6) in the medulla of the kidney was observed in the medium control group.
9.2 At the end of the recovery term Male: in the medium control group, small granuloma (+, 1/6) of the liver and in the 1,000 mg/kg group, follicle hypertrophy (++, 1/1) of the spleen observed
--. Female: no examination carried out
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31
/"N Discussion
The forced oral administration
carned out to Crj: CD (SD) IGS
rats at 4 dose levels of 1,000, 200,40 and 10 mg/kg/day to carry out 28-day toxicity test and 14-
day recovery test.
In the present study, no fatal case considered to be attributable to the test substance
administration was observed. Moreover, no effects by the test substance administration were
observed on the results of feed intake during the administration term, hematological tests, urinary
tests and dissection carried out at the end of the administration term.
In the general condition, both males and females of those groups with a dose of 200
mg/kg or higher showed soft stool considered to be caused by the test substance administration.
However, no effects were observed on the results of pathological tests for changes in the
digestive tract, etc. Furthermore with respect to body weight, the increases were observed to be
inhibited in males of the 1,000 mg/kg group from day 12 to day 28.
As a result of the hematobiochemical tests carried out, the males of the 200 mg/kg or
higher groups showed reduced albumin, but the changes were all fluctuations within the
background value range of the Laboratory11 the dose-dependency of the results was found to be
poor, and consequently, the changes were not considered as an effect of the test substance
administration.
In the measurements of organ weights, the relative weight of the liver was observed to be
increased in the females of the 1,000 mg/kg group. Furthermore, as a result of the
histopathological examination, centrilobular hepatic cell hypertrophy and single cell necrosis of
the liver were observed in the males of the 1,000 mg/kg group. Those changes were considered
to be attributable to the effects of the test substance administration on the liver.
In addition, there were changes other than those described above observed at the end of
the administration term, but they were observed only sporadically, no dose-dependency was
observed, and they were considered to be accidental changes.
In the recovery test, the soft stool in both males and females of the 1,000 mg/kg group
was continued during the recovery term, but both males and females showed no soft stool on day
4 showing that it was a recoverable change. In addition, the bodyweight was found to remain low
in the males of the 1,000 mg/kg group, but the increases were found to be roughly the same as
those observed in the medium control group, and consequently, it was considered to be a
recoverable change. In addition, several items showed sporadic changes, but they were not
observed at the end of the administration term; furthermore, no related changes were observed,
and consequently, they were considered to be accidental changes.
As effects of the administration f ^ ||j j |j j j j j 0 J B B so^ stoob bodyweight increase inhibition and changes in the liver were suggested from those results obtained, and those changes
Company Sanitized. Does not contain TSCACS4
32
were considered all recoverable changes. Incidentally, the NOEL of
rats
under the conditions of the present study was estimated to be 40 mg/kg/day because of soft stool
observed in both males and females of the groups with a dose of 200 mg/kg/day or higher.
1) Background value of the Laboratory (at the end of the administration term): medium/pure water (containing gum arabic and CMC)__________________________________________
______Item______________ Sex________ n___________Mean 2 S.D.______________
Albumin (g/dL)
Male_______ 228_________2.7 0.2___________________
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))
Fig, 1-1 Twenty-eight-day repeated-dose oral to x ic ity study in ra ts Body weights : Male
Company Sanitized. Does not contain TSGACBI
m m pm f Sanitized, Does not contain TSCAcm
Administration
N--------------------- :------------------------------------------------------- H
rr
13
i ------ --- i------------------- 1----------------- r
8 15. 22 28
Fig, 2-1 Twenty-eight-day repeated-dose oral toxicity study in rats Food intakes : Hale
o ; Vehicle control : 10 mg/kg/day A : 40 mg/kg/day O : 200 mg/kg/day
: 1,000 mg/kg/day
Recovery
H---------------------------H
1 :i
48
!,
14 (days)
UU>J
)
40-i
)
)
30-
cd 30-
cd Ho
10-
Administration
H---------------------------------------------------------------------------- H
i i------------ --i----------------- -~i------------------ i---------------- r
1' 3
B
15
un
Fig. 2-2 Twenty-eight-day repeated-dose oral toxicity study in rats Food Intakes : Female
*
O : Vehicle control : 10 mg/kg/day a : 40 mg/kg/day' o : - 200 mg/kg/day ; 1,000 mg/kg/day
Recovery
H------------ --------------H
T
4
T 14 (days)
UO>s
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37
Table i Twenty-eight-day repeated-dose oral toxicity study in rats Summary of clinical signs
Sex Signs
Administration Period
Male N o abnormalities detected
mgdcg/day VC
ta 6a) S
VC (R) ta 6 6
10
ta 6 6
40 200
ta ta 66 6
Soft stool Female
N o abnormalities detected
6 ta ta ta ta ta 6a) 6 6 6 6 66 6 6 4
Soft stool
a) Number of animals examined. VC, Vehicle control; (R), Recovery, ta, terminal autopsy.
2
1,000
ta 6
6 ta 6
6
1,000 (R) ta 6
6 ta 6
6
Recovery Period VC 1,000
ta ta 66 6
6 ta ta 66 61
5
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Table 2-1
lwenly-eight-day repeated-dose oral toxicity study in rats
Summary o f body w eig h ts(g )
ls
Sex Hale
Female
Exp.group (mg/kg/day)
Vehicle control
10
40
200
1,000
Vehicle control
10
40
200
1,000
Mean S ,D ,
Number of
animals -2 12 i1249.,14 6 i1249..81. e i 1220..68 6 129.3 i 4.1 12 i1249..25 12 112.0 i 3.8 6 i1142..29 e 11142..44 0 i 1132..72 12 i 1132..94
1.
148.4 1 5;. 9 i1448..35 11449..81 i1459..20 1447...53 11264..31 11245..77 11265..22 i1245..20 i1245,.89
3
11666..84 i1648..19 11685..32 11675..30 i1641..65
134.2 1 5.7 136.0 t 5.4 135.1 1 6,3 i 1343..72 t 1343..52
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* * tH? f e r e nt f r o v e h ic l e contrc a t PC0.Q5. S ig n ific a n tly d i f f e r e n t from vehicle conti a t P<0.01.
8
2 1 4 .0 1 9.8
2 0 9 .8 1 10.0
2 1 4 .0 1 8.3
2 0 8 .5 i 12.4
2 0 3 .4 i 7.1
1 5 4 .5 i 8.0
1 5 5 ,3 i 12.2
1 5 4 .7 1 9.0
1 5 4 .7 t 5.6
1 5 3 .2 1 6.9
Administration period 12 17
2 4 9 .9 1 12.3
2 4 2 ,2 1 11.1
2 4 5 .4 1 8.6
2 4 1 .5 i 17.5
2 3 3 .6 1 10.6
1 6 6 .8 f 8.1
1 6 7 .2 1 17.3
1 6 8 .1 1 11.4
1 6 8 .4 i 7 .8
1 6 5 .6 i 9,1
2 9 1 .4 1 13.8
283;. 5 i 12|.6
2 8 8 .1 1 8.4
2 8 2 .3 1 23.6
2 7 3 .8
i 14.8
179;.9 i 10.2
i1 8 1 .8 2 0 .5
185;. 3 1 13.3
183..8 1 11.1
1 8 1 .0 1 9.6-
21
3 2 1 .5 1 14.6
3 1 3 .5 1 1 6 .8
3 1 5 .8 1 12.1
3 0 9 ,-4 i 29.2
302-, 5 1 19.1
1 9 0 .8 i 11.8
1 9 3 .6 1 24.2
1 9 7 .0 i 16.3
1 9 3 .3 1 10.6
1 9 4 .2 i 10.6
26
3 5 7 .4 1 17.2
3 4 4 .8 1 19.2
3 4 9 .4 1 13.7
3 4 2 .6 1 34.2
3 3 2 .8 1 23.0
2 0 1 .1 i 11.9
2 0 5 .0 1 24.1
2 0 5 .9 1 14.3
2 0 5 .8 1 14,0
2 0 7 .5 1 13.1
28 (days)
3 6 7 .7 1 1 6 .6
1 3 25 05 ,,50
3 58.6 1 1 5 .1
3 5 4 .8 1 36 .8
3 4 2 .3 1 24.6
2 0 7 .2 1 13.6
2 0 8 .0 1 2 6 .6
2 1 0 .5 1 18.3
2 0 9 .3 1 10.7
2 1 1 .4 1 13.8
LO
CO
) )
Company Sanitized, Does
TablB 2-2 Twenty-eight-day repeated-dose oral to x icity study in ra ts Summary o f body w eig h ts (g )
Sex Exp,group Number of (mg/hg/day) animals
1
Recovery period 5 10
Hale Female
Vehicle control 1 ,0 0 0
Vehicle control 1 ,0 0 0
6 370.5 i 13,4
8 337.9** 1 20.8
6 209.4 i 15.9
6 214.5 1 16.6
3 9 2 .8 i 15.1
3 6 5 .0 * i 19.7
2 1 8 .6 i 16.9
2 3 1 .1 i 17.1
4 2 1 .2 i 13.7
3 8 8 .4 * i 23.9
2 2 9 .0 i 14.2
2 4 1 .2 i 22.8
Mean + S .D , * S ig n ific a n tly d if f e r e n t from vehicle control a t P<0.05. ** S ig n ific a n tly d i f f e r e n t from vehicle control a t P<0,01,
1 4 (days)
4 4 0 .0 i 14.9
404.1** i 22.6
2 3 2 .7 i 14.9
2 4 4 .0 25.7
oj
)) )
Company Sanitized. Does not contain TSCA CBf
s.TM ; r ; , r i S S " X T
Sex Exp.group Number of
(mg/kg/day) animals
Male Female
Vehicle control
10
40
200
1,000
Vehicle control
10
40
200
1,000
12 1 9 . 8
i 1.8
20.2
1 1.1
1 9 .6 i 1.4
1 201..00 12 20,
1, 12 1 6 . 7
1 .3
1 16 ..04
1 6 .3
1.2
1 8 .4 0 .4
12 1 6 . 9
1 .3
Mean S ,D .
,l" " 11 r,ts
21.2
i 1 . 8'
2 1 .3
1 1.1
2 1 .4
1 1.2
2 0 .9 t 1 .4
20.5-
i 0.8
1 6 .6
1.1 1 18 ., 08 1 16 ..65
1 5 .8 0 .7
1 16 .. 21
Administration period 15
2 3 .2
1.8 221.;68
2 3 .1
1.2 22.2
1 .9
220...80 16:. 6 1.0
1 61. ..05
1 6 ,5 1 .4
1 16 ..80
1 6 .7 1 .3
24.
2.
2 41,.
2 41.,
2 23 .. 66 221.,
1 61.
1 5 .9 1 .4
1 8 .5 1 .5
1 16 .. 25
1 6 .3 1 .5
L Si f n i i i - a n t ! i di i f ereflt f r o v e h i c l e c o n tro l a t P<0.05. S i g n i f i c a n t l y d i f f e r e n t from v e h i c l e c o n tr o l a t P<O.Gi.
22
2 18 ..83
2 6 .0 2 .3
2 51..52
2 5 .2 3 .4
2 5 .1
1.6
1 7 .0
1. 1
1 6 .7 1 .7
17.4
1 .7
1 7 .0 1 .3
1 17 ..58
28 (days)
2 7.4 1 .7
2 6 .2 2 .7
2 8 .2 1 .8
2 6 .2 3 .8
2 25 ..29
1 7 .8 1.3
1 7 .1 1 .4
1 7 .9 2 .3
1 7 .6
1.2
1 8 .2 1 .9
O
U.e iu o 0 io u sa o a-P ^ UBS
o i>3s<
mo> aS3
Table 3-2 Twanty-eiglit-day repeated-dose oral toxicity study in rats Summary o f food i n t a k e s ( g / r a t / d a y ) '
Sex Exp.group Number o f
(mg/kg/day) animals
4
ilecovery period 8
Male Female
Vehicle control 1,000
Vehicle control 1 ,0 0 0
6 27.6 1 .5
8 27.7 2.1
6 18.6 i 1..1
6 20.6 1 2.1
2 7 .6 i 1 .4
2 6 .9 i 1 .7
1 8 .1 i 1.1
2 0 . 2* i 2.0
Mean S .D . * S ig n ific a n tly d i f f e r e n t from vehicle c o n tr o l a t P<0.05. ** S ig n ifican tly d iffe re n t from vehicle control a t P<0,01,
14 (days)
2 8 .0 i 1.8
2 6 .5 f 1.4
1 9 .3 1 1.7
2 0 .2 i 1.9
>
Table 4.1
Twenty-eight-day repeated-dose-oral toxicity Summary o f h em atolo gica l examinations
study
in
rats
Sex Mai e
Exp.group (ms/lcg/day)
Vehicle control
10
40
200
1 ,0 0 0 recovery
Nupber of animals
6
6
6 6 6
REG WBC U lO `>/juL) U 102
757 i 15
i 21
778 i 37
89 1 14
769 i 26
92 i 13
753 1 13
97 i 20
757 96
i 29
i J
-------- ---------*--
Hb
14.8 1 0.4
15.0 i 0.4
15.1 i 0.4
14,7 i 0.4
1.105 ..,13
lit
(%) .48.1
i 0.9
48.9 i 1.8
46.1 1 1.5
45.0 i 0.9
46.5 i 0 .9
Female
control
796 1 30
1,000
803 i 31
Vehicle
6
783
control
i 34
10 6 785
i 32
4 0 6 784 i 17
6 802 i 43
111232 i 102S1
82 i 12
95 1 21
88 i 15
85 1 29
14.9 i 0.5
15.1 i 0.3
15.3 i p.3
15,4 t 0.5
15-.5 i 0.3
15.3 i 0.6
Recovery"
6 783
93 1 5 .1
...................... . J _ 22_____ J . J . l ___ ___1 0 . 4
Vehicle control
1,000
.6 8
808 i 35
789 1 30
81 i 14
81 1 20
15.1 0,7
14.8 1 0.8
Mean S .D .
45.9 i 2 . 3
48.2
46.3 i 1.1
46.9 i 1.3
46,8 f 1.0
46.4 1 2.1
45,8 ___ . . L A .
45.1 i 1.9
44,1 1 2.0
diHfrent fTM VB,liclBcontro1 at P<D-05.
* S i g n i f i c a n t l y d i f f e r e n t from v e h i c l e co n tro l a t P<0 . 0 1 .
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HCV
(ft)
80.9 t 1.0
80.3 1 2.0
60.0 i 1.4
59.8 1 1.7
81.5 1 1.8
HCH
(Pg)
19.6 1 0.4
19.3 1 0,8
18.6 1 0,4
19.5 i 0.7
19,9 1 0.5
57.6 1.6
57.5 1 1.0
58.4 1 l.S
59,8 1 1.1
59.8 1 1.3
57.9 1 1.0
58.5 1 1.0
18.8 1 0.5
18.8 1 0.5
19,3 1 0.6
19.6 ' 0.4
19.8 0,4
19.1 1 0.5
19.3. 1 0.2
55.8 1 1.3
' 55.8 1 1.0
18,7 i 0.4
18.8 1 0.4
HCliC
Eg/dli)
32.2 1 0,4
32.1 1 0.4
32.6 0.4
32.8 1 0.3
32.4 1 0.3
32.8 i 0.7
32.7 i 0.7
33.0 1 0.2
32.8 1 0,2
33.1 i 0.2
33.0 i 0.3
32.9 1 0.4
33.5 1 0.4
33.0 1 0.3;
P latelet Reticulo (xlOV/iL) (%)
114.3 6.9
110.5 1 3.8
112.9 i 7.5
105.2 1 12.4
105.7
2.6 10.4
2,6 10.3
2.6 10.2
2.7 10.3
2.7
PT
21.1 1 2.9
20.9 1 6.3
18.3 1 3.3.
17.4 1 3.9
16.3
113.1 i 4.8
115.8 1 8.0
109.2 1 5.7
113.7 i 16.0
110,1 + 10,6
114,2 1 2.9
110.1
2.4 10.4
2.4 10.3
2.1 10.4
1.8 10.2
2.0 10.2
2.0 10.2
1.9
17.3 1 3.5
18.6 1 4.5
13.6 1 0.7
13.7 1 1 .0
13.4 1 1.0
13.4 1 1.2
14.0
124.6 1 8.5
127.1 1 11.7
2.1 10.2
2.4 10.6
13.3 1 0.4
13.0 1 0 .3
APTT
38.4 + 3.0
34.5 1 3.9
33.2 1 2 .7
28.9** 1 6.1
32,8
31.2 1 3.1
36.8 1 6.1
23.8 1 0.7
25,4 1 1.3
24.7 1 2.3
25.5 1 2.0
24.4
24.8 1 2.1
24.9 1 3.1
to
)>
....... o r a l ti Suiiiiiiary o f hem ato lo g ical examinatio ns
Exp.group (ms/kg/day)
Number o f anim als N-Band
Differentiation of leukocyte (%)
N-Seg
Eos ino
Baso
Lymph
Male
Female
Recovery Vehicle control
1,000
Vehicle control
10
40
200
1,000
Recovery' Vehicle control
1,000
Mean S ,D ,
e
6 1.9
0.9
1.7 11.5
1.3 10.4
111..31 1.8
11.4
1.9 JO ,.?..
2.0
10.9
1.6
10. S
1 72..88.
8.7 1 3.5
1 29.,12 10.2
1 5,1
8.8
1 4.9
11 20 ..51
11.1
1 2.9
8.9 1 2.7
100..78
0.5 10.4
0.8
10.4
0.3 10.4
0.9 10.7
0.8
_.i_0_,5..
0.8 10.8
110..83
* S i g n i f i c a n t l y d i f f e r e n t from v e h i c l e c o n tr o l a t P<0 .Q5 , S i g n i f i c a n t l y d i f f e r e n t from v e h i c l e c o n tro l a t P<0 , 0 1 .
100,.00 0.0
lo.o
100..00 100.,00 100,.00 100..12 0.0
..10,0
100,.00 100..00
87.8 1 2.4
88.8
1 3.8
88.8
1 4.0
88.5 1 2.5
87.9 1 5.0
18 B8:..53
86.4
-i.iJL
1845..53
8-7,9 1 3,4
Mono
0.4 10.7
0.4 10.5
100..46
0.3 10.3
0.2 joj.
100..86 0.8
10.5
100.,44-
0.3 10.4
0.3 10.3
100..00
0.4
MlL 0.8
10.7
0.3 10.5
OJ
Company Sanitized. Does not contain TSCACBi
iatue U-l Twenty-eight-day repeated-dose oral toxicity
Summary o f b lood chemical exam inatio ns
study in rats
Exp.group Humber o f Sex (mg/hg/day) animals
Vehicle control
10
40
Hale 200
1,000
Recovery Vehicle control
1,000
Vehicle control
10
6 6
Female
40
200
1,000
Recovery Vehicle control
1,000
0 6 6
6 6
Mean + S .D .
GOT
(IU/L)
74 i8
78 i8 71 18 80 13
74 16
78 19
84 115
70 i4
81 ill
81 U1 70 6
72
86 18
82 16
GPT
UU/L)
28 13
27 15
27 12
30 15
25
ALP
(IU/L)
422 1 53
470 1 80
518* 1 48
459 1 86
388
24 321 1 2 1 40
27 378 1 3 1 63
20 240 1 1 1 59
25 313 110 1 58
23 274 1 4 1 44
18 227 1 2 1 40
19 251
22 . i4
24 10
214 15
. 192 1 23
ChE
m/i)
50 1 15
45 18
50 19
45 1 10
48
48 18
49 1 14 283 1 35 321 1147 287 1107
225 1 72
282
369 1158
315 1 04
F i g u r e ( s ) in p a r e n t h e s e s i n d i c a t e number o f anim als use d f o r mean c a l c u l a t i o n . * S i g n i f i c a n t l y d i f f e r e n t ' f r o m v e h i c l e c o n tr o l a t P<0 . 0B.
** S i g n i f i c a n t l y d i f f e r e n t from v e h ic l e c o n t r o l a t P<0 . 0 1 .
jjCompanjfSanitized. Does not contain TSCAC il
r-srp
UU/L)
0.9 10.5
1.1 10.5
0.8 10.8
0,6 +0.3
0,8 10.2
0.7 10.3
100..92 1.0
10.4
0.9 10.3
0.8 10.3
0.8 10.4
1.2 +0.4
0.9
10 ,,3
100..80
T-Cho
(ig/dL)
50 17
51 115
47 +8
46 17
39 18
55 13
t4u2
74 18
60 18
72 +7
80 122
88
JU 68
in
H6Q1
TO:
(flig/dU
86 114
58 124
50 +12
78 132
65 129
71
+18
88
118
22. 10
25 1 4:
+2111
28: +14
30.
112
23: 14
19 17
Glucose (rag/dL)
128 1 10(5)
131 1 13
132 1 24
129 19
118 +9
138 1 15
120* 1 12
121 1 20
128 1 14
121 1 13
120 19
120
T -P rotein Albumin
(g/dl,)
(g/dL)
5.4 +0 . 1
5.4 +0 . 2
6.3 10.2
5.3 +0 , 2
5.2 10.1
2.9 10.1
2,8 10.1
2.8 +0 . 1
2 , B** 10.1
2.7*
5,4 10.2
5.3 +0.3
5.5 +0 . 2
5.8 10.4
5,8 +0.4
5,7 10.3
5.5
2.7 10.1
2.7
10.1
2.9 +0 . 1
3.0 10.2
3.0 10.2
3.1 10.2
3.0
A/ 0 r a t i o
1.15 10.07
1.10 10.08
1.10 +0.04
1.02 +0 . 1 2
1.10
0.95 +0.04
1.00
+0.00
1.15 +0.05
1.14 10.07
1.19 +0 . 1 0
1.20 +0.05
1.22
125 1 10
128
1T
5.7 10.3
5.7
10.2
120..92
2.9
+ 0.2
1.05 10.08
1.05 10.11
4^
) ')
)
lauje c-x
iwenty-eight-day repeated-dose oral toxicity study in rats Summary o f blood chemical exam inatio ns
Exp.group Sex (mg/kg/day)
Vehicle control
10
40
Hale 200
1.000
. Recovery Vehicle control
1,000
Female
Vehicle control
10
40
200
1,000
Recovery Vehicle control
1,000
Mean S .D .
Number of BUN animals (mg/dt)
1113 ..18
12.8
i 0.9
13,7 1 1.2
14.4
1 1.8
14.5
....
15.9 i 1.2
14.7
i 1,8
14.7 1 1.9
18.1 1 1.5
13.6 1,9"
15.6 i 1.2
15.9
i 2.6
17.2 1 2.4
17.2 i 2.7
Creatinine T-Bil
(mg/dl)
img/dL)
0.22
10.02
0.18 10.03
0.20
0.03
0.09
10.02
0,09 10,01
100,.0082
100..1091
0.22 10.02
0.08
10.01
0.08
J -0 ..9 J L
0.25 0.03
0.11
10.02
0.23 10.03
0.21
10,02
0,22 0.02
0.22 10.02
0.09
10.01
00,.0091
0.11
10.03
0.11
10.01
0.23
10.02
0.22
0,03
0.09
10.02
0.08
10.02
0.26 0.03
0.26
10.04
0.12 10.02
0.12 10.02
d| f ^ r e n t f ro a ve hi d e co n tro l a t P<0.05. g n i f i c a n t l y d i f f e r e n t from v e h ic l e c o n tr o l a t P<0 , 0 1 ,
Ca
(mg/dl)
1100.,20
10.1 1 0.2
1100..11
10.0
1 0.3 8.9
9.9 1 0.3
9.8
1 0.2
9.8 1 0.3
1 80..19
10.0
1 0,2
10.0
1 0,2
9.9
1 0.2
9.8 1 0,3
9.8 1 0.3
IP
(mg/dL)
8.2
10.4
8.2
10.4
7,9 0.4
7.8 10.5
8,0 ,0_._4_
7.2 10.5
7.1 10.5
7.2 10.4
7.8 10.8
7.4 10.0
7.3 10.6
7.7
10.8
7.1 10.7
8.8
10,4
Na
(mEq/L)
11421
142
i .1 11411
143 i1
142 J__. L
141
11 11411
142 i1
11411
141
11 11421
142 i1
140 i1
140 11
K
(mEq/l)
_ 4.3
10.1
4.3 10.3
4.3 10.4
4.3 0.3
4.2 10 .3
4.3 10.3
4.4 10.4
3.9 10.4
4.0 10.4
4.1 10.4
3.9
10.2
4.1 10,3
140..32
4.1 10.4
Cl
(mEq/L)
105.4 1 1.3
106.2 1 1.9
105.7 1 1.1
106.8 1 1.9
108.1
105.1
1 2.0
11 0 16..14.
108.4 1 1.2
107.8 1 0.7
107.8 1 0.3
108.9. 1 1.3
107.9
---Li.
107.1 1 1.2
108.1 1 1.8
u,
Company Sanitized. Does not contain TSCACBI
B N
&
23
sOO g 5* s a
Table6 S S '`tei' fa6oralloly^ in rats
Exp.group
Number of Volume' 1
__ Sex Male
(mg/kg/dny) Vehicle control 10
. 40
200
1,000
animals_______ (mL)
6 13
8
6 16
8
6 18
i6
6 19 5
8 18
Recovery
Vehicle
6
control
1,000 6
18*
______ _______ 8
Vehicle control
10
Female
40 200
1,000
Recovery-
6 6 6 g 6
10 2
5 3
:i6 7
4
8
4
Vehicle control
1,000
6 6
6 2
7
3
a) Mean S.D,
* S'BniBcsnUy different from vehicle control at P<0.06. _* Significantly different from vehicle control at P<0.01 SY, Slightly yellow.
Y, Yellow.
0, Brown.
Color SY Y B
3 30
4 20 4 20 4 20
5 10
06 0 24 0
330
1 5 0.
4 20
14 1 24 0
06 0 06 0
PH 6.0 6.5 7.0 0 42 0- 5 1 051 024 051
240 1 32
0 5I 0 51 0 51 0 51 0 51
32 1 3 30
Protein - + + ++ 0 240 0330 0 420 0 420 0 420
Ketones - + K 14 i 1 50 240 051 150
Bilirubin 6 6 6 6 6
0 240 0 330
0600 0 14 1 14 10 0240 0 5 10
-0 5 1 132
600 600 600 6 00 600
6 6
6 6 6 6 6
Occult Blood -- f* ++ 5 100 6 0 00 5 1 0 0. 5 100 6 100
6000 4 1 10
6000 6 0 0- 0 6000 50 0 1 60 00
Glucose
_
6
Urobilinogen (EU/dL) 0.1
6
6G
66
86
86
86 66
66 66 66 66 66
1320 140 1
600 600
6 6
6000 500 1
6. 6
G 6
)
f
Table 7
.
. ojmoi.eu-aose ora
Summary o f a b so 1u te organ weights
hex Exp,group (mg/kg/dby)
Vehicle
control
10
Mala
40
200
1,000
Recovery Vehicle control
1,000
Vehicle control
10
Female -
40
200
1,000
Recovery
Vehicle control
1,000
Mean 5 . D ,
Humber o f animals
6
0
6 6
6
Liver (g)
1 0 .2 9 1 0.9 0
9 .7 8 1 1.00
10.12
i 0.87
1 0 .4 6 i 1.91
i-110-.03 07
6 1 1 ,. 9 0 t 1 ,, 1 8
6 1 0 ,, 5 2 i 1 ,. 1 2
6 5'.. 7 6 i 0 ,, 4 5
6 5, 64 i 0 ,58
6 5..76 i 0 ,. 6 6
6 5, 95 i 0 ., 6 2
6 6 .. 4 4
6 6.13
0 .44
6 6.33
0 .6 0
Kidney (g)
2 .7 3 1 0.16
2 .7 1 i 0.23
2 .8 0 i 0.31
2 .8 0 i 0.33
j,,_20..6223
2 .91 + 0 ,32
2 .91 f 0 ,. 2 7
1 .64 i 0 ,07
1 . 57 i 0 ,08
1 , 66 i 0 ,, 1 9
1 ,. 5 7 i 0 .09
1 ,. 6 2
1 .5 9
1 0.10
1 .6 7
1 0.20
,, r 0<U a n a l y s l s was not a p p li e d .
P<Q.Q5** S i m i r a n t M di ^ f e n l fro111 vehio!e co n tro l a t S ig n ific a n tly d i f f e r e n t from vehicle control a t P<o.oi
Company Sanitized. Does not contain TSCA C M
in rats
Testis (g)
2 .84 + 0 ,. 2 8
2 ,02 i 0 ,. 1 4
2 . 99 i 0 ,28
2 .79 4 0 ,. 2 3
2 .74 ___i,,. . 0 ,. 1 1
3,.0 5 i 0 ,. 1 9
3,. 11 1 0 ,. 4 1
-
-
-
-
-
-
-
Ovary (aig)
-
-
-
74. 0 1 8 .9 72. 2 t 9. 3 74. 8
i 10.4
75. 1 i 10.1
70. 0
t 99
84. 4 + 16. 0
88.5 i 14. 9
Brain (g)
1 .08 i 0 ,. 0 6
1 .92 i 0 .06
2 ,. 0 5 i 0 .04
1 .93 1 0 .04
1 . 98 40
2 .00 1 0 ,. 0 8
2 .01 1 0 ,. 0 4
1 .79 1 0 ,. 0 7
1 .85 i 0..06
1 .76 i 0 .09
1 .83
i 0 .06
1 .78 0 ,. 0 4
1 ,. 8 3 i 0 ,. 0 7
1 .83 0 ,. 0 4
Spleen (g)
0 . 65 4 0 ,. 0 7
0 ,. 6 5 4 0 .10
0 . 62 i 0 ,. 0 8
0 , 68 i 0 . 17
0 ,. 5 3
0 ,. 7 2 i 0 ,. 1 2
0 ,. 7 5 i 0 ,. 2 4
0 ,. 4 2 ' i 0 .07
0 .42 1 0 .11
0 .41 1 0 ,. 0 6
0 ,. 4 0 1 0 ,. 0 4
0 .36 + 0 .. 0 2
0 .43 i 0 ,. 0 4
0 ,. 4 5 4 0 .05
Adrenal (mg)
52. 5 i 7 .6
51. 8 4 8 .8
52 . 2 8 .5
47. 9 i 4. 5
51. 5
53 . 7 i 7. 9
52. 8 1 4. 8
60. 5 + 10.0
65 . 0 4 6.9
61. 3 1 7. 4
62. 4 i 7. 2
62 . 7 t 7 .6'
71. 9 8,6
76 . 6 6.6
Body weight a > (g)
340.. 5 4 19 . 8
326 . 6 4 19 . 7
3 3 4 ,. 0 + 13 . 1
327 . 0 i 32 . 3
324 . 3
412 .4 + 17 .1
379 . 6 4 23 , 1
1 9 3 ,. 9 i 12 . 6
193 . 0 f 2 2 ,. 3
1 9 7 ,. 5 + 16 ,2
195 . 2 i 8 ., 5
1 9 7 ., 8 48
218. 5 t 1 2 ,. 4
2 3 1 ..2 22 . 2
--6o-
))
Table 8
taw i' !t* ' r,ts
Sex
Exp group Number o f (mg/kg/day) animals
Liver (g/lOOg)
Kidney (g/lOOg)
Hale Peale
Vehicle control
10
40
200
1 ,0 0 0 Recovery
Vehicle control 1 ,0 0 0
Vehicle control
10
40
200
1,000 Recovery
8 3.02 10.20
6 2.98 10.13
8 3.03 10.22
6 3.1 8 1 0 .2 7
6 3.20
0 .8 0 10.00
0 .8 3 10.06
0.8 4 10.07
0 .8 8 10.06
0 .8 1 1 0 .03
6 2.88 10.20
0 .7 1 10.06
6 2.77 10.22
0 .7 7 10.08
6 2.97 10.11
0 .8 5 10.05
8 2.93 1 0 .1 3
0 .8 2 1 0 .0 8
6 2.91 1 0 .1 4
0 .8 4 1 0 .0 5
6 3.0 4
0 .8 0
10.19 .
10.05
8 3.28*
0 .8 2
-- ___j Q . 20_ ______1 0 . 04_
Vehicle control 1 ,0 0 0
Mean S .D .
0 2.80 1 0 .1 4
6 2.74 10.21
0 .7 3 1 0 .0 4
0 .7 2 10,03
a ) S t a t i s t i c s 1 a n a l y s i s was n o t a p p li e d .
**' S i M i f i a n t K d^ f 6nt frcTM v e h ic le control a t P<0,05. S ig n if ic a n tly d i f f e r e n t from v e h ic le co n tro l a t PcO.Ol.
Testis (g/lOOg)
0.8 4 1 0 .0 7
0 .8 0 1 0 .0 6
0 .8 9 10.08
100..1816
0.86
J O . 08
0 .7 4 1 0 .0 4
0 .8 2 * 10.08
Company Sanitized. Does not contain TSCA CB1
Ovary (fflg/lOOg)
-
-
-
-
-
-
3 8 .2 i 3.9 3 7 .4 i 1.3 3 7 .8 i 3.5 3 8 .5 i 5.4 3 5 .4 i 4.4
3 8 .5 i 6.3
3 8 .2 i 3.9
Brain ( g / 100g
0 .5 8 0.Q 5
0 .5 9 10.05
o .ei 10.03
0 .6 0 10.05
0 .6 2 10.07
0 .4 8 10.03
0.53* 10.04
0 .9 2 10.06
0 .9 7 10.10
0 .9 0 10.06
0 .9 4 10.05
0 .9 0 10.04
0 .8 4 10.04
0 .8 0 10.07
Spleen (g /100g)
0 .1 9 10.02
0 .2 0 10.03
0 .1 9 10.02
0 .2 1 1 0 .0 3
0 .1 6
0 .1 7 10.02
0 .2 0 1 0 .0 7
0 .2 2 1 0 .0 4
0.21 1 0 .0 4
0 .2 1 10.02
0 .2 0 10.02
0 .1 8
0 .2 0 10.02
0 .2 0 10.02
Adrenal (mg/100g)
1 5 .4 1 1.9
1 5 .0 i 2.7
15 . 6 1 2 .4
1 4 .7 1.7
1 6 .0
Body weight ) (g)
3 4 0 .5 i 19.8
3 2 6 .6 1 19.7
3 3 4 .0 i 13.1
3 2 7 .0 32.3
3 2 4 .3
1 3 .0 i 1.8
1 3 .9 1 1.1
3 1 .1 1 4 .0
3 3 .9 1 3.6
3 1 .1 i 3.0
3 2 .1 i 4.7
3 1 .7
4 1 2 .4 1 17.1
3 7 9 .6 i 23.1
1 9 3 .9 12.6
1 9 3 .0 1 22.3
1 9 7 .5 1 16.2
195.. 2 i 8.5
1 9 7 .8
3 2 .8 1 2.5
3 3 .4 1 4 .0
2 1 8 .5 i 12.4
2 3 1 .2 1 22.2
4^
oo
))
Company Sanitized. Does not contain TSCAGBI
Table 9 Twenly-eight-day repeated-dose oral toxicity study in tats _________ Summary o f macroscopic examinations
Male
Findings
Vehicle Vehicle
control control
(Recovery) ta ta
10 ta
40 200 ta ta
6`> 6
6 6' 6
No abnormalities detected Kidney
Pelvic dilatation Spleen
Nodule
Whitish region la, terminal autopsy, a) Number of animals examined.
5
1
0 0
6 655
0 0 10
0 000 0 001
1,000 1,000
(Recovery) ta ta 66 65
00
01 00
Vehicle Vehicle
control control
(Recovery) ta ta 66 66
00
00 00
Female
10 40 200
ta ta 66 6- 6
ta 6 6
00 0
000 000
1,000 . ...
,
1,000 (Recovery) O ^ g / d a y )
ta ta 66 66
00
00 00
4^
vo
)
Table 10-1 Twenty-eight-day repeated-dose oral toxicity sludy in tats ____________ Summary ofhistppathological examinations______________________
Male
Findings
Vehicle Vehicle
control Grade control
(Recovery) ta ta
10 ta
1,000 40 200 1,000
(Recovery)
ta ta ta
ta
Forestomach N o abnormalities detected
Glandular stomach N o abnormalities detected
Duodenum N o abnormalities detected
Jejunum N o abnormalities detected
Ileum No abnormalities detected
Cecum N o abnormalities detected
Colon N o abnormalities detected
Rectum N o abnormalities detected
Liver N o abnormalities detected Centrilobular hypertrophy of bepatocytes
6 *' 6/ 6b) 6/6 6/6
6/6 6/6 6/6 6/6 6/6 6/6 + 0 /6
6 6666 6
__
6/6 _
_ __ _
6/6
-- _ ,,,. _ 6/6 -- -- -- 6/6
_ --
_ _ _ _ 6/6 ...
_ -- _ - 6/6 _
_ __
6/6 _
_ _ 6/6
_
5/6 0/6 -
5/6 1/6 0/6 3/6
6/6 0/6
Microgranuloma
+ 0/6
1/6
Single cell necrosis of hepatocytes
0/6 0/6
ta, terminal autopsy. a) Number of animals autopsied, b) Number of animals affected / Number of animals examined. --, N o t examined. -I-, slight.
-
1/6 0/6 - 0/6 4/6
0/6 0/6
Vehicle Vehicle
control control
(Recovery) ta ta 66
6/6 6/6 6/6 6/6 6/6 6/6 6/6
6/6 6/6 0/6 0/6 0/6
_ _ -- _ -- _ --
-
Female
1,000 r ,,
\
10 40 2 0 0 1,000
(Recovery) (m8/kg/day)
ta ta ta ta 666 6
ta 6
-- _ 6/6 _ _ _ 6/6
-- _
_ _ _ 6/6 -- _ 6/6
-- _
__ _ _ 6/6 _ _ _ 6/6
-- --
_ _ _ 6/6
--
-- -- -- 6/6
--
--
6/6
- - - 0/6
--
0/6
--
0/6
-
,,
-
o
jmpany Sanitized. Does not contain TSCA CBt
))
I
Table 10-2 Twenty-eight-day repeated-dose oral toxicity study in rats _________ Summary o f histopathological examinations
Findings
Vehicle Vehicle
control Grade control
(Recovery) ta ta
Male 10 40 ta ta
Heart N o abnormalities delected
Kidney
6 ' 6/6
6 -
N o abnormalities detected
5/6 -
Pelvic dilatation
1/6 -
Solitary cyst in medulla Spleen
No abnormalities detected
+ 0/6 6/6
_
Focal necrosis
-H- 0 /6
-
Follicular hypertrophy Adrenal
++ 0/6
-
No abnormalities detected
6/6 -
ta, terminal autopsy.
a) Number of animals autopsied.
b) Number of animals affected / Number of animals examined.
Not examined.
+, slight; ++, moderate.
6 -
-
6
-
0/1 1/1 0/1
_
-
-
1,000 200 1,000
(Recovery)
ta ta 66
ta 6
-- ` 6/6
-
- 6/6 - 0/6 - 0/6
-- -
0/1 6/6 1/1 0 /6 0/1 0/6
0/1 0/1 1/1
- 6/6
-
Vehicle Vehicle
control control
(Recovery) ta ta 66
6/6 -
5/6 . 0/6 -- 1/6 -
6/6 _ 0/6 0/6 -
6/6 -
Female
,
1,000 , ,,
,
10 40 200 1,000
(Recovery) (tng/kgWay)
ta ta ta ta 666 6
ta 6
- - - 6/6
-
---.-~
__ ---
- 6/6 - 0/6 - 0/6
_ 6/6
- 0/6 - 0/6
-
_ -
- - - 6/6
-
Sanitized. Dees not certain TSCA CM
Attached document Physicochemical test report
December 5,2003, Person in charge of analysis: Yoshiharu Hara
.52
Company Sanitized. Does not contain TSCA CBI
53
Study object
A stability test is to be carried out for the test substance used in "Rat 28-day repeated oral
administration toxicity test of
rats'^ | 0 0 H i during the administration
term. Furthermore, the homogeneity and stability are to be tested for the test substance in its
preparation solutions.
Test item Stability test for test substance Homogeneity and stability test of test substance in its preparation solution
Measurement date
Test substance stability test
June 4, 2003 (before the start of administration)
August 27,2003 (after the end of administration)
Stability test of test substance in preparation solution
July 1, 2003
- July 8,2003
Homogeneity test of test substance in preparation solution July 1, 2003
Test results The test substance used in "Rat 28-day repeated oral administration toxicity test of in was func*t0 stable during the administration term. The test substance in the preparation solution was found to be stable for 7 days after
preparation. Furthermore, the relative standard deviation of the test substance concentrations at various sampling positions was less than 5% confirming the solution has good homogeneity.
Company Sanitized. Does not contain TSCACBI
D4-
1. Test materials
/" " "N
1.1 Test substance
1) Name
2) Lot no.
3) Source DuPont K.K.
4) Storage condition It was stored at a room temperature (in the test substance storage room, cabinet No. 6).
1.2 Test substance preparation solution 1) Concentration
2) Medium Pure water
3) Storage condition Stored at a cool and dark place (Biotron Building (7), Test room 3, refrigerator).
2. Testing method 2.1 Stability test for test substance
The stability of the test substance was confirmed by measuring the infrared absorption spectrum before and after the administration term.
The infrared absorption spectrum measurements were carried out using a Fourier transform infrared spectrophotometer (Model FTS 135, Nippon Bio-Rad Laboratories K.K.) in the range of 4,000 cm'1- 400 cm'1. Before the start of the administration, the identification was carried out by comparing with a spectrum provided by the test requester, and in the measurement carried out after completing the administration term, the spectrum before the administration was used to compare to find any change.
2.2 Homogeneity and stability test for test substance in preparation solution For the homogeneity of the test substance solutions prepared, the 10.0 w/v% and 0.05
w/v% solutions immediately after their preparations were sampled at top, middle, and bottom layers with n=3 for each layer, the samples were diluted with methanol, the test substance concentration was measured using high performance liquid chromatography (HPLC), and the homogeneity was confirmed from the relative standard deviation of the test substance concentrations at respective sampling sites. For the stability confirmation, the 10.0 w/v% and
Company Sanitized. Does not contain TSCACBS
0.05 w/v% solutions were stored in a cool and dark place, sampled from the middle layer with n=3 after 3 days and 7 days, the samples were diluted with methanol, the test substance concentration was measured by using HPLC, and the stability was confirmed by finding any change from the concentrations immediately after preparation (results of homogeneity test).
2.3 Standard solution preparation In methanol, 0.1029 g of the accurately weighed test substance was dissolved, and it was
made up to exactly 100 mL to obtain a 1.029 /g/mL standard stock solution. It was diluted with methanol to prepare standard solutions.
Standard solution concentrations: 103,206, and 309 gg/mL A suitable amount of the standard stock solution was diluted 500 times with pure water and then methanol to obtain a medium-added standard solution for test substance concentration measurement in the 10 w/v% preparation solution. Standard solution concentrations: 103,206, and 309 gg/mL A suitable amount of the standard stock solution was diluted 2.5 times with pure water and then methanol to obtain a medium-added standard solution for test substance concentration measurement in the 0.05 w/v% preparation solution. Standard solution concentrations: 103,206, and 309 gg/mL
2.4 Pretreatment 1) Test substance stability test
The KBr solution film method was used. 2) Homogeneity and stability of test substance in preparation solution
The preparation solution was stirred thoroughly with a magnetic stirrer, and the following pretreatment procedures were carried out.
(1) 10 w/v% Preparation solution To 0.5 mL of the preparation solution, methanol was added to accurately make up to 25 mL. From the solution prepared, 1 mL was taken, and methanol, was added to accurately make up to 10 mL. The solution prepared was used as an HPLC sample (dilution proportion of 500). (2) 0.05 w/v% Preparation solution To 4 mL of the preparation solution, methanol was added to accurately make up to 10 mL. The solution prepared was used as an HPLC sample (dilution proportion of 2.5).
2.5 Measurement condition 1) Infrared absorption spectrum measurement condition
(1) Instrument used
0ntpanjf Sanjtfaeed, Does not contain TSCACB
56
Infrared spectrophotometer: Model FTS 135 (Nippon BioRad Laboratories K.K.) (2) Measurement condition Wave number: 4,000 cm'1- 400 cm'1 2) HPLC analysis condition (1) Instrument used (HPLC1) Interface: Model D-7000IF (Hitachi, Ltd.) Pump: Model L-7100 (Hitachi, Ltd.) Auto-sampler: Model L-7200 (Hitachi, Ltd.) RI detector: Model L-7490 (Hitachi, Ltd.) Column oven: Model L-5020 (Hitachi, Ltd.) Date processor: Model D-7000 HPLC System Manager (Hitachi, Ltd.) (2) Measurement condition Column: Shodex Asahipak GF-310HQ 7.6 mm I.D. x 300 mm Column temperature: 40C Moving phase: methanol Flow rate: 1 mL/min Amount injected: 50 iL
^ \ 3. Data processing in homogeneity and stability test for standard substance in preparation solution 3.1 Detected value The peak area was used as a detected value.
3.2 Working curve preparation Standard solutions were prepared according to procedures in 2.5 and section 2), and from
the detected values on the chromatograms obtained and known concentrations, a working curve was prepared. The working curve prepared passed the origin and showed good linearity, but the detected values and chromatograms of the test substance were different depending on the content, of the medium used in the preparation solutions, and thus, for the quantitative determination of the test substance in the 10 w/v% preparation solution and 0.05 w/v% preparation solution, medium-added standard solutions were used. The standard solutions of the 10 w/v% preparation solution and 0.05 w/v% preparation solution were prepared according to procedures in 2.5 and section 2), and from the detected values on the chromatograms obtained and known concentrations, working curves were prepared. The working curves prepared passed the origin and. showed good linearity. Therefore, the quantitative determination of analytical samples was
'Company Sanitized. Does not contain TSCACN
57
carried out using a standard solution of a medium concentration with one-point weight determination.
3.3 Computation of test substance concentration in analytical samples The following formula was used to calculate the concentration (C: w/v%) of the test
substance, and the results of the computation were round up to 3 digits. C = CsxAxD / Asx 10,000 Cs: test substance concentration in standard solution Oug/mL) As: peak area of test substance in standard solution A: peak area of test substance in each HPLC sample D: dilution proportion of each HPLC sample
4. Test result 4.1 Test substance stability test
The infrared absorption spectrum (Figure 1) provided by the study requester was found to coincide with an infrared absorption spectrum (Figure 2) of the test substance measured prior to the start of test substance administration at the Hita Laboratory of the Institution. Furthermore, an infrared absorption spectrum (Figure 3) measured after completion of the administration /*"n showed no change.
4.2 Quantitative determination Figure 4 and Figure 5 show working curves, and Figure 6 and Figure 7 show typical
chromatograms. The working curves showed good linearity with correlation coefficient R=0.999.
4.3 Stability test in test substance in preparation solution Table 1 shows the results of the stability test for the test substance in preparation
solutions. For the 10 and 0.05 w/v% preparation solutions, the means of the test substance
concentration immediately after preparation were in the range of 100 10% of the prescribed values. In addition, the test substance concentrations after 3 days and 7 days were within 100 10% of the results on the test substance concentration immediately after preparation.
Company
58
Table 1 Chemical stability o f the test substance in dose formulations
Nominal
Mean conc.(w/v% )
conc.(w/v%) Immediately*
3 days*
7 days*
R.P. (%)
10 10.8 10.8 10.7 99.1
0.05
0.0538
0.0539
0.0538 100
after preparation
R~P.(%): Rate o f tbe final concentration to the concentration measured immediately
after preparation
4.4 Homogeneity test of test substance in preparation Table 2 shows the results of the homogeneity test carried out for the test substance in the
preparation solutions. The results on the relative standard deviation of the test substance concentrations sampled
at respective layers was less than 5% for all concentrations of 10 and 0.05 w/v%.
Table 2 Physical stability o f the test substance in dose formulations
Nominal cone.
Layer o f
Actual cone.
(w/v%)
measurement
(w /v% )
Mean cone. (w/v%)
R.S.D. (%)
top 10.8
10
middle
10.9
10.8
0.5
bottom
10.8
top 0.0540
0.05
middle
0.0536
0.0538
0.4
bottom
0.0537
R.S.D.(%): Relative standard deviation
Company Sanitized. Does not containTSCACBS.
1.2 1'.1IJIclbZ a- L
59
11
0 .5 -
. 0 .4 -
0 .3 - .
2-
ai-
ao,, tt
4Q0D
nr1
5500
"".1' " 1 1. 1'
300P
2500.
2000
Nonfifarrlfoodfam-1)
1500 '
1000
' 5BO.
Fig.1 IR spectrum provided by the sponsor
Company Sanitized. Does not contain TSCACBI
60
uetu
3500 300 5Wavenumber(c2r0o-0i0)' 3 1000
Fig.3 IR spectrum measured afterthe end of the administration period
Peak area
Concentration (pg/mL) Fig.4 Calibration curve for 10 w/v% dose formulation analysis
Concentration (pg/rdL) 103 206 309
PeakArea 24,647 50,615 77,345
Q m p^mwi
Does no,'tcontain
Concentration (|jg/mL) Fig.5 Calibration curve for 0.05 w/v% dose formulation analysis
Concentration (jig/mL) 103 206 309
Peak Area 18334 37,778 57,769
Signal density (mV)
Fig.6 Typical chromatogram for i 0 w/v% dose formulation analysis
Company Sanitized. Does not contain TSCA CBf
Signal density (mV)
62
Company Sanitized. Does not contain TSCACBS
63
Photo. 1
Liver of a male rat from vehide control group. Normal. No. 1 animal. HE. *360.
Photo. 2
Liver of a male rat from 1,000 mg/kg/day group. Centrilobular hypertrophy and single cell necrosis ofhepatocytes. No. 35 animal HE. x360.
Company Sanitized. Does notcontain TSCACBI
64
Adde ndum 1-1 Twenty-eight -day repeated-dose oral toxicity study in rats Clinical signs of individual animals Vehicle control
Signs N o abnormalities detected
a) Animal number.
Sex Male
Female
]
1,2,3,4,^
5' 6.7'8' 9,30,11,
12 43,44,45,
4 6 '4 7 '4 8 ' 49,50,51, 52.53.54
Administration
23
1,2,3,4, 1,2,3,4,
5,6,7,8, 5,6,7,8,
9,10,11, 9,10,11,
12 12 43,44,45, 43,44,45,
4 6 '4 7 '4 8 ' 49,50,51, 52.53.54
46,47,48, 49,50,51, 52.53.54
4 1,2,3,4, 5,6,7,8, 9,10,11,
12 43,44,45, 46,47,48, 49,50,5!, 52,53.54
Recovery 12
7,8,9,10, 7,8,9,10,
11,12
11,12
49,50,51, 49,50,51, 52,53,54 52,53,54
(week)
Addendum 1-2 Twenty-eight-day repeated-dose oral toxicity study in rats Clinical signs o f individual animals
10 rng/kg/day
.... ...........
Signs N o abnormalities detected
a) Animal number.
Sex Male
Female
Administration
12 3 13,14,15,13 13,14,15, 13,14,15, 16.17.18 16,17,18 16,17,18 55,56,57, 55,56,57, 55,56,57, 58,59,60 58,59,60 58,59,60
4 13,14,15, 16,17,18 55,56,57, 58,59,60
Recovery 12
(week)
Addendum 1-3 Twenty-eight-day repeated-dose oral toxicity study in rats Clinical signs o f individual animals 40 mg/ kg/ da y ______
Signs N o abnormalities detected
a) Animal number.
Sex Male
Female
Administration
32 3
1 9 , 2 0 , 2 1 , a) 22,23,24 61,62,63, 64,65,66
19,20,21, 22.23,24 61,62,63, 64,65,66
19,20,21, 22,23,24 61,62,63, 64,65,66
4 19,20,21, 22,23,24 61,62,63, 64,65,66
Recovery 12
(week)
Ad d e ndum 1-4 Twenty-eight-day r epeatd-dose oral toxicity study in rats
Clinical signs of individual animals
200 mg/kg/day
Administration
Signs No abnormalities detected
Soft stool
Sex Male Female Male
12 25,26,27,a> 25,26,27, 28J29.30 28,29,30 67,68,69, 67,68,69, 70,71,72 70,71,72
.3
67,70,71, 72
25,26,28, 29,30
4
28
67,68,70, 71,72
25,26,27, 29.30 .
Female
68,69
69
a) Animal number.
Recovery 12
-
(week)
Company Sanitized,. Does not contain TSCAC81
Addendum 1-5 Twenty-eight-dayrqjeated-dose oral toxicity study in rats
Clinical signs o f individual animais
1,000 rog/kg/day__________________
Signs No abnormalities detected
Soft stool
a) Animal number.
Sex Male Female
Male
Female
1 32,36,37/
41,42 73,74,75, 76,78,80,
81,83
Administration 23
36,38,42 38,42
31,33,34, 35,38,39,
40
->4,35,37, 39,40,41
S
37 39 40 '
77,79,82, 84
73,74,76, 77,78,80,
84
4
78,79
31,32,33, 34,35,36, 37,38,39, 40,41,42 73,74,75, 76,77,80, 81,82,83,
84
Recovery 1 2 (week)
37,38,39, 40,41,42 79,80,81, 80 82,83,84
37,38,39, 40,41,42
79,81,82, 83,84
f San ses not contain TSCACEU
)
Company Sanitized. Does noi
ss
S S'
I
o S
Addendum 2 -1
Twenty-eight-day repeated-dose oral toxicity Body wei ght s o f i ndi vi dua l animals(g)
study
in
rats
Exp.group
( ag/ kg/ day) Animal No, - 2
1 129.8 2 134.1
3 125.5
4 127.4
Vehicle control
5
8 7 8 9 10 ,1112
128.3
132.2 129.0 129.7 128.0 136.1
120.7 132.3
13 1 2 5 . 5
14 1 3 7 .2
10 16 1 2 9 . 9 16 1 3 0 . 3
17 1 2 8 .8
22121280Male
18 126.9
120.5
40
133.3 127.9
129.0
23 1 2 6 .5
24 132.3
25 1 2 6 .5
200 2 6 1 3 1 . 1 27 1 2 4 .2
28 1 2 9 .9
29 1 2 8 . 0
30 136.1
31 1 3 6 .5
32 1 3 2 .2 33 1 2 8 .9
34 1 2 6 .8
1,000
35 1 2 2 .9 36 1 2 9 .7
37 1 2 9 .6
38 128.7
38 1 3 0 .8
40 1 25.0
41 1 3 6 .7
42 1 2 8 .7
145.5 156.4 141.9 143.8 146.1
152.6 145.4 151.4 144.6 159.0 141.7 151.7
143.1 155.6 151.1 150.9
149.6 145.4 T T 73 155.2 150.4 150.0 143.1
151.7
146.0 150.5 142 . B 146.5 153.2 156.3
158.4 150.6 145.5 148.5 141.8 146.6 144.7 151.' 8
148.3 143.4 150.9
142.9
3
158.3 172.2 162.3 160.1 164.5 175.2 164.8 171.4 161.8 179.6 159.6 197.3
158.8 173.7 167.5 166.2 166.9 163.9
161.6 174.0 169.0 171.1
162.4 171.8
158.4 167.9 158.8 160.2 172.9 173.5
167.3 185.3 180.4 163.5 153.1 162.7 156.8 166.3 161.7 156.1 165,9' 158.3
8
204.7 229.3 207.5 199.2 213.1 229.0 208.7 219.1 211.2 225.7 206.5 213.9 198.3 221.9 220.9 1 9 9 .B 208.9 208.7 20b .U 224.4 216.9 221.0 204.0 212.'6
19 9.5 220.2 193.1 199.7 217.7 221.0
215.0 206.1 200.9 211.1 190.7 205.9 196.2 212.0 201.3 189.3 204.3 198.1
Administration period 12 17
242.6 296.8 240.9 227.0
253,2 268.6 247.9 257.5 244.5 263.0 242.8 243.5 233.1 255.0 253.6 226.5 242.3 242.9
234.0 258.1 245.2 252.5 241.8 241.0
226.0 258.1 220.3 232.2 250.7 261.5
250.4 238.3 229.5 242.8 212.2 239.6 223.4 243.5
227.7 229.1
240.0 227.1
284.1 308.3 284.2 267.0 292.5 316.2 286.3 297.8 287.2 307.0 285.4 280.2
275.2 294.9 297.1 283.9 281.7 288.1
280.1 301.6 282.4 294.9 285.5. 283.8
257.3 301.6 258.1 273.1
288.6 315.1
297.6 280.2 271.2 285.6 244.9 284.5 258.8 285.3
288.2 265.6 284.7 280.9
21
314.6 333.4 314.9 294.5 325.2 347.1 313.6 331.8 317.6 340.3 316.0 309.4 299.9 322.3 337.2 292.7 305.6 323.2
303.5 337.1 309.9 322.2 312.2 300.9
276.0 331.0 279.5 300.8 319.7 349.3
325.8 312.3 297.6 321.5 263.8 318.1 282.9 312,8 296.6 291.3 320.6 286.6
26
350.4 373.5 350.8 326.2 364.1 389.4 344.5 367.4 357.0 374.2 349.5 341.8 329.5 350.0 372.3 318.8 340.4 356.5
334.3 372.0 340.9 358.8 346.9 343.5
303.0 367.7 306.8 337.4 350.3 390.5 380.3 343.9 327.9 358.2 283.9 353.1 309.8 335.5 331.7 328.2 352.5 310.1
28 (days)
355.9 377.7 361 . 6 337.0 372.1 397.0 356.6 377,5 368.3 390.9 361.8 355 9 335.9 359.0 388.0 332.5 349.9 364 7
338.8 380.5 348.2 370.8 358.1 354 9 312.5 375.5 314.8 351.7 366.5 407 7
366.3 358.1 336.2 370.6 294.4 368.2 316.8 343.3 339.3 331.5 366.2 318.6
OON'
)
I
Company Sanitized. Does not contain TSCA CBl
Sex Fe ma l e
Exp,group (mg/kg/day)
Vehicle control
10
40
200
1,000
Aniaal Mo.
43 44 45 48 47 48 48 50 51 52 53 54
55 56 57 58 59
60 51
82 83 64 65
66
87
68
69 70 71 72
73 74 75 76 77 78 79 80 81 82 83 84
-2
117.0 108.0 108,5 116.2 113.2 112.3 108.3 113.9 118.3
112.2
115.4 107.4
110170..65
115.5 113.0
111.2
119.5
106.8 114.1 118.0
111.8
108.0 115.9
111.6
108.5 112.7 117.1 108.0
115.5
111140..60
114.7 112.5 107.3 116.8 109.8 115.8
104.4
11 11 13 ..67
117.9
1
130.8 119.5 119.1 132.4 123.3 128.9 115.6 128., 6 132.1 115.'. 5 124.6 119.4
122'. 5 121.7 130.1 124.7 122.4 132.9
110.6
129.4 132.6
122.6
1 1 7 ..2 129'.; 5
126.3 121.4 124.0 129.8 119.2 128.0
128.4 124.2 130.0 124.0 121.3 132.4 124.8 128.7 116.0 126.9 123.4 130.6
3
137.4 128.4 127.7 138.5 133.7 137.5 131.3 141.3 141.9 125.3 138.3 129.0
135.9 130.2 144.7 135.3 132.8 141.0
127.6 137.8 141.6 133.0 128.7 142.1
134.7 128.0 131.6 141.0 129.3 134.6
132.2 132.3 136.9 131.8 130.5 136.9 133.2 139.7 123.1
131.5 131.4 138.7
8
X0 o . 0 144.6 147.1 162.8 155.6 155.6 154.8 160.8 162.8 137.9 182.7 150.6 161.8 139.9 171,5 156.3 142.2 180.2 143.8
157.2 161.5 151.8 146.4 167.2
152. 155.8 160.0 147.3 151.1
150.5 153.0 147.3 158.2' 156.1 159.8 152.5 161.9
139. B 151.1 145.8 162.0
Administration peri od 12 17
173.4 156.6 162.5 172.0 168.1 167.7 168.0 171.4 176.2 148.2 178.0 162.0
172.8" 144.1 188.9 168.3 149.8 179.5
154.3 173.7 178.2 186.8 154.9 180.5
176.5 172.8 167.8 173.8 155.2 164.1
165.1 165.5 153.3 169.2 109.7 177.2 164.6
177.3 146.5 164.2 160.9 173.9
190.4 166.1 171.8 180.7 183.6 182.8 181.2 187.2 191.5 158.0 188.9 170.8
188.1 156.8 205.7 185.1 157.1 197.7
109.8 191.7 196.6 187.7 167.7 198.1
187.8 194.8 187.1
192.0 165.6
175.3
188.9
182.5 167.5
181.3 179.9 189.1 173.0
192.6
160.3 188.0 182.0 188.5
21
200.4 172.6 186.0 190.0 194.5 197.8 102.0 190.0 202.7 165.7 204.5 186.7 202.3 164.8 218.5 197.5 163.3 215.0
178.3 208.0 208.9 198.4 175.5 212.9
9 6 .9 204.3 198.1 199.2 175.5 185.9
201.5
198.3 182.2 192.6 189.3 200.4 184.1
208.7 171.7 198.5 199.6 203.6
26
216.0 183.3 203.3 193.9 197.9 206.9 200.3 214.0 212.3
178.3 210.1 197.2
211.3 176.1 232.3 205.2 177.4 227.6
192.0 209.3 218.3 212.0 184.6 219.0 207.7 224.3 212.3 208.9 182.7 199.1
216.3 215.2 190.6 210.9 207.5 204.7
195.3
230.4 181.4 210.1 216.2 211.8
28 (days)
227.2 183.9 212.8 206.8 203.5 213.4 210.0 211.6 218.5 181.2 220.1 1 QQ ff
212.5 177.9 238.3 212.3 174.8 232 0
187.2 220.4 224.9 213.1 188.4 2?.H n
212.4 220.5 213.9 216.0 191.9 200 9
209.2 218.4 189.7 213.4 213.0 216.9 197.4 232.9
187.5 211.6 221.0 225.7
.< m
H a, ao<m0
not contain TSCACBi
Sex Male
Fe ma l e
. , r,
'UU55 u i ai L
Body wei ght s o f i ndi vi dua l animals(g)
Sxp,group
Vehicle control
1,000
Vehicle control
1,000
7 8 8 10 11 12
37 38 39 40 41 42 .
49 50 51 52 53 54 79 80 81 82 83 84
X
382.3 380.3 369.4 392.2 362.3 356.7 315.0 348.6 336.5 335.0 372.5 319.9
208.7 219.0 220.7 180.4 222.7 204.9 201,4 220.7 187.8 217.0 222.8 228.0
5
385.1 400.0 390.8 418.0 380.8 375.1
339.7 376.4 367.0 382.8 395.0 349.1
213.6 229.1 234.5 188,8 230.6 215.0
218.3 249.0 204.6 22B.9 238.8 245.8
Recovery period
10
412.9 430.2 414.6 444.0 419.6 406.1 359.2 397.1 391.3 393.7 424.6 9 8 4 9.
218.4 242.3 241.5 207.3 238.5 226.2 227.6 266.5 203.0 243.8 250.8 255.. 7
14 (days)
431.9 448.7 430.3 466.3 435.0
373.5 415.1
406.2 410.3 436.1
-
228.2 248.3 248.8 209.9 238.3
225,5 275.9 205.8 241.4 257.3 261.5
Ooo'
Addendum
FnnH
oral toxicity study
ood inta ke s of indivi dual animal a ( g / r a t / d a y )
Sex Exp. group
" ~ -- ---
(mg/kg/day) Animal No. ------ 1 ----------------- ------------------------- J t o i s W a j ^ e n o d
------ -------------- d 8 lg 22 28 (days)
1 18.7
20 20.8 2202..06 22.2 22.2Vehicle
3 17.6 4 18.4 5 19.2
22.2c o n t r o l
7 18.2
8 20.0 21.82 1 . 3
9 18,1
10 22.62 3 . 2
11 1 9 . 7
12 21.21 9 . 6
22.01 3 1 8 . 4 20.2 20,114
10 10 2201..19 2212..81 21.115
19.8
20.7 19.7
24.7
22.5 19.3 23.9
19.6 19.4
20.3
21.5 25.9
20.7 23.0 26.8
24.3 22.4 24.3 23.2
23.7 24.4
24.2 27.8 22.9
25.3 28.8 22.7 26.0
25.3 25.4 23.1, 22.4 25.8 25.8
25.0 28.6 25.4 24.7 25.9 30.2 24.1 26.9 25.1
27.2 27.5 24.6
23.1 26.7 29.0
'
26.7 29 .1 28.7 2 5 .g 27.6
31.2 24.7 27.5 28.1 28.9
27.6 26 .3
22.2 27.1 30.1
222120 22.2 21.8Haie
40
17 2 0 .5 18 1 9 .9 19 1 7 . 7
21.3 18.8
19.8 23 1 8 .9
22.3
21.6 20.6 21.8 20.1
22.7
23.2 23.0 21.9 24.4
24.5
24.4 2 5 1
22.7 25.5 23.0 24.7
23.6
24.6
28.2
26.5
2 7 . 6 _________ 2 6 . 9
24., 1 2 7 ,. 8 25,.0 2 6 ., 8
24,, ' 29,,0 25,. 1 27,,7
200 21,2 2200..20 2221..11 21.8iS 1,000 37 2211..21 22221011....1518 2222211222.....20188 22222211....25283
24
25 2 0 .4 26 1 9 .1 27 1 9 .8 28 18.7 29
30 2 0 .9 31
32 2 0 .3 33 1 8 .8 34 19.5 35 1 9 .3 36 1 9 .4
19.6 38 2 3 .4 39 19.6 40 1 9 .4 41 2 1 .4 42 19.9
22.7 19.4 21.4
18.7 22.7 22.4 20.3
20.7 19.1 20.4 19.6
20.4
21.7 18.5
23.4
23.2 19.5
23.8 24.3
21.3 23.0 21.5
21.6 21.6
23.3 20.9
21.9
24.5 24.3
24.9 20.9
23.7 28.0 24.0 23.0 22.7 24.1
23.0
23.6
23-, 1 24.3 21.3
2 5 ., 1 25.,4
2 2 ., 3 20. 2 21,,3 24,, 9 25.,7 30,, 9
28,.1 25,,8 24,. Z 27,.3 22,.1 28,, 6 23,, 5 25,.3 24.,4 24., 6 27 , 5 23,.8
25.. 6 25 , 8
2 2 ,. 0 26,,3 22,. 9 26,. 5 26,,9 32.,7
25 ,6 27 . 2 28 ,0 28 .4 22 .0 28 .5 23 .0 25 . 1 25,. 9 25 ,1 2 9 ., 4 24 , 1
o\
)
Sex Fe ma l e
enty-Bignt-day repeated-dose oral toxicity study in rats Food i n t a k e s o f i n d i v i d u a l a ni ma l s ( g / r a t / d a y )
Exp,group
Animal No,
Vehicle control
10 40 200
1,000
44 45 46 47 48 49 50 51 52 53 54
55 56 57 58 59 60
61 62 63 64 65 66
67 68 69 70 71 72 73
74 75 76 77 78 79 80 81 82 83 84
i
18.7 14.5 15.7 18.0 16.7 17.3 15.7 17.3 18.0 15.3 17.1 15.8 16.3 15.2 17.3 15.3 17.0 17.3
15.5 17.2 18.0 14.9 15.4 17.0
17.0 16.0 16.1 16.5 15.9 16.7 1 fi n
15.9 17.1
15.0 16.7 18.0 16.6 17.7 15.5 16.9 18.7
20.0
3-
18.3 15.8 15.6 17.2 16.0 17.2 15.8 17.2 17.7 15.8 19.0 15.1
17.3 15.8 18.4 18.0 17.3 16.2
14.0 16.2 17.8 15.8 15.8 18.7
16.4 14.7 16.3 16,1 15,9 15.3
15.8 15.8 15.1 15.2 15.9 17.0 18.1 14.2
1186..00
18.5
AOiBinlstration op.rind 8 15
16.4 16.0 15.8 17.9 16.0 16.6 16.4 17.1 17.2 14.9 18.5 18.3 16.7 15.3 18.2 16.3 15.9 18.8
15.1 16.1 17.4 15.9 15.5 18.9
17.7 18.3 18.2 16.4 16.2 15.8
16. 15. 18.6 16.8 16.8 .1 6 .8 18.4 14.5 17.3 16.0 19.4
16.9 15.6 17.0 16.2 15.8 16.5 15.6 16.4 17.8 15.1 18.3 15.5
15.4 14.4 17.4 16.2 14.4 17.4
14.8 16.2 17.8 17.2 14.9 18.3
17.5
16.7 18.0 16.7 15.1 15.0
16.4 15.5
14.3 15.2
10.1
17.0 14.8 18.2
14.4 18.0 10.9 18.7
22
17.7 14.8 17.4 16.3 16.8 17.3 16.5 17.1 18.5 15.7 18.8 16 8 16.4. 14.8 17.9 16.8 15.0
1Q 1
16.0 17.3 18.8 17.8 15.9 19 8
17.1 17.5 18.9 17.6 15.6 15.4 17.8 17.2 15.3 15.8 17.3 17.9 15.3 19.7
14.9 19.2 19.3
20.0
28 (days)
18.8 15.4 18.4 17.7 16.4 '18.6 17.3 18.0 19.1 16.4 19.9
16.7 15.6 17.9 17.4 15.8
15.3 18.0 19.5 17.4 15.8
17.3 18.2 19.4 18.0 16.2 16.2 18.2 18.1 15.7 18 .9 18.5 18.9 15.2
20.6
16.5 18.6 19 .6
21.8
o
Company Sanitized. Does not contain TSCA CBI
)
)
Company Sanitized. Does noi contain TSCACSI
Addendum 3-3 Twent y-ei ght -day r epeat ed- dose o r a l t o x i c i t y st udy In r a t s Food inta ke s o f i ndi vidual a ni ma l s t g / r a t / d a y )
Sex Male
Fe ma l e
Exp.group (mg/kg/day)
Animal No.
Vehicle control
1,000
Vehicle control
1,000
7 8 9 10 11 12 37 38 39 40 41 42
49 50 51 52 53 54
79 80 81 82 83 84
4
26.7 28.7 26.2 30.2 26.7 27.1 24.0 27.1 27.4 29.5 29.8 28.2 17.6 20.2 3.9.5 17.6
18.4 18.1
18.3 23.0 18.3 18.9 21.3 22.7
Recovery period
8
26.0 28.8 26.2 28.5 29.2 27.0
24.2 26.9 26.9 28.2 28.2 26.2
17.6 18.2 19.8 16.7; 18.8 17.2 18.0 21,7 17.4 20.6 21.2 22.4
1 4 (days)-
26,7 29.5 25.0 29.8 28.2 28.7 24.1 20.7 26.0 28.2 27 .7 26.5 17.2 20.0 21.8 17.7 20.1
18.9
18.3 22.4 18.0 19.7 20.6 22.1
k--~<j*
)
1
Addendum 4-1
? r a l > t y study in ra ts
Sex
Exp.group (mg/kg/day)
BBC NBC Hb Animal No. (xI O V m L) X l0 2 /x il) (6/dU
Ht {%)
Ve hi c l e control
1 772 2 740 3 753 4 776 5 '759 .8 ... 7 4 3
108 68
118 67 87
80
15.2 14.9
14.4 15.1
15.0 14.4
46.5 46.3
45.5 48.8 46.8
Hale
7 761
8 787 8 819
10 832
U 780 12 815
13 776 14 825 10 15 772 16 741 17 738 18 816
19 . 735
40
20 21
763 776
22 814 23 758
24 766
106 96 93
152 110 123
81 100
86 83 108 68
92 99 78 109 97
75
14.2 15.0 15.3
16.5 14.8 14.8 15.7 14.9 14.8 14.8 14.6 15.4
14.8 15.1 15.0 15 . B
14.6 15.3
42.6 45.3 48.7 48.5 44.9
48.7 47.4 46.0 46.1 44.8 48 4
45.0 46.5 45.5 48,4 44.2 A7 1
200 1,000
25 20 27 28 28 30
31 32 33 34 35 36
Recovery
775 754 753 755 736 745
734 737 784 744 813 752
86 105
63 102 103 122
124 84 87 85 76
111
14.7 15.2 14.5 14.2 15.0 14.4
15.1 14.8 15.0 14.9 15.6 14.0
45.1
46.1 44.5 44.2 46.0 44 ?
46.8 45.9 47.0 45.6 48.0 45.8
37 773 38 828 39 853 40 782 41 793 42 778
146 86 95 98 95
108
14.7 15.3 15.5 15.1 15.2
14.9
43.9 48.5 47.7
46.0 45.9
45.3
Company S an tteai. D oes wo contain TSCA C8I
HCV
(ft)
60.3 62.8 60.5 60.3 61.7 59.9
55.9 59.0 59.4 58.2 57.5 55.7 82.8 57.4 59.8 62.3 60.5 59.3 61.2 60.8 58.7 59.5 58.3 61.6 58.2 61.1 59.0 58.6 62.8 59.3 83.8 02.3 01.5 81.3 59.1 80.9
56.8 58.6 55.9 58.0 57.8 58.1
MC
(pg)
19.7 20.2 19.1 19.4 19.8 19.4
18.8 19.5 18.7 18.7 18.0 18.1 20.3 18.1 19.2 19.9 19.7 18.8 20.1 19.8 19.4 19.1 18.2 20.0
19.0 20.2 18.2 18.8 20.4 19.3 20.6 20.1 19.6 20.1 19.2 19.8
18.0 18.4 18.1 19.1 19.1 19.2
MGHC
(e/dL)
32.6 32.2 31.5 32.2 32,032.4
33.2 33.1 31.5 32.0 33.0 32.6 32.3 31.5 32.2 32.0 32.6 31.7
32.8 32.4 33.1 32.1 33.0 32.4
32.6 33.0 32.6 32.2 32.0 32.5 32.3 32.2 31.9 32.7 32.5 32.5
33.5 31.4 32.4 32.9 33.1 33.0
Plateleb
( x l O* / , u L)
119.5 123.7 115.2 112.0 104.0
Retculo
<%)
2.8 2.0 3.1 2.4 2.9
112.2 113.1
116.4 119.7 106.4 111.8
114.4 115. B 109.5 106.3 108.2 108.8
115.8 103.8 118.2 123.5' 108.4 107.8
118.8 105.0
90.7 121.3
96.7 98.7
104.6 122.5 107.9
91.6 103.3
2.1 2.7
1.8 2.9 2.0 2.3
2.8 2.0 2.8 2.8 2.4
2.6
2.3 2.6 2.4 2.7 2.0 2.8
2.3 3.0 2.7 2.3 2.6 3.1
3.0 2.5 3.2 2.7 2.0
128.5 102.7 120.2
109.4 115.1 119.1
2.9 2.0 2.2
2.6 2.2 2.5
PT
(sec)
21.4 23.7 17.8 24.9 17.9
APTT
(sec)
33.8 33'. 6 39 . 3 40.9 34.8
22.0 14.3 14.6 14.3 21.0 17.3 18.8 19.9 15.0 33.3 18.6 19,7
15.9 19.3 17.6 18.0 14.8 24.1
14.7 23.5 16.1 21.0 15.3 13.7
14.6 17.8 14.7 17.9 14.6
33.1 25.6 31.1 31.8 34.7
32.T 32.2 31.8 42.2 33.4
32.7 30.6 33.7 33.7 30.4 37 8
27.8 33.8 33.7 32.5 27.5 17 9
30.8 31 . 3 30.7 33.4 33.9
21.1
20.2 15.2 15.7 25.7 13.9
41.2 42.7 34.2 30.5 43.0 29.8
"-J to
Sex
Exp,group (g/kg/day)
HflC WBC Hb Animal No. (xl<H/xiL) (xlOz'/xiL) (e/ dl )
lit (%)
Vehicle control
TiT 44 45 46 47 48
764 848 756 778 801
812
63 88 73 95 83
88
14.9 15.6 15.1
15.2 15.6 15.2
44.8 47.5
45.8 45.5 47.8
~
49 785 50 784 51 800 52 777
53 835 54 866
87 73 79
60 87 102
15.3 14.3 14.9
14.5
15.4 10.1
45.2 42.4 44.4 44.1 46.3
o 1,000 --11. .JjL-.iLFemale
55 828 56 772 10 57 750 58 808 59 801 60 745
01 .814 62 771 40 63 783 64 790 65 778 60 786 67 747 68 755 200 69 827 70 799 71 834 72 851
73 791
779 75 804 76 799 77 744
-- 78.... 778 Recovery'
103 58
110 116 .
93 91
77 69 87 107 83 .105
70 89 93 60 78 139
122 77 70 81
141
16.2 15.3 15.1 15.1 15.7 14 8
15.7 15.0 15.0 15.9
15.2 15.4
14.4 15.0 16.8 15.3 15.5 16.0
15.1
15.0 15.3 15.7 14.4 14.9
49.0 '46.8 46.0 46.8 47.8
47.5 45.5 46.8 48.3 45.8
43.4 45.0 47.8 46.0 47.1
ft 7
45.6 45.8 47.9 48.4
riot contain TSCACBI
8279 8 0 7
80 768 81 738
818 83 802 84 800
59 67 93 113 78
74
14.9
14.8 13.6 15.1
15.2 15.3
44.8 43.4 40.3 45.0 45.1
45.7
MCV
fL )
" SST? 5'6.1 60.6 58.8 50.5 57.0
MCI1
(pg)
19.5
1280..04
19.5 19.5 18.7
57,, 6 54 .0 55,,5
56,.8 55 , 5 55 .4 59 ,2 80..4 60,. 9
57,,9 59,,7 60,,7
18,.5 18,, 2 18,. 6
18,,7 18.,4 18,.6
19.. 6 19.. 8 19,,9 18,.8 19 ,, 6 1 9 , , 9.
58..3 59..0 59,,8 81..2 58., 9
61,,3
1 9 , ,3 19., 5 20.,0 20, 1 19 . 5 2 0 , ,,1
58-0 59.7 57.8
19.3 19.8 19.1
57.5
18.1
56.5
18.5
5 7 . 9 _______ 1 8 . 8
59.0
19.1
58.6
19.3
56.9
19,0
59.9 58.3
19.6 19.4
58.5
19.1
55.5 56.5
54-6 55.0 56.3
___ 5 1 , 1
18.5 19.2
18.4 18.5 19.0
19.1
MGHC
(g/dL)
33.2 32.7 33.1 33.3 32.8 32.8
33.9 33.6 33.5 32.9 33.2 33.6 33.1 32.8 32.7 32.4 32.9 32.7 33.1 33.1 33.4 32.9 33.1 32.8 33.2 33.4 33.0 33.2 32.8 32.5 32.3 33.0 33.3 32.8 33.2 32.7
33.3 34.1 33.6 33.8 33.7 33.5
P latelet
Qd(H / ul)
105.9 115.1 112.0
99.5 110.3
R etculo
(%)
2.3 1.6 2.4 2.3 1.6
135.9 127.1 124.7 108.6 125.6 124.9 119.7
98.0 108.7 112.1 101.4 142.3
119.21..26 11 20 61..17 110180,.65
119.2 113.8 113.4 115.5
112.6 110180..11 111082..22
123.1 99.1
125.2 110.5 125.9 146.2 131.0
123.0
1.5 1.9 1.5 2.0 1.7 1.9
1.6 21..53
1.9 1.9 2.3
2.2 1.7 3.4 2.5 2.1 2.3
PT
(sec)
14.8 13 . 9 13.5 13.4 13.2
12.7 13.3 13.0 13.9 13.0
12.8 12.9 15.5 14.3 13.5 13.2 13.1
1122..84
12.9 15.1 13.8 15.4 13.2 13.3 13.5
1131..38
14.1 15.5 14.1 13.4 13.4 13.6
13.1 12.9 12.9 13.6 12.8 12.9
APT!
(sec)
2 4r 1 24.9 23,6 23.6 22.7
2213 ..64 20.8
24.4 26.5
26.5 23.9 24.1 26 5 24.7 26.4
22,0
27.2
2252(.80
27.6 23.8 26.2 24.0 27.0 23.7 28.4 23.8 26.0 24.6 24.0
2261..81
23.6
26.5 19.0 26.3 24.0 27.3 26 . Q
Company Sanitized, Does not contain TSCA
I
Addendum 4 3 Twenty-eight -day repBat ed-dose o r a l t o x i c i t y st udy in r a t s Hematological data of individual animals
Sex Male
Exp.group (mg/kg/day)
Vehicle control
10 40 200
. 1,000
Animal No. N-Band
1 2.0 2 1.0 3 1.0 4 2.5 5 2.5 6 .........3 . 0
7 1. 5 8 1.0 9 0.5 10 1 .5 11 0 .5 12 2 .0
13 5 .5 14 1 .5 15 1 .0 18 2 . 0 17 2 .0 18 1 .0
19 3 .5 20 2 .5 21 2 .0 22 4 . 0 23 4 . 0 24 2 .5 &b 1 . 5 28 3 .5 27 4 . 5 28 2 .6 29 1 .0 30 5 .5
31 1 .0 32 2 .5 33 0 . 5 34 3 .0 35 3 . 0 36 3 .0
37 1 .5 38 2 .0 39 2 .5 40 2.0
41 0 .5 42 3 .0
Differentiation of leukocyte (%)
N-Seg
Eos ino
Baso
8.5 3.5 12.5 10.5 7.0
0.5 1.0 0.5 0.5 0.0
0.0 0.0 0.0 0.0 0.0
12.0
1.0
8.5 1.5 0.0 9.0 0.0 0.0 13.0 0.5 0.0 11.0 0.5 0.0 7.5 0.5 0.0 11.0 1.0 0.0 13.0 1.0 0.0 9.5 1.0 0.0 4.5 1.5 0.0 7.5 0.5 0.0 17.0 1.0 0.0 10.0 0.5 0.0 7.5 1.0 0.0 4.5 0.5 0.0 1 8 . 0 2 . 0 O.'O 14.5 0.5 0.0 8.0 0.5 0.0 8.0 1.5 0.5 9.5 2.0 0,0 8.0 0.0 0.0 15.0 0.5 0.0 11.0 0.0 0.0 7.0 2.0 0.0 1 1 . 5 1 . 0 O'. 0 5.0 1.5 0.0 11.0 1.0 0.0 9.5 1.5 0.0 13.5- 1 .5 0 .0 20.0 0.5 0.0 15,5
8.5 5.5
9.5 7.0
4.5 12.0
0.0 1.5 0.5 1.0 0.0 1.0
0.0 0.0 0.0 0.0 0.0 0.0
Lymph
89.0 94.5 86.0 86.5 89.5
87.5 89.5 88.0 87.0 91.0 R/t K
80.5 87.0 92.5 90.0 79.0 RR ^
87.5 92.5 76.5 81.0 87.5 R7 n 87.0 88.0 79.5 86.0 90.0 82 0 92.5 85.5 88,0 82.0 76.0
90.0 90.5 88.0 89.5 94.0 83.0
0.0 0.0 0.0 0.0 1.0
1.0 0.5 0.0 0.0 0.5 1,5 . 0.0 1.0 0.5 0.0 1.0 u ,u 0.5 0.0 1 . 5' 0.0 0.0
0.0 0.5 0.5 0.5 0.0
0.0 0.0 0.5 0,0 0.5
0.0 0.5 1.5 0.5 1.0 1.0
)>
Company Sanitized. Does not contain TSCACBi
Addendum 4 4 Twenty e i g h t - d a y r epea t e d- dos e o r a l t o x i c i t y st udy in r a t s
___________
Hematological data of individual animals
Sex Fe mal e
Exp.group (uig/kg/day)
Vehicle control
10 40 200
1,000
Animal No. N-Band
43 0 .5 44 3 .0 45 4 .0 46 0 .5 47 1 .5 48 0 .5
49 50 51
52 53
54
55 56 57 58 59 60
61 62 83 64 65 66
67 68 69 70 71 72
73 74
75 76 77 78
Recovery 78
' 80 81 82 83
84
3.0 2.5 1.5 1.0 1.0 3.0 1.5 1.5 2.0 1.0 1.0 1.0
0.5 1.0 0.5 0.5 3.0 -2.5 0.5 1.53.5 3.0 0.0 2.0 2.0 1.5 3.5 2.0 1-.5 1.0
2.0 1.0 2.5 1.5 1.5 1.0
Differentiation of leukocyte (%) N-Seg
9.5 1.0 0.0
10.5 0.5 0.0
7.0 1.0 0.0
4.0 0.0 0.0
7.0 0.5 0.0
14.0
0.0
14.0 9.0
12.5 8.5 8.0
14.5
10.0 8.5
11.5 8.0
11.0 5.5
8.5 . 8.0
19.5 12.5
8.0 6.5
6.0 16.5
8.5 12.5
3.5 5.5
10'. 5 8.0
11.0 11.0 14.0
8.5
2.0 1.5 0.0 0.5 0.5 0.5
0.0 1.0 1.0 1.0 0.5 1.0
0.0 0.0 0.5 1.0 0.0 0.0
0.0 2.0 1.5 1.0 0.5 0.5
0.5 0.5 1.5 0.0 1.0 1.0
0.0 0,0 0.0
0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0
0.0 0,0 0.0 0.0 0.0 0.0
0.0 0.0 0.5 0.0 0.0 0.0
0.0 0.0
0.0 0.0 0.0 0.0
8.0 14.0
8.5 7.5 6.0 9.5
'
2.0 2.0 0.5 0.5 0.5 2.0
0.0 0.0
0.0
0.0
00..00
89.0 85.0 87.5 95.5 90.5 85.0
79.0 86.5 86.0 89.5 90.0
88.0 88.5 85.5 90.0 86.5 92 e
91.0 92.5. 79.0 85.5 88.5 91 0 93.5 80.0 88.0 83.5 96.0 97 n
86.5 89.5
83.5 86.5 83.0 89 5
88.0 82.0 87.5 90.5 92.0 87.5
nono
0.0 1.0 0.5 0.0 0.5
2.0 0.5 0.0 0.5 0.5
0.5 0.5 0.0 0.0 1.0
0.0 0.5 0.5 0.5 0,5
0.0 0,0 0.0 0.0 0.0
0.5 0.5 0.5 0.5 0.5 ........... o_. ou______
0.0 1.0 1.0 0.0 0.0 0.0
-j
Ul
))
Company Sanitized. Poes not contain T5CA Cl
I
m
Addendum 5-1 Twenty-eight-day repeated-dose oral toxicity study in rats Dlood chemical data of individua!- animals
Sex Ha l e
Exp.group (mg/kg/day)
Ve h i c l e control
10 40 200
1,000
GOT Animal No. U/L)
GPT (IG/L)
' ALP (IU/l)
ChE (IU/L)
1 76 2 78 3 89
4 71 5 66 ____6 _____ _ J 5 ______
Recovery
25 25 25
340 42 422 67 490 70
31 431 41
22 387 32
...2.6.___ ____ 4 6 0 ........... .. .. 48____
7
8 9 10 11 12
13 14 15' 18 17 18
19 20 21
22 23 24
25 20 27
28 29 30
31 32 33 34 35 36
Recovery
90 70 83 69 87 72
65 86 83 75 86 80
62 67 81 73 78 64
75 61 91 76 99 75
77 70 73 84 82 . . 7 5 ______
22 26 27 25 24
22'
22 26 36 24 28 25
26 28
29 28 27 24
27 23 36 26 34 34
23 24 28 21 31 25
331 55. 286 46 398 34 300 49 313 55 300 58
513 38 377 36 419 51 598 44 489 66 426 43
498 53 446 53 552 38 514 64 589 47 511 47
386 33 371 38 519 61 518 50 488 45 472 42
356 40 413 48 438 32 307 64 295 36 415 74
37 77 38 72 39 89 40 67 41 92
42 106
22 25 32 28
28
28
371 42 314 34 350 70 362 56
390 35 496 54
r-GTP
UU/L)
1.6 1.2 0.4 0.4 1.0 0.7
0.7 0.8 1.0 1.0 0.5
0.5 '0.8
1.7 0.8 0.8 X <u 0.4 0.4 1.2 1.7 0.3
0,5 0.8 0.2 0.8 0.9
0.8 0.8 0.6 0.4 0.2 0.5
1.2 0.9 0.9 1.1 0.6 no
- . . . . . vai uei sj was excluded from the s t a t i s t i c a l anal ysi s because the abnormality not r'elated'
T-Cho
(mg/dl)
67 63 59 47 54 53
37 61 53 74 58 47 87 39 62 29 48 80 38 60 41 43 50 47
52 53 43 37 41 52 38 40 37 49 31 41
TG
(rag/dL)
57
7676
45 83 63
6866
76 89 60 47 72 63
2954
52 41
44 52
68
61 40 37
60
1 2586.
85 34 92
53 91 38 108 36 64
Glucose
Crag/dL)
130 2 0 2 a) 119 124 143 122
140 131 138 181 144 115
123 158 123 130 124 170 130 115
110415
128 125 125 118 128 130 145
113 116 103 120 125 130
25 57 40 72 49 42' 55 85 3 5 6.1 48 89
to treatment was detected.
109 130 131 132
112 108
T-Protein
(g/dL)
5.5 5.3 5.5 5.3 5.3
Albumin
(g/dL)
3.0 2.7 3.0 2.8 2.9
5.2 2.6 5.8 2.8 5.4 2.6 5,6 2.8 5.4 2.6 5.2 2.5
5.4 2.8 5.4 2.8 5.6 2.9 5.4 2.7 5.1 2.8
5,4 2.9
22..87 22,.76
5.5 2.5 5.2 2.8 5.2 2.7 5.3 2 8 5.3 2 8 5.1 2.7
2.5
5.2 2.6 5.1 2,5 5.0 2.6 5.5 2 8 5.4 2 6 5.7 2.8
A/G r a t i o
1.20 1.04 1.20 1.12 1.21
1.00 0.93 0.93 1.00 0.93 0.93 1.08 1.08 1.07 1.00 1.22 1.18
1.12 1.12
1.16 1.04 1.08 1.08 1.04 1.08 1.17 0.93 1.04 0.83
17
011822 0102
1.00 0.96 1.08 1.04 0.93 0.97
)
A-aBiiaim 5 -2
Sex Female
i.- n . S X T
Exp.group (mg/kg/day)
Vehicle control
10 40 200
1,000
GOT Animal No. UU/L)
43 66 44 63 45 72 46 72 47 70 48 74
49 50 51 52 53 54
55 56 57 58 58 60
61 62 63 64 * 65 66
67 68 69 70 71
72
73 74 75 76 77 78
lleoovery 79 80 81
82 83 84
77 99 110 96 64 69
75 102
78 79 83 70
81 78 78 70 102 79
85 77 75 86 71 64 ioo 70 77 88 53 62
73 94 106 76 82 62
i . s i : 11' ' * * -
GPT
UU/Ii)
18 19 20 21 19 21
24 26 24 22 14 19 16 45 24 23 23 19 29 17 22 22 25 24 18 17 21 16 18 17 19 18 23 18 15
19 20 30 20 33 21
ALP
CIU/L)
226 150 275 265 207
CliE
UU/L)
244 217 269 321 275 25D
221 207 215 209 212 21 7
365 237 386 307 323 259
285 264 214335 240 305
200 195 200 225 299 245
356 209 198 282 209 253
379 642 203 431 315
591 350 158 303 245
478 300 303 219 188
202 353 183 167 179
SR 9
294 222 266 232 294 _____26_4__
198 240 227 293
194 290 191 349 186 426 155 294
Company Sanitized. Doss notcontain TSCACBf
7-GTP
U/.L)
0. 1.3 1.3 0.5
1.2
_0._9^
0.6 01..60
1.2 1.2 0.5
0.6 011...31B0.8 0.6
0.7 1.4 0.5
01..70 1.1 1.1 01 ..85 0.8
0.4 0.5
1.8 01 ..64 11..00 1.1
0.6
0.4 1.3
00 ..83
1.4
T-Cho
TQ
(rag/dL)
(mg/dt)
68 2B 66 11 73 28 71 23
84 19
85______ 2 0 __
75 28 47 26 62 20 69 19 63 21
78 21
60 21 60 24 49 24 70 29 68 31
54 22
72 10 74 11. 84 36' 64 24 68 14 70 31
80 27 107 40
89 21 75 45 41 7 90 28
55 24 81 40
63 16
60 38 69 45 80 18
58 18 77 28
60 10 58 21 46 23 67 13
Glucosi)
(mg/dL)
114 102 153 136 106 116
118 119 125 113 138 135 114 124 141 149 120 119
115 110 146 121 112 120 119 129 118 131 108 114 107 100
89 129 158
131 118 127 131 123 139
T -P ro te in
(g/dL)
5 .6 5.5 5.8 5.1 5.7
AI traudii
(g/dL)
3.0 2.S 3.1 2.7 3.0
A/G r a tio
1.15 1.12 1.24 1.12 1.11
5.7 2.8 0.97 5.7 3.0 1.11 5.5 2.8 1.04 5.3 2.8 1.12 6.2 3.2 1.07 5.8 2.9 1.00
5"55.-'940 _5 3322...0078____ 1111....00218307
565---84 2 333...411
111...231155
555--325 ____ 222...889____ 111..,021147
5-6 3.0 1.15
65665-..54015_____33333.....04020 ____ 11111.,..,2221260540
55555---..83654 33333.....00011 11111....,4121215955
.5.i.4_ 2.8
1.08
5.5 3.0 1.20
5.8 2.9 1.00
5.3
2.6
0.96
5.7 2.9 1.04
5.8 2.8 0.93
5.8 3.1 1.16
)
Sex Male
vuauii^ otuuy Blood chemical da t a of i n d m d u a l \ n i m a l s
Exp.group (mg/kg/day)
Vehicle control
10
40
200
1,000
goo Animal No. (mg/dL)
1 2 3 4 5 6
:overy 7 8 9
10 11 12
12.7 13.1 15.0 12.7 14.0 15.2
17.1 14.5 15.8 15,8 17.3 14.6
13 1 3 .2
14 13 .7 15 1 3 .8 16 1 2 .8
17 1 1 .9
-- 13
1 1 -fi
19 1 5 .3 20 12.4
21 1 3 .4
22 1 4 .8
23 -- 24
14.0 12,3
25 1 2 .7
26 1 1 .7 27 1 4 .8
28 1 5 .2
28 -- 30
15.3 16.4
31 1 6 .5
32 13.3
33 1 7 .0
34 14.7
35 12.9
. . . 3 6 _______ 1 2 . 6
Recovery
37 1 1 .8
38 16.6
39 15.5 40 15,3
41 14.0
___4 2
14.9
Creatinine T-Bii
(mg/dL)
(mg/dL)
0.20 0.25 0.22 0.19
0.06 0.10 0.10 0.07
0.22
0.12
O.l.2.3.________ 0,._.09____
0.27 0.24 0.30 0 . 2'3 0.24 0.23
0.09 0.11
0.09 0.11 0.11
0.15
0.24 ' 0.18
0.20
0.17 0.18 0.14
0.07 0.10 0.09 0.09 0.07 0.10
0.25 0.20 0.21 0.19 0.19
0.16
0.09 0.06 o-.oe 0.10 0.09 0.10
0,20
0.08
0,20
0.07
0.17
0.09
0.20
O'. 0 8
0.19
0.08
0 . 2 0 - ________0 . 0 8
0.23'
0.07
0.20
0.08
0.23
0.08
0.23
0.08
0.22
0.09
0_._18_________ 0 , 0 7
0.18 0.26 0.27 0.25 0.22
0.21
0.09 0.07 0.10 0.10 0.10 0.08
wO
Company Sanitized, Does not contain TSCA
Ca
(ng/dL)
1O0.0'
.9 -9 9.9
10.2
10.3
9.8 10.0 10.. 1 10.2
9.7 9.5 9.9 10.0 10.3 9.9 9.9 10.4 10.1 10.0 10.0 10.0 10.1 10.1
9.7 10.2
9.6 10.0 10.0 10.4 10.0 10.0
9.8 10.0
9.9 9.7
9-5 99-.88
10.2 9,0
10.0
IP
(mg/dL)
8i. 5 8;. 4 7;. 8 7:, 9 8. 0 8.7
7.5 7.4 7.1 7.0, 7.7 6.2 7 i. 5 8!. 0 8.5 8:. 4 8,0 8.7
7.0 7.6 7.4 8:. 3 7:, 9 8.5 7l 2 7.4 7.4 8:. 4 8 i. 3 8;. 1 8i.O 7 ;.7 8,1 7.9 7,4 8,7
7.0 76..14
8.1 7,1 7.0
Na
(mEq/L)
144 142 141 142 142
141 140 142 141 141 142 142 142 143 143. 142' 141 140. 141 141 143 141 140. 142 144 142 143 142 142 142 142 141 141 142
140 141 143 142 142 140
K
(aEq/L)
4.3 4.1 4.3 4.4 4.3
4.0 4.6 4.7 4.0 4.5 4.2 4.7 4.0 4.0 4.0 4.3 4.5 4.2 4.0 4.9 3.9 4.4 4.3 4.2 3.8 4.2 4.4 4.0 4 .5 4.5 3.9 4.5 4.3 4.0
4.4 4.4 4.0 4,3 4.3 5.1
C1
(nBq/L)
105.9 105 1 102.9 106.5 106.3
110042..99
105.8 104.7 103.7 1 0 8 5 108.2
11 00 62..67
106.9 106.4 106.6 106.7 106.6 lore. 9 106.1 104.0 104.9 107.1 106.4 109.4 108.1 106.1 103.9 107.6 104.0 107.4 104.7 107.0 105.6
106.1 105.1 107.1 103.9 105.5 104.9
0-O0
))
nuuenQum 0 - 4
B^ni l y7 iEll' t ' i ay r e p e a t e d"i o3e o r a l t o x i c i t y s t udy
Blood chemical da t a o f i ndividual animals
*
Sex female
Exp.group (g/kg/day)
Vehicle control
10 40 200
1,000
BUN
Animal Ho. (mg/dL)
43 44 45 46 47 __ _48_ ........
14.5 15.0 11.9 16.9 16.5
Recovery""
49 1 7 .8 50 2 0 .6 51 1 9 . 0 52 1 5 .7 53 1 6 . 2 54 1 4 .0
55 1 5 .3 56 1 5 .5 57 1 7 .8 58 1 5 .7 59 1 4 .4 80 1 8 .1
81 1 5 . 3 62 1 1 .5 63 1 4 . 6 64 1 3 .5 65 1 5 .5 66 1 1 .2 67 1 4 .7 68 1 5 .0 89 1 7 .4 70 14.3 71 1 5 .2 72 16 .7
73 1 7 .7 74 16.7 75 19.1 76 16,3 77 12.9-
78 1 2 .8
Recovery
79 17.2
80 21.3 81 18.9 82 14.2 83 1 7 .2 84 14.4
Creatinine
(mg/dL)
0.23 0.20 0.18 0.23 0.19 _____ .Q .-.2 0 ___
0.27 0.30 0.28 0.23 0.22 0.25
0.22 0.21 0.23 0.22 0.20. 0.25
0.24 0.22 0.21 0.19 0.23 0.20
0.25 0.23 0.24 0.20 0.22 0.2?.
0.26 0.24 0.23 0.22 0.18 0.20
0.25 0.26 0.32 0.21 0.26 0.25
T-Bil
(mg/dL)
0.09 0.09 0.08 0.11 0.08 0,10
0.11 0.14 0.10 0.14 0.12
0.09 0.11 0.08 0.15 0.09 n 11
0.11 0 .1 1 0,09 0 .1 1 0.12 0 09 0.08 0.07 0.08 0.07 0.13 n no
0.08 0.09 0.09 0.08 0.05 0.09
0.08 0.13 0.13 0.13 0.15 0.11
Company Sanitized. Dees not contain TSCA CBi
>
Ca
Cttg/dL)
10.0 9.6
10,0 9.4 9.9
10.1
IP
(ig/dL)
6.8 8.8 6.8 7.3 7,6 7.7
99 ..89 66..74
9.5 6 .g
9.5 6.6
10.0
8.3
1 0 . 1 ______ 7 6
9.9 7.3
9.7 6.9
10.0
8.5
10.0
8.4
9.8 7.0
10.1
9.8
R.A
6.8
9.9 7.4
10.0
7.0
10.0
8.3
8.8 7.8
1 0 3_________ 7 , 5
10.1
6.9
1 09..71
76 ..98
9.9 7,8
9.7 6.5
10.2_____ 7,6
10.0
10.0
9.6
8.3
6,8
6,6
9.9 9.6
10.2
8.2 8,2
8.2
9.7 6.5
9.8 7.4 9.1 6.5 9.9 7.2
9.9 7.0 101_____ 6,3
Ha
(mEq/L)
141 140 143 142 141
139 139 139 140 140 141 142 140 141 142 140 141 141 141 142 140 142 141 141 142 143 141 142 140 141 142 141 141 141 144
139 139 140 140 140 142
K
(mEq/L)
4.2 3.8 3.4 3.6 4.6
4.5 4.3 4.5 4.3 4.1 4.1 3.7 3.8 4.2 3.6 4.2 4.6 4.0 3.7 3.9 3.9 4.5 4.6 4.2
43..70
3.8 3.8 4.1 4.6 4.0 4.4 4.1 3.9 3.7
4.0 4.6 3.4 4.3 4.1 4.3
(siEq/L)
"TTT
109.3 106.6 107.4 109.3 108.5
107.5 1 0 7 .g 106.9 108.5 104.9 106.7 0 8 .5 107.3 108.4 106.8 107.7 108.3 108.3 107.6 107.4 107.8 107.8 107.7 108.2 108.7 110.7 107.9 110.4 107.5
107.5 107.9 109.9 108.5 105.9 107.5
108.8 108.4 106.6 105.4 109.1 110.5
'O
))
I ,oxbitystudy*in rats
Bxp.group Sex (mg/kg/day)
Vehicle control
Male
10 40 200
1,000
SY, Slightly yellow. Y, Yellow,
Animal No.
T~
2
3
4
b
7Recovery
8
9
10
11
12
13 14
15 15 17 18
19
20 21 22 23 24
25 26
22B7 20
30
31 32 33
34 36 36
Recovery 37 38 39 40 41 42
Volume
(mL)
~5~
13 11 25 20 J_
118
8 9 6
12
12 7 22 16 29 10
21 18 9 19 27 12
19
1109
23 23 17
20 30 16 15 14 14
24 14 28 18 15 7
Color
Y SY Y SY SY Y
Y Y Y Y Y Y SY Y SY SY SY Y
SY SY Y SY SY Y
SY SY Y SY SY Y
SY SY SY SY Y SY
SY Y SY Y Y Y
pH
6.5 6.5 6.5 7.0 7.0 6.5
6.5 6.5 6.5
6 .0
6.5 5.0
7,0 6.5 6.5 6.5
66..65
7.0
6.6
6.5 6.5 6.5 6.5 7.0 6.5 6.5 7.0 7.0 7.0
6.5 7.0 6.5 6.5 6.5 6.5
6.5 7.0 6.5 7.0 6.5 6.0
Company Sanitized* Does not sentala TSCACSt
Protein
+ + +
+
+ + + + + +
+ + + +
V + +
"1"
+ 4-
Ketones
4*
-4-
-- +
+
-- zfc
-- ~f* +
*i 4* 4-
4. +
-
Bilirubin
-- -- -- -- -- --
-- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- --
-- -- --
-- --
--
-- -
Occult Blond
_ -- --
-- --
-- -- -- -- -- -- -- -- --
-- -- -- -- -- -- -- -- -- -- -- -- --
4-- --
--
-
Cducose
-- -- -- -- -- -
-- -- -- -- *-- --
--
-
-
-- -- -- -- -- -- -- -- -- -- -- -- -- ~
_
--
--
--
-
Urobilinogen (EU/dL)
0 .1 0 .1 0 .1 0 .1 0 .1 0 .1
0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1
0 .1 0 .1
0 .1 0 .1 0 .1 0 .1 0 .1 0 .1
0 ,1 0 ,1 0 .1 0 .1 0 .1 0 .1
0 .1 0 .1 0 .1
Q.l
0 .1 0 .1
oOo
Sompanf Sanitized. Doe* not contain TSCACBt
Addendum6-2
Uxp.group
Sex (m g/kg/day)
Vehicle control
10
Female
40 200
1,000
SY, "slightly yellow. Y, Yellow. B,Brown.
~
Animal No.
43 44 45` 46 47 48
Recovery 49 50 51 52 53 54
55 56 57 58 59 60
61 62 63 64 65 66
67 68 69 70 71 72
73 74 75 76 77 , 78
Recovery 79 80 81 82 83
Volume
(mL)
13 11 10 9
J12
9 8 6 4 54
4
115
3 2 6
9 13 7 21 12 4
14 4 3 8 6 5
7 15 7 5
5 9 5 3 10 8
Color
SY SY Y Y SY Y
Y Y Y Y Y Y
Y Y SY Y' Y Y
SY. SY Y SY SY _Y
SY Y Y Y Y B
Y SY Y Y SY Y
Y YY Y Y Y
PH
6.5 6.5 7.0 6.5 6.5 6.5
6.5 6.0 6.6
5.0 76..00
6.5 6.5 7.0 6.5 6.5 6.5
6.5 7.0 6.5 6.5 6.5 6.5
6.5 6.5 6.5 6.5 6.5 7.0
6.5 7.0 6.5 6.6 6.5 6.5
6.5 6.5 6.0 6.0 6.5 6.0
Protein
--
i
+ + + +
44
+ +.
-- +
+
+
+
+
+4--
Ketones
--
-- -- --
--
_
--
-
--
-- --
--
-- -- -- -- _ -- -- -- -- -- -- --
-- -- -- -- -- -- -- -- --
-- -- -- --
Bilirubin
Occult Blood
-
~ -- ~ --
-
_
-- --
-- *
-
--
-- --
--
-
-- --
-- -- -- -- -- -- --
-- -- -- -- -- --
_
-- -- -- --
"
-- --
--
-
_
-- --
--
-- -
,,
-- --
-- --
--
-- --
--
-- -- -
-- -- -- -- 4+
-- -- -- -- -- -
--
-- +4 --
~
Glucose
~ -- -- -- --
-
_
--
_
-- -- -
-- -- -- -- --
"
-
-- --
-- --
-- -- -- -- -- -- -- --
_
~ -- -- --
-
Urobilinogen (BU/dL)
0 .1 0 .1 0 .1 0 ,1 0 .1 0 .1
0 .1 0 .1 0 .1 0 .1
o.t
0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1 0 .1
0 .1 0 .1 0 .1
0 .1 0 .1 0 .1 0 .1 OA 0 .1
0 .1 0 .1 0 .1 0 .1 0 .1 0 .1
0 .L 0 .1 0 .1
(1.1
0 .1 0 .1
oo
I
SanHied* Does no
Addendum 7-1 Twenty-eight -day r epeat ed- dose or a l t o x i c i t y st udy in r a t s
_____
Absoll]tfl organ weights o f Indi vi dual animals
Sex Hale
Exp.group (mg/kg/day) Animal No.
Liver (g)
Vehicle control
10
' 40 200
1,000
1 9.29 2 11.53
3 9.70 4 9.90 5 10.04 _____ 6______1 1 . 2 8 Recovery
7 10,93 8 13.08
9 10
11 __ 1 2
10.85 13.22
12.59 10,75
13 9 .1 3
14 9.56 15 11.68 16 8 .9 0
IV 9 .4 7 1 8 _______ 9 . 9 6
19 9 .7 0 20 10.23 21 9 .1 5 22 1 1 .7 2 23 9 .8 8
24 10.06
25 8.91
26 11.38 27 8,77 28 9 .5 2
29 -- 30
10.37 13,82
31 1 0 .6 0 32 10.66
33 1 0 .3 6
3354 1 81 .. 43 44
____3 6 _____ 0 . 8 1
Recovery 37 38 30 40 41 42
9 .33 11 .10
9 ,. 0 7 10..50 11..94 11,,15
Ki dne y
Testis
(5)
2^78
(E)
OF
2.74
2-41 2-77 2.70
2.79
2.88 2.31 3.04
2 . 8 7 ________ 2 . 9 3.
2.68
3.17
2-46
3.15
3.25
2.70
3.28
3.23
3.12 J L l_78
2.95 2.94
2.37
2.68
2.96 2.85
3.04 2.86
22.80
59 3 . 0 3 2.84
2.89
2.84
2.28
3.08
3 - 03 3 .2 1
2 - 58 3 .2 2
3 - 08 2 ,6 3
2-94
3.16
2 - 9 2 _2 , 6 2
2.40
2.71
2.74 2.69
3.08 2.99
2.53
2.50
33-32
05 2 .8 4 2.59
2-53 2.76
2.82 2.84
2.57
2.78
2-83
2.55
2-21
2.67
2 1 . 7 9 ________ 2 . 7 5
2-95 2-60 22-88
3JL-1.1
2.0.0 2.87 8.3 3 . 0 8 2.98
31 3 .7 7 3.34
Ovary (mg) TM -
----- -------------------
Brain (g)
1 .98 2 .02 2 .05 2 . 00 1 . 90 X. 90
- i .98 1 . 93 1 , 90 2 . 04 2 . 07 2 . 08 i .95 1 . 87 X.89 2 .00 1 . 84 i .96
. a .03 2 . 06 2 .01 1 ,99 2 XX 2 . 07
-- i , 86 1 . 96 1 . 97 X.93 1 . 94 1 , 94
2 .ii 2 .03 1 . yb 1 . 86
1 .98 1 . 97
--------------- ---------
2 .02
1 .96 2 . 07 1 . 98 2 ,. 0 1
2 . 00
Spleen (g)
0 .59 0 .64 0 .71 0 .59 0 .81 0
0 .74 0 .79 0 .53 0 .85 0 . 04 0 . 76 0 . 53 0 .72 0 .67 0 .59 0 .79 0 .58 0 . 58 0 ,. 7 2 0 .68 0 . 52 0 .66 0 .59 0 .53 0 . 67 0 .61 0 . 59 0 ,66 1 .01 0 .61 0 .57 0 .60 0 .49 0 .39 0
0 .75 0 .66 0 .47 0 .56 0 ,. 9 0 1 . 13
Adrenal (mg)
46 . 3 02 .2 54 . 5 46 . 7 44 . 9
Body weight (g)
326 . 8345.. X 334 . 3 313 . 8 354 .0
50 . 2 53 . 7 53 .4 53 . 7 67 . 8 43 5
48,.8 62,, 3 49,. 5 40 .7 62,, 5 47, 2
43,,4 55 ,7 55,, 5 54., 6 63,,2 40. 7
45.,8 45.,2 4 7 ,, 9 43,,5 56,,2 48. 9
48,,3 54,,4 52,, 9 58,.3 48..1
402 . 3 421 . 6
404 . 2 442 . 8 406 . 9 396 7
309 . 3 330 . 9
360 . 6 308 . i 321 .3 33X 5
317.,X 355 .0 324 , 6 3 4 0 ,. 3 335 , X 332 1
289 , X
3 4 5 ., 0 295.,3 321. 6
335 . 3 37K 0
341., 2
334,, 5 311,. 1 3 4 2 ., 2 273 . X
45,. 6 54., 6 59,. 6 49,,5 54..7 52. 9
3 4 5 ., 3 390..0 3 7 7 ., 3 385 . 6 413 .7 365 . 9
oioo
)
Sex Fe ma l e
Exp.group (g/kg/day)
Vehicle control
10 40 200
1,000
Animal No.
Liver (g)
43 44 45 40 47 ____ 4 8 __
Recovery 49 50 51 52 53
______ 5 4 55 58 57 58 59
61 62 63 84 65 66 67
IT
5.17
6.05 5.62 5.35 . 8 . 04
6.16
8.10 6.40 5.35 6.67 6.07
5.86 5.15 5.88 5.65 4.88 , ffcd
5,16 5.80 6.43 5.54 4.99 6 . 61
68 6.6 7 69 6 .1 9 70 8.01 71 4.9 9 72 5.4 6
73
74 6.56 75 . 5.59 76 6.23 77 7 .2 6 7 8 ____ .6 j. 6.3__ .....
Kidney (s)
1.69 1.57 1.59
75 63 63'
1.65 1 . 63' 1.54 1.47 1.73
1.5 2;
1 . 58'
11.. 65 88-
1.47 1.47 1.62 1.62 1.73 1.92 1.55 1.37 1.75 1.48 1.72 1.50 1.56 1.54 1.60
1.62 1.73 1.46 1.47 1.71 1.75
79 6 .5 4
1.55
80 6 .5 8 81 5 .1 4 82 6.57
1.84 1.31 1.71
83 6 . 3 4 84 6.8 0
1.80 1.78
Testis is)
-
--
-
Ovary (mg)
80.5 61.0 73.2
8896,,
73.4
63.9 9 3 .. 7 82.8 73.5
111.6
80.7 '73.0 63.3 78.2 72.0
85.9
68.4 74.8 73.1 80.0 60.8 91.4 82.1 77.5 58.8 85.0 80.1 67.0
78.4 68.8 63.8 58.4 65.3
74,2 96.5 74.1 77.6 102.0 106.7
Brain (SE
1.86
1.78 1.67 1.83 1.77 1.80
78 79 92 82 91
78
1.92 1.76 1.91 1.86
1.81
1.73 1.76 1.68 1.83 1.66 1.91
1.76 1.91 1.85 1.81 1.87 1.76
1.75 1.81
1.74 1.84 1.75
' '
1.84 1.85 1.76 1.86
1.84 1.85
Spleen (X)
0.48 0.40 0.39 0.53 0.39 0 . 3 3
0.48 0.40 0.44 0.37 0.45 0.46 0 . 44' 0.26 0.45 0.42
0.59 0.38 0.48 0.36 0.39 0.35 0 48 0.41 0,34 0.39 0.43 0.37 0 44 0.36 0.37 0.32 0.35 0,38
0.46 0.48 0 .370.50 0.39 0.48
Adrenal (mg)
73.3 48.4 50.4 69.4 59.4 62_._3_
65.1
7846..70
62.6 73.7 69.1 58.4 62.8
66.2
61.6 OZ . 0 78.2 57.6 65.8 53.9 67.3 53.1
67. 1 51.9 55.6 67.8 69.8
74.3 57.0 54.2 58.8 63.1
Body weight (g)
212.4 174.5 194.2 189.4 191.5
.201_.2_
210.6 231.6 230.2
201.5
225.8
211.1
194.8 169.1 217.5 195.7 165.0 215.6 179.9 208.8 211.0 197.1 175.9 212.3
200.8 204.8 198.0 197.3 181.2 189.4
201.1 202.4 180.7 198.3 199.4
73.1 68.7 74.6 81.9 74.6 86.8
212.6 259 . 6 199.2 229.5 242.5 244.0
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I
Addentimi 8-1 Twenty-eight-day repeated-dose oral toxicity study in rats
ffelative organ weights of individual animals
Sex Ma l e
Exp.group (ng/kg/day)
M icie control
10 40 <200
1.. 0 0 0
Animal Ho.
1 2 3 4 5 8
7 8 9 10 11 12
13 14 15 16 17 18
19 20 21 22 23 24 25 26 27 28 29 30
31 32 33 34 35 36
Recovery 37 38 39 40 41 42
Liver (e/lOOg)
2.84 3.34 2.90 3.15 2.84 3.08
2.72 3.10 2.68 2.99 3.09 2.71 2.95 2.89 3.24 2.91 2.95 3.00 3.06 2.88 2.82 3.44 2,95 3.03 3.08 3.30 2.97 2.96 3.09 3.68
3.11 3.19 3.33 3.31 3.09 3.15
2.70 2.85 2.40 2.72 2.89 3.05
Kidney {g/100g)
0.85 0.79 0.72 0.88 0.79
0.67 0.75 0.61 0.74 0.77 0.70 0.77 0.89 0.79 0.8-6 0.81 0.87 0 . 7 2 0.85 0.79 0.90 0.88 0.88 0.85 0.79 0.91 0.79 0.91 0.88 0.74 0.83 0.83 0.83 0.81 0.81
0.85 0.67' 0.70 0.75 0.80 0.85
Testis ( g/ l OOg)
0.95 0.81 0.86 0.74 0.86
0.78 0.77 0.68 0.73 0.72 0 74 0.87 0.92 0.82 0.99 0.88 0 Rfl
0.97 0.90 0.99 0.77 0.94 0 79 0.94 0.89 1.01 0.78 0.85 0.69 0.83 0.85 0.89 0.75 0.98 0.80
0.75 0.74 0.82 0.77 0.91 0.91
Company Sanitized. Does not contain TSCACBi
Ovary (tng/lOOg)
Brain ig /100g)
O :
0.59
0.61 0.64
0.54 -- " _________ 0 . 5 1
- 0.49 0.46 0.47 0.46 0.51 0 . 52
-- 0.63 0.57 0 . i}` 0 . B5 0.67
0.69 ~ 0.64
0.58 0.62 0.58 0.63 0.62
0.64 0.57 0.67 0.60 0.58 0.52
- 0.62
0.61
0.63
0,54
" 0.73 0.57
- 0.58
0 . bU . 55 " 0.51 0 . 49
0.55
Spleen (g /100g)
U8
0.19
0.21 0.19
0.17
0.21
0.18 0.19 0.13 0.19 0.16 0.19 0.17 0.22 0.19 0.19 0.25 0.18 0.18 0.20 0.21 0.15 0.-20 0.18 0,18 0.19 0.21 0.18 0.20 0.27
0.18
0.17
0.19
0.14 0.14
Adrenal (mg/lQOg)
14.2
18.0
10.3 14.9 12.7
16.4
12.5 12.7 13.2 12.1 16.7 11.0 15,8 18.8 13.7 13.3 19,5 14.2 13.7 15.7 17.1 16.0 ' 18.9 12.3 15.8 13.1 18.2 13.5 16.8 13.0
14.2
16.3 17.0 17.0 17.8
Body weight (g)
326.8 345.1
334.3 313.8 364.0
369.0
402.3 421.6 404.2 442.8 408.9 396 7 309.3 330.9 360.6 308.1 321.3 3.11 K 317.1 365.0 324.6 340.3 335.1 3 .1 ?! 1 289.1 345.0 295,3 321.6 335.3 3 7 5 f?
341.2 334.5 311.1 342.2 273.1
0.22 0.17 0.12 0.15 0.22 0.31
13.2 14.0 15.8 12.8 13.2 14.5
345.3 390.0 377.3 385.6 413.7 365.9
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Addendum 8-Z
i i ! ! u i T e i 5 h t ~day i'Bpeat8(1~<iose o r a l t o x i c i t y st udy in r a t s
Relative organ weights of individual animals
"
Sex
Exp.group (mg/kg/day) Animal No,
Liver (B/100g)
Ki dne y ( g/ i OOg)
Testis (g/100g)
Vehicle control
43 44 45 46 47 48
Recovsry
2.98 2.86 3.12 2.97 2.79 3.00
0.80 0.90 0.82 0.92 0.85
-
49 2 .9 2
0.78
50 2 .6 3 ' 51 2 .7 8 52 2 .6 8 53 2 . 9 5
54 2 .8 8
0.70 0.67 0.73 0.77 0.72
-
55 3 .0 1
0.81
10
56 3 . 0 5 57 2 .7 0
0.93 0.77
58 2 .8 9 59 2 .9 6
0.75 0.89
-
60 2 .9 8
0.75
61 2 .8 7
0.90
Female
40
62 2 .7 8 63 3 . 0 5
0.83 0.91
64 2 .8 1
0.79
-
65 2 . 8 4
0.78
66 3 .1 1
0.82
67 3 .1 8
0.74
200
68 3 .2 6 69 3 . 1 3
0.84 0.76
70 3 .0 5
0.79
-
71 2 .7 5
0.85
72 2 .8 8
0.84
73 3 .1 8
0.81
74 3.2 4 75 3 .0 9
0.85 0.81
-
76 3 .1 4
0.74
3a 1 , 0 0 0
77 3 .6 4 ____7 8 ____. 3 . 2 4
0.86 0.85
oo
Recovery 79
3.08
0.73
S,
3
80 2 .5 3 81 2 .5 8
82 2 .8 6
0.71 0.66 0.75
m 83 2.61
0,74 ,
84 2.79
0.73
o
B
)
Ovary (mg/100g)
37.8 35.0 37.7 45.8 36.1 36.5
30.3 40.5 38.0 36.5 49.4 38.2
37.5 37.4 36.0 36.8 36.8 39.8 38.0 35.8 34.6 40.6 34.8 43.1
40.9 37.9 29.7 43.1 44.2 35.4 39.0 34.0 35.4 29.5 32.7 41.6
34.8 37.2 37.2 33.8 42.1 43.7
Brain ( e / l OOg)
0.88 1.02 0.86
0.97 0.92 0.89
0.85 0.77
00..98 03
0.85 0.84 0.99 1 .04
0.88
0.95'
1.10
0.84 0.98 0.84 0.80 0.93 0.84 0 . BO
0.88
0.93 0.93 0.92 1.03 0.93 0.87 0.89 0.96 0.93
0.88 0.88
0.87 0.71 0.88 0.81 0.76 0.76
Spleen ( g/ i OOg)
0.23 0.23
0.20
0.28
0.20
0.16
0,23 0.17 0.19 0.18
0.20 0.22
0.23 0.15 0.21 0.21 0.20
0.27
0.21
0.23 0.17
0.20 0.20
0.23
0.20
0.17
0.20 0.22 0.20
0.23 0.18 0.18 0.18 0.18 0.19
0.18
0.22 0.18 0.19
0.22 0.16 0.20
Adrenal (mg/lOOg)
34.5 27.7 26.0 36.6 31.0 31.0
30.9 32.0 37.7 31.1 32.6 32.7 30,0 37.1 30.4 31.5 37.9 36.3 32.0 31.5 25.5 34.1 30.2 33.1 33.4 25.4 28.1 34.4 38.5 32.9 36.9 28.2 30.0 29.7 31.6 33.5
34.4 26.5 37.4 35,7 30.8 35,6
Body weight
(s)
212.4 174.5 194.2 189.4 181.5 201.2
210.6 231.6 230.2 201.5 225.8 211.1
194.8 169.1 217.5 195.7 165.0 215.6 179.9 208.8 211,0 197.1 175.9 212.3
200.8
204.6 198.0 197.3 1.81.2 189.4 201.
202,
180 198, 199 , 204.7
212.6 259.8 199.2
229.5 242.5 244.0
./-"N,
Addendum 9-1 Twenty-eight-day repeated-dose oral toxicity study in rats
Pathological findings o f individual animals
Sex
Exp.group
Animal Fate
No.
Macroscopic findings
Histopathologica] findings3-1
1 ta N o abnormalities detected
N o abnormalities detected
2 ta Kidney
Kidney
Male
Vehicle control
Pelvic dilatation (right) 3 ta No abnormalities detected
Pelvic dilatation + No abnormalities detected
4 ta N o abnormalities detected
No abnormalities detected
5 ta No abnormalities detected
N o abnormalities detected
6 ta N o abnormalities detected
N o abnormalities detected
a) Organs/tissues examined as follows: forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, colon, rectum,
liver, heart, kidneys, spleen and adrenals,
ta, terminal autopsy.
+, slight
Addendum 9-2 Twenty-eight-day repeated-dose oral toxicity study in rats
_______________Pathological findings o f individual animals ___________
Sex
Exp.group
Animal Fate
No.
Macroscopic findings
7 ta N o abnormalities detected
8 ta No abnormalities detected
Male
Vehicle control (Recovery)
9 ta N o abnormalities detected 10 ta N o abnormalities detected
11 ta N o abnormalities detected
12 ta N o abnormalities detected
a) Organs/tissues examined as follows: liver.
ta, terminal autopsy. +, slight.
Histopathological findings3-*
N o abnormalities detected N o abnormalities detected Liver Microgranuloma + No abnormalities detected No abnormalities detected No abnormalities detected
Addendum 9-3 Twenty-eight-day repeated-dose oral toxicity study in rats
Pathological findings of individual animals
Sex
Exp.group.
Animal Fate
(mg/kg/day)
No.
Macroscopic findings
13 ta No abnormalities detected
14 ta N o abnormalities detected
15 ta N o abnormalities detected
Male
10
16 ta N o abnormalities detected
17 ta No abnormalities detected
18 ta N o abnormalities detected
ta, terminal autopsy.
Histopathological findings
N ot examined N ot examined Not examined N ot examined N ot examined Not examined
Company Sanitized. Does not contain TSCACM
87
Addendum 9-4 Tweniy-eight-day repeated-dose oral toxicity study in rats ________________ pa-fa0]0gjca] findings o f individual animals_____________
Sex
Exp.group (mg/kg/day)
Animal Fate: No.
Macroscopic findings
19 ta No abnormalities detected
20 ta No abnormalities detected
21 ta N o abnormalities detected
Male 40 22 ta Kidney
Pelvic dilatation (right)
23 ta N o abnormalities detected
24 ta N o abnormalities detected
a) Organs/tissues examined as follows-: macroscopic lesion,
ta, terminal autopsy.
+, slight
Addendum 9-5 Twenty-eight-day repeated-dose oral toxicity study in rats
Pathological findings o f individual animals
Sex
Exp.group (mg/kg/day)
Animal Fate
No.
Macroscopic findings
25 ta N o abnormalities detected
2 6 ta No abnormalities detected
Male 200 27 ta N o abnormalities detected 28 ta No abnormalities detected 29 ta No abnormalities detected 30 ta Spleen Whitish region ( 3 mm)
a) Qrgans/tissues examined as follows: liver and macroscopic lesion, ta, terminal autopsy. +, slight; ++, moderate.
Histopathologica] findings3' Not examined Not examined N ot examined Kidney Pelvic dilatation + N ot examined Not examined
Histopathological findings2' No abnormalities detected Liver Microgranuloma + No abnormalities detected No abnormalities detected No abnormalities detected Spleen Focal necrosis ++
Compmt s a n i t i . Doss noi oonlatoTSCACM
Addendum 9-6 Twenty-eight-day repeated-dose ora] toxicity study in rats
Pathological findings o f individual animals
Sex
Exp.group (mg/kg/day)
Animal Fate
No.
Macroscopic findings
Histopathological findings3.
31 ta No abnormalities detected
Liver
Centrilobular hypertrophy of
hepatocytes +
Single cell necrosis of
hepatocytes +
32 ta No abnormalities detected
Liver
Single cell necrosis of
33 ta No abnormalities detected
hepatocytes + Liver
Male 1,000
Single cell necrosis o f hepatocytes +
34 ta N o abnormalities detected
Liver
35 ta No abnormalities detected
Centrilobular hypertrophy of hepatocytes +
Liver
Centrilobular hypertrophy o f hepatocytes +
Single cell necrosis o f
hepatocytes +
36 ta N o abnormalities detected
N o abnormalities detected
a) Organs/tissues examined as follows: forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, colon, rectum, liver, heart, kidneys, spleen and adrenals,
ta, terminal autopsy. +, slight.
Addendum 9-7 Twenty-eight-day repeated-dose oral toxicity study in rats
Pathological findings o f individual animals
Sex
Exp.group (mg/ka/day)
Animal Fate N.
Macroscopic findings
37 ta No abnormalities detected
38 ta No abnormalities detected
Male
1,000 (Recovery)
39 ta No abnormalities detected 40 ta No abnormalities detected 41 ta No abnormalities detected
42 ta Spleen
Nodule ( $ 7 mm)
a) Organs/tissues examined as follows: liver and macroscopic lesion,
ta, terminal autopsy,
++, moderate.
Histopathological findings35
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Spleen Follicular hypertrophy ++
Pompane Sanitized. Does notcontato ISCA CBJ
89
Addendum 9-8 Twenty-eight-day repeated-dose oral toxicity study in rats
Pathological findings of individual animals
Animal
Sex Exp.group
Fate Macroscopic findings
No.
Histopathological findings*-1
43 ta No abnormalities detected
No abnormalities detected
44 ' ta No abnormalities detected
No abnormalities detected
45 ta No abnormalities detected
No abnormalities detected
Female Vehicle control
46 ta No abnormalities detected
Kidney
Solitary cyst in medulla +
47 ta No abnormalities detected
No abnormalities detected
48 ta No abnormalities detected
No abnormalities detected
a) Organs/tissues examined as follows: forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, colon, rectum,
liver, heart, kidneys, spleen and adrenals,
ta, terminal autopsy.
+, slight.
Addendum 9-9 Twenty-eight-day repeated-dose oral toxicity study in rats ______________ Pathological findings o f individual animals_____________
Sex
Exp.group
'^ N o ^ Fate
Macroscopic findings
Female
Vehicle control (Recovery)
ta, terminal autopsy.
49 ta No abnormalities detected 50 ta No abnormalities detected 51 ta No abnormalities detected 52 ta No abnormalities detected 53 ta No abnormalities detected 54 ta N o abnormalities detected
Histopathological findings
Not examined Not examined Not examined Not examined Not examined Not examined
Addendum 9-10 Twenty-eight-day repeated-dose oral toxicity study in rats
Pathological findings o f individual animals
Exp.group
Animal
Sex
(mg/kg/day)
Fate No.
Macroscopic findings
55 ta No abnormalities detected
56 ta No abnormalities detected
Female
10
57 ta No abnormalities detected 58 ta No abnormalities detected
59 ta N o abnormalities detected
60 ta No abnormalities detected
ta, terminal autopsy.
Addendum 9-11 Twenty-eight-day repeated-dose oral toxicity study in rats
Pathological findings o f individual animals
Sex
Exp.group (mg/kg/day)
Anima] Fate
No.
Macroscopic findings
61 ta No abnormalities detected
62 ta No abnormalities detected.
Female
40
63 ta No abnormalities detected 64 ta No abnormalities detected
65 ta No abnormalities detected
66 ta No abnormalities detected
ta, terminal autopsy.
Histopathological findings Not examined N ot examined N ot examined N ot examined Not examined Not examined
Histopathological findings Not examined Not examined Not examined Not examined Not examined Not examined
Company Sanitized. Does not contain TSOA CBI
90
Addendum 9-12 Twenty-eight-day repeated-dose oral toxicity study in rats
_______________ Pathological findings o f individual animals
Exp .group
Animal
Sex
(ms/kg/day)
Fate No.
Macroscopic findings
67 ta No abnormalities detected
68 ta No abnormalities detected
Female
200
69 ta No abnormalities detected 70 ta No abnormalities detected
71 ta No abnormalities detected
ta, terminal autopsy.
72 ta No abnormalities detected
Histopathoiogica] findings
Not examined Not examined Not examined Not examined Not examined Not examined
Addendum 9-13 Twenty-eight-day repeated-dose oral toxicity study in rats
Pathological findings o f individual animals
Sex
Exp.group (mg/kg/day)
Animal Fate No.
Macroscopic findings
73 - tar No abnormalities detected
Histopathological findings2' No abnormalities-detected
74 ta No abnormalities detected
No abnormalities detected
Female
1,000
75 ta No abnormalities detected 76 ta No abnormalities detected 77 ta No abnormalities detected
No abnormalities detected No abnormalities detected N o abnormalities detected
78 ta No abnormalities detected
No abnormalities detected
a) Organs/tissues examined as follows: forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, colon, rectum,
liver, heart, kidneys, spleen and adrenals,
ta, terminal autopsy.
Addendum 9-14 Twenty-eight-day repeated-dose oral toxicity study in rats
________________ Pathological findings o f individual animals
Sex
Exp.group
Animal
(mg/kg/day) No. Fate
Macroscopic findings
79 ta No abnormalities detected
80 ta No abnormalities detected
Female
1,000 (Recovery)
81 ta No abnormalities detected 82 ta No abnormalities detected
83 ta N o abnormalities detected
84 ta No abnormalities detected
ta, terminal autopsy.
Histopathological findings
Not examined Not examined Not examined Not examined Not examined Not examined
Language Services Unit Phoenix Translations February 2, 2004
Comparii Sanitized, Does not contain TSCA C M
[MSOfficel]Check with translator; I think there should be a `not' in this sentence. [MSOffice2]Same as above; check with translator; I think there should be a `not' in this sentence.
.Company Sanitized. Does not contain TSCACBI
